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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia parainfluenzae viral'. | Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.
BACKGROUND
The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.
OBJECTIVE
To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna.
RESULTS
We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia.
CONCLUSIONS
Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.
Introduction
Multiple Myeloma (MM) is the second most frequent hematologic malignancy in the U.S. and Europe (Rollig et al. 2015). It is characterized by an uncontrolled proliferation of clonal plasma cells in the bone marrow and the accumulation of abnormal intact or incomplete immunoglobulins in serum and/or urine (Moreau et al. 2017; Raab et al. 2009). The median age at diagnosis of MM is 69 years with most subjects being diagnosed above the age of 55 years and a male predominance (Raab et al. 2016). Advances in therapeutic strategies have led to an increase in median overall survival of patients from three to six years within the last two decades, owing to novel compounds like proteasome inhibitors (PIs, e.g. bortezomib, carfilzomib, ixazomib) immunomodulatory drugs (IMIDs, e.g. thalidomide, lenalidomide, pomalidomide), alkylating agents (e.g. melphalan) or histone deacetylase inhibitors (e.g. panobinostat). Multi-drug combinations improve the long-term treatment outcome and might overcome drug resistance (Schreder and Knop 2019), but most patients continue to have relapses and will eventually become refractory to available drugs. Every subsequent relapse induces a shortened progression-free interval (Yong et al. 2016); therefore, novel treatment approaches are needed.
Immunotherapy holds great promise for MM therapy. MoAbs selectively target antigens on the myeloma cell surface which are critical for signaling, tumor growth, and survival (van de Donk et al. 2016). Elotuzumab is a humanized monoclonal IgGκ-antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7) or CS1 (CD2 subset-1), a glycoprotein universally and highly expressed on the surface of normal and malignant plasma cells as well as natural killer cells (Einsele and Schreder 2016). Elotuzumab) exhibited significant in vitro antibody-dependent cellular cytotoxicity (ADCC) using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. Furthermore, in vivo assays showed antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in mice (Hsi et al. 2008). The specificity enables elotuzumab to selectively kill myeloma cells and induce minimal damage on healthy tissue. In a randomized phase III trial, the addition of elotuzumab to lenalidomide and low-dose dexamethasone (Rd) resulted in a sustained improvement of progression-free survival (PFS) compared to Rd, leading to approval of the triplet regimen by the FDA and EMA (Lonial et al. 2015). However, patients who were refractory or intolerant to lenalidomide were excluded from the registration trial.
As pomalidomide is known to induce objective responses in len-refractory patients, we substituted lenalidomide for pomalidomide in patients with very advanced MM who were otherwise eligible for treatment with elotuzumab, dexamethasone and an IMID. Meanwhile, the results of a small randomized phase II study comparing elotuzumab/pomalidomide/dexamethasone (elo/pom/dex) with pom/dex have been reported, demonstrating a high efficacy of the triplet regimen in patients with relapsed/refractory MM (Dimopoulos et al. 2018). Here, we present the outcome of 22 consecutive MM patients with very advanced disease who received the triplet combination of elo/pom/dex outside of a clinical trial at two tertiary care centers.
Methods
We queried the databases of the university hospitals of Würzburg and Vienna to identify patients with relapsed and refractory multiple myeloma receiving elo/pom/dex in an individualized treatment concept when no other option was available. Patients had to have measurable disease according to the IMWG criteria (Rajkumar et al. 2014). Pretreatment with pomalidomide was allowed, but patients refractory to the compound were excluded. All patients provided written informed consent.
Elotuzumab was given intravenously at a dose of 10 mg/kg bodyweight on days 1, 8, 15 and 22 of a 28-day cycle in cycles 1 and 2 and on days 1 and 15 in subsequent cycles. Pomalidomide was administered orally at a dose of 4 mg on days 1 through 21 of each cycle. Dexamethasone was given weekly at a dose of 28 mg orally plus 8 mg intravenously on elotuzumab treatment days and 40 mg orally in weeks without elotuzumab. Dose reductions of pomalidomide and dexamethasone were performed in the event of toxicities according to the SmPC. Patients received antimicrobial prophylaxis with aciclovir and cotrimoxazole as well as low molecular weight heparin or acetylsalicylic acid (aspirin®) as prophylaxis of thromboembolic events throughout the treatment period. Treatment was continued until disease progression (PD) or unacceptable toxicity. Responses were defined according to IMWG criteria (Kumar et al. 2016). Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v. 4.0.
The database was locked on 1st February 2020. Statistical analysis was done with IBM SPSS statistics (IBM, Ehningen, Germany) and Prism (Graph Pad Software, San Diego, CA, USA). PFS was calculated according to Kaplan–Meier method from first dose of elo/pom/dex to disease progression or death, whatever occurred first. Patients proceeding to an autologous stem cell transplantation (SCT) were censored at time of transplant. Overall survival (OS) was calculated from first dose of elo/pom/dex to death from any cause or loss of follow up.
Results
Patients
We identified 22 patients with a median age of 61.5 years (range 39–81); the median duration of myeloma was 6.7 years (range 0.3–11.7). The baseline characteristics of the study population are shown in Table 1. The first patients began treatment in October 2015 and the last patient was started on elo/pom/dex in January 2017. A baseline bone marrow (BM) biopsy was performed in 18 patients. The median plasma cell infiltration was 35% (range 5–90) and 4 patients (18%) had high-risk cytogenetic abnormalities. The median number of prior treatment lines was 5 (range 1–16). All patients had been exposed to bortezomib and lenalidomide, 18 (82%) had previously undergone a stem cell transplantation. Only two patients had received prior daratumumab and five patients had been exposed to carfilzomib. Fifteen patients (68%) had been treated with pomalidomide during any previous regimen; of these, ten patients had received pomalidomide in the most recent line of therapy and were consecutively switched to elo/pom/dex after failing to achieve an objective response. 13 patients (59%) had been refractory to both their most recent line of therapy and earlier lenalidomide.Table 1 Clinical characteristics of patients at baseline
Characteristic Value (n = 22)
Age, median (range), years 61.5 (39–81)
Male sex, n (%) 16 (73)
Type of myeloma, n (%)
IgG 13 (59)
IgA 5 (23)
IgD 1 (4)
Light chain 3 (14)
International Staging System (ISS) stage at study entry, n (%)
I–II 13 (59)
III 5 (23)
Missing data 4 (18)
BM plasma cell infiltration, (%)
< 30% 7 (32)
30–59% 6 (27)
≥ 60 5 (23)
Not reported 4 (18)
Cytogenetic abnormality, n (%)
del17p, t(4;14), or t(14;16)
Yes 4 (18)
No 15 (68)
Data not available
1q21 3 (14)
Yes 2 (9)
No 16 (73)
Data not available 4 (18)
Primary refractory to first line treatment, n (%) 7 (32)
Median No. of previous treatment regimens (range) 5 (1–16)
Median time since initial diagnosis (range), years 6.7 (0.3–11.7)
Prior autologous stem cell transplantation, n (%) 17 (77)
Prior allogeneic stem cell transplantation, n (%) 1 (4)
Prior pomalidomide, n (%) 15 (68)
Prior carfilzomib, n (%) 5 (23)
Prior daratumumab, n (%) 2 (9)
Refractory to most recent line of therapy, n (%) 13 (59)
Refractory to lenalidomide, n (%) 13 (59)
Treatment exposure
At database lock all patients had discontinued treatment, with disease progression as the most common reason. Only one patient discontinued early due to side effects. Two patients requested to stop IV treatment with elotuzumab after 6 and 10 cycles of the triplet combination, respectively, and continued on pom/dex. Another two patients went on to receive an autologous stem cell transplantation as a means of consolidation. The median number of treatment cycles was 5 (range 1–30).
Efficacy
All 22 patients were evaluable for response. 11 patients achieved a partial response (PR), yielding an overall response rate of 50%. Of note, five of these patients had been primary refractory to their first line regimen.
The median PFS was 6.4 months. In a landmark analysis, 35% and 28% of patients were progression-free at 12 months and 18 months, respectively (Figs. 1, 2). Patients with high-risk cytogenetics had identical PFS compared to those with standard-risk disease (6.5 v 6.4 months, p = 0.77). There was a clear trend for shorter PFS in patients with ISS stage III at study entry compared to those with stage I and II disease (6.5 vs. 13.5 months), which did not reach statistical significance due to small sample size.Fig. 1 Progression-free (dashed line) and overall survival (solid line) with elotuzumab, pomalidomide, and dexamethasone. PFS and OS rates at 12 and 18 months from start of treatment are displayed
Fig. 2 Progression-free survival with elotuzumab/pomalidomide/dexamethasone according to a response to prior lenalidomide, b prior exposure tp pomalidomide and c number of prior lines of therapy
Patients refractory to lenalidomide showed no difference in their PFS compared to non-refractory patients (p = 0.98, Fig. 2a). Among patients who had previously received pomalidomide, 5 (33%) responded and another 3 (20%) had stable disease with most responses seen in patients who had pomalidomide immediately prior to elo/pom/dex (4 PR, 2 SD). Median PFS in pomalidomide-exposed patients was identical to that seen in pom-naïve patients (p = 0.90, Fig. 2b). When elo/pom/dex was given directly after a pomalidomide-containing regimen (e.g., carfilzomib/pom/dex, bortezomib/doxorubicin/pom/dex), an absolute gain in PFS of 4.3 months (p = 0.192) was seen when compared to patients with a regimen that did not include pomalidomide in the preceding line.
Responses were also observed in 3 out of 5 patients who had been pretreated with a carfilzomib-based regimen; PFS did not differ significantly when compared to carfilzomib-naïve subjects. At database lock, 14 of 22 patients (64%) had achieved a longer PFS to elo/pom/dex when compared to their most recent line of therapy.
PFS did not differ in intensely pretreated (> 4 prior therapies) versus less heavily pretreated patients (p = 0.99, Fig. 2c).
The median follow-up for the study population was 42.5 months. The median overall survival (95% CI) was not reached (23.6 months—not estimable). At 12 months, 82% of patients (n = 18) were still alive; the 18-month OS rate was 73% (Fig. 1).
In total, 17 of 21 patients (81%) received subsequent systemic therapy. One patient was lost to follow-up after discontinuation of elo/pom/dex. Two thirds of patients were treated with a daratumumab-containing regimen (n = 14); median exposure to the anti-CD38 antibody was 13.5 months. 4 patients underwent a salvage autologous stem cell transplant, two immediately after elo/pom/dex and another two later in the course of their disease. Other alkylating agents (most commonly, bendamustine or cyclophosphamide) were used in 57% and carfilzomib-based combinations in 43% of patients, respectively.
Toxicity
No infusion-related reactions were observed. In three patients, grade 3/4 neutropenia was recorded. In two of them the absolute neutrophil count dropped below 500/µl (grade 4), but no patient experienced neutropenic fever. One patient had grade 3 thrombocytopenia following the accidental continuous intake of pomalidomide.
Four patients were diagnosed with a grade 3/4 respiratory infection, two of whom sustained a pneumonia grade 3. Streptococcus pneumoniae was isolated from one patient and parainfluenza II virus in another patient; in the remaining cases, the offending pathogen could not be identified. All patients resumed treatment after resolution of symptoms.
Discussion
In recent years, immunotherapy has attracted significant attention in the treatment of relapsed or refractory MM. One milestone was the pivotal phase 2 study of daratumumab demonstrating single agent activity in patients with PI- and IMiD-refractory MM with a 3.7 months PFS and a median OS of 17.5 months. Meanwhile, daratumumab-based regimens are widely used in relapsed disease (Dimopoulos et al. 2016a; Mateos et al. 2020) and have recently been approved for frontline therapy in both transplant-eligible (Moreau et al. 2019a) and transplant-ineligible patients (Facon et al. 2019; Mateos et al. 2018).
While many patients will now receive CD38 antibody-based treatment, immunotherapy directed at alternative antigens are needed. Elotuzumab targets SLAMF7, acts synergistically with IMiDs and was shown to induce durable remissions in relapsed MM with a PFS of 19.4 months when combined with len/dex (Lonial et al. 2015). However, most patients now receive len as part of their first-line regimen and a considerable fraction will develop len-resistant disease (Moreau et al. 2019b). In this setting, pomalidomide/dex is active with a modest PFS of 4.0 months in the registration trial (Dimopoulos et al. 2016b), but long-lasting remissions are also observed (Danhof et al. 2015). The addition of elotuzumab to pom/dex aiming at prolonged disease control appears tempting and was proven effective in a randomized phase II trial (Dimopoulos et al. 2018). This study reported a median PFS of 10.3 months with elo/pom/dex in patients with a median number of 3 prior lines of therapy.
Since only 60 patients were included in the experimental arm of the ELOQUENT-3 study, we sought to expand clinical experience with elo/pom/dex in a “real-world” cohort of advanced MM. Compared to the published dataset, the 22 subjects of our current retrospective analysis had a longer interval since diagnosis of their MM (6.7 vs 4.8 years) and were more heavily pretreated (median, 5 vs 3 prior lines). Remarkably, 32% (n = 7) of them had been primary refractory to first-line treatment; 59% (n = 13) were refractory to lenalidomide and two thirds had previously received pomalidomide.
In this unfavorable cohort, we were still able to demonstrate a median PFS of 6.4 months with PFS rates at 12 and 18 months that were comparable to those reported in a recent update of ELOQUENT-3 (35% and 28% vs 43% and 34%, respectively) (Dimopoulos 2019). An overall response rate of 50% compared equally well to the published data. Of note, 64% of subjects achieved a longer PFS when compared to their most recent line of therapy and we were able to confirm responses in pomalidomide-exposed patients, most of whom had received pomalidomide in the most recent line prior to elo/pom/dex. This observation would thus justify the addition of elotuzumab to a doublet regimen of pom/dex in the absence of frank progression which in our hands led to objective responses in 4 of 10 patients. Incremental gain of median PFS with Elo/Pd was 4.3 months when compared to PFS with the most recent line of therapy. We believe this constitutes a clinically relevant benefit, as median PFS in a very advanced patient cohort was recently reported to be 3.4 months (Gandhi et al. 2019).
Even though none of our patients reached a complete remission (CR), we observed remarkably durable remissions of more than 20 months in 4 patients. In another two patients, elo/pom/dex served as a bridging therapy to autologous stem cell transplantation.
Subgroup analyses were limited due to the small sample size. Neither cytogenetic risk nor the number and type of prior therapy predicted for outcome in our cohort. Patients with low tumor burden as defined by ISS stages I and II at start of treatment appeared to gain increased benefit compared to those with stage III disease, confirming our previous observation (Danhof et al. 2019). We could also demonstrate that highly pretreated patients (> 4 prior therapies) showed a similar PFS compared to patients with a lower number of previous therapies, justifying the use of this regimen even in late stage MM.
In terms of toxicity, no new safety signals were seen. In general, treatment with elo/pom/dex was well tolerated; there was no allergic reaction or other infusion-related reaction recorded.
In one case a drug-related rash grade 2 was reported, diminishing under ongoing treatment. Like in many reported trials in advanced MM, respiratory infections were among the most common adverse events and were found to be severe in four patients, two of them presenting with grade 3 pneumonia. Both patients could resume therapy and achieved a PR. Hematologic toxicity was low with only a small number of patients experiencing grade 3/4 neutropenia. Grade 3 thrombocytopenia in one patient could be attributed to accidental continuous intake of pomalidomide. Taken together, adverse event rates were comparable to those reported in the ELOQUENT-3 trial.
Not least due to the favurable safety profile, 81% of our patients were able to receive subsequent systemic treatment upon progression on elo/pom/dex. Like in ELOQUENT-3, all but 2 patients had not been exposed to an anti-CD38 antibody and received daratumumab-based regimens for a median duration of more than one year. Overall survival rates of 86% and 81% at 12 and 18 months, respectively, are profoundly remarkable for heavily pretreated MM patients and are compare positively with published results. However, many patients with late-stage disease will now be pretreated with daratumumab; as in our study, these are largely underrepresented in current trials e.g. with pomalidomide-based combinations (Attal et al. 2019; Richardson et al. 2019) and will represent a formidable therapeutic challenge in the near future. A recent trial reported responses in 48% of daratumumab-exposed patients and acceptable toxicity with a quadruplet regimen of elo/pom/dex and bortezomib (Yee 2019), further corroborating our findings.
In summary, despite the small number of patients included here, our results suggest the combination of elo/pom/dex to represent an effective and exceptionally well-tolerated option in the treatment of advanced MM that may be considered in the len-refractory or even pom-exposed patient.
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Acknowledgements
Open Access funding provided by Projekt DEAL.
Author contributions
DH, MS, HG and SK: conception, data acquisition, data analysis, preparation and writing of the manuscript. MTK, RS and BG: data acquisition. JH: statistical calculation and critical revision of the manuscript. SS and SD: data analysis, critical revision of the manuscript. HE: conception, critical revision of the manuscript.
Funding
The authors received no funding for this work.
Availability of data and material
The data generated and used for this study, are included in the published article. Additional data are available from the authors upon reasonable and individual request.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest. S.K.: Honoraria from Celgene GmbH and Bristol-Myers Squibb GmbH. S.D.: Advisory Board for Bristol-Myers Squibb GmbH. MS: Advisory board for Celgene and Bristol-Myers Squibb.
Code availability
IBM SPSS Statistics. | ACYCLOVIR, DEXAMETHASONE, ELOTUZUMAB, POMALIDOMIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY | 32683487 | 19,054,245 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia pneumococcal'. | Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.
BACKGROUND
The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.
OBJECTIVE
To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna.
RESULTS
We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia.
CONCLUSIONS
Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.
Introduction
Multiple Myeloma (MM) is the second most frequent hematologic malignancy in the U.S. and Europe (Rollig et al. 2015). It is characterized by an uncontrolled proliferation of clonal plasma cells in the bone marrow and the accumulation of abnormal intact or incomplete immunoglobulins in serum and/or urine (Moreau et al. 2017; Raab et al. 2009). The median age at diagnosis of MM is 69 years with most subjects being diagnosed above the age of 55 years and a male predominance (Raab et al. 2016). Advances in therapeutic strategies have led to an increase in median overall survival of patients from three to six years within the last two decades, owing to novel compounds like proteasome inhibitors (PIs, e.g. bortezomib, carfilzomib, ixazomib) immunomodulatory drugs (IMIDs, e.g. thalidomide, lenalidomide, pomalidomide), alkylating agents (e.g. melphalan) or histone deacetylase inhibitors (e.g. panobinostat). Multi-drug combinations improve the long-term treatment outcome and might overcome drug resistance (Schreder and Knop 2019), but most patients continue to have relapses and will eventually become refractory to available drugs. Every subsequent relapse induces a shortened progression-free interval (Yong et al. 2016); therefore, novel treatment approaches are needed.
Immunotherapy holds great promise for MM therapy. MoAbs selectively target antigens on the myeloma cell surface which are critical for signaling, tumor growth, and survival (van de Donk et al. 2016). Elotuzumab is a humanized monoclonal IgGκ-antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7) or CS1 (CD2 subset-1), a glycoprotein universally and highly expressed on the surface of normal and malignant plasma cells as well as natural killer cells (Einsele and Schreder 2016). Elotuzumab) exhibited significant in vitro antibody-dependent cellular cytotoxicity (ADCC) using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. Furthermore, in vivo assays showed antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in mice (Hsi et al. 2008). The specificity enables elotuzumab to selectively kill myeloma cells and induce minimal damage on healthy tissue. In a randomized phase III trial, the addition of elotuzumab to lenalidomide and low-dose dexamethasone (Rd) resulted in a sustained improvement of progression-free survival (PFS) compared to Rd, leading to approval of the triplet regimen by the FDA and EMA (Lonial et al. 2015). However, patients who were refractory or intolerant to lenalidomide were excluded from the registration trial.
As pomalidomide is known to induce objective responses in len-refractory patients, we substituted lenalidomide for pomalidomide in patients with very advanced MM who were otherwise eligible for treatment with elotuzumab, dexamethasone and an IMID. Meanwhile, the results of a small randomized phase II study comparing elotuzumab/pomalidomide/dexamethasone (elo/pom/dex) with pom/dex have been reported, demonstrating a high efficacy of the triplet regimen in patients with relapsed/refractory MM (Dimopoulos et al. 2018). Here, we present the outcome of 22 consecutive MM patients with very advanced disease who received the triplet combination of elo/pom/dex outside of a clinical trial at two tertiary care centers.
Methods
We queried the databases of the university hospitals of Würzburg and Vienna to identify patients with relapsed and refractory multiple myeloma receiving elo/pom/dex in an individualized treatment concept when no other option was available. Patients had to have measurable disease according to the IMWG criteria (Rajkumar et al. 2014). Pretreatment with pomalidomide was allowed, but patients refractory to the compound were excluded. All patients provided written informed consent.
Elotuzumab was given intravenously at a dose of 10 mg/kg bodyweight on days 1, 8, 15 and 22 of a 28-day cycle in cycles 1 and 2 and on days 1 and 15 in subsequent cycles. Pomalidomide was administered orally at a dose of 4 mg on days 1 through 21 of each cycle. Dexamethasone was given weekly at a dose of 28 mg orally plus 8 mg intravenously on elotuzumab treatment days and 40 mg orally in weeks without elotuzumab. Dose reductions of pomalidomide and dexamethasone were performed in the event of toxicities according to the SmPC. Patients received antimicrobial prophylaxis with aciclovir and cotrimoxazole as well as low molecular weight heparin or acetylsalicylic acid (aspirin®) as prophylaxis of thromboembolic events throughout the treatment period. Treatment was continued until disease progression (PD) or unacceptable toxicity. Responses were defined according to IMWG criteria (Kumar et al. 2016). Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v. 4.0.
The database was locked on 1st February 2020. Statistical analysis was done with IBM SPSS statistics (IBM, Ehningen, Germany) and Prism (Graph Pad Software, San Diego, CA, USA). PFS was calculated according to Kaplan–Meier method from first dose of elo/pom/dex to disease progression or death, whatever occurred first. Patients proceeding to an autologous stem cell transplantation (SCT) were censored at time of transplant. Overall survival (OS) was calculated from first dose of elo/pom/dex to death from any cause or loss of follow up.
Results
Patients
We identified 22 patients with a median age of 61.5 years (range 39–81); the median duration of myeloma was 6.7 years (range 0.3–11.7). The baseline characteristics of the study population are shown in Table 1. The first patients began treatment in October 2015 and the last patient was started on elo/pom/dex in January 2017. A baseline bone marrow (BM) biopsy was performed in 18 patients. The median plasma cell infiltration was 35% (range 5–90) and 4 patients (18%) had high-risk cytogenetic abnormalities. The median number of prior treatment lines was 5 (range 1–16). All patients had been exposed to bortezomib and lenalidomide, 18 (82%) had previously undergone a stem cell transplantation. Only two patients had received prior daratumumab and five patients had been exposed to carfilzomib. Fifteen patients (68%) had been treated with pomalidomide during any previous regimen; of these, ten patients had received pomalidomide in the most recent line of therapy and were consecutively switched to elo/pom/dex after failing to achieve an objective response. 13 patients (59%) had been refractory to both their most recent line of therapy and earlier lenalidomide.Table 1 Clinical characteristics of patients at baseline
Characteristic Value (n = 22)
Age, median (range), years 61.5 (39–81)
Male sex, n (%) 16 (73)
Type of myeloma, n (%)
IgG 13 (59)
IgA 5 (23)
IgD 1 (4)
Light chain 3 (14)
International Staging System (ISS) stage at study entry, n (%)
I–II 13 (59)
III 5 (23)
Missing data 4 (18)
BM plasma cell infiltration, (%)
< 30% 7 (32)
30–59% 6 (27)
≥ 60 5 (23)
Not reported 4 (18)
Cytogenetic abnormality, n (%)
del17p, t(4;14), or t(14;16)
Yes 4 (18)
No 15 (68)
Data not available
1q21 3 (14)
Yes 2 (9)
No 16 (73)
Data not available 4 (18)
Primary refractory to first line treatment, n (%) 7 (32)
Median No. of previous treatment regimens (range) 5 (1–16)
Median time since initial diagnosis (range), years 6.7 (0.3–11.7)
Prior autologous stem cell transplantation, n (%) 17 (77)
Prior allogeneic stem cell transplantation, n (%) 1 (4)
Prior pomalidomide, n (%) 15 (68)
Prior carfilzomib, n (%) 5 (23)
Prior daratumumab, n (%) 2 (9)
Refractory to most recent line of therapy, n (%) 13 (59)
Refractory to lenalidomide, n (%) 13 (59)
Treatment exposure
At database lock all patients had discontinued treatment, with disease progression as the most common reason. Only one patient discontinued early due to side effects. Two patients requested to stop IV treatment with elotuzumab after 6 and 10 cycles of the triplet combination, respectively, and continued on pom/dex. Another two patients went on to receive an autologous stem cell transplantation as a means of consolidation. The median number of treatment cycles was 5 (range 1–30).
Efficacy
All 22 patients were evaluable for response. 11 patients achieved a partial response (PR), yielding an overall response rate of 50%. Of note, five of these patients had been primary refractory to their first line regimen.
The median PFS was 6.4 months. In a landmark analysis, 35% and 28% of patients were progression-free at 12 months and 18 months, respectively (Figs. 1, 2). Patients with high-risk cytogenetics had identical PFS compared to those with standard-risk disease (6.5 v 6.4 months, p = 0.77). There was a clear trend for shorter PFS in patients with ISS stage III at study entry compared to those with stage I and II disease (6.5 vs. 13.5 months), which did not reach statistical significance due to small sample size.Fig. 1 Progression-free (dashed line) and overall survival (solid line) with elotuzumab, pomalidomide, and dexamethasone. PFS and OS rates at 12 and 18 months from start of treatment are displayed
Fig. 2 Progression-free survival with elotuzumab/pomalidomide/dexamethasone according to a response to prior lenalidomide, b prior exposure tp pomalidomide and c number of prior lines of therapy
Patients refractory to lenalidomide showed no difference in their PFS compared to non-refractory patients (p = 0.98, Fig. 2a). Among patients who had previously received pomalidomide, 5 (33%) responded and another 3 (20%) had stable disease with most responses seen in patients who had pomalidomide immediately prior to elo/pom/dex (4 PR, 2 SD). Median PFS in pomalidomide-exposed patients was identical to that seen in pom-naïve patients (p = 0.90, Fig. 2b). When elo/pom/dex was given directly after a pomalidomide-containing regimen (e.g., carfilzomib/pom/dex, bortezomib/doxorubicin/pom/dex), an absolute gain in PFS of 4.3 months (p = 0.192) was seen when compared to patients with a regimen that did not include pomalidomide in the preceding line.
Responses were also observed in 3 out of 5 patients who had been pretreated with a carfilzomib-based regimen; PFS did not differ significantly when compared to carfilzomib-naïve subjects. At database lock, 14 of 22 patients (64%) had achieved a longer PFS to elo/pom/dex when compared to their most recent line of therapy.
PFS did not differ in intensely pretreated (> 4 prior therapies) versus less heavily pretreated patients (p = 0.99, Fig. 2c).
The median follow-up for the study population was 42.5 months. The median overall survival (95% CI) was not reached (23.6 months—not estimable). At 12 months, 82% of patients (n = 18) were still alive; the 18-month OS rate was 73% (Fig. 1).
In total, 17 of 21 patients (81%) received subsequent systemic therapy. One patient was lost to follow-up after discontinuation of elo/pom/dex. Two thirds of patients were treated with a daratumumab-containing regimen (n = 14); median exposure to the anti-CD38 antibody was 13.5 months. 4 patients underwent a salvage autologous stem cell transplant, two immediately after elo/pom/dex and another two later in the course of their disease. Other alkylating agents (most commonly, bendamustine or cyclophosphamide) were used in 57% and carfilzomib-based combinations in 43% of patients, respectively.
Toxicity
No infusion-related reactions were observed. In three patients, grade 3/4 neutropenia was recorded. In two of them the absolute neutrophil count dropped below 500/µl (grade 4), but no patient experienced neutropenic fever. One patient had grade 3 thrombocytopenia following the accidental continuous intake of pomalidomide.
Four patients were diagnosed with a grade 3/4 respiratory infection, two of whom sustained a pneumonia grade 3. Streptococcus pneumoniae was isolated from one patient and parainfluenza II virus in another patient; in the remaining cases, the offending pathogen could not be identified. All patients resumed treatment after resolution of symptoms.
Discussion
In recent years, immunotherapy has attracted significant attention in the treatment of relapsed or refractory MM. One milestone was the pivotal phase 2 study of daratumumab demonstrating single agent activity in patients with PI- and IMiD-refractory MM with a 3.7 months PFS and a median OS of 17.5 months. Meanwhile, daratumumab-based regimens are widely used in relapsed disease (Dimopoulos et al. 2016a; Mateos et al. 2020) and have recently been approved for frontline therapy in both transplant-eligible (Moreau et al. 2019a) and transplant-ineligible patients (Facon et al. 2019; Mateos et al. 2018).
While many patients will now receive CD38 antibody-based treatment, immunotherapy directed at alternative antigens are needed. Elotuzumab targets SLAMF7, acts synergistically with IMiDs and was shown to induce durable remissions in relapsed MM with a PFS of 19.4 months when combined with len/dex (Lonial et al. 2015). However, most patients now receive len as part of their first-line regimen and a considerable fraction will develop len-resistant disease (Moreau et al. 2019b). In this setting, pomalidomide/dex is active with a modest PFS of 4.0 months in the registration trial (Dimopoulos et al. 2016b), but long-lasting remissions are also observed (Danhof et al. 2015). The addition of elotuzumab to pom/dex aiming at prolonged disease control appears tempting and was proven effective in a randomized phase II trial (Dimopoulos et al. 2018). This study reported a median PFS of 10.3 months with elo/pom/dex in patients with a median number of 3 prior lines of therapy.
Since only 60 patients were included in the experimental arm of the ELOQUENT-3 study, we sought to expand clinical experience with elo/pom/dex in a “real-world” cohort of advanced MM. Compared to the published dataset, the 22 subjects of our current retrospective analysis had a longer interval since diagnosis of their MM (6.7 vs 4.8 years) and were more heavily pretreated (median, 5 vs 3 prior lines). Remarkably, 32% (n = 7) of them had been primary refractory to first-line treatment; 59% (n = 13) were refractory to lenalidomide and two thirds had previously received pomalidomide.
In this unfavorable cohort, we were still able to demonstrate a median PFS of 6.4 months with PFS rates at 12 and 18 months that were comparable to those reported in a recent update of ELOQUENT-3 (35% and 28% vs 43% and 34%, respectively) (Dimopoulos 2019). An overall response rate of 50% compared equally well to the published data. Of note, 64% of subjects achieved a longer PFS when compared to their most recent line of therapy and we were able to confirm responses in pomalidomide-exposed patients, most of whom had received pomalidomide in the most recent line prior to elo/pom/dex. This observation would thus justify the addition of elotuzumab to a doublet regimen of pom/dex in the absence of frank progression which in our hands led to objective responses in 4 of 10 patients. Incremental gain of median PFS with Elo/Pd was 4.3 months when compared to PFS with the most recent line of therapy. We believe this constitutes a clinically relevant benefit, as median PFS in a very advanced patient cohort was recently reported to be 3.4 months (Gandhi et al. 2019).
Even though none of our patients reached a complete remission (CR), we observed remarkably durable remissions of more than 20 months in 4 patients. In another two patients, elo/pom/dex served as a bridging therapy to autologous stem cell transplantation.
Subgroup analyses were limited due to the small sample size. Neither cytogenetic risk nor the number and type of prior therapy predicted for outcome in our cohort. Patients with low tumor burden as defined by ISS stages I and II at start of treatment appeared to gain increased benefit compared to those with stage III disease, confirming our previous observation (Danhof et al. 2019). We could also demonstrate that highly pretreated patients (> 4 prior therapies) showed a similar PFS compared to patients with a lower number of previous therapies, justifying the use of this regimen even in late stage MM.
In terms of toxicity, no new safety signals were seen. In general, treatment with elo/pom/dex was well tolerated; there was no allergic reaction or other infusion-related reaction recorded.
In one case a drug-related rash grade 2 was reported, diminishing under ongoing treatment. Like in many reported trials in advanced MM, respiratory infections were among the most common adverse events and were found to be severe in four patients, two of them presenting with grade 3 pneumonia. Both patients could resume therapy and achieved a PR. Hematologic toxicity was low with only a small number of patients experiencing grade 3/4 neutropenia. Grade 3 thrombocytopenia in one patient could be attributed to accidental continuous intake of pomalidomide. Taken together, adverse event rates were comparable to those reported in the ELOQUENT-3 trial.
Not least due to the favurable safety profile, 81% of our patients were able to receive subsequent systemic treatment upon progression on elo/pom/dex. Like in ELOQUENT-3, all but 2 patients had not been exposed to an anti-CD38 antibody and received daratumumab-based regimens for a median duration of more than one year. Overall survival rates of 86% and 81% at 12 and 18 months, respectively, are profoundly remarkable for heavily pretreated MM patients and are compare positively with published results. However, many patients with late-stage disease will now be pretreated with daratumumab; as in our study, these are largely underrepresented in current trials e.g. with pomalidomide-based combinations (Attal et al. 2019; Richardson et al. 2019) and will represent a formidable therapeutic challenge in the near future. A recent trial reported responses in 48% of daratumumab-exposed patients and acceptable toxicity with a quadruplet regimen of elo/pom/dex and bortezomib (Yee 2019), further corroborating our findings.
In summary, despite the small number of patients included here, our results suggest the combination of elo/pom/dex to represent an effective and exceptionally well-tolerated option in the treatment of advanced MM that may be considered in the len-refractory or even pom-exposed patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Open Access funding provided by Projekt DEAL.
Author contributions
DH, MS, HG and SK: conception, data acquisition, data analysis, preparation and writing of the manuscript. MTK, RS and BG: data acquisition. JH: statistical calculation and critical revision of the manuscript. SS and SD: data analysis, critical revision of the manuscript. HE: conception, critical revision of the manuscript.
Funding
The authors received no funding for this work.
Availability of data and material
The data generated and used for this study, are included in the published article. Additional data are available from the authors upon reasonable and individual request.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest. S.K.: Honoraria from Celgene GmbH and Bristol-Myers Squibb GmbH. S.D.: Advisory Board for Bristol-Myers Squibb GmbH. MS: Advisory board for Celgene and Bristol-Myers Squibb.
Code availability
IBM SPSS Statistics. | ACYCLOVIR, DEXAMETHASONE, ELOTUZUMAB, POMALIDOMIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY | 32683487 | 19,057,523 | 2021-01 |
What was the administration route of drug 'ELOTUZUMAB'? | Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.
BACKGROUND
The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.
OBJECTIVE
To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna.
RESULTS
We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia.
CONCLUSIONS
Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.
Introduction
Multiple Myeloma (MM) is the second most frequent hematologic malignancy in the U.S. and Europe (Rollig et al. 2015). It is characterized by an uncontrolled proliferation of clonal plasma cells in the bone marrow and the accumulation of abnormal intact or incomplete immunoglobulins in serum and/or urine (Moreau et al. 2017; Raab et al. 2009). The median age at diagnosis of MM is 69 years with most subjects being diagnosed above the age of 55 years and a male predominance (Raab et al. 2016). Advances in therapeutic strategies have led to an increase in median overall survival of patients from three to six years within the last two decades, owing to novel compounds like proteasome inhibitors (PIs, e.g. bortezomib, carfilzomib, ixazomib) immunomodulatory drugs (IMIDs, e.g. thalidomide, lenalidomide, pomalidomide), alkylating agents (e.g. melphalan) or histone deacetylase inhibitors (e.g. panobinostat). Multi-drug combinations improve the long-term treatment outcome and might overcome drug resistance (Schreder and Knop 2019), but most patients continue to have relapses and will eventually become refractory to available drugs. Every subsequent relapse induces a shortened progression-free interval (Yong et al. 2016); therefore, novel treatment approaches are needed.
Immunotherapy holds great promise for MM therapy. MoAbs selectively target antigens on the myeloma cell surface which are critical for signaling, tumor growth, and survival (van de Donk et al. 2016). Elotuzumab is a humanized monoclonal IgGκ-antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7) or CS1 (CD2 subset-1), a glycoprotein universally and highly expressed on the surface of normal and malignant plasma cells as well as natural killer cells (Einsele and Schreder 2016). Elotuzumab) exhibited significant in vitro antibody-dependent cellular cytotoxicity (ADCC) using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. Furthermore, in vivo assays showed antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in mice (Hsi et al. 2008). The specificity enables elotuzumab to selectively kill myeloma cells and induce minimal damage on healthy tissue. In a randomized phase III trial, the addition of elotuzumab to lenalidomide and low-dose dexamethasone (Rd) resulted in a sustained improvement of progression-free survival (PFS) compared to Rd, leading to approval of the triplet regimen by the FDA and EMA (Lonial et al. 2015). However, patients who were refractory or intolerant to lenalidomide were excluded from the registration trial.
As pomalidomide is known to induce objective responses in len-refractory patients, we substituted lenalidomide for pomalidomide in patients with very advanced MM who were otherwise eligible for treatment with elotuzumab, dexamethasone and an IMID. Meanwhile, the results of a small randomized phase II study comparing elotuzumab/pomalidomide/dexamethasone (elo/pom/dex) with pom/dex have been reported, demonstrating a high efficacy of the triplet regimen in patients with relapsed/refractory MM (Dimopoulos et al. 2018). Here, we present the outcome of 22 consecutive MM patients with very advanced disease who received the triplet combination of elo/pom/dex outside of a clinical trial at two tertiary care centers.
Methods
We queried the databases of the university hospitals of Würzburg and Vienna to identify patients with relapsed and refractory multiple myeloma receiving elo/pom/dex in an individualized treatment concept when no other option was available. Patients had to have measurable disease according to the IMWG criteria (Rajkumar et al. 2014). Pretreatment with pomalidomide was allowed, but patients refractory to the compound were excluded. All patients provided written informed consent.
Elotuzumab was given intravenously at a dose of 10 mg/kg bodyweight on days 1, 8, 15 and 22 of a 28-day cycle in cycles 1 and 2 and on days 1 and 15 in subsequent cycles. Pomalidomide was administered orally at a dose of 4 mg on days 1 through 21 of each cycle. Dexamethasone was given weekly at a dose of 28 mg orally plus 8 mg intravenously on elotuzumab treatment days and 40 mg orally in weeks without elotuzumab. Dose reductions of pomalidomide and dexamethasone were performed in the event of toxicities according to the SmPC. Patients received antimicrobial prophylaxis with aciclovir and cotrimoxazole as well as low molecular weight heparin or acetylsalicylic acid (aspirin®) as prophylaxis of thromboembolic events throughout the treatment period. Treatment was continued until disease progression (PD) or unacceptable toxicity. Responses were defined according to IMWG criteria (Kumar et al. 2016). Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v. 4.0.
The database was locked on 1st February 2020. Statistical analysis was done with IBM SPSS statistics (IBM, Ehningen, Germany) and Prism (Graph Pad Software, San Diego, CA, USA). PFS was calculated according to Kaplan–Meier method from first dose of elo/pom/dex to disease progression or death, whatever occurred first. Patients proceeding to an autologous stem cell transplantation (SCT) were censored at time of transplant. Overall survival (OS) was calculated from first dose of elo/pom/dex to death from any cause or loss of follow up.
Results
Patients
We identified 22 patients with a median age of 61.5 years (range 39–81); the median duration of myeloma was 6.7 years (range 0.3–11.7). The baseline characteristics of the study population are shown in Table 1. The first patients began treatment in October 2015 and the last patient was started on elo/pom/dex in January 2017. A baseline bone marrow (BM) biopsy was performed in 18 patients. The median plasma cell infiltration was 35% (range 5–90) and 4 patients (18%) had high-risk cytogenetic abnormalities. The median number of prior treatment lines was 5 (range 1–16). All patients had been exposed to bortezomib and lenalidomide, 18 (82%) had previously undergone a stem cell transplantation. Only two patients had received prior daratumumab and five patients had been exposed to carfilzomib. Fifteen patients (68%) had been treated with pomalidomide during any previous regimen; of these, ten patients had received pomalidomide in the most recent line of therapy and were consecutively switched to elo/pom/dex after failing to achieve an objective response. 13 patients (59%) had been refractory to both their most recent line of therapy and earlier lenalidomide.Table 1 Clinical characteristics of patients at baseline
Characteristic Value (n = 22)
Age, median (range), years 61.5 (39–81)
Male sex, n (%) 16 (73)
Type of myeloma, n (%)
IgG 13 (59)
IgA 5 (23)
IgD 1 (4)
Light chain 3 (14)
International Staging System (ISS) stage at study entry, n (%)
I–II 13 (59)
III 5 (23)
Missing data 4 (18)
BM plasma cell infiltration, (%)
< 30% 7 (32)
30–59% 6 (27)
≥ 60 5 (23)
Not reported 4 (18)
Cytogenetic abnormality, n (%)
del17p, t(4;14), or t(14;16)
Yes 4 (18)
No 15 (68)
Data not available
1q21 3 (14)
Yes 2 (9)
No 16 (73)
Data not available 4 (18)
Primary refractory to first line treatment, n (%) 7 (32)
Median No. of previous treatment regimens (range) 5 (1–16)
Median time since initial diagnosis (range), years 6.7 (0.3–11.7)
Prior autologous stem cell transplantation, n (%) 17 (77)
Prior allogeneic stem cell transplantation, n (%) 1 (4)
Prior pomalidomide, n (%) 15 (68)
Prior carfilzomib, n (%) 5 (23)
Prior daratumumab, n (%) 2 (9)
Refractory to most recent line of therapy, n (%) 13 (59)
Refractory to lenalidomide, n (%) 13 (59)
Treatment exposure
At database lock all patients had discontinued treatment, with disease progression as the most common reason. Only one patient discontinued early due to side effects. Two patients requested to stop IV treatment with elotuzumab after 6 and 10 cycles of the triplet combination, respectively, and continued on pom/dex. Another two patients went on to receive an autologous stem cell transplantation as a means of consolidation. The median number of treatment cycles was 5 (range 1–30).
Efficacy
All 22 patients were evaluable for response. 11 patients achieved a partial response (PR), yielding an overall response rate of 50%. Of note, five of these patients had been primary refractory to their first line regimen.
The median PFS was 6.4 months. In a landmark analysis, 35% and 28% of patients were progression-free at 12 months and 18 months, respectively (Figs. 1, 2). Patients with high-risk cytogenetics had identical PFS compared to those with standard-risk disease (6.5 v 6.4 months, p = 0.77). There was a clear trend for shorter PFS in patients with ISS stage III at study entry compared to those with stage I and II disease (6.5 vs. 13.5 months), which did not reach statistical significance due to small sample size.Fig. 1 Progression-free (dashed line) and overall survival (solid line) with elotuzumab, pomalidomide, and dexamethasone. PFS and OS rates at 12 and 18 months from start of treatment are displayed
Fig. 2 Progression-free survival with elotuzumab/pomalidomide/dexamethasone according to a response to prior lenalidomide, b prior exposure tp pomalidomide and c number of prior lines of therapy
Patients refractory to lenalidomide showed no difference in their PFS compared to non-refractory patients (p = 0.98, Fig. 2a). Among patients who had previously received pomalidomide, 5 (33%) responded and another 3 (20%) had stable disease with most responses seen in patients who had pomalidomide immediately prior to elo/pom/dex (4 PR, 2 SD). Median PFS in pomalidomide-exposed patients was identical to that seen in pom-naïve patients (p = 0.90, Fig. 2b). When elo/pom/dex was given directly after a pomalidomide-containing regimen (e.g., carfilzomib/pom/dex, bortezomib/doxorubicin/pom/dex), an absolute gain in PFS of 4.3 months (p = 0.192) was seen when compared to patients with a regimen that did not include pomalidomide in the preceding line.
Responses were also observed in 3 out of 5 patients who had been pretreated with a carfilzomib-based regimen; PFS did not differ significantly when compared to carfilzomib-naïve subjects. At database lock, 14 of 22 patients (64%) had achieved a longer PFS to elo/pom/dex when compared to their most recent line of therapy.
PFS did not differ in intensely pretreated (> 4 prior therapies) versus less heavily pretreated patients (p = 0.99, Fig. 2c).
The median follow-up for the study population was 42.5 months. The median overall survival (95% CI) was not reached (23.6 months—not estimable). At 12 months, 82% of patients (n = 18) were still alive; the 18-month OS rate was 73% (Fig. 1).
In total, 17 of 21 patients (81%) received subsequent systemic therapy. One patient was lost to follow-up after discontinuation of elo/pom/dex. Two thirds of patients were treated with a daratumumab-containing regimen (n = 14); median exposure to the anti-CD38 antibody was 13.5 months. 4 patients underwent a salvage autologous stem cell transplant, two immediately after elo/pom/dex and another two later in the course of their disease. Other alkylating agents (most commonly, bendamustine or cyclophosphamide) were used in 57% and carfilzomib-based combinations in 43% of patients, respectively.
Toxicity
No infusion-related reactions were observed. In three patients, grade 3/4 neutropenia was recorded. In two of them the absolute neutrophil count dropped below 500/µl (grade 4), but no patient experienced neutropenic fever. One patient had grade 3 thrombocytopenia following the accidental continuous intake of pomalidomide.
Four patients were diagnosed with a grade 3/4 respiratory infection, two of whom sustained a pneumonia grade 3. Streptococcus pneumoniae was isolated from one patient and parainfluenza II virus in another patient; in the remaining cases, the offending pathogen could not be identified. All patients resumed treatment after resolution of symptoms.
Discussion
In recent years, immunotherapy has attracted significant attention in the treatment of relapsed or refractory MM. One milestone was the pivotal phase 2 study of daratumumab demonstrating single agent activity in patients with PI- and IMiD-refractory MM with a 3.7 months PFS and a median OS of 17.5 months. Meanwhile, daratumumab-based regimens are widely used in relapsed disease (Dimopoulos et al. 2016a; Mateos et al. 2020) and have recently been approved for frontline therapy in both transplant-eligible (Moreau et al. 2019a) and transplant-ineligible patients (Facon et al. 2019; Mateos et al. 2018).
While many patients will now receive CD38 antibody-based treatment, immunotherapy directed at alternative antigens are needed. Elotuzumab targets SLAMF7, acts synergistically with IMiDs and was shown to induce durable remissions in relapsed MM with a PFS of 19.4 months when combined with len/dex (Lonial et al. 2015). However, most patients now receive len as part of their first-line regimen and a considerable fraction will develop len-resistant disease (Moreau et al. 2019b). In this setting, pomalidomide/dex is active with a modest PFS of 4.0 months in the registration trial (Dimopoulos et al. 2016b), but long-lasting remissions are also observed (Danhof et al. 2015). The addition of elotuzumab to pom/dex aiming at prolonged disease control appears tempting and was proven effective in a randomized phase II trial (Dimopoulos et al. 2018). This study reported a median PFS of 10.3 months with elo/pom/dex in patients with a median number of 3 prior lines of therapy.
Since only 60 patients were included in the experimental arm of the ELOQUENT-3 study, we sought to expand clinical experience with elo/pom/dex in a “real-world” cohort of advanced MM. Compared to the published dataset, the 22 subjects of our current retrospective analysis had a longer interval since diagnosis of their MM (6.7 vs 4.8 years) and were more heavily pretreated (median, 5 vs 3 prior lines). Remarkably, 32% (n = 7) of them had been primary refractory to first-line treatment; 59% (n = 13) were refractory to lenalidomide and two thirds had previously received pomalidomide.
In this unfavorable cohort, we were still able to demonstrate a median PFS of 6.4 months with PFS rates at 12 and 18 months that were comparable to those reported in a recent update of ELOQUENT-3 (35% and 28% vs 43% and 34%, respectively) (Dimopoulos 2019). An overall response rate of 50% compared equally well to the published data. Of note, 64% of subjects achieved a longer PFS when compared to their most recent line of therapy and we were able to confirm responses in pomalidomide-exposed patients, most of whom had received pomalidomide in the most recent line prior to elo/pom/dex. This observation would thus justify the addition of elotuzumab to a doublet regimen of pom/dex in the absence of frank progression which in our hands led to objective responses in 4 of 10 patients. Incremental gain of median PFS with Elo/Pd was 4.3 months when compared to PFS with the most recent line of therapy. We believe this constitutes a clinically relevant benefit, as median PFS in a very advanced patient cohort was recently reported to be 3.4 months (Gandhi et al. 2019).
Even though none of our patients reached a complete remission (CR), we observed remarkably durable remissions of more than 20 months in 4 patients. In another two patients, elo/pom/dex served as a bridging therapy to autologous stem cell transplantation.
Subgroup analyses were limited due to the small sample size. Neither cytogenetic risk nor the number and type of prior therapy predicted for outcome in our cohort. Patients with low tumor burden as defined by ISS stages I and II at start of treatment appeared to gain increased benefit compared to those with stage III disease, confirming our previous observation (Danhof et al. 2019). We could also demonstrate that highly pretreated patients (> 4 prior therapies) showed a similar PFS compared to patients with a lower number of previous therapies, justifying the use of this regimen even in late stage MM.
In terms of toxicity, no new safety signals were seen. In general, treatment with elo/pom/dex was well tolerated; there was no allergic reaction or other infusion-related reaction recorded.
In one case a drug-related rash grade 2 was reported, diminishing under ongoing treatment. Like in many reported trials in advanced MM, respiratory infections were among the most common adverse events and were found to be severe in four patients, two of them presenting with grade 3 pneumonia. Both patients could resume therapy and achieved a PR. Hematologic toxicity was low with only a small number of patients experiencing grade 3/4 neutropenia. Grade 3 thrombocytopenia in one patient could be attributed to accidental continuous intake of pomalidomide. Taken together, adverse event rates were comparable to those reported in the ELOQUENT-3 trial.
Not least due to the favurable safety profile, 81% of our patients were able to receive subsequent systemic treatment upon progression on elo/pom/dex. Like in ELOQUENT-3, all but 2 patients had not been exposed to an anti-CD38 antibody and received daratumumab-based regimens for a median duration of more than one year. Overall survival rates of 86% and 81% at 12 and 18 months, respectively, are profoundly remarkable for heavily pretreated MM patients and are compare positively with published results. However, many patients with late-stage disease will now be pretreated with daratumumab; as in our study, these are largely underrepresented in current trials e.g. with pomalidomide-based combinations (Attal et al. 2019; Richardson et al. 2019) and will represent a formidable therapeutic challenge in the near future. A recent trial reported responses in 48% of daratumumab-exposed patients and acceptable toxicity with a quadruplet regimen of elo/pom/dex and bortezomib (Yee 2019), further corroborating our findings.
In summary, despite the small number of patients included here, our results suggest the combination of elo/pom/dex to represent an effective and exceptionally well-tolerated option in the treatment of advanced MM that may be considered in the len-refractory or even pom-exposed patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Open Access funding provided by Projekt DEAL.
Author contributions
DH, MS, HG and SK: conception, data acquisition, data analysis, preparation and writing of the manuscript. MTK, RS and BG: data acquisition. JH: statistical calculation and critical revision of the manuscript. SS and SD: data analysis, critical revision of the manuscript. HE: conception, critical revision of the manuscript.
Funding
The authors received no funding for this work.
Availability of data and material
The data generated and used for this study, are included in the published article. Additional data are available from the authors upon reasonable and individual request.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest. S.K.: Honoraria from Celgene GmbH and Bristol-Myers Squibb GmbH. S.D.: Advisory Board for Bristol-Myers Squibb GmbH. MS: Advisory board for Celgene and Bristol-Myers Squibb.
Code availability
IBM SPSS Statistics. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 32683487 | 19,057,439 | 2021-01 |
What was the administration route of drug 'POMALIDOMIDE'? | Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.
BACKGROUND
The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.
OBJECTIVE
To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna.
RESULTS
We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia.
CONCLUSIONS
Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.
Introduction
Multiple Myeloma (MM) is the second most frequent hematologic malignancy in the U.S. and Europe (Rollig et al. 2015). It is characterized by an uncontrolled proliferation of clonal plasma cells in the bone marrow and the accumulation of abnormal intact or incomplete immunoglobulins in serum and/or urine (Moreau et al. 2017; Raab et al. 2009). The median age at diagnosis of MM is 69 years with most subjects being diagnosed above the age of 55 years and a male predominance (Raab et al. 2016). Advances in therapeutic strategies have led to an increase in median overall survival of patients from three to six years within the last two decades, owing to novel compounds like proteasome inhibitors (PIs, e.g. bortezomib, carfilzomib, ixazomib) immunomodulatory drugs (IMIDs, e.g. thalidomide, lenalidomide, pomalidomide), alkylating agents (e.g. melphalan) or histone deacetylase inhibitors (e.g. panobinostat). Multi-drug combinations improve the long-term treatment outcome and might overcome drug resistance (Schreder and Knop 2019), but most patients continue to have relapses and will eventually become refractory to available drugs. Every subsequent relapse induces a shortened progression-free interval (Yong et al. 2016); therefore, novel treatment approaches are needed.
Immunotherapy holds great promise for MM therapy. MoAbs selectively target antigens on the myeloma cell surface which are critical for signaling, tumor growth, and survival (van de Donk et al. 2016). Elotuzumab is a humanized monoclonal IgGκ-antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7) or CS1 (CD2 subset-1), a glycoprotein universally and highly expressed on the surface of normal and malignant plasma cells as well as natural killer cells (Einsele and Schreder 2016). Elotuzumab) exhibited significant in vitro antibody-dependent cellular cytotoxicity (ADCC) using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. Furthermore, in vivo assays showed antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in mice (Hsi et al. 2008). The specificity enables elotuzumab to selectively kill myeloma cells and induce minimal damage on healthy tissue. In a randomized phase III trial, the addition of elotuzumab to lenalidomide and low-dose dexamethasone (Rd) resulted in a sustained improvement of progression-free survival (PFS) compared to Rd, leading to approval of the triplet regimen by the FDA and EMA (Lonial et al. 2015). However, patients who were refractory or intolerant to lenalidomide were excluded from the registration trial.
As pomalidomide is known to induce objective responses in len-refractory patients, we substituted lenalidomide for pomalidomide in patients with very advanced MM who were otherwise eligible for treatment with elotuzumab, dexamethasone and an IMID. Meanwhile, the results of a small randomized phase II study comparing elotuzumab/pomalidomide/dexamethasone (elo/pom/dex) with pom/dex have been reported, demonstrating a high efficacy of the triplet regimen in patients with relapsed/refractory MM (Dimopoulos et al. 2018). Here, we present the outcome of 22 consecutive MM patients with very advanced disease who received the triplet combination of elo/pom/dex outside of a clinical trial at two tertiary care centers.
Methods
We queried the databases of the university hospitals of Würzburg and Vienna to identify patients with relapsed and refractory multiple myeloma receiving elo/pom/dex in an individualized treatment concept when no other option was available. Patients had to have measurable disease according to the IMWG criteria (Rajkumar et al. 2014). Pretreatment with pomalidomide was allowed, but patients refractory to the compound were excluded. All patients provided written informed consent.
Elotuzumab was given intravenously at a dose of 10 mg/kg bodyweight on days 1, 8, 15 and 22 of a 28-day cycle in cycles 1 and 2 and on days 1 and 15 in subsequent cycles. Pomalidomide was administered orally at a dose of 4 mg on days 1 through 21 of each cycle. Dexamethasone was given weekly at a dose of 28 mg orally plus 8 mg intravenously on elotuzumab treatment days and 40 mg orally in weeks without elotuzumab. Dose reductions of pomalidomide and dexamethasone were performed in the event of toxicities according to the SmPC. Patients received antimicrobial prophylaxis with aciclovir and cotrimoxazole as well as low molecular weight heparin or acetylsalicylic acid (aspirin®) as prophylaxis of thromboembolic events throughout the treatment period. Treatment was continued until disease progression (PD) or unacceptable toxicity. Responses were defined according to IMWG criteria (Kumar et al. 2016). Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v. 4.0.
The database was locked on 1st February 2020. Statistical analysis was done with IBM SPSS statistics (IBM, Ehningen, Germany) and Prism (Graph Pad Software, San Diego, CA, USA). PFS was calculated according to Kaplan–Meier method from first dose of elo/pom/dex to disease progression or death, whatever occurred first. Patients proceeding to an autologous stem cell transplantation (SCT) were censored at time of transplant. Overall survival (OS) was calculated from first dose of elo/pom/dex to death from any cause or loss of follow up.
Results
Patients
We identified 22 patients with a median age of 61.5 years (range 39–81); the median duration of myeloma was 6.7 years (range 0.3–11.7). The baseline characteristics of the study population are shown in Table 1. The first patients began treatment in October 2015 and the last patient was started on elo/pom/dex in January 2017. A baseline bone marrow (BM) biopsy was performed in 18 patients. The median plasma cell infiltration was 35% (range 5–90) and 4 patients (18%) had high-risk cytogenetic abnormalities. The median number of prior treatment lines was 5 (range 1–16). All patients had been exposed to bortezomib and lenalidomide, 18 (82%) had previously undergone a stem cell transplantation. Only two patients had received prior daratumumab and five patients had been exposed to carfilzomib. Fifteen patients (68%) had been treated with pomalidomide during any previous regimen; of these, ten patients had received pomalidomide in the most recent line of therapy and were consecutively switched to elo/pom/dex after failing to achieve an objective response. 13 patients (59%) had been refractory to both their most recent line of therapy and earlier lenalidomide.Table 1 Clinical characteristics of patients at baseline
Characteristic Value (n = 22)
Age, median (range), years 61.5 (39–81)
Male sex, n (%) 16 (73)
Type of myeloma, n (%)
IgG 13 (59)
IgA 5 (23)
IgD 1 (4)
Light chain 3 (14)
International Staging System (ISS) stage at study entry, n (%)
I–II 13 (59)
III 5 (23)
Missing data 4 (18)
BM plasma cell infiltration, (%)
< 30% 7 (32)
30–59% 6 (27)
≥ 60 5 (23)
Not reported 4 (18)
Cytogenetic abnormality, n (%)
del17p, t(4;14), or t(14;16)
Yes 4 (18)
No 15 (68)
Data not available
1q21 3 (14)
Yes 2 (9)
No 16 (73)
Data not available 4 (18)
Primary refractory to first line treatment, n (%) 7 (32)
Median No. of previous treatment regimens (range) 5 (1–16)
Median time since initial diagnosis (range), years 6.7 (0.3–11.7)
Prior autologous stem cell transplantation, n (%) 17 (77)
Prior allogeneic stem cell transplantation, n (%) 1 (4)
Prior pomalidomide, n (%) 15 (68)
Prior carfilzomib, n (%) 5 (23)
Prior daratumumab, n (%) 2 (9)
Refractory to most recent line of therapy, n (%) 13 (59)
Refractory to lenalidomide, n (%) 13 (59)
Treatment exposure
At database lock all patients had discontinued treatment, with disease progression as the most common reason. Only one patient discontinued early due to side effects. Two patients requested to stop IV treatment with elotuzumab after 6 and 10 cycles of the triplet combination, respectively, and continued on pom/dex. Another two patients went on to receive an autologous stem cell transplantation as a means of consolidation. The median number of treatment cycles was 5 (range 1–30).
Efficacy
All 22 patients were evaluable for response. 11 patients achieved a partial response (PR), yielding an overall response rate of 50%. Of note, five of these patients had been primary refractory to their first line regimen.
The median PFS was 6.4 months. In a landmark analysis, 35% and 28% of patients were progression-free at 12 months and 18 months, respectively (Figs. 1, 2). Patients with high-risk cytogenetics had identical PFS compared to those with standard-risk disease (6.5 v 6.4 months, p = 0.77). There was a clear trend for shorter PFS in patients with ISS stage III at study entry compared to those with stage I and II disease (6.5 vs. 13.5 months), which did not reach statistical significance due to small sample size.Fig. 1 Progression-free (dashed line) and overall survival (solid line) with elotuzumab, pomalidomide, and dexamethasone. PFS and OS rates at 12 and 18 months from start of treatment are displayed
Fig. 2 Progression-free survival with elotuzumab/pomalidomide/dexamethasone according to a response to prior lenalidomide, b prior exposure tp pomalidomide and c number of prior lines of therapy
Patients refractory to lenalidomide showed no difference in their PFS compared to non-refractory patients (p = 0.98, Fig. 2a). Among patients who had previously received pomalidomide, 5 (33%) responded and another 3 (20%) had stable disease with most responses seen in patients who had pomalidomide immediately prior to elo/pom/dex (4 PR, 2 SD). Median PFS in pomalidomide-exposed patients was identical to that seen in pom-naïve patients (p = 0.90, Fig. 2b). When elo/pom/dex was given directly after a pomalidomide-containing regimen (e.g., carfilzomib/pom/dex, bortezomib/doxorubicin/pom/dex), an absolute gain in PFS of 4.3 months (p = 0.192) was seen when compared to patients with a regimen that did not include pomalidomide in the preceding line.
Responses were also observed in 3 out of 5 patients who had been pretreated with a carfilzomib-based regimen; PFS did not differ significantly when compared to carfilzomib-naïve subjects. At database lock, 14 of 22 patients (64%) had achieved a longer PFS to elo/pom/dex when compared to their most recent line of therapy.
PFS did not differ in intensely pretreated (> 4 prior therapies) versus less heavily pretreated patients (p = 0.99, Fig. 2c).
The median follow-up for the study population was 42.5 months. The median overall survival (95% CI) was not reached (23.6 months—not estimable). At 12 months, 82% of patients (n = 18) were still alive; the 18-month OS rate was 73% (Fig. 1).
In total, 17 of 21 patients (81%) received subsequent systemic therapy. One patient was lost to follow-up after discontinuation of elo/pom/dex. Two thirds of patients were treated with a daratumumab-containing regimen (n = 14); median exposure to the anti-CD38 antibody was 13.5 months. 4 patients underwent a salvage autologous stem cell transplant, two immediately after elo/pom/dex and another two later in the course of their disease. Other alkylating agents (most commonly, bendamustine or cyclophosphamide) were used in 57% and carfilzomib-based combinations in 43% of patients, respectively.
Toxicity
No infusion-related reactions were observed. In three patients, grade 3/4 neutropenia was recorded. In two of them the absolute neutrophil count dropped below 500/µl (grade 4), but no patient experienced neutropenic fever. One patient had grade 3 thrombocytopenia following the accidental continuous intake of pomalidomide.
Four patients were diagnosed with a grade 3/4 respiratory infection, two of whom sustained a pneumonia grade 3. Streptococcus pneumoniae was isolated from one patient and parainfluenza II virus in another patient; in the remaining cases, the offending pathogen could not be identified. All patients resumed treatment after resolution of symptoms.
Discussion
In recent years, immunotherapy has attracted significant attention in the treatment of relapsed or refractory MM. One milestone was the pivotal phase 2 study of daratumumab demonstrating single agent activity in patients with PI- and IMiD-refractory MM with a 3.7 months PFS and a median OS of 17.5 months. Meanwhile, daratumumab-based regimens are widely used in relapsed disease (Dimopoulos et al. 2016a; Mateos et al. 2020) and have recently been approved for frontline therapy in both transplant-eligible (Moreau et al. 2019a) and transplant-ineligible patients (Facon et al. 2019; Mateos et al. 2018).
While many patients will now receive CD38 antibody-based treatment, immunotherapy directed at alternative antigens are needed. Elotuzumab targets SLAMF7, acts synergistically with IMiDs and was shown to induce durable remissions in relapsed MM with a PFS of 19.4 months when combined with len/dex (Lonial et al. 2015). However, most patients now receive len as part of their first-line regimen and a considerable fraction will develop len-resistant disease (Moreau et al. 2019b). In this setting, pomalidomide/dex is active with a modest PFS of 4.0 months in the registration trial (Dimopoulos et al. 2016b), but long-lasting remissions are also observed (Danhof et al. 2015). The addition of elotuzumab to pom/dex aiming at prolonged disease control appears tempting and was proven effective in a randomized phase II trial (Dimopoulos et al. 2018). This study reported a median PFS of 10.3 months with elo/pom/dex in patients with a median number of 3 prior lines of therapy.
Since only 60 patients were included in the experimental arm of the ELOQUENT-3 study, we sought to expand clinical experience with elo/pom/dex in a “real-world” cohort of advanced MM. Compared to the published dataset, the 22 subjects of our current retrospective analysis had a longer interval since diagnosis of their MM (6.7 vs 4.8 years) and were more heavily pretreated (median, 5 vs 3 prior lines). Remarkably, 32% (n = 7) of them had been primary refractory to first-line treatment; 59% (n = 13) were refractory to lenalidomide and two thirds had previously received pomalidomide.
In this unfavorable cohort, we were still able to demonstrate a median PFS of 6.4 months with PFS rates at 12 and 18 months that were comparable to those reported in a recent update of ELOQUENT-3 (35% and 28% vs 43% and 34%, respectively) (Dimopoulos 2019). An overall response rate of 50% compared equally well to the published data. Of note, 64% of subjects achieved a longer PFS when compared to their most recent line of therapy and we were able to confirm responses in pomalidomide-exposed patients, most of whom had received pomalidomide in the most recent line prior to elo/pom/dex. This observation would thus justify the addition of elotuzumab to a doublet regimen of pom/dex in the absence of frank progression which in our hands led to objective responses in 4 of 10 patients. Incremental gain of median PFS with Elo/Pd was 4.3 months when compared to PFS with the most recent line of therapy. We believe this constitutes a clinically relevant benefit, as median PFS in a very advanced patient cohort was recently reported to be 3.4 months (Gandhi et al. 2019).
Even though none of our patients reached a complete remission (CR), we observed remarkably durable remissions of more than 20 months in 4 patients. In another two patients, elo/pom/dex served as a bridging therapy to autologous stem cell transplantation.
Subgroup analyses were limited due to the small sample size. Neither cytogenetic risk nor the number and type of prior therapy predicted for outcome in our cohort. Patients with low tumor burden as defined by ISS stages I and II at start of treatment appeared to gain increased benefit compared to those with stage III disease, confirming our previous observation (Danhof et al. 2019). We could also demonstrate that highly pretreated patients (> 4 prior therapies) showed a similar PFS compared to patients with a lower number of previous therapies, justifying the use of this regimen even in late stage MM.
In terms of toxicity, no new safety signals were seen. In general, treatment with elo/pom/dex was well tolerated; there was no allergic reaction or other infusion-related reaction recorded.
In one case a drug-related rash grade 2 was reported, diminishing under ongoing treatment. Like in many reported trials in advanced MM, respiratory infections were among the most common adverse events and were found to be severe in four patients, two of them presenting with grade 3 pneumonia. Both patients could resume therapy and achieved a PR. Hematologic toxicity was low with only a small number of patients experiencing grade 3/4 neutropenia. Grade 3 thrombocytopenia in one patient could be attributed to accidental continuous intake of pomalidomide. Taken together, adverse event rates were comparable to those reported in the ELOQUENT-3 trial.
Not least due to the favurable safety profile, 81% of our patients were able to receive subsequent systemic treatment upon progression on elo/pom/dex. Like in ELOQUENT-3, all but 2 patients had not been exposed to an anti-CD38 antibody and received daratumumab-based regimens for a median duration of more than one year. Overall survival rates of 86% and 81% at 12 and 18 months, respectively, are profoundly remarkable for heavily pretreated MM patients and are compare positively with published results. However, many patients with late-stage disease will now be pretreated with daratumumab; as in our study, these are largely underrepresented in current trials e.g. with pomalidomide-based combinations (Attal et al. 2019; Richardson et al. 2019) and will represent a formidable therapeutic challenge in the near future. A recent trial reported responses in 48% of daratumumab-exposed patients and acceptable toxicity with a quadruplet regimen of elo/pom/dex and bortezomib (Yee 2019), further corroborating our findings.
In summary, despite the small number of patients included here, our results suggest the combination of elo/pom/dex to represent an effective and exceptionally well-tolerated option in the treatment of advanced MM that may be considered in the len-refractory or even pom-exposed patient.
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Acknowledgements
Open Access funding provided by Projekt DEAL.
Author contributions
DH, MS, HG and SK: conception, data acquisition, data analysis, preparation and writing of the manuscript. MTK, RS and BG: data acquisition. JH: statistical calculation and critical revision of the manuscript. SS and SD: data analysis, critical revision of the manuscript. HE: conception, critical revision of the manuscript.
Funding
The authors received no funding for this work.
Availability of data and material
The data generated and used for this study, are included in the published article. Additional data are available from the authors upon reasonable and individual request.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest. S.K.: Honoraria from Celgene GmbH and Bristol-Myers Squibb GmbH. S.D.: Advisory Board for Bristol-Myers Squibb GmbH. MS: Advisory board for Celgene and Bristol-Myers Squibb.
Code availability
IBM SPSS Statistics. | Oral | DrugAdministrationRoute | CC BY | 32683487 | 19,057,439 | 2021-01 |
What was the dosage of drug 'ACYCLOVIR'? | Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.
BACKGROUND
The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.
OBJECTIVE
To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna.
RESULTS
We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia.
CONCLUSIONS
Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.
Introduction
Multiple Myeloma (MM) is the second most frequent hematologic malignancy in the U.S. and Europe (Rollig et al. 2015). It is characterized by an uncontrolled proliferation of clonal plasma cells in the bone marrow and the accumulation of abnormal intact or incomplete immunoglobulins in serum and/or urine (Moreau et al. 2017; Raab et al. 2009). The median age at diagnosis of MM is 69 years with most subjects being diagnosed above the age of 55 years and a male predominance (Raab et al. 2016). Advances in therapeutic strategies have led to an increase in median overall survival of patients from three to six years within the last two decades, owing to novel compounds like proteasome inhibitors (PIs, e.g. bortezomib, carfilzomib, ixazomib) immunomodulatory drugs (IMIDs, e.g. thalidomide, lenalidomide, pomalidomide), alkylating agents (e.g. melphalan) or histone deacetylase inhibitors (e.g. panobinostat). Multi-drug combinations improve the long-term treatment outcome and might overcome drug resistance (Schreder and Knop 2019), but most patients continue to have relapses and will eventually become refractory to available drugs. Every subsequent relapse induces a shortened progression-free interval (Yong et al. 2016); therefore, novel treatment approaches are needed.
Immunotherapy holds great promise for MM therapy. MoAbs selectively target antigens on the myeloma cell surface which are critical for signaling, tumor growth, and survival (van de Donk et al. 2016). Elotuzumab is a humanized monoclonal IgGκ-antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7) or CS1 (CD2 subset-1), a glycoprotein universally and highly expressed on the surface of normal and malignant plasma cells as well as natural killer cells (Einsele and Schreder 2016). Elotuzumab) exhibited significant in vitro antibody-dependent cellular cytotoxicity (ADCC) using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. Furthermore, in vivo assays showed antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in mice (Hsi et al. 2008). The specificity enables elotuzumab to selectively kill myeloma cells and induce minimal damage on healthy tissue. In a randomized phase III trial, the addition of elotuzumab to lenalidomide and low-dose dexamethasone (Rd) resulted in a sustained improvement of progression-free survival (PFS) compared to Rd, leading to approval of the triplet regimen by the FDA and EMA (Lonial et al. 2015). However, patients who were refractory or intolerant to lenalidomide were excluded from the registration trial.
As pomalidomide is known to induce objective responses in len-refractory patients, we substituted lenalidomide for pomalidomide in patients with very advanced MM who were otherwise eligible for treatment with elotuzumab, dexamethasone and an IMID. Meanwhile, the results of a small randomized phase II study comparing elotuzumab/pomalidomide/dexamethasone (elo/pom/dex) with pom/dex have been reported, demonstrating a high efficacy of the triplet regimen in patients with relapsed/refractory MM (Dimopoulos et al. 2018). Here, we present the outcome of 22 consecutive MM patients with very advanced disease who received the triplet combination of elo/pom/dex outside of a clinical trial at two tertiary care centers.
Methods
We queried the databases of the university hospitals of Würzburg and Vienna to identify patients with relapsed and refractory multiple myeloma receiving elo/pom/dex in an individualized treatment concept when no other option was available. Patients had to have measurable disease according to the IMWG criteria (Rajkumar et al. 2014). Pretreatment with pomalidomide was allowed, but patients refractory to the compound were excluded. All patients provided written informed consent.
Elotuzumab was given intravenously at a dose of 10 mg/kg bodyweight on days 1, 8, 15 and 22 of a 28-day cycle in cycles 1 and 2 and on days 1 and 15 in subsequent cycles. Pomalidomide was administered orally at a dose of 4 mg on days 1 through 21 of each cycle. Dexamethasone was given weekly at a dose of 28 mg orally plus 8 mg intravenously on elotuzumab treatment days and 40 mg orally in weeks without elotuzumab. Dose reductions of pomalidomide and dexamethasone were performed in the event of toxicities according to the SmPC. Patients received antimicrobial prophylaxis with aciclovir and cotrimoxazole as well as low molecular weight heparin or acetylsalicylic acid (aspirin®) as prophylaxis of thromboembolic events throughout the treatment period. Treatment was continued until disease progression (PD) or unacceptable toxicity. Responses were defined according to IMWG criteria (Kumar et al. 2016). Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v. 4.0.
The database was locked on 1st February 2020. Statistical analysis was done with IBM SPSS statistics (IBM, Ehningen, Germany) and Prism (Graph Pad Software, San Diego, CA, USA). PFS was calculated according to Kaplan–Meier method from first dose of elo/pom/dex to disease progression or death, whatever occurred first. Patients proceeding to an autologous stem cell transplantation (SCT) were censored at time of transplant. Overall survival (OS) was calculated from first dose of elo/pom/dex to death from any cause or loss of follow up.
Results
Patients
We identified 22 patients with a median age of 61.5 years (range 39–81); the median duration of myeloma was 6.7 years (range 0.3–11.7). The baseline characteristics of the study population are shown in Table 1. The first patients began treatment in October 2015 and the last patient was started on elo/pom/dex in January 2017. A baseline bone marrow (BM) biopsy was performed in 18 patients. The median plasma cell infiltration was 35% (range 5–90) and 4 patients (18%) had high-risk cytogenetic abnormalities. The median number of prior treatment lines was 5 (range 1–16). All patients had been exposed to bortezomib and lenalidomide, 18 (82%) had previously undergone a stem cell transplantation. Only two patients had received prior daratumumab and five patients had been exposed to carfilzomib. Fifteen patients (68%) had been treated with pomalidomide during any previous regimen; of these, ten patients had received pomalidomide in the most recent line of therapy and were consecutively switched to elo/pom/dex after failing to achieve an objective response. 13 patients (59%) had been refractory to both their most recent line of therapy and earlier lenalidomide.Table 1 Clinical characteristics of patients at baseline
Characteristic Value (n = 22)
Age, median (range), years 61.5 (39–81)
Male sex, n (%) 16 (73)
Type of myeloma, n (%)
IgG 13 (59)
IgA 5 (23)
IgD 1 (4)
Light chain 3 (14)
International Staging System (ISS) stage at study entry, n (%)
I–II 13 (59)
III 5 (23)
Missing data 4 (18)
BM plasma cell infiltration, (%)
< 30% 7 (32)
30–59% 6 (27)
≥ 60 5 (23)
Not reported 4 (18)
Cytogenetic abnormality, n (%)
del17p, t(4;14), or t(14;16)
Yes 4 (18)
No 15 (68)
Data not available
1q21 3 (14)
Yes 2 (9)
No 16 (73)
Data not available 4 (18)
Primary refractory to first line treatment, n (%) 7 (32)
Median No. of previous treatment regimens (range) 5 (1–16)
Median time since initial diagnosis (range), years 6.7 (0.3–11.7)
Prior autologous stem cell transplantation, n (%) 17 (77)
Prior allogeneic stem cell transplantation, n (%) 1 (4)
Prior pomalidomide, n (%) 15 (68)
Prior carfilzomib, n (%) 5 (23)
Prior daratumumab, n (%) 2 (9)
Refractory to most recent line of therapy, n (%) 13 (59)
Refractory to lenalidomide, n (%) 13 (59)
Treatment exposure
At database lock all patients had discontinued treatment, with disease progression as the most common reason. Only one patient discontinued early due to side effects. Two patients requested to stop IV treatment with elotuzumab after 6 and 10 cycles of the triplet combination, respectively, and continued on pom/dex. Another two patients went on to receive an autologous stem cell transplantation as a means of consolidation. The median number of treatment cycles was 5 (range 1–30).
Efficacy
All 22 patients were evaluable for response. 11 patients achieved a partial response (PR), yielding an overall response rate of 50%. Of note, five of these patients had been primary refractory to their first line regimen.
The median PFS was 6.4 months. In a landmark analysis, 35% and 28% of patients were progression-free at 12 months and 18 months, respectively (Figs. 1, 2). Patients with high-risk cytogenetics had identical PFS compared to those with standard-risk disease (6.5 v 6.4 months, p = 0.77). There was a clear trend for shorter PFS in patients with ISS stage III at study entry compared to those with stage I and II disease (6.5 vs. 13.5 months), which did not reach statistical significance due to small sample size.Fig. 1 Progression-free (dashed line) and overall survival (solid line) with elotuzumab, pomalidomide, and dexamethasone. PFS and OS rates at 12 and 18 months from start of treatment are displayed
Fig. 2 Progression-free survival with elotuzumab/pomalidomide/dexamethasone according to a response to prior lenalidomide, b prior exposure tp pomalidomide and c number of prior lines of therapy
Patients refractory to lenalidomide showed no difference in their PFS compared to non-refractory patients (p = 0.98, Fig. 2a). Among patients who had previously received pomalidomide, 5 (33%) responded and another 3 (20%) had stable disease with most responses seen in patients who had pomalidomide immediately prior to elo/pom/dex (4 PR, 2 SD). Median PFS in pomalidomide-exposed patients was identical to that seen in pom-naïve patients (p = 0.90, Fig. 2b). When elo/pom/dex was given directly after a pomalidomide-containing regimen (e.g., carfilzomib/pom/dex, bortezomib/doxorubicin/pom/dex), an absolute gain in PFS of 4.3 months (p = 0.192) was seen when compared to patients with a regimen that did not include pomalidomide in the preceding line.
Responses were also observed in 3 out of 5 patients who had been pretreated with a carfilzomib-based regimen; PFS did not differ significantly when compared to carfilzomib-naïve subjects. At database lock, 14 of 22 patients (64%) had achieved a longer PFS to elo/pom/dex when compared to their most recent line of therapy.
PFS did not differ in intensely pretreated (> 4 prior therapies) versus less heavily pretreated patients (p = 0.99, Fig. 2c).
The median follow-up for the study population was 42.5 months. The median overall survival (95% CI) was not reached (23.6 months—not estimable). At 12 months, 82% of patients (n = 18) were still alive; the 18-month OS rate was 73% (Fig. 1).
In total, 17 of 21 patients (81%) received subsequent systemic therapy. One patient was lost to follow-up after discontinuation of elo/pom/dex. Two thirds of patients were treated with a daratumumab-containing regimen (n = 14); median exposure to the anti-CD38 antibody was 13.5 months. 4 patients underwent a salvage autologous stem cell transplant, two immediately after elo/pom/dex and another two later in the course of their disease. Other alkylating agents (most commonly, bendamustine or cyclophosphamide) were used in 57% and carfilzomib-based combinations in 43% of patients, respectively.
Toxicity
No infusion-related reactions were observed. In three patients, grade 3/4 neutropenia was recorded. In two of them the absolute neutrophil count dropped below 500/µl (grade 4), but no patient experienced neutropenic fever. One patient had grade 3 thrombocytopenia following the accidental continuous intake of pomalidomide.
Four patients were diagnosed with a grade 3/4 respiratory infection, two of whom sustained a pneumonia grade 3. Streptococcus pneumoniae was isolated from one patient and parainfluenza II virus in another patient; in the remaining cases, the offending pathogen could not be identified. All patients resumed treatment after resolution of symptoms.
Discussion
In recent years, immunotherapy has attracted significant attention in the treatment of relapsed or refractory MM. One milestone was the pivotal phase 2 study of daratumumab demonstrating single agent activity in patients with PI- and IMiD-refractory MM with a 3.7 months PFS and a median OS of 17.5 months. Meanwhile, daratumumab-based regimens are widely used in relapsed disease (Dimopoulos et al. 2016a; Mateos et al. 2020) and have recently been approved for frontline therapy in both transplant-eligible (Moreau et al. 2019a) and transplant-ineligible patients (Facon et al. 2019; Mateos et al. 2018).
While many patients will now receive CD38 antibody-based treatment, immunotherapy directed at alternative antigens are needed. Elotuzumab targets SLAMF7, acts synergistically with IMiDs and was shown to induce durable remissions in relapsed MM with a PFS of 19.4 months when combined with len/dex (Lonial et al. 2015). However, most patients now receive len as part of their first-line regimen and a considerable fraction will develop len-resistant disease (Moreau et al. 2019b). In this setting, pomalidomide/dex is active with a modest PFS of 4.0 months in the registration trial (Dimopoulos et al. 2016b), but long-lasting remissions are also observed (Danhof et al. 2015). The addition of elotuzumab to pom/dex aiming at prolonged disease control appears tempting and was proven effective in a randomized phase II trial (Dimopoulos et al. 2018). This study reported a median PFS of 10.3 months with elo/pom/dex in patients with a median number of 3 prior lines of therapy.
Since only 60 patients were included in the experimental arm of the ELOQUENT-3 study, we sought to expand clinical experience with elo/pom/dex in a “real-world” cohort of advanced MM. Compared to the published dataset, the 22 subjects of our current retrospective analysis had a longer interval since diagnosis of their MM (6.7 vs 4.8 years) and were more heavily pretreated (median, 5 vs 3 prior lines). Remarkably, 32% (n = 7) of them had been primary refractory to first-line treatment; 59% (n = 13) were refractory to lenalidomide and two thirds had previously received pomalidomide.
In this unfavorable cohort, we were still able to demonstrate a median PFS of 6.4 months with PFS rates at 12 and 18 months that were comparable to those reported in a recent update of ELOQUENT-3 (35% and 28% vs 43% and 34%, respectively) (Dimopoulos 2019). An overall response rate of 50% compared equally well to the published data. Of note, 64% of subjects achieved a longer PFS when compared to their most recent line of therapy and we were able to confirm responses in pomalidomide-exposed patients, most of whom had received pomalidomide in the most recent line prior to elo/pom/dex. This observation would thus justify the addition of elotuzumab to a doublet regimen of pom/dex in the absence of frank progression which in our hands led to objective responses in 4 of 10 patients. Incremental gain of median PFS with Elo/Pd was 4.3 months when compared to PFS with the most recent line of therapy. We believe this constitutes a clinically relevant benefit, as median PFS in a very advanced patient cohort was recently reported to be 3.4 months (Gandhi et al. 2019).
Even though none of our patients reached a complete remission (CR), we observed remarkably durable remissions of more than 20 months in 4 patients. In another two patients, elo/pom/dex served as a bridging therapy to autologous stem cell transplantation.
Subgroup analyses were limited due to the small sample size. Neither cytogenetic risk nor the number and type of prior therapy predicted for outcome in our cohort. Patients with low tumor burden as defined by ISS stages I and II at start of treatment appeared to gain increased benefit compared to those with stage III disease, confirming our previous observation (Danhof et al. 2019). We could also demonstrate that highly pretreated patients (> 4 prior therapies) showed a similar PFS compared to patients with a lower number of previous therapies, justifying the use of this regimen even in late stage MM.
In terms of toxicity, no new safety signals were seen. In general, treatment with elo/pom/dex was well tolerated; there was no allergic reaction or other infusion-related reaction recorded.
In one case a drug-related rash grade 2 was reported, diminishing under ongoing treatment. Like in many reported trials in advanced MM, respiratory infections were among the most common adverse events and were found to be severe in four patients, two of them presenting with grade 3 pneumonia. Both patients could resume therapy and achieved a PR. Hematologic toxicity was low with only a small number of patients experiencing grade 3/4 neutropenia. Grade 3 thrombocytopenia in one patient could be attributed to accidental continuous intake of pomalidomide. Taken together, adverse event rates were comparable to those reported in the ELOQUENT-3 trial.
Not least due to the favurable safety profile, 81% of our patients were able to receive subsequent systemic treatment upon progression on elo/pom/dex. Like in ELOQUENT-3, all but 2 patients had not been exposed to an anti-CD38 antibody and received daratumumab-based regimens for a median duration of more than one year. Overall survival rates of 86% and 81% at 12 and 18 months, respectively, are profoundly remarkable for heavily pretreated MM patients and are compare positively with published results. However, many patients with late-stage disease will now be pretreated with daratumumab; as in our study, these are largely underrepresented in current trials e.g. with pomalidomide-based combinations (Attal et al. 2019; Richardson et al. 2019) and will represent a formidable therapeutic challenge in the near future. A recent trial reported responses in 48% of daratumumab-exposed patients and acceptable toxicity with a quadruplet regimen of elo/pom/dex and bortezomib (Yee 2019), further corroborating our findings.
In summary, despite the small number of patients included here, our results suggest the combination of elo/pom/dex to represent an effective and exceptionally well-tolerated option in the treatment of advanced MM that may be considered in the len-refractory or even pom-exposed patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Open Access funding provided by Projekt DEAL.
Author contributions
DH, MS, HG and SK: conception, data acquisition, data analysis, preparation and writing of the manuscript. MTK, RS and BG: data acquisition. JH: statistical calculation and critical revision of the manuscript. SS and SD: data analysis, critical revision of the manuscript. HE: conception, critical revision of the manuscript.
Funding
The authors received no funding for this work.
Availability of data and material
The data generated and used for this study, are included in the published article. Additional data are available from the authors upon reasonable and individual request.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest. S.K.: Honoraria from Celgene GmbH and Bristol-Myers Squibb GmbH. S.D.: Advisory Board for Bristol-Myers Squibb GmbH. MS: Advisory board for Celgene and Bristol-Myers Squibb.
Code availability
IBM SPSS Statistics. | ADMINISTERED THROUGHOUT THE TREATMENT PERIOD | DrugDosageText | CC BY | 32683487 | 19,057,439 | 2021-01 |
What was the dosage of drug 'ELOTUZUMAB'? | Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.
BACKGROUND
The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.
OBJECTIVE
To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna.
RESULTS
We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia.
CONCLUSIONS
Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.
Introduction
Multiple Myeloma (MM) is the second most frequent hematologic malignancy in the U.S. and Europe (Rollig et al. 2015). It is characterized by an uncontrolled proliferation of clonal plasma cells in the bone marrow and the accumulation of abnormal intact or incomplete immunoglobulins in serum and/or urine (Moreau et al. 2017; Raab et al. 2009). The median age at diagnosis of MM is 69 years with most subjects being diagnosed above the age of 55 years and a male predominance (Raab et al. 2016). Advances in therapeutic strategies have led to an increase in median overall survival of patients from three to six years within the last two decades, owing to novel compounds like proteasome inhibitors (PIs, e.g. bortezomib, carfilzomib, ixazomib) immunomodulatory drugs (IMIDs, e.g. thalidomide, lenalidomide, pomalidomide), alkylating agents (e.g. melphalan) or histone deacetylase inhibitors (e.g. panobinostat). Multi-drug combinations improve the long-term treatment outcome and might overcome drug resistance (Schreder and Knop 2019), but most patients continue to have relapses and will eventually become refractory to available drugs. Every subsequent relapse induces a shortened progression-free interval (Yong et al. 2016); therefore, novel treatment approaches are needed.
Immunotherapy holds great promise for MM therapy. MoAbs selectively target antigens on the myeloma cell surface which are critical for signaling, tumor growth, and survival (van de Donk et al. 2016). Elotuzumab is a humanized monoclonal IgGκ-antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7) or CS1 (CD2 subset-1), a glycoprotein universally and highly expressed on the surface of normal and malignant plasma cells as well as natural killer cells (Einsele and Schreder 2016). Elotuzumab) exhibited significant in vitro antibody-dependent cellular cytotoxicity (ADCC) using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. Furthermore, in vivo assays showed antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in mice (Hsi et al. 2008). The specificity enables elotuzumab to selectively kill myeloma cells and induce minimal damage on healthy tissue. In a randomized phase III trial, the addition of elotuzumab to lenalidomide and low-dose dexamethasone (Rd) resulted in a sustained improvement of progression-free survival (PFS) compared to Rd, leading to approval of the triplet regimen by the FDA and EMA (Lonial et al. 2015). However, patients who were refractory or intolerant to lenalidomide were excluded from the registration trial.
As pomalidomide is known to induce objective responses in len-refractory patients, we substituted lenalidomide for pomalidomide in patients with very advanced MM who were otherwise eligible for treatment with elotuzumab, dexamethasone and an IMID. Meanwhile, the results of a small randomized phase II study comparing elotuzumab/pomalidomide/dexamethasone (elo/pom/dex) with pom/dex have been reported, demonstrating a high efficacy of the triplet regimen in patients with relapsed/refractory MM (Dimopoulos et al. 2018). Here, we present the outcome of 22 consecutive MM patients with very advanced disease who received the triplet combination of elo/pom/dex outside of a clinical trial at two tertiary care centers.
Methods
We queried the databases of the university hospitals of Würzburg and Vienna to identify patients with relapsed and refractory multiple myeloma receiving elo/pom/dex in an individualized treatment concept when no other option was available. Patients had to have measurable disease according to the IMWG criteria (Rajkumar et al. 2014). Pretreatment with pomalidomide was allowed, but patients refractory to the compound were excluded. All patients provided written informed consent.
Elotuzumab was given intravenously at a dose of 10 mg/kg bodyweight on days 1, 8, 15 and 22 of a 28-day cycle in cycles 1 and 2 and on days 1 and 15 in subsequent cycles. Pomalidomide was administered orally at a dose of 4 mg on days 1 through 21 of each cycle. Dexamethasone was given weekly at a dose of 28 mg orally plus 8 mg intravenously on elotuzumab treatment days and 40 mg orally in weeks without elotuzumab. Dose reductions of pomalidomide and dexamethasone were performed in the event of toxicities according to the SmPC. Patients received antimicrobial prophylaxis with aciclovir and cotrimoxazole as well as low molecular weight heparin or acetylsalicylic acid (aspirin®) as prophylaxis of thromboembolic events throughout the treatment period. Treatment was continued until disease progression (PD) or unacceptable toxicity. Responses were defined according to IMWG criteria (Kumar et al. 2016). Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v. 4.0.
The database was locked on 1st February 2020. Statistical analysis was done with IBM SPSS statistics (IBM, Ehningen, Germany) and Prism (Graph Pad Software, San Diego, CA, USA). PFS was calculated according to Kaplan–Meier method from first dose of elo/pom/dex to disease progression or death, whatever occurred first. Patients proceeding to an autologous stem cell transplantation (SCT) were censored at time of transplant. Overall survival (OS) was calculated from first dose of elo/pom/dex to death from any cause or loss of follow up.
Results
Patients
We identified 22 patients with a median age of 61.5 years (range 39–81); the median duration of myeloma was 6.7 years (range 0.3–11.7). The baseline characteristics of the study population are shown in Table 1. The first patients began treatment in October 2015 and the last patient was started on elo/pom/dex in January 2017. A baseline bone marrow (BM) biopsy was performed in 18 patients. The median plasma cell infiltration was 35% (range 5–90) and 4 patients (18%) had high-risk cytogenetic abnormalities. The median number of prior treatment lines was 5 (range 1–16). All patients had been exposed to bortezomib and lenalidomide, 18 (82%) had previously undergone a stem cell transplantation. Only two patients had received prior daratumumab and five patients had been exposed to carfilzomib. Fifteen patients (68%) had been treated with pomalidomide during any previous regimen; of these, ten patients had received pomalidomide in the most recent line of therapy and were consecutively switched to elo/pom/dex after failing to achieve an objective response. 13 patients (59%) had been refractory to both their most recent line of therapy and earlier lenalidomide.Table 1 Clinical characteristics of patients at baseline
Characteristic Value (n = 22)
Age, median (range), years 61.5 (39–81)
Male sex, n (%) 16 (73)
Type of myeloma, n (%)
IgG 13 (59)
IgA 5 (23)
IgD 1 (4)
Light chain 3 (14)
International Staging System (ISS) stage at study entry, n (%)
I–II 13 (59)
III 5 (23)
Missing data 4 (18)
BM plasma cell infiltration, (%)
< 30% 7 (32)
30–59% 6 (27)
≥ 60 5 (23)
Not reported 4 (18)
Cytogenetic abnormality, n (%)
del17p, t(4;14), or t(14;16)
Yes 4 (18)
No 15 (68)
Data not available
1q21 3 (14)
Yes 2 (9)
No 16 (73)
Data not available 4 (18)
Primary refractory to first line treatment, n (%) 7 (32)
Median No. of previous treatment regimens (range) 5 (1–16)
Median time since initial diagnosis (range), years 6.7 (0.3–11.7)
Prior autologous stem cell transplantation, n (%) 17 (77)
Prior allogeneic stem cell transplantation, n (%) 1 (4)
Prior pomalidomide, n (%) 15 (68)
Prior carfilzomib, n (%) 5 (23)
Prior daratumumab, n (%) 2 (9)
Refractory to most recent line of therapy, n (%) 13 (59)
Refractory to lenalidomide, n (%) 13 (59)
Treatment exposure
At database lock all patients had discontinued treatment, with disease progression as the most common reason. Only one patient discontinued early due to side effects. Two patients requested to stop IV treatment with elotuzumab after 6 and 10 cycles of the triplet combination, respectively, and continued on pom/dex. Another two patients went on to receive an autologous stem cell transplantation as a means of consolidation. The median number of treatment cycles was 5 (range 1–30).
Efficacy
All 22 patients were evaluable for response. 11 patients achieved a partial response (PR), yielding an overall response rate of 50%. Of note, five of these patients had been primary refractory to their first line regimen.
The median PFS was 6.4 months. In a landmark analysis, 35% and 28% of patients were progression-free at 12 months and 18 months, respectively (Figs. 1, 2). Patients with high-risk cytogenetics had identical PFS compared to those with standard-risk disease (6.5 v 6.4 months, p = 0.77). There was a clear trend for shorter PFS in patients with ISS stage III at study entry compared to those with stage I and II disease (6.5 vs. 13.5 months), which did not reach statistical significance due to small sample size.Fig. 1 Progression-free (dashed line) and overall survival (solid line) with elotuzumab, pomalidomide, and dexamethasone. PFS and OS rates at 12 and 18 months from start of treatment are displayed
Fig. 2 Progression-free survival with elotuzumab/pomalidomide/dexamethasone according to a response to prior lenalidomide, b prior exposure tp pomalidomide and c number of prior lines of therapy
Patients refractory to lenalidomide showed no difference in their PFS compared to non-refractory patients (p = 0.98, Fig. 2a). Among patients who had previously received pomalidomide, 5 (33%) responded and another 3 (20%) had stable disease with most responses seen in patients who had pomalidomide immediately prior to elo/pom/dex (4 PR, 2 SD). Median PFS in pomalidomide-exposed patients was identical to that seen in pom-naïve patients (p = 0.90, Fig. 2b). When elo/pom/dex was given directly after a pomalidomide-containing regimen (e.g., carfilzomib/pom/dex, bortezomib/doxorubicin/pom/dex), an absolute gain in PFS of 4.3 months (p = 0.192) was seen when compared to patients with a regimen that did not include pomalidomide in the preceding line.
Responses were also observed in 3 out of 5 patients who had been pretreated with a carfilzomib-based regimen; PFS did not differ significantly when compared to carfilzomib-naïve subjects. At database lock, 14 of 22 patients (64%) had achieved a longer PFS to elo/pom/dex when compared to their most recent line of therapy.
PFS did not differ in intensely pretreated (> 4 prior therapies) versus less heavily pretreated patients (p = 0.99, Fig. 2c).
The median follow-up for the study population was 42.5 months. The median overall survival (95% CI) was not reached (23.6 months—not estimable). At 12 months, 82% of patients (n = 18) were still alive; the 18-month OS rate was 73% (Fig. 1).
In total, 17 of 21 patients (81%) received subsequent systemic therapy. One patient was lost to follow-up after discontinuation of elo/pom/dex. Two thirds of patients were treated with a daratumumab-containing regimen (n = 14); median exposure to the anti-CD38 antibody was 13.5 months. 4 patients underwent a salvage autologous stem cell transplant, two immediately after elo/pom/dex and another two later in the course of their disease. Other alkylating agents (most commonly, bendamustine or cyclophosphamide) were used in 57% and carfilzomib-based combinations in 43% of patients, respectively.
Toxicity
No infusion-related reactions were observed. In three patients, grade 3/4 neutropenia was recorded. In two of them the absolute neutrophil count dropped below 500/µl (grade 4), but no patient experienced neutropenic fever. One patient had grade 3 thrombocytopenia following the accidental continuous intake of pomalidomide.
Four patients were diagnosed with a grade 3/4 respiratory infection, two of whom sustained a pneumonia grade 3. Streptococcus pneumoniae was isolated from one patient and parainfluenza II virus in another patient; in the remaining cases, the offending pathogen could not be identified. All patients resumed treatment after resolution of symptoms.
Discussion
In recent years, immunotherapy has attracted significant attention in the treatment of relapsed or refractory MM. One milestone was the pivotal phase 2 study of daratumumab demonstrating single agent activity in patients with PI- and IMiD-refractory MM with a 3.7 months PFS and a median OS of 17.5 months. Meanwhile, daratumumab-based regimens are widely used in relapsed disease (Dimopoulos et al. 2016a; Mateos et al. 2020) and have recently been approved for frontline therapy in both transplant-eligible (Moreau et al. 2019a) and transplant-ineligible patients (Facon et al. 2019; Mateos et al. 2018).
While many patients will now receive CD38 antibody-based treatment, immunotherapy directed at alternative antigens are needed. Elotuzumab targets SLAMF7, acts synergistically with IMiDs and was shown to induce durable remissions in relapsed MM with a PFS of 19.4 months when combined with len/dex (Lonial et al. 2015). However, most patients now receive len as part of their first-line regimen and a considerable fraction will develop len-resistant disease (Moreau et al. 2019b). In this setting, pomalidomide/dex is active with a modest PFS of 4.0 months in the registration trial (Dimopoulos et al. 2016b), but long-lasting remissions are also observed (Danhof et al. 2015). The addition of elotuzumab to pom/dex aiming at prolonged disease control appears tempting and was proven effective in a randomized phase II trial (Dimopoulos et al. 2018). This study reported a median PFS of 10.3 months with elo/pom/dex in patients with a median number of 3 prior lines of therapy.
Since only 60 patients were included in the experimental arm of the ELOQUENT-3 study, we sought to expand clinical experience with elo/pom/dex in a “real-world” cohort of advanced MM. Compared to the published dataset, the 22 subjects of our current retrospective analysis had a longer interval since diagnosis of their MM (6.7 vs 4.8 years) and were more heavily pretreated (median, 5 vs 3 prior lines). Remarkably, 32% (n = 7) of them had been primary refractory to first-line treatment; 59% (n = 13) were refractory to lenalidomide and two thirds had previously received pomalidomide.
In this unfavorable cohort, we were still able to demonstrate a median PFS of 6.4 months with PFS rates at 12 and 18 months that were comparable to those reported in a recent update of ELOQUENT-3 (35% and 28% vs 43% and 34%, respectively) (Dimopoulos 2019). An overall response rate of 50% compared equally well to the published data. Of note, 64% of subjects achieved a longer PFS when compared to their most recent line of therapy and we were able to confirm responses in pomalidomide-exposed patients, most of whom had received pomalidomide in the most recent line prior to elo/pom/dex. This observation would thus justify the addition of elotuzumab to a doublet regimen of pom/dex in the absence of frank progression which in our hands led to objective responses in 4 of 10 patients. Incremental gain of median PFS with Elo/Pd was 4.3 months when compared to PFS with the most recent line of therapy. We believe this constitutes a clinically relevant benefit, as median PFS in a very advanced patient cohort was recently reported to be 3.4 months (Gandhi et al. 2019).
Even though none of our patients reached a complete remission (CR), we observed remarkably durable remissions of more than 20 months in 4 patients. In another two patients, elo/pom/dex served as a bridging therapy to autologous stem cell transplantation.
Subgroup analyses were limited due to the small sample size. Neither cytogenetic risk nor the number and type of prior therapy predicted for outcome in our cohort. Patients with low tumor burden as defined by ISS stages I and II at start of treatment appeared to gain increased benefit compared to those with stage III disease, confirming our previous observation (Danhof et al. 2019). We could also demonstrate that highly pretreated patients (> 4 prior therapies) showed a similar PFS compared to patients with a lower number of previous therapies, justifying the use of this regimen even in late stage MM.
In terms of toxicity, no new safety signals were seen. In general, treatment with elo/pom/dex was well tolerated; there was no allergic reaction or other infusion-related reaction recorded.
In one case a drug-related rash grade 2 was reported, diminishing under ongoing treatment. Like in many reported trials in advanced MM, respiratory infections were among the most common adverse events and were found to be severe in four patients, two of them presenting with grade 3 pneumonia. Both patients could resume therapy and achieved a PR. Hematologic toxicity was low with only a small number of patients experiencing grade 3/4 neutropenia. Grade 3 thrombocytopenia in one patient could be attributed to accidental continuous intake of pomalidomide. Taken together, adverse event rates were comparable to those reported in the ELOQUENT-3 trial.
Not least due to the favurable safety profile, 81% of our patients were able to receive subsequent systemic treatment upon progression on elo/pom/dex. Like in ELOQUENT-3, all but 2 patients had not been exposed to an anti-CD38 antibody and received daratumumab-based regimens for a median duration of more than one year. Overall survival rates of 86% and 81% at 12 and 18 months, respectively, are profoundly remarkable for heavily pretreated MM patients and are compare positively with published results. However, many patients with late-stage disease will now be pretreated with daratumumab; as in our study, these are largely underrepresented in current trials e.g. with pomalidomide-based combinations (Attal et al. 2019; Richardson et al. 2019) and will represent a formidable therapeutic challenge in the near future. A recent trial reported responses in 48% of daratumumab-exposed patients and acceptable toxicity with a quadruplet regimen of elo/pom/dex and bortezomib (Yee 2019), further corroborating our findings.
In summary, despite the small number of patients included here, our results suggest the combination of elo/pom/dex to represent an effective and exceptionally well-tolerated option in the treatment of advanced MM that may be considered in the len-refractory or even pom-exposed patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Open Access funding provided by Projekt DEAL.
Author contributions
DH, MS, HG and SK: conception, data acquisition, data analysis, preparation and writing of the manuscript. MTK, RS and BG: data acquisition. JH: statistical calculation and critical revision of the manuscript. SS and SD: data analysis, critical revision of the manuscript. HE: conception, critical revision of the manuscript.
Funding
The authors received no funding for this work.
Availability of data and material
The data generated and used for this study, are included in the published article. Additional data are available from the authors upon reasonable and individual request.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest. S.K.: Honoraria from Celgene GmbH and Bristol-Myers Squibb GmbH. S.D.: Advisory Board for Bristol-Myers Squibb GmbH. MS: Advisory board for Celgene and Bristol-Myers Squibb.
Code availability
IBM SPSS Statistics. | ON DAYS 1, 8, 15 AND 22 OF A 28?DAY CYCLE IN CYCLES 1 AND 2 AND ON DAYS 1 AND 15 IN THE SUBSEQUEN... | DrugDosageText | CC BY | 32683487 | 19,057,439 | 2021-01 |
What was the dosage of drug 'POMALIDOMIDE'? | Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.
BACKGROUND
The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.
OBJECTIVE
To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna.
RESULTS
We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia.
CONCLUSIONS
Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.
Introduction
Multiple Myeloma (MM) is the second most frequent hematologic malignancy in the U.S. and Europe (Rollig et al. 2015). It is characterized by an uncontrolled proliferation of clonal plasma cells in the bone marrow and the accumulation of abnormal intact or incomplete immunoglobulins in serum and/or urine (Moreau et al. 2017; Raab et al. 2009). The median age at diagnosis of MM is 69 years with most subjects being diagnosed above the age of 55 years and a male predominance (Raab et al. 2016). Advances in therapeutic strategies have led to an increase in median overall survival of patients from three to six years within the last two decades, owing to novel compounds like proteasome inhibitors (PIs, e.g. bortezomib, carfilzomib, ixazomib) immunomodulatory drugs (IMIDs, e.g. thalidomide, lenalidomide, pomalidomide), alkylating agents (e.g. melphalan) or histone deacetylase inhibitors (e.g. panobinostat). Multi-drug combinations improve the long-term treatment outcome and might overcome drug resistance (Schreder and Knop 2019), but most patients continue to have relapses and will eventually become refractory to available drugs. Every subsequent relapse induces a shortened progression-free interval (Yong et al. 2016); therefore, novel treatment approaches are needed.
Immunotherapy holds great promise for MM therapy. MoAbs selectively target antigens on the myeloma cell surface which are critical for signaling, tumor growth, and survival (van de Donk et al. 2016). Elotuzumab is a humanized monoclonal IgGκ-antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7) or CS1 (CD2 subset-1), a glycoprotein universally and highly expressed on the surface of normal and malignant plasma cells as well as natural killer cells (Einsele and Schreder 2016). Elotuzumab) exhibited significant in vitro antibody-dependent cellular cytotoxicity (ADCC) using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. Furthermore, in vivo assays showed antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in mice (Hsi et al. 2008). The specificity enables elotuzumab to selectively kill myeloma cells and induce minimal damage on healthy tissue. In a randomized phase III trial, the addition of elotuzumab to lenalidomide and low-dose dexamethasone (Rd) resulted in a sustained improvement of progression-free survival (PFS) compared to Rd, leading to approval of the triplet regimen by the FDA and EMA (Lonial et al. 2015). However, patients who were refractory or intolerant to lenalidomide were excluded from the registration trial.
As pomalidomide is known to induce objective responses in len-refractory patients, we substituted lenalidomide for pomalidomide in patients with very advanced MM who were otherwise eligible for treatment with elotuzumab, dexamethasone and an IMID. Meanwhile, the results of a small randomized phase II study comparing elotuzumab/pomalidomide/dexamethasone (elo/pom/dex) with pom/dex have been reported, demonstrating a high efficacy of the triplet regimen in patients with relapsed/refractory MM (Dimopoulos et al. 2018). Here, we present the outcome of 22 consecutive MM patients with very advanced disease who received the triplet combination of elo/pom/dex outside of a clinical trial at two tertiary care centers.
Methods
We queried the databases of the university hospitals of Würzburg and Vienna to identify patients with relapsed and refractory multiple myeloma receiving elo/pom/dex in an individualized treatment concept when no other option was available. Patients had to have measurable disease according to the IMWG criteria (Rajkumar et al. 2014). Pretreatment with pomalidomide was allowed, but patients refractory to the compound were excluded. All patients provided written informed consent.
Elotuzumab was given intravenously at a dose of 10 mg/kg bodyweight on days 1, 8, 15 and 22 of a 28-day cycle in cycles 1 and 2 and on days 1 and 15 in subsequent cycles. Pomalidomide was administered orally at a dose of 4 mg on days 1 through 21 of each cycle. Dexamethasone was given weekly at a dose of 28 mg orally plus 8 mg intravenously on elotuzumab treatment days and 40 mg orally in weeks without elotuzumab. Dose reductions of pomalidomide and dexamethasone were performed in the event of toxicities according to the SmPC. Patients received antimicrobial prophylaxis with aciclovir and cotrimoxazole as well as low molecular weight heparin or acetylsalicylic acid (aspirin®) as prophylaxis of thromboembolic events throughout the treatment period. Treatment was continued until disease progression (PD) or unacceptable toxicity. Responses were defined according to IMWG criteria (Kumar et al. 2016). Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v. 4.0.
The database was locked on 1st February 2020. Statistical analysis was done with IBM SPSS statistics (IBM, Ehningen, Germany) and Prism (Graph Pad Software, San Diego, CA, USA). PFS was calculated according to Kaplan–Meier method from first dose of elo/pom/dex to disease progression or death, whatever occurred first. Patients proceeding to an autologous stem cell transplantation (SCT) were censored at time of transplant. Overall survival (OS) was calculated from first dose of elo/pom/dex to death from any cause or loss of follow up.
Results
Patients
We identified 22 patients with a median age of 61.5 years (range 39–81); the median duration of myeloma was 6.7 years (range 0.3–11.7). The baseline characteristics of the study population are shown in Table 1. The first patients began treatment in October 2015 and the last patient was started on elo/pom/dex in January 2017. A baseline bone marrow (BM) biopsy was performed in 18 patients. The median plasma cell infiltration was 35% (range 5–90) and 4 patients (18%) had high-risk cytogenetic abnormalities. The median number of prior treatment lines was 5 (range 1–16). All patients had been exposed to bortezomib and lenalidomide, 18 (82%) had previously undergone a stem cell transplantation. Only two patients had received prior daratumumab and five patients had been exposed to carfilzomib. Fifteen patients (68%) had been treated with pomalidomide during any previous regimen; of these, ten patients had received pomalidomide in the most recent line of therapy and were consecutively switched to elo/pom/dex after failing to achieve an objective response. 13 patients (59%) had been refractory to both their most recent line of therapy and earlier lenalidomide.Table 1 Clinical characteristics of patients at baseline
Characteristic Value (n = 22)
Age, median (range), years 61.5 (39–81)
Male sex, n (%) 16 (73)
Type of myeloma, n (%)
IgG 13 (59)
IgA 5 (23)
IgD 1 (4)
Light chain 3 (14)
International Staging System (ISS) stage at study entry, n (%)
I–II 13 (59)
III 5 (23)
Missing data 4 (18)
BM plasma cell infiltration, (%)
< 30% 7 (32)
30–59% 6 (27)
≥ 60 5 (23)
Not reported 4 (18)
Cytogenetic abnormality, n (%)
del17p, t(4;14), or t(14;16)
Yes 4 (18)
No 15 (68)
Data not available
1q21 3 (14)
Yes 2 (9)
No 16 (73)
Data not available 4 (18)
Primary refractory to first line treatment, n (%) 7 (32)
Median No. of previous treatment regimens (range) 5 (1–16)
Median time since initial diagnosis (range), years 6.7 (0.3–11.7)
Prior autologous stem cell transplantation, n (%) 17 (77)
Prior allogeneic stem cell transplantation, n (%) 1 (4)
Prior pomalidomide, n (%) 15 (68)
Prior carfilzomib, n (%) 5 (23)
Prior daratumumab, n (%) 2 (9)
Refractory to most recent line of therapy, n (%) 13 (59)
Refractory to lenalidomide, n (%) 13 (59)
Treatment exposure
At database lock all patients had discontinued treatment, with disease progression as the most common reason. Only one patient discontinued early due to side effects. Two patients requested to stop IV treatment with elotuzumab after 6 and 10 cycles of the triplet combination, respectively, and continued on pom/dex. Another two patients went on to receive an autologous stem cell transplantation as a means of consolidation. The median number of treatment cycles was 5 (range 1–30).
Efficacy
All 22 patients were evaluable for response. 11 patients achieved a partial response (PR), yielding an overall response rate of 50%. Of note, five of these patients had been primary refractory to their first line regimen.
The median PFS was 6.4 months. In a landmark analysis, 35% and 28% of patients were progression-free at 12 months and 18 months, respectively (Figs. 1, 2). Patients with high-risk cytogenetics had identical PFS compared to those with standard-risk disease (6.5 v 6.4 months, p = 0.77). There was a clear trend for shorter PFS in patients with ISS stage III at study entry compared to those with stage I and II disease (6.5 vs. 13.5 months), which did not reach statistical significance due to small sample size.Fig. 1 Progression-free (dashed line) and overall survival (solid line) with elotuzumab, pomalidomide, and dexamethasone. PFS and OS rates at 12 and 18 months from start of treatment are displayed
Fig. 2 Progression-free survival with elotuzumab/pomalidomide/dexamethasone according to a response to prior lenalidomide, b prior exposure tp pomalidomide and c number of prior lines of therapy
Patients refractory to lenalidomide showed no difference in their PFS compared to non-refractory patients (p = 0.98, Fig. 2a). Among patients who had previously received pomalidomide, 5 (33%) responded and another 3 (20%) had stable disease with most responses seen in patients who had pomalidomide immediately prior to elo/pom/dex (4 PR, 2 SD). Median PFS in pomalidomide-exposed patients was identical to that seen in pom-naïve patients (p = 0.90, Fig. 2b). When elo/pom/dex was given directly after a pomalidomide-containing regimen (e.g., carfilzomib/pom/dex, bortezomib/doxorubicin/pom/dex), an absolute gain in PFS of 4.3 months (p = 0.192) was seen when compared to patients with a regimen that did not include pomalidomide in the preceding line.
Responses were also observed in 3 out of 5 patients who had been pretreated with a carfilzomib-based regimen; PFS did not differ significantly when compared to carfilzomib-naïve subjects. At database lock, 14 of 22 patients (64%) had achieved a longer PFS to elo/pom/dex when compared to their most recent line of therapy.
PFS did not differ in intensely pretreated (> 4 prior therapies) versus less heavily pretreated patients (p = 0.99, Fig. 2c).
The median follow-up for the study population was 42.5 months. The median overall survival (95% CI) was not reached (23.6 months—not estimable). At 12 months, 82% of patients (n = 18) were still alive; the 18-month OS rate was 73% (Fig. 1).
In total, 17 of 21 patients (81%) received subsequent systemic therapy. One patient was lost to follow-up after discontinuation of elo/pom/dex. Two thirds of patients were treated with a daratumumab-containing regimen (n = 14); median exposure to the anti-CD38 antibody was 13.5 months. 4 patients underwent a salvage autologous stem cell transplant, two immediately after elo/pom/dex and another two later in the course of their disease. Other alkylating agents (most commonly, bendamustine or cyclophosphamide) were used in 57% and carfilzomib-based combinations in 43% of patients, respectively.
Toxicity
No infusion-related reactions were observed. In three patients, grade 3/4 neutropenia was recorded. In two of them the absolute neutrophil count dropped below 500/µl (grade 4), but no patient experienced neutropenic fever. One patient had grade 3 thrombocytopenia following the accidental continuous intake of pomalidomide.
Four patients were diagnosed with a grade 3/4 respiratory infection, two of whom sustained a pneumonia grade 3. Streptococcus pneumoniae was isolated from one patient and parainfluenza II virus in another patient; in the remaining cases, the offending pathogen could not be identified. All patients resumed treatment after resolution of symptoms.
Discussion
In recent years, immunotherapy has attracted significant attention in the treatment of relapsed or refractory MM. One milestone was the pivotal phase 2 study of daratumumab demonstrating single agent activity in patients with PI- and IMiD-refractory MM with a 3.7 months PFS and a median OS of 17.5 months. Meanwhile, daratumumab-based regimens are widely used in relapsed disease (Dimopoulos et al. 2016a; Mateos et al. 2020) and have recently been approved for frontline therapy in both transplant-eligible (Moreau et al. 2019a) and transplant-ineligible patients (Facon et al. 2019; Mateos et al. 2018).
While many patients will now receive CD38 antibody-based treatment, immunotherapy directed at alternative antigens are needed. Elotuzumab targets SLAMF7, acts synergistically with IMiDs and was shown to induce durable remissions in relapsed MM with a PFS of 19.4 months when combined with len/dex (Lonial et al. 2015). However, most patients now receive len as part of their first-line regimen and a considerable fraction will develop len-resistant disease (Moreau et al. 2019b). In this setting, pomalidomide/dex is active with a modest PFS of 4.0 months in the registration trial (Dimopoulos et al. 2016b), but long-lasting remissions are also observed (Danhof et al. 2015). The addition of elotuzumab to pom/dex aiming at prolonged disease control appears tempting and was proven effective in a randomized phase II trial (Dimopoulos et al. 2018). This study reported a median PFS of 10.3 months with elo/pom/dex in patients with a median number of 3 prior lines of therapy.
Since only 60 patients were included in the experimental arm of the ELOQUENT-3 study, we sought to expand clinical experience with elo/pom/dex in a “real-world” cohort of advanced MM. Compared to the published dataset, the 22 subjects of our current retrospective analysis had a longer interval since diagnosis of their MM (6.7 vs 4.8 years) and were more heavily pretreated (median, 5 vs 3 prior lines). Remarkably, 32% (n = 7) of them had been primary refractory to first-line treatment; 59% (n = 13) were refractory to lenalidomide and two thirds had previously received pomalidomide.
In this unfavorable cohort, we were still able to demonstrate a median PFS of 6.4 months with PFS rates at 12 and 18 months that were comparable to those reported in a recent update of ELOQUENT-3 (35% and 28% vs 43% and 34%, respectively) (Dimopoulos 2019). An overall response rate of 50% compared equally well to the published data. Of note, 64% of subjects achieved a longer PFS when compared to their most recent line of therapy and we were able to confirm responses in pomalidomide-exposed patients, most of whom had received pomalidomide in the most recent line prior to elo/pom/dex. This observation would thus justify the addition of elotuzumab to a doublet regimen of pom/dex in the absence of frank progression which in our hands led to objective responses in 4 of 10 patients. Incremental gain of median PFS with Elo/Pd was 4.3 months when compared to PFS with the most recent line of therapy. We believe this constitutes a clinically relevant benefit, as median PFS in a very advanced patient cohort was recently reported to be 3.4 months (Gandhi et al. 2019).
Even though none of our patients reached a complete remission (CR), we observed remarkably durable remissions of more than 20 months in 4 patients. In another two patients, elo/pom/dex served as a bridging therapy to autologous stem cell transplantation.
Subgroup analyses were limited due to the small sample size. Neither cytogenetic risk nor the number and type of prior therapy predicted for outcome in our cohort. Patients with low tumor burden as defined by ISS stages I and II at start of treatment appeared to gain increased benefit compared to those with stage III disease, confirming our previous observation (Danhof et al. 2019). We could also demonstrate that highly pretreated patients (> 4 prior therapies) showed a similar PFS compared to patients with a lower number of previous therapies, justifying the use of this regimen even in late stage MM.
In terms of toxicity, no new safety signals were seen. In general, treatment with elo/pom/dex was well tolerated; there was no allergic reaction or other infusion-related reaction recorded.
In one case a drug-related rash grade 2 was reported, diminishing under ongoing treatment. Like in many reported trials in advanced MM, respiratory infections were among the most common adverse events and were found to be severe in four patients, two of them presenting with grade 3 pneumonia. Both patients could resume therapy and achieved a PR. Hematologic toxicity was low with only a small number of patients experiencing grade 3/4 neutropenia. Grade 3 thrombocytopenia in one patient could be attributed to accidental continuous intake of pomalidomide. Taken together, adverse event rates were comparable to those reported in the ELOQUENT-3 trial.
Not least due to the favurable safety profile, 81% of our patients were able to receive subsequent systemic treatment upon progression on elo/pom/dex. Like in ELOQUENT-3, all but 2 patients had not been exposed to an anti-CD38 antibody and received daratumumab-based regimens for a median duration of more than one year. Overall survival rates of 86% and 81% at 12 and 18 months, respectively, are profoundly remarkable for heavily pretreated MM patients and are compare positively with published results. However, many patients with late-stage disease will now be pretreated with daratumumab; as in our study, these are largely underrepresented in current trials e.g. with pomalidomide-based combinations (Attal et al. 2019; Richardson et al. 2019) and will represent a formidable therapeutic challenge in the near future. A recent trial reported responses in 48% of daratumumab-exposed patients and acceptable toxicity with a quadruplet regimen of elo/pom/dex and bortezomib (Yee 2019), further corroborating our findings.
In summary, despite the small number of patients included here, our results suggest the combination of elo/pom/dex to represent an effective and exceptionally well-tolerated option in the treatment of advanced MM that may be considered in the len-refractory or even pom-exposed patient.
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Acknowledgements
Open Access funding provided by Projekt DEAL.
Author contributions
DH, MS, HG and SK: conception, data acquisition, data analysis, preparation and writing of the manuscript. MTK, RS and BG: data acquisition. JH: statistical calculation and critical revision of the manuscript. SS and SD: data analysis, critical revision of the manuscript. HE: conception, critical revision of the manuscript.
Funding
The authors received no funding for this work.
Availability of data and material
The data generated and used for this study, are included in the published article. Additional data are available from the authors upon reasonable and individual request.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest. S.K.: Honoraria from Celgene GmbH and Bristol-Myers Squibb GmbH. S.D.: Advisory Board for Bristol-Myers Squibb GmbH. MS: Advisory board for Celgene and Bristol-Myers Squibb.
Code availability
IBM SPSS Statistics. | ON DAYS 1 THROUGH 21 OF EACH CYCLE | DrugDosageText | CC BY | 32683487 | 19,057,439 | 2021-01 |
What was the dosage of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.
BACKGROUND
The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.
OBJECTIVE
To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna.
RESULTS
We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia.
CONCLUSIONS
Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.
Introduction
Multiple Myeloma (MM) is the second most frequent hematologic malignancy in the U.S. and Europe (Rollig et al. 2015). It is characterized by an uncontrolled proliferation of clonal plasma cells in the bone marrow and the accumulation of abnormal intact or incomplete immunoglobulins in serum and/or urine (Moreau et al. 2017; Raab et al. 2009). The median age at diagnosis of MM is 69 years with most subjects being diagnosed above the age of 55 years and a male predominance (Raab et al. 2016). Advances in therapeutic strategies have led to an increase in median overall survival of patients from three to six years within the last two decades, owing to novel compounds like proteasome inhibitors (PIs, e.g. bortezomib, carfilzomib, ixazomib) immunomodulatory drugs (IMIDs, e.g. thalidomide, lenalidomide, pomalidomide), alkylating agents (e.g. melphalan) or histone deacetylase inhibitors (e.g. panobinostat). Multi-drug combinations improve the long-term treatment outcome and might overcome drug resistance (Schreder and Knop 2019), but most patients continue to have relapses and will eventually become refractory to available drugs. Every subsequent relapse induces a shortened progression-free interval (Yong et al. 2016); therefore, novel treatment approaches are needed.
Immunotherapy holds great promise for MM therapy. MoAbs selectively target antigens on the myeloma cell surface which are critical for signaling, tumor growth, and survival (van de Donk et al. 2016). Elotuzumab is a humanized monoclonal IgGκ-antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7) or CS1 (CD2 subset-1), a glycoprotein universally and highly expressed on the surface of normal and malignant plasma cells as well as natural killer cells (Einsele and Schreder 2016). Elotuzumab) exhibited significant in vitro antibody-dependent cellular cytotoxicity (ADCC) using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. Furthermore, in vivo assays showed antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in mice (Hsi et al. 2008). The specificity enables elotuzumab to selectively kill myeloma cells and induce minimal damage on healthy tissue. In a randomized phase III trial, the addition of elotuzumab to lenalidomide and low-dose dexamethasone (Rd) resulted in a sustained improvement of progression-free survival (PFS) compared to Rd, leading to approval of the triplet regimen by the FDA and EMA (Lonial et al. 2015). However, patients who were refractory or intolerant to lenalidomide were excluded from the registration trial.
As pomalidomide is known to induce objective responses in len-refractory patients, we substituted lenalidomide for pomalidomide in patients with very advanced MM who were otherwise eligible for treatment with elotuzumab, dexamethasone and an IMID. Meanwhile, the results of a small randomized phase II study comparing elotuzumab/pomalidomide/dexamethasone (elo/pom/dex) with pom/dex have been reported, demonstrating a high efficacy of the triplet regimen in patients with relapsed/refractory MM (Dimopoulos et al. 2018). Here, we present the outcome of 22 consecutive MM patients with very advanced disease who received the triplet combination of elo/pom/dex outside of a clinical trial at two tertiary care centers.
Methods
We queried the databases of the university hospitals of Würzburg and Vienna to identify patients with relapsed and refractory multiple myeloma receiving elo/pom/dex in an individualized treatment concept when no other option was available. Patients had to have measurable disease according to the IMWG criteria (Rajkumar et al. 2014). Pretreatment with pomalidomide was allowed, but patients refractory to the compound were excluded. All patients provided written informed consent.
Elotuzumab was given intravenously at a dose of 10 mg/kg bodyweight on days 1, 8, 15 and 22 of a 28-day cycle in cycles 1 and 2 and on days 1 and 15 in subsequent cycles. Pomalidomide was administered orally at a dose of 4 mg on days 1 through 21 of each cycle. Dexamethasone was given weekly at a dose of 28 mg orally plus 8 mg intravenously on elotuzumab treatment days and 40 mg orally in weeks without elotuzumab. Dose reductions of pomalidomide and dexamethasone were performed in the event of toxicities according to the SmPC. Patients received antimicrobial prophylaxis with aciclovir and cotrimoxazole as well as low molecular weight heparin or acetylsalicylic acid (aspirin®) as prophylaxis of thromboembolic events throughout the treatment period. Treatment was continued until disease progression (PD) or unacceptable toxicity. Responses were defined according to IMWG criteria (Kumar et al. 2016). Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v. 4.0.
The database was locked on 1st February 2020. Statistical analysis was done with IBM SPSS statistics (IBM, Ehningen, Germany) and Prism (Graph Pad Software, San Diego, CA, USA). PFS was calculated according to Kaplan–Meier method from first dose of elo/pom/dex to disease progression or death, whatever occurred first. Patients proceeding to an autologous stem cell transplantation (SCT) were censored at time of transplant. Overall survival (OS) was calculated from first dose of elo/pom/dex to death from any cause or loss of follow up.
Results
Patients
We identified 22 patients with a median age of 61.5 years (range 39–81); the median duration of myeloma was 6.7 years (range 0.3–11.7). The baseline characteristics of the study population are shown in Table 1. The first patients began treatment in October 2015 and the last patient was started on elo/pom/dex in January 2017. A baseline bone marrow (BM) biopsy was performed in 18 patients. The median plasma cell infiltration was 35% (range 5–90) and 4 patients (18%) had high-risk cytogenetic abnormalities. The median number of prior treatment lines was 5 (range 1–16). All patients had been exposed to bortezomib and lenalidomide, 18 (82%) had previously undergone a stem cell transplantation. Only two patients had received prior daratumumab and five patients had been exposed to carfilzomib. Fifteen patients (68%) had been treated with pomalidomide during any previous regimen; of these, ten patients had received pomalidomide in the most recent line of therapy and were consecutively switched to elo/pom/dex after failing to achieve an objective response. 13 patients (59%) had been refractory to both their most recent line of therapy and earlier lenalidomide.Table 1 Clinical characteristics of patients at baseline
Characteristic Value (n = 22)
Age, median (range), years 61.5 (39–81)
Male sex, n (%) 16 (73)
Type of myeloma, n (%)
IgG 13 (59)
IgA 5 (23)
IgD 1 (4)
Light chain 3 (14)
International Staging System (ISS) stage at study entry, n (%)
I–II 13 (59)
III 5 (23)
Missing data 4 (18)
BM plasma cell infiltration, (%)
< 30% 7 (32)
30–59% 6 (27)
≥ 60 5 (23)
Not reported 4 (18)
Cytogenetic abnormality, n (%)
del17p, t(4;14), or t(14;16)
Yes 4 (18)
No 15 (68)
Data not available
1q21 3 (14)
Yes 2 (9)
No 16 (73)
Data not available 4 (18)
Primary refractory to first line treatment, n (%) 7 (32)
Median No. of previous treatment regimens (range) 5 (1–16)
Median time since initial diagnosis (range), years 6.7 (0.3–11.7)
Prior autologous stem cell transplantation, n (%) 17 (77)
Prior allogeneic stem cell transplantation, n (%) 1 (4)
Prior pomalidomide, n (%) 15 (68)
Prior carfilzomib, n (%) 5 (23)
Prior daratumumab, n (%) 2 (9)
Refractory to most recent line of therapy, n (%) 13 (59)
Refractory to lenalidomide, n (%) 13 (59)
Treatment exposure
At database lock all patients had discontinued treatment, with disease progression as the most common reason. Only one patient discontinued early due to side effects. Two patients requested to stop IV treatment with elotuzumab after 6 and 10 cycles of the triplet combination, respectively, and continued on pom/dex. Another two patients went on to receive an autologous stem cell transplantation as a means of consolidation. The median number of treatment cycles was 5 (range 1–30).
Efficacy
All 22 patients were evaluable for response. 11 patients achieved a partial response (PR), yielding an overall response rate of 50%. Of note, five of these patients had been primary refractory to their first line regimen.
The median PFS was 6.4 months. In a landmark analysis, 35% and 28% of patients were progression-free at 12 months and 18 months, respectively (Figs. 1, 2). Patients with high-risk cytogenetics had identical PFS compared to those with standard-risk disease (6.5 v 6.4 months, p = 0.77). There was a clear trend for shorter PFS in patients with ISS stage III at study entry compared to those with stage I and II disease (6.5 vs. 13.5 months), which did not reach statistical significance due to small sample size.Fig. 1 Progression-free (dashed line) and overall survival (solid line) with elotuzumab, pomalidomide, and dexamethasone. PFS and OS rates at 12 and 18 months from start of treatment are displayed
Fig. 2 Progression-free survival with elotuzumab/pomalidomide/dexamethasone according to a response to prior lenalidomide, b prior exposure tp pomalidomide and c number of prior lines of therapy
Patients refractory to lenalidomide showed no difference in their PFS compared to non-refractory patients (p = 0.98, Fig. 2a). Among patients who had previously received pomalidomide, 5 (33%) responded and another 3 (20%) had stable disease with most responses seen in patients who had pomalidomide immediately prior to elo/pom/dex (4 PR, 2 SD). Median PFS in pomalidomide-exposed patients was identical to that seen in pom-naïve patients (p = 0.90, Fig. 2b). When elo/pom/dex was given directly after a pomalidomide-containing regimen (e.g., carfilzomib/pom/dex, bortezomib/doxorubicin/pom/dex), an absolute gain in PFS of 4.3 months (p = 0.192) was seen when compared to patients with a regimen that did not include pomalidomide in the preceding line.
Responses were also observed in 3 out of 5 patients who had been pretreated with a carfilzomib-based regimen; PFS did not differ significantly when compared to carfilzomib-naïve subjects. At database lock, 14 of 22 patients (64%) had achieved a longer PFS to elo/pom/dex when compared to their most recent line of therapy.
PFS did not differ in intensely pretreated (> 4 prior therapies) versus less heavily pretreated patients (p = 0.99, Fig. 2c).
The median follow-up for the study population was 42.5 months. The median overall survival (95% CI) was not reached (23.6 months—not estimable). At 12 months, 82% of patients (n = 18) were still alive; the 18-month OS rate was 73% (Fig. 1).
In total, 17 of 21 patients (81%) received subsequent systemic therapy. One patient was lost to follow-up after discontinuation of elo/pom/dex. Two thirds of patients were treated with a daratumumab-containing regimen (n = 14); median exposure to the anti-CD38 antibody was 13.5 months. 4 patients underwent a salvage autologous stem cell transplant, two immediately after elo/pom/dex and another two later in the course of their disease. Other alkylating agents (most commonly, bendamustine or cyclophosphamide) were used in 57% and carfilzomib-based combinations in 43% of patients, respectively.
Toxicity
No infusion-related reactions were observed. In three patients, grade 3/4 neutropenia was recorded. In two of them the absolute neutrophil count dropped below 500/µl (grade 4), but no patient experienced neutropenic fever. One patient had grade 3 thrombocytopenia following the accidental continuous intake of pomalidomide.
Four patients were diagnosed with a grade 3/4 respiratory infection, two of whom sustained a pneumonia grade 3. Streptococcus pneumoniae was isolated from one patient and parainfluenza II virus in another patient; in the remaining cases, the offending pathogen could not be identified. All patients resumed treatment after resolution of symptoms.
Discussion
In recent years, immunotherapy has attracted significant attention in the treatment of relapsed or refractory MM. One milestone was the pivotal phase 2 study of daratumumab demonstrating single agent activity in patients with PI- and IMiD-refractory MM with a 3.7 months PFS and a median OS of 17.5 months. Meanwhile, daratumumab-based regimens are widely used in relapsed disease (Dimopoulos et al. 2016a; Mateos et al. 2020) and have recently been approved for frontline therapy in both transplant-eligible (Moreau et al. 2019a) and transplant-ineligible patients (Facon et al. 2019; Mateos et al. 2018).
While many patients will now receive CD38 antibody-based treatment, immunotherapy directed at alternative antigens are needed. Elotuzumab targets SLAMF7, acts synergistically with IMiDs and was shown to induce durable remissions in relapsed MM with a PFS of 19.4 months when combined with len/dex (Lonial et al. 2015). However, most patients now receive len as part of their first-line regimen and a considerable fraction will develop len-resistant disease (Moreau et al. 2019b). In this setting, pomalidomide/dex is active with a modest PFS of 4.0 months in the registration trial (Dimopoulos et al. 2016b), but long-lasting remissions are also observed (Danhof et al. 2015). The addition of elotuzumab to pom/dex aiming at prolonged disease control appears tempting and was proven effective in a randomized phase II trial (Dimopoulos et al. 2018). This study reported a median PFS of 10.3 months with elo/pom/dex in patients with a median number of 3 prior lines of therapy.
Since only 60 patients were included in the experimental arm of the ELOQUENT-3 study, we sought to expand clinical experience with elo/pom/dex in a “real-world” cohort of advanced MM. Compared to the published dataset, the 22 subjects of our current retrospective analysis had a longer interval since diagnosis of their MM (6.7 vs 4.8 years) and were more heavily pretreated (median, 5 vs 3 prior lines). Remarkably, 32% (n = 7) of them had been primary refractory to first-line treatment; 59% (n = 13) were refractory to lenalidomide and two thirds had previously received pomalidomide.
In this unfavorable cohort, we were still able to demonstrate a median PFS of 6.4 months with PFS rates at 12 and 18 months that were comparable to those reported in a recent update of ELOQUENT-3 (35% and 28% vs 43% and 34%, respectively) (Dimopoulos 2019). An overall response rate of 50% compared equally well to the published data. Of note, 64% of subjects achieved a longer PFS when compared to their most recent line of therapy and we were able to confirm responses in pomalidomide-exposed patients, most of whom had received pomalidomide in the most recent line prior to elo/pom/dex. This observation would thus justify the addition of elotuzumab to a doublet regimen of pom/dex in the absence of frank progression which in our hands led to objective responses in 4 of 10 patients. Incremental gain of median PFS with Elo/Pd was 4.3 months when compared to PFS with the most recent line of therapy. We believe this constitutes a clinically relevant benefit, as median PFS in a very advanced patient cohort was recently reported to be 3.4 months (Gandhi et al. 2019).
Even though none of our patients reached a complete remission (CR), we observed remarkably durable remissions of more than 20 months in 4 patients. In another two patients, elo/pom/dex served as a bridging therapy to autologous stem cell transplantation.
Subgroup analyses were limited due to the small sample size. Neither cytogenetic risk nor the number and type of prior therapy predicted for outcome in our cohort. Patients with low tumor burden as defined by ISS stages I and II at start of treatment appeared to gain increased benefit compared to those with stage III disease, confirming our previous observation (Danhof et al. 2019). We could also demonstrate that highly pretreated patients (> 4 prior therapies) showed a similar PFS compared to patients with a lower number of previous therapies, justifying the use of this regimen even in late stage MM.
In terms of toxicity, no new safety signals were seen. In general, treatment with elo/pom/dex was well tolerated; there was no allergic reaction or other infusion-related reaction recorded.
In one case a drug-related rash grade 2 was reported, diminishing under ongoing treatment. Like in many reported trials in advanced MM, respiratory infections were among the most common adverse events and were found to be severe in four patients, two of them presenting with grade 3 pneumonia. Both patients could resume therapy and achieved a PR. Hematologic toxicity was low with only a small number of patients experiencing grade 3/4 neutropenia. Grade 3 thrombocytopenia in one patient could be attributed to accidental continuous intake of pomalidomide. Taken together, adverse event rates were comparable to those reported in the ELOQUENT-3 trial.
Not least due to the favurable safety profile, 81% of our patients were able to receive subsequent systemic treatment upon progression on elo/pom/dex. Like in ELOQUENT-3, all but 2 patients had not been exposed to an anti-CD38 antibody and received daratumumab-based regimens for a median duration of more than one year. Overall survival rates of 86% and 81% at 12 and 18 months, respectively, are profoundly remarkable for heavily pretreated MM patients and are compare positively with published results. However, many patients with late-stage disease will now be pretreated with daratumumab; as in our study, these are largely underrepresented in current trials e.g. with pomalidomide-based combinations (Attal et al. 2019; Richardson et al. 2019) and will represent a formidable therapeutic challenge in the near future. A recent trial reported responses in 48% of daratumumab-exposed patients and acceptable toxicity with a quadruplet regimen of elo/pom/dex and bortezomib (Yee 2019), further corroborating our findings.
In summary, despite the small number of patients included here, our results suggest the combination of elo/pom/dex to represent an effective and exceptionally well-tolerated option in the treatment of advanced MM that may be considered in the len-refractory or even pom-exposed patient.
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Acknowledgements
Open Access funding provided by Projekt DEAL.
Author contributions
DH, MS, HG and SK: conception, data acquisition, data analysis, preparation and writing of the manuscript. MTK, RS and BG: data acquisition. JH: statistical calculation and critical revision of the manuscript. SS and SD: data analysis, critical revision of the manuscript. HE: conception, critical revision of the manuscript.
Funding
The authors received no funding for this work.
Availability of data and material
The data generated and used for this study, are included in the published article. Additional data are available from the authors upon reasonable and individual request.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest. S.K.: Honoraria from Celgene GmbH and Bristol-Myers Squibb GmbH. S.D.: Advisory Board for Bristol-Myers Squibb GmbH. MS: Advisory board for Celgene and Bristol-Myers Squibb.
Code availability
IBM SPSS Statistics. | ADMINISTERED THROUGHOUT THE TREATMENT PERIOD | DrugDosageText | CC BY | 32683487 | 19,057,439 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Empyema'. | Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report.
We report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium-glucose cotransporter 2 inhibitors during thoracic surgery. A 59-year-old man had a 12-year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium-glucose cotransporter 2 inhibitors, especially during thoracic surgery.
Introduction
Sodium–glucose cotransporter 2 inhibitors (SGLT2is) are widely used in patients with diabetes mellitus. However, regulatory agencies issued a warning that SGLT2is could cause diabetic ketoacidosis (DKA) 1 . DKA associated with SGLT2is can even occur when glucose levels are lower than expected, known as euglycemic DKA (eDKA), and often occurs during the perioperative period 1 , 2 . Cases of eDKA associated with SGLT2is have been reported after surgery 1 , 2 , but there is no report of occurrence during the surgery. Here, we present a patient with type 2 diabetes and bacterial empyema, who underwent surgery without a sufficient period of empagliflozin withdrawal. He developed intraoperative eDKA, but rapidly recovered after its early identification and management.
Case Report
A 59‐year‐old man had a 12‐year history of type 2 diabetes mellitus initiated with 10 mg of empagliflozin 18 months earlier, and clinically titrated to 25 mg along with intensive insulin therapy. During the period of treatment with empagliflozin, uric ketone had not been detected at every visit. The patient presented with high fever and chest pain for 2 weeks, and was admitted to a neighboring hospital. He was diagnosed as having left bacterial empyema, and treated with antibiotics for 4 days; however, as his symptoms persisted, he was transferred to Wakayama Medica University (Wakayama, Japan) for surgical treatment. He had a fever of 37.2°C, and weak pulmonary sound on the left side. The patient’s bodyweight, height and body mass index were 69 kg, 169 cm and 24.1 kg/m2, respectively. Laboratory data showed a severe infectious state (Table 1). Chest radiography and computed tomography images showed a large pleural effusion (Figure 1). On the day the patient was transferred to our hospital, he was treated with empagliflozin and insulin for diabetes at the former hospital (day 0; Figure 2). Empagliflozin was taken for the last time 28 h before surgery. He had no appetite loss nor digestive symptoms on that day. He was treated with insulin glargine 13 h before surgery.
Table 1 Laboratory data on admission
Hematology/biochemistry
WBC 15,620/μL AMY 39 U/L
RBC 357 × 104/μL Na 139 mEq/L
Hb 11.2 g/dL K 4.8 mEq/L
Plt 27.3 × 104/μL Cl 103 mEq/L
TP 5.4 g/dL PG 209 mg/dL
Alb 2.2 g/dL HbA1c 9.4%
AST 70 U/L C‐peptide 0.95 ng/mL
ALT 47 U/L Lactate 10.6 mg/dL
LDH 219 U/L
CPK 364 U/L Serological examination
γ‐GTP 81 U/L C‐reactive protein 29.8 mg/dL
BUN 16.6 mg/dL Anti‐GAD Ab <5.0 U/mL
Cr 1.11 mg/dL Anti‐IA‐2 Ab <0.6 U/mL
γ‐GTP, gamma‐glutamyl transpeptidase; Ab, antibodies; Alb, albumin; ALT, alanine aminotransferase; AMY, amylase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine kinase; Cr, creatinine; GAD, glutamic acid decarboxylase; Hb, hemoglobin; HbA1c, glycated hemoglobin; IA‐2, islet antigen 2; LDH, lactate dehydrogenase; PG, plasma glucose; Plt, platelets; RBC, red blood cells; TP, total protein; WBC, white blood cells.
John Wiley & Sons, Ltd
Figure 1 Chest radiography (a) and computed tomography (b) before thoracoscopic debridement and intrathoracic lavage (day 0).
Figure 2 Patient’s clinical course. Black circles and blank circles represent blood glucose and C‐reactive protein levels, respectively.
After overnight fasting for 18 h, the patient underwent thoracoscopic debridement and intrathoracic lavage (day 1; Figure 2). His surgery was initiated with drip infusion of extracellular fluid with 1% glucose without insulin. Based on the information of having diabetes from the former hospital, his arterial blood gas was measured during surgery. Approximately 2 h after the initiation of surgery, he was found to be acidotic on arterial blood gas with 162 mg/dL of blood glucose level (Figure 2). A urine test for ketone showed a positive result. Laboratory tests showed elevated levels of total ketone bodies, acetoacetic acid and 3‐hydroxybutyric acid in serum (Figure 2). Subsequently, the patient was started on an insulin infusion with drip infusion of 5% glucose immediately after the consultation from the anesthesiologist to the first department of medicine. He awoke from anesthesia normally and showed no digestive symptoms. After the continuous insulin infusion, his acidosis and ketosis gradually resolved over the next 24 h. Approximately 2 weeks later, his bacterial empyema had almost resolved. During these 2 weeks, he was treated with insulin alone for diabetes and did not present ketosis or acidosis.
Written informed consent was obtained from the patient.
Discussion
SGLT2is are widely used as excellent agents for managing diabetes, while providing metabolic, cardiovascular and renal benefits 1 , 3 , 4 . However, several adverse effects are concerned. DKA is a significant risk for patients taking SGLT2is, especially when there are precipitating factors, such as illness, infection and surgery 1 , 2 . In several countries, it is recommended that SGLT2is be discontinued preoperatively. The half‐life of 25 mg empagliflozin is reported to be 18.0 h according to the package insert. In the present case, empagliflozin was taken for the last time 28 h before surgery. However, in the case of surgery, it might be necessary to consider the potential effects of anesthesia and muscle relaxants on the half‐life. In Australia, for example, cessation at least 3 days preoperatively is recommended based on the half‐life and dose‐dependent offset time of SGLT2is 1 . In the present case, besides the use of SGLT2is with an insufficient withdrawal period, the patient was speculated to have infection with empyema and surgery as risk factors of DKA. In particular, as the present patient initially showed mixed acidemia, possibly as a result of the retention of carbon dioxide under the isolated one‐lung ventilation in addition to accumulation of ketone, it is necessary to pay attention to the management of DKA during thoracic surgery. In addition, the initial drip infusion during surgery was at a low concentration of glucose without insulin. Although insulin glargine was injected the night before, it is also possible that an insufficient dosage of glucose and insulin made the DKA worse in the present case.
Early detection and intervention are critical for management of DKA associated with SGLT2is. The US Food and Drug Administration highlighted awareness among practitioners, DKA symptoms and the potential for lower than expected blood glucose levels when precipitating factors for DKA associated with SGLT2is are present in patients 5 . However, as the symptoms are atypical and the blood glucose levels could be lower than expected, the diagnosis tends to be delayed in DKA associated with SGLT2is. In the present case, it is possible that eDKA had already developed before the surgery, although the patient had no symptoms of acidemia at that point. Thus, when it is difficult to take a sufficient withdrawal period of SGLT2is preoperatively, it is important to monitor ketone and acidosis, even before surgery, for the early detection and immediate management of DKA.
Several situations/diseases are raised as the general differential diagnosis of euglycemic ketoacidosis: pregnancy, restriction on caloric intake, glycogen storage diseases or defective gluconeogenesis as a result of alcohol abuse or chronic liver disease. As for the mechanism of eDKA associated with SGLT2is under stress, situations, such as delivery of a potentially low dose of insulin, increased secretion of counter hormones and dehydration status on the surgical day, could be speculated 1 , 6 , 7 . Under stress, such as surgery or illness, increased secretion of counter hormones, such as glucagon, leads to ketogenesis owing to such reasons as lipolysis providing sufficient free fatty acid substrate for production of ketone bodies or hepatic glucose production. Meanwhile, in patients treated with both SGLT2is and insulin, increased renal excretion of glucose might result in treatment with insufficient insulin to suppress lipolysis and ketogenesis, even if blood glucose levels are not increased. Therefore, sufficient insulin delivery, and careful clinical and biochemical monitoring are required to prevent perioperative eDKA in patients treated with dual SGLT2is and insulin.
In summary, we presented a patient with type 2 diabetes and bacterial empyema, who developed intraoperative eDKA associated with empagliflozin. This is the first case of eDKA associated with SGLT2is during thoracic surgery, which could be rapidly resolved by emergent intervention. When patients are taking SGLT2is, especially those with precipitating factors, it is clinically important to be aware of the potential risk of eDKA and to increase monitoring for the immediate initiation of treatment.
DISCLOSURE
The authors declare no conflict of interest.
Acknowledgments
We acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center at Wakayama Medical University. This work was supported by SRF (TA). | EMPAGLIFLOZIN, INSULIN GLARGINE | DrugsGivenReaction | CC BY-NC-ND | 32686282 | 18,088,625 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Euglycaemic diabetic ketoacidosis'. | Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report.
We report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium-glucose cotransporter 2 inhibitors during thoracic surgery. A 59-year-old man had a 12-year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium-glucose cotransporter 2 inhibitors, especially during thoracic surgery.
Introduction
Sodium–glucose cotransporter 2 inhibitors (SGLT2is) are widely used in patients with diabetes mellitus. However, regulatory agencies issued a warning that SGLT2is could cause diabetic ketoacidosis (DKA) 1 . DKA associated with SGLT2is can even occur when glucose levels are lower than expected, known as euglycemic DKA (eDKA), and often occurs during the perioperative period 1 , 2 . Cases of eDKA associated with SGLT2is have been reported after surgery 1 , 2 , but there is no report of occurrence during the surgery. Here, we present a patient with type 2 diabetes and bacterial empyema, who underwent surgery without a sufficient period of empagliflozin withdrawal. He developed intraoperative eDKA, but rapidly recovered after its early identification and management.
Case Report
A 59‐year‐old man had a 12‐year history of type 2 diabetes mellitus initiated with 10 mg of empagliflozin 18 months earlier, and clinically titrated to 25 mg along with intensive insulin therapy. During the period of treatment with empagliflozin, uric ketone had not been detected at every visit. The patient presented with high fever and chest pain for 2 weeks, and was admitted to a neighboring hospital. He was diagnosed as having left bacterial empyema, and treated with antibiotics for 4 days; however, as his symptoms persisted, he was transferred to Wakayama Medica University (Wakayama, Japan) for surgical treatment. He had a fever of 37.2°C, and weak pulmonary sound on the left side. The patient’s bodyweight, height and body mass index were 69 kg, 169 cm and 24.1 kg/m2, respectively. Laboratory data showed a severe infectious state (Table 1). Chest radiography and computed tomography images showed a large pleural effusion (Figure 1). On the day the patient was transferred to our hospital, he was treated with empagliflozin and insulin for diabetes at the former hospital (day 0; Figure 2). Empagliflozin was taken for the last time 28 h before surgery. He had no appetite loss nor digestive symptoms on that day. He was treated with insulin glargine 13 h before surgery.
Table 1 Laboratory data on admission
Hematology/biochemistry
WBC 15,620/μL AMY 39 U/L
RBC 357 × 104/μL Na 139 mEq/L
Hb 11.2 g/dL K 4.8 mEq/L
Plt 27.3 × 104/μL Cl 103 mEq/L
TP 5.4 g/dL PG 209 mg/dL
Alb 2.2 g/dL HbA1c 9.4%
AST 70 U/L C‐peptide 0.95 ng/mL
ALT 47 U/L Lactate 10.6 mg/dL
LDH 219 U/L
CPK 364 U/L Serological examination
γ‐GTP 81 U/L C‐reactive protein 29.8 mg/dL
BUN 16.6 mg/dL Anti‐GAD Ab <5.0 U/mL
Cr 1.11 mg/dL Anti‐IA‐2 Ab <0.6 U/mL
γ‐GTP, gamma‐glutamyl transpeptidase; Ab, antibodies; Alb, albumin; ALT, alanine aminotransferase; AMY, amylase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine kinase; Cr, creatinine; GAD, glutamic acid decarboxylase; Hb, hemoglobin; HbA1c, glycated hemoglobin; IA‐2, islet antigen 2; LDH, lactate dehydrogenase; PG, plasma glucose; Plt, platelets; RBC, red blood cells; TP, total protein; WBC, white blood cells.
John Wiley & Sons, Ltd
Figure 1 Chest radiography (a) and computed tomography (b) before thoracoscopic debridement and intrathoracic lavage (day 0).
Figure 2 Patient’s clinical course. Black circles and blank circles represent blood glucose and C‐reactive protein levels, respectively.
After overnight fasting for 18 h, the patient underwent thoracoscopic debridement and intrathoracic lavage (day 1; Figure 2). His surgery was initiated with drip infusion of extracellular fluid with 1% glucose without insulin. Based on the information of having diabetes from the former hospital, his arterial blood gas was measured during surgery. Approximately 2 h after the initiation of surgery, he was found to be acidotic on arterial blood gas with 162 mg/dL of blood glucose level (Figure 2). A urine test for ketone showed a positive result. Laboratory tests showed elevated levels of total ketone bodies, acetoacetic acid and 3‐hydroxybutyric acid in serum (Figure 2). Subsequently, the patient was started on an insulin infusion with drip infusion of 5% glucose immediately after the consultation from the anesthesiologist to the first department of medicine. He awoke from anesthesia normally and showed no digestive symptoms. After the continuous insulin infusion, his acidosis and ketosis gradually resolved over the next 24 h. Approximately 2 weeks later, his bacterial empyema had almost resolved. During these 2 weeks, he was treated with insulin alone for diabetes and did not present ketosis or acidosis.
Written informed consent was obtained from the patient.
Discussion
SGLT2is are widely used as excellent agents for managing diabetes, while providing metabolic, cardiovascular and renal benefits 1 , 3 , 4 . However, several adverse effects are concerned. DKA is a significant risk for patients taking SGLT2is, especially when there are precipitating factors, such as illness, infection and surgery 1 , 2 . In several countries, it is recommended that SGLT2is be discontinued preoperatively. The half‐life of 25 mg empagliflozin is reported to be 18.0 h according to the package insert. In the present case, empagliflozin was taken for the last time 28 h before surgery. However, in the case of surgery, it might be necessary to consider the potential effects of anesthesia and muscle relaxants on the half‐life. In Australia, for example, cessation at least 3 days preoperatively is recommended based on the half‐life and dose‐dependent offset time of SGLT2is 1 . In the present case, besides the use of SGLT2is with an insufficient withdrawal period, the patient was speculated to have infection with empyema and surgery as risk factors of DKA. In particular, as the present patient initially showed mixed acidemia, possibly as a result of the retention of carbon dioxide under the isolated one‐lung ventilation in addition to accumulation of ketone, it is necessary to pay attention to the management of DKA during thoracic surgery. In addition, the initial drip infusion during surgery was at a low concentration of glucose without insulin. Although insulin glargine was injected the night before, it is also possible that an insufficient dosage of glucose and insulin made the DKA worse in the present case.
Early detection and intervention are critical for management of DKA associated with SGLT2is. The US Food and Drug Administration highlighted awareness among practitioners, DKA symptoms and the potential for lower than expected blood glucose levels when precipitating factors for DKA associated with SGLT2is are present in patients 5 . However, as the symptoms are atypical and the blood glucose levels could be lower than expected, the diagnosis tends to be delayed in DKA associated with SGLT2is. In the present case, it is possible that eDKA had already developed before the surgery, although the patient had no symptoms of acidemia at that point. Thus, when it is difficult to take a sufficient withdrawal period of SGLT2is preoperatively, it is important to monitor ketone and acidosis, even before surgery, for the early detection and immediate management of DKA.
Several situations/diseases are raised as the general differential diagnosis of euglycemic ketoacidosis: pregnancy, restriction on caloric intake, glycogen storage diseases or defective gluconeogenesis as a result of alcohol abuse or chronic liver disease. As for the mechanism of eDKA associated with SGLT2is under stress, situations, such as delivery of a potentially low dose of insulin, increased secretion of counter hormones and dehydration status on the surgical day, could be speculated 1 , 6 , 7 . Under stress, such as surgery or illness, increased secretion of counter hormones, such as glucagon, leads to ketogenesis owing to such reasons as lipolysis providing sufficient free fatty acid substrate for production of ketone bodies or hepatic glucose production. Meanwhile, in patients treated with both SGLT2is and insulin, increased renal excretion of glucose might result in treatment with insufficient insulin to suppress lipolysis and ketogenesis, even if blood glucose levels are not increased. Therefore, sufficient insulin delivery, and careful clinical and biochemical monitoring are required to prevent perioperative eDKA in patients treated with dual SGLT2is and insulin.
In summary, we presented a patient with type 2 diabetes and bacterial empyema, who developed intraoperative eDKA associated with empagliflozin. This is the first case of eDKA associated with SGLT2is during thoracic surgery, which could be rapidly resolved by emergent intervention. When patients are taking SGLT2is, especially those with precipitating factors, it is clinically important to be aware of the potential risk of eDKA and to increase monitoring for the immediate initiation of treatment.
DISCLOSURE
The authors declare no conflict of interest.
Acknowledgments
We acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center at Wakayama Medical University. This work was supported by SRF (TA). | EMPAGLIFLOZIN, INSULIN GLARGINE | DrugsGivenReaction | CC BY-NC-ND | 32686282 | 18,088,625 | 2021-04 |
What is the weight of the patient? | Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report.
We report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium-glucose cotransporter 2 inhibitors during thoracic surgery. A 59-year-old man had a 12-year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium-glucose cotransporter 2 inhibitors, especially during thoracic surgery.
Introduction
Sodium–glucose cotransporter 2 inhibitors (SGLT2is) are widely used in patients with diabetes mellitus. However, regulatory agencies issued a warning that SGLT2is could cause diabetic ketoacidosis (DKA) 1 . DKA associated with SGLT2is can even occur when glucose levels are lower than expected, known as euglycemic DKA (eDKA), and often occurs during the perioperative period 1 , 2 . Cases of eDKA associated with SGLT2is have been reported after surgery 1 , 2 , but there is no report of occurrence during the surgery. Here, we present a patient with type 2 diabetes and bacterial empyema, who underwent surgery without a sufficient period of empagliflozin withdrawal. He developed intraoperative eDKA, but rapidly recovered after its early identification and management.
Case Report
A 59‐year‐old man had a 12‐year history of type 2 diabetes mellitus initiated with 10 mg of empagliflozin 18 months earlier, and clinically titrated to 25 mg along with intensive insulin therapy. During the period of treatment with empagliflozin, uric ketone had not been detected at every visit. The patient presented with high fever and chest pain for 2 weeks, and was admitted to a neighboring hospital. He was diagnosed as having left bacterial empyema, and treated with antibiotics for 4 days; however, as his symptoms persisted, he was transferred to Wakayama Medica University (Wakayama, Japan) for surgical treatment. He had a fever of 37.2°C, and weak pulmonary sound on the left side. The patient’s bodyweight, height and body mass index were 69 kg, 169 cm and 24.1 kg/m2, respectively. Laboratory data showed a severe infectious state (Table 1). Chest radiography and computed tomography images showed a large pleural effusion (Figure 1). On the day the patient was transferred to our hospital, he was treated with empagliflozin and insulin for diabetes at the former hospital (day 0; Figure 2). Empagliflozin was taken for the last time 28 h before surgery. He had no appetite loss nor digestive symptoms on that day. He was treated with insulin glargine 13 h before surgery.
Table 1 Laboratory data on admission
Hematology/biochemistry
WBC 15,620/μL AMY 39 U/L
RBC 357 × 104/μL Na 139 mEq/L
Hb 11.2 g/dL K 4.8 mEq/L
Plt 27.3 × 104/μL Cl 103 mEq/L
TP 5.4 g/dL PG 209 mg/dL
Alb 2.2 g/dL HbA1c 9.4%
AST 70 U/L C‐peptide 0.95 ng/mL
ALT 47 U/L Lactate 10.6 mg/dL
LDH 219 U/L
CPK 364 U/L Serological examination
γ‐GTP 81 U/L C‐reactive protein 29.8 mg/dL
BUN 16.6 mg/dL Anti‐GAD Ab <5.0 U/mL
Cr 1.11 mg/dL Anti‐IA‐2 Ab <0.6 U/mL
γ‐GTP, gamma‐glutamyl transpeptidase; Ab, antibodies; Alb, albumin; ALT, alanine aminotransferase; AMY, amylase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine kinase; Cr, creatinine; GAD, glutamic acid decarboxylase; Hb, hemoglobin; HbA1c, glycated hemoglobin; IA‐2, islet antigen 2; LDH, lactate dehydrogenase; PG, plasma glucose; Plt, platelets; RBC, red blood cells; TP, total protein; WBC, white blood cells.
John Wiley & Sons, Ltd
Figure 1 Chest radiography (a) and computed tomography (b) before thoracoscopic debridement and intrathoracic lavage (day 0).
Figure 2 Patient’s clinical course. Black circles and blank circles represent blood glucose and C‐reactive protein levels, respectively.
After overnight fasting for 18 h, the patient underwent thoracoscopic debridement and intrathoracic lavage (day 1; Figure 2). His surgery was initiated with drip infusion of extracellular fluid with 1% glucose without insulin. Based on the information of having diabetes from the former hospital, his arterial blood gas was measured during surgery. Approximately 2 h after the initiation of surgery, he was found to be acidotic on arterial blood gas with 162 mg/dL of blood glucose level (Figure 2). A urine test for ketone showed a positive result. Laboratory tests showed elevated levels of total ketone bodies, acetoacetic acid and 3‐hydroxybutyric acid in serum (Figure 2). Subsequently, the patient was started on an insulin infusion with drip infusion of 5% glucose immediately after the consultation from the anesthesiologist to the first department of medicine. He awoke from anesthesia normally and showed no digestive symptoms. After the continuous insulin infusion, his acidosis and ketosis gradually resolved over the next 24 h. Approximately 2 weeks later, his bacterial empyema had almost resolved. During these 2 weeks, he was treated with insulin alone for diabetes and did not present ketosis or acidosis.
Written informed consent was obtained from the patient.
Discussion
SGLT2is are widely used as excellent agents for managing diabetes, while providing metabolic, cardiovascular and renal benefits 1 , 3 , 4 . However, several adverse effects are concerned. DKA is a significant risk for patients taking SGLT2is, especially when there are precipitating factors, such as illness, infection and surgery 1 , 2 . In several countries, it is recommended that SGLT2is be discontinued preoperatively. The half‐life of 25 mg empagliflozin is reported to be 18.0 h according to the package insert. In the present case, empagliflozin was taken for the last time 28 h before surgery. However, in the case of surgery, it might be necessary to consider the potential effects of anesthesia and muscle relaxants on the half‐life. In Australia, for example, cessation at least 3 days preoperatively is recommended based on the half‐life and dose‐dependent offset time of SGLT2is 1 . In the present case, besides the use of SGLT2is with an insufficient withdrawal period, the patient was speculated to have infection with empyema and surgery as risk factors of DKA. In particular, as the present patient initially showed mixed acidemia, possibly as a result of the retention of carbon dioxide under the isolated one‐lung ventilation in addition to accumulation of ketone, it is necessary to pay attention to the management of DKA during thoracic surgery. In addition, the initial drip infusion during surgery was at a low concentration of glucose without insulin. Although insulin glargine was injected the night before, it is also possible that an insufficient dosage of glucose and insulin made the DKA worse in the present case.
Early detection and intervention are critical for management of DKA associated with SGLT2is. The US Food and Drug Administration highlighted awareness among practitioners, DKA symptoms and the potential for lower than expected blood glucose levels when precipitating factors for DKA associated with SGLT2is are present in patients 5 . However, as the symptoms are atypical and the blood glucose levels could be lower than expected, the diagnosis tends to be delayed in DKA associated with SGLT2is. In the present case, it is possible that eDKA had already developed before the surgery, although the patient had no symptoms of acidemia at that point. Thus, when it is difficult to take a sufficient withdrawal period of SGLT2is preoperatively, it is important to monitor ketone and acidosis, even before surgery, for the early detection and immediate management of DKA.
Several situations/diseases are raised as the general differential diagnosis of euglycemic ketoacidosis: pregnancy, restriction on caloric intake, glycogen storage diseases or defective gluconeogenesis as a result of alcohol abuse or chronic liver disease. As for the mechanism of eDKA associated with SGLT2is under stress, situations, such as delivery of a potentially low dose of insulin, increased secretion of counter hormones and dehydration status on the surgical day, could be speculated 1 , 6 , 7 . Under stress, such as surgery or illness, increased secretion of counter hormones, such as glucagon, leads to ketogenesis owing to such reasons as lipolysis providing sufficient free fatty acid substrate for production of ketone bodies or hepatic glucose production. Meanwhile, in patients treated with both SGLT2is and insulin, increased renal excretion of glucose might result in treatment with insufficient insulin to suppress lipolysis and ketogenesis, even if blood glucose levels are not increased. Therefore, sufficient insulin delivery, and careful clinical and biochemical monitoring are required to prevent perioperative eDKA in patients treated with dual SGLT2is and insulin.
In summary, we presented a patient with type 2 diabetes and bacterial empyema, who developed intraoperative eDKA associated with empagliflozin. This is the first case of eDKA associated with SGLT2is during thoracic surgery, which could be rapidly resolved by emergent intervention. When patients are taking SGLT2is, especially those with precipitating factors, it is clinically important to be aware of the potential risk of eDKA and to increase monitoring for the immediate initiation of treatment.
DISCLOSURE
The authors declare no conflict of interest.
Acknowledgments
We acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center at Wakayama Medical University. This work was supported by SRF (TA). | 69 kg. | Weight | CC BY-NC-ND | 32686282 | 18,088,625 | 2021-04 |
What was the outcome of reaction 'Empyema'? | Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report.
We report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium-glucose cotransporter 2 inhibitors during thoracic surgery. A 59-year-old man had a 12-year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium-glucose cotransporter 2 inhibitors, especially during thoracic surgery.
Introduction
Sodium–glucose cotransporter 2 inhibitors (SGLT2is) are widely used in patients with diabetes mellitus. However, regulatory agencies issued a warning that SGLT2is could cause diabetic ketoacidosis (DKA) 1 . DKA associated with SGLT2is can even occur when glucose levels are lower than expected, known as euglycemic DKA (eDKA), and often occurs during the perioperative period 1 , 2 . Cases of eDKA associated with SGLT2is have been reported after surgery 1 , 2 , but there is no report of occurrence during the surgery. Here, we present a patient with type 2 diabetes and bacterial empyema, who underwent surgery without a sufficient period of empagliflozin withdrawal. He developed intraoperative eDKA, but rapidly recovered after its early identification and management.
Case Report
A 59‐year‐old man had a 12‐year history of type 2 diabetes mellitus initiated with 10 mg of empagliflozin 18 months earlier, and clinically titrated to 25 mg along with intensive insulin therapy. During the period of treatment with empagliflozin, uric ketone had not been detected at every visit. The patient presented with high fever and chest pain for 2 weeks, and was admitted to a neighboring hospital. He was diagnosed as having left bacterial empyema, and treated with antibiotics for 4 days; however, as his symptoms persisted, he was transferred to Wakayama Medica University (Wakayama, Japan) for surgical treatment. He had a fever of 37.2°C, and weak pulmonary sound on the left side. The patient’s bodyweight, height and body mass index were 69 kg, 169 cm and 24.1 kg/m2, respectively. Laboratory data showed a severe infectious state (Table 1). Chest radiography and computed tomography images showed a large pleural effusion (Figure 1). On the day the patient was transferred to our hospital, he was treated with empagliflozin and insulin for diabetes at the former hospital (day 0; Figure 2). Empagliflozin was taken for the last time 28 h before surgery. He had no appetite loss nor digestive symptoms on that day. He was treated with insulin glargine 13 h before surgery.
Table 1 Laboratory data on admission
Hematology/biochemistry
WBC 15,620/μL AMY 39 U/L
RBC 357 × 104/μL Na 139 mEq/L
Hb 11.2 g/dL K 4.8 mEq/L
Plt 27.3 × 104/μL Cl 103 mEq/L
TP 5.4 g/dL PG 209 mg/dL
Alb 2.2 g/dL HbA1c 9.4%
AST 70 U/L C‐peptide 0.95 ng/mL
ALT 47 U/L Lactate 10.6 mg/dL
LDH 219 U/L
CPK 364 U/L Serological examination
γ‐GTP 81 U/L C‐reactive protein 29.8 mg/dL
BUN 16.6 mg/dL Anti‐GAD Ab <5.0 U/mL
Cr 1.11 mg/dL Anti‐IA‐2 Ab <0.6 U/mL
γ‐GTP, gamma‐glutamyl transpeptidase; Ab, antibodies; Alb, albumin; ALT, alanine aminotransferase; AMY, amylase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine kinase; Cr, creatinine; GAD, glutamic acid decarboxylase; Hb, hemoglobin; HbA1c, glycated hemoglobin; IA‐2, islet antigen 2; LDH, lactate dehydrogenase; PG, plasma glucose; Plt, platelets; RBC, red blood cells; TP, total protein; WBC, white blood cells.
John Wiley & Sons, Ltd
Figure 1 Chest radiography (a) and computed tomography (b) before thoracoscopic debridement and intrathoracic lavage (day 0).
Figure 2 Patient’s clinical course. Black circles and blank circles represent blood glucose and C‐reactive protein levels, respectively.
After overnight fasting for 18 h, the patient underwent thoracoscopic debridement and intrathoracic lavage (day 1; Figure 2). His surgery was initiated with drip infusion of extracellular fluid with 1% glucose without insulin. Based on the information of having diabetes from the former hospital, his arterial blood gas was measured during surgery. Approximately 2 h after the initiation of surgery, he was found to be acidotic on arterial blood gas with 162 mg/dL of blood glucose level (Figure 2). A urine test for ketone showed a positive result. Laboratory tests showed elevated levels of total ketone bodies, acetoacetic acid and 3‐hydroxybutyric acid in serum (Figure 2). Subsequently, the patient was started on an insulin infusion with drip infusion of 5% glucose immediately after the consultation from the anesthesiologist to the first department of medicine. He awoke from anesthesia normally and showed no digestive symptoms. After the continuous insulin infusion, his acidosis and ketosis gradually resolved over the next 24 h. Approximately 2 weeks later, his bacterial empyema had almost resolved. During these 2 weeks, he was treated with insulin alone for diabetes and did not present ketosis or acidosis.
Written informed consent was obtained from the patient.
Discussion
SGLT2is are widely used as excellent agents for managing diabetes, while providing metabolic, cardiovascular and renal benefits 1 , 3 , 4 . However, several adverse effects are concerned. DKA is a significant risk for patients taking SGLT2is, especially when there are precipitating factors, such as illness, infection and surgery 1 , 2 . In several countries, it is recommended that SGLT2is be discontinued preoperatively. The half‐life of 25 mg empagliflozin is reported to be 18.0 h according to the package insert. In the present case, empagliflozin was taken for the last time 28 h before surgery. However, in the case of surgery, it might be necessary to consider the potential effects of anesthesia and muscle relaxants on the half‐life. In Australia, for example, cessation at least 3 days preoperatively is recommended based on the half‐life and dose‐dependent offset time of SGLT2is 1 . In the present case, besides the use of SGLT2is with an insufficient withdrawal period, the patient was speculated to have infection with empyema and surgery as risk factors of DKA. In particular, as the present patient initially showed mixed acidemia, possibly as a result of the retention of carbon dioxide under the isolated one‐lung ventilation in addition to accumulation of ketone, it is necessary to pay attention to the management of DKA during thoracic surgery. In addition, the initial drip infusion during surgery was at a low concentration of glucose without insulin. Although insulin glargine was injected the night before, it is also possible that an insufficient dosage of glucose and insulin made the DKA worse in the present case.
Early detection and intervention are critical for management of DKA associated with SGLT2is. The US Food and Drug Administration highlighted awareness among practitioners, DKA symptoms and the potential for lower than expected blood glucose levels when precipitating factors for DKA associated with SGLT2is are present in patients 5 . However, as the symptoms are atypical and the blood glucose levels could be lower than expected, the diagnosis tends to be delayed in DKA associated with SGLT2is. In the present case, it is possible that eDKA had already developed before the surgery, although the patient had no symptoms of acidemia at that point. Thus, when it is difficult to take a sufficient withdrawal period of SGLT2is preoperatively, it is important to monitor ketone and acidosis, even before surgery, for the early detection and immediate management of DKA.
Several situations/diseases are raised as the general differential diagnosis of euglycemic ketoacidosis: pregnancy, restriction on caloric intake, glycogen storage diseases or defective gluconeogenesis as a result of alcohol abuse or chronic liver disease. As for the mechanism of eDKA associated with SGLT2is under stress, situations, such as delivery of a potentially low dose of insulin, increased secretion of counter hormones and dehydration status on the surgical day, could be speculated 1 , 6 , 7 . Under stress, such as surgery or illness, increased secretion of counter hormones, such as glucagon, leads to ketogenesis owing to such reasons as lipolysis providing sufficient free fatty acid substrate for production of ketone bodies or hepatic glucose production. Meanwhile, in patients treated with both SGLT2is and insulin, increased renal excretion of glucose might result in treatment with insufficient insulin to suppress lipolysis and ketogenesis, even if blood glucose levels are not increased. Therefore, sufficient insulin delivery, and careful clinical and biochemical monitoring are required to prevent perioperative eDKA in patients treated with dual SGLT2is and insulin.
In summary, we presented a patient with type 2 diabetes and bacterial empyema, who developed intraoperative eDKA associated with empagliflozin. This is the first case of eDKA associated with SGLT2is during thoracic surgery, which could be rapidly resolved by emergent intervention. When patients are taking SGLT2is, especially those with precipitating factors, it is clinically important to be aware of the potential risk of eDKA and to increase monitoring for the immediate initiation of treatment.
DISCLOSURE
The authors declare no conflict of interest.
Acknowledgments
We acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center at Wakayama Medical University. This work was supported by SRF (TA). | Recovering | ReactionOutcome | CC BY-NC-ND | 32686282 | 18,088,625 | 2021-04 |
What was the outcome of reaction 'Euglycaemic diabetic ketoacidosis'? | Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report.
We report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium-glucose cotransporter 2 inhibitors during thoracic surgery. A 59-year-old man had a 12-year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium-glucose cotransporter 2 inhibitors, especially during thoracic surgery.
Introduction
Sodium–glucose cotransporter 2 inhibitors (SGLT2is) are widely used in patients with diabetes mellitus. However, regulatory agencies issued a warning that SGLT2is could cause diabetic ketoacidosis (DKA) 1 . DKA associated with SGLT2is can even occur when glucose levels are lower than expected, known as euglycemic DKA (eDKA), and often occurs during the perioperative period 1 , 2 . Cases of eDKA associated with SGLT2is have been reported after surgery 1 , 2 , but there is no report of occurrence during the surgery. Here, we present a patient with type 2 diabetes and bacterial empyema, who underwent surgery without a sufficient period of empagliflozin withdrawal. He developed intraoperative eDKA, but rapidly recovered after its early identification and management.
Case Report
A 59‐year‐old man had a 12‐year history of type 2 diabetes mellitus initiated with 10 mg of empagliflozin 18 months earlier, and clinically titrated to 25 mg along with intensive insulin therapy. During the period of treatment with empagliflozin, uric ketone had not been detected at every visit. The patient presented with high fever and chest pain for 2 weeks, and was admitted to a neighboring hospital. He was diagnosed as having left bacterial empyema, and treated with antibiotics for 4 days; however, as his symptoms persisted, he was transferred to Wakayama Medica University (Wakayama, Japan) for surgical treatment. He had a fever of 37.2°C, and weak pulmonary sound on the left side. The patient’s bodyweight, height and body mass index were 69 kg, 169 cm and 24.1 kg/m2, respectively. Laboratory data showed a severe infectious state (Table 1). Chest radiography and computed tomography images showed a large pleural effusion (Figure 1). On the day the patient was transferred to our hospital, he was treated with empagliflozin and insulin for diabetes at the former hospital (day 0; Figure 2). Empagliflozin was taken for the last time 28 h before surgery. He had no appetite loss nor digestive symptoms on that day. He was treated with insulin glargine 13 h before surgery.
Table 1 Laboratory data on admission
Hematology/biochemistry
WBC 15,620/μL AMY 39 U/L
RBC 357 × 104/μL Na 139 mEq/L
Hb 11.2 g/dL K 4.8 mEq/L
Plt 27.3 × 104/μL Cl 103 mEq/L
TP 5.4 g/dL PG 209 mg/dL
Alb 2.2 g/dL HbA1c 9.4%
AST 70 U/L C‐peptide 0.95 ng/mL
ALT 47 U/L Lactate 10.6 mg/dL
LDH 219 U/L
CPK 364 U/L Serological examination
γ‐GTP 81 U/L C‐reactive protein 29.8 mg/dL
BUN 16.6 mg/dL Anti‐GAD Ab <5.0 U/mL
Cr 1.11 mg/dL Anti‐IA‐2 Ab <0.6 U/mL
γ‐GTP, gamma‐glutamyl transpeptidase; Ab, antibodies; Alb, albumin; ALT, alanine aminotransferase; AMY, amylase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine kinase; Cr, creatinine; GAD, glutamic acid decarboxylase; Hb, hemoglobin; HbA1c, glycated hemoglobin; IA‐2, islet antigen 2; LDH, lactate dehydrogenase; PG, plasma glucose; Plt, platelets; RBC, red blood cells; TP, total protein; WBC, white blood cells.
John Wiley & Sons, Ltd
Figure 1 Chest radiography (a) and computed tomography (b) before thoracoscopic debridement and intrathoracic lavage (day 0).
Figure 2 Patient’s clinical course. Black circles and blank circles represent blood glucose and C‐reactive protein levels, respectively.
After overnight fasting for 18 h, the patient underwent thoracoscopic debridement and intrathoracic lavage (day 1; Figure 2). His surgery was initiated with drip infusion of extracellular fluid with 1% glucose without insulin. Based on the information of having diabetes from the former hospital, his arterial blood gas was measured during surgery. Approximately 2 h after the initiation of surgery, he was found to be acidotic on arterial blood gas with 162 mg/dL of blood glucose level (Figure 2). A urine test for ketone showed a positive result. Laboratory tests showed elevated levels of total ketone bodies, acetoacetic acid and 3‐hydroxybutyric acid in serum (Figure 2). Subsequently, the patient was started on an insulin infusion with drip infusion of 5% glucose immediately after the consultation from the anesthesiologist to the first department of medicine. He awoke from anesthesia normally and showed no digestive symptoms. After the continuous insulin infusion, his acidosis and ketosis gradually resolved over the next 24 h. Approximately 2 weeks later, his bacterial empyema had almost resolved. During these 2 weeks, he was treated with insulin alone for diabetes and did not present ketosis or acidosis.
Written informed consent was obtained from the patient.
Discussion
SGLT2is are widely used as excellent agents for managing diabetes, while providing metabolic, cardiovascular and renal benefits 1 , 3 , 4 . However, several adverse effects are concerned. DKA is a significant risk for patients taking SGLT2is, especially when there are precipitating factors, such as illness, infection and surgery 1 , 2 . In several countries, it is recommended that SGLT2is be discontinued preoperatively. The half‐life of 25 mg empagliflozin is reported to be 18.0 h according to the package insert. In the present case, empagliflozin was taken for the last time 28 h before surgery. However, in the case of surgery, it might be necessary to consider the potential effects of anesthesia and muscle relaxants on the half‐life. In Australia, for example, cessation at least 3 days preoperatively is recommended based on the half‐life and dose‐dependent offset time of SGLT2is 1 . In the present case, besides the use of SGLT2is with an insufficient withdrawal period, the patient was speculated to have infection with empyema and surgery as risk factors of DKA. In particular, as the present patient initially showed mixed acidemia, possibly as a result of the retention of carbon dioxide under the isolated one‐lung ventilation in addition to accumulation of ketone, it is necessary to pay attention to the management of DKA during thoracic surgery. In addition, the initial drip infusion during surgery was at a low concentration of glucose without insulin. Although insulin glargine was injected the night before, it is also possible that an insufficient dosage of glucose and insulin made the DKA worse in the present case.
Early detection and intervention are critical for management of DKA associated with SGLT2is. The US Food and Drug Administration highlighted awareness among practitioners, DKA symptoms and the potential for lower than expected blood glucose levels when precipitating factors for DKA associated with SGLT2is are present in patients 5 . However, as the symptoms are atypical and the blood glucose levels could be lower than expected, the diagnosis tends to be delayed in DKA associated with SGLT2is. In the present case, it is possible that eDKA had already developed before the surgery, although the patient had no symptoms of acidemia at that point. Thus, when it is difficult to take a sufficient withdrawal period of SGLT2is preoperatively, it is important to monitor ketone and acidosis, even before surgery, for the early detection and immediate management of DKA.
Several situations/diseases are raised as the general differential diagnosis of euglycemic ketoacidosis: pregnancy, restriction on caloric intake, glycogen storage diseases or defective gluconeogenesis as a result of alcohol abuse or chronic liver disease. As for the mechanism of eDKA associated with SGLT2is under stress, situations, such as delivery of a potentially low dose of insulin, increased secretion of counter hormones and dehydration status on the surgical day, could be speculated 1 , 6 , 7 . Under stress, such as surgery or illness, increased secretion of counter hormones, such as glucagon, leads to ketogenesis owing to such reasons as lipolysis providing sufficient free fatty acid substrate for production of ketone bodies or hepatic glucose production. Meanwhile, in patients treated with both SGLT2is and insulin, increased renal excretion of glucose might result in treatment with insufficient insulin to suppress lipolysis and ketogenesis, even if blood glucose levels are not increased. Therefore, sufficient insulin delivery, and careful clinical and biochemical monitoring are required to prevent perioperative eDKA in patients treated with dual SGLT2is and insulin.
In summary, we presented a patient with type 2 diabetes and bacterial empyema, who developed intraoperative eDKA associated with empagliflozin. This is the first case of eDKA associated with SGLT2is during thoracic surgery, which could be rapidly resolved by emergent intervention. When patients are taking SGLT2is, especially those with precipitating factors, it is clinically important to be aware of the potential risk of eDKA and to increase monitoring for the immediate initiation of treatment.
DISCLOSURE
The authors declare no conflict of interest.
Acknowledgments
We acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center at Wakayama Medical University. This work was supported by SRF (TA). | Recovered | ReactionOutcome | CC BY-NC-ND | 32686282 | 18,088,625 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Constipation'. | Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study.
OBJECTIVE
A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH.
METHODS
A prospective cohort study was performed between May 2012 and November 2015 at the Headache Center and Toxicology Unit of the Careggi University Hospital. Eligible patients were treated with prophylactic LDM and followed up for 12 months. Headache exacerbations, pain intensity, use of rescue medications, and occurrence of adverse drug reactions (ADRs) were recorded.
RESULTS
Thirty patients (24 females, median age 48 years) were enrolled. Nineteen (63%) patients dropped out, mainly because of early ADRs (n = 10), including nausea, vomiting, and constipation. At last available follow-up, LDM was associated with a significant decrease in the number of headache attacks/month (from a median of 45 (interquartile range 30-150) to 16 (5-30), p < 0.001), in pain intensity (from 8.5 (8-9) to 5 (3-6), p < 0.001), and in the number of rescue medications consumed per month (from 95 (34-240) to 15 (3-28), p < 0.001). No misuse or diversion cases were observed.
CONCLUSIONS
LDM could represent a valuable and effective option in selected patients affected by RCM with continuous headache and MOH, although the frequency of early ADRs poses major safety concerns. Randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Introduction
Chronic migraine is increasingly disabling, making patients with continuous headache the most disabled in the spectrum of chronic migraineurs [1]. Chronic migraine affects at least 1% of the general population [2], and refractoriness to treatments (RCM, refractory chronic migraine) [3] and medication-overuse headache (MOH) [1] often aggravate this condition. Even if there is no conclusive consensus on its definition, refractoriness is a clinically relevant phenomenon that refers to the failure of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. As the prophylaxis fails, the risk for the patient to experience medication overuse and, consequently, undergo MOH significantly increases. Importantly, even if the majority of patients who discontinued medication overuse substantially improve [5–8], drug discontinuation is not always sufficient for the reduction of headache attack frequency or intensity. In a considerable portion of patients, chronic pain and exposure to adverse drug reactions (ADRs), due to the intense consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and/or triptans, lead to a vicious cycle that progressively deteriorates patients’ health and quality of life.
Despite some drawbacks, including the potential for misuse and diversion and the risk of cognitive impairment, continuous opioid therapy represents a reasonable prophylactic option for patients affected by RCM with continuous headache and MOH [9]. In 2009, the American Pain Society proposed chronic headaches as one of the four chronic pain conditions where continuous opioid therapy might be taken into consideration [10]. According to the data from longitudinal studies and a long-standing experience with refractory patients and opioid schedules, guidelines for the selection of patients eligible to continuous opioid therapy have been proposed [11].
Little evidence is available regarding the preferred opioid schedules for RCM with continuous headache and MOH. Methadone, because of the peculiar pharmacological profile of its racemic mixture of (R)- and (S)-isomers, seems to be a better candidate compared with other opioids, in particular for its duration of action (long-acting opioid), with an analgesic effect that persists for 4–6 h [12]. Methadone has a mean bioavailability of about 80%, which is much higher than for the other opioid; in addition, it also has a long terminal half-life ranging from 7 to 65 h compared with other clinically used opioids [13]. Although metabolism and disposition are highly variable among subjects, the appropriate dosage tailoring allows to maximally benefit of the pharmacokinetic profile of methadone for patients’ treatment. Its primary analgesic effect is mediated by the agonism of the sole (R)-methadone on μ-opioid receptors. However, both isomers act as antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor [14], likely contributing to a reduced opioid tolerance [15] especially at low doses [16, 17]. The favorable profile of methadone in terms of reduced tolerance in comparison with other opioids is another key point for the administration of methadone for chronic pain therapy. Some preclinical evidence suggests it has an optimal profile regarding the ability to induce opioid receptor internalization that may explain this clinical phenomenon [18]. Despite its proven efficacy, methadone has a relevant potential for drug interactions and may be associated with serious ADRs, among which is the dose-independent prolongation of the QT interval [19] leading to rare but potentially fatal arrhythmias. Thus, the clinical use of methadone requires trained physicians, a careful education of patients, and a strict monitoring; nevertheless, the use of low dosages is recommended.
In this clinical context, the aim of the present study was to evaluate the effectiveness and safety, at 12 months of treatment, of low doses of methadone (LDM) in patients affected by RCM with continuous headache and MOH.
Methods
Study design and setting
A prospective cohort study was performed at the Headache Center and Toxicology Unit of the Careggi University Hospital. The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA). The study was performed following all the guidelines for observational studies with human subjects required by the institution with which all the authors are affiliated. A written informed consent for research was obtained from all participants.
Study population
Between May 2012 and November 2015, patients aged ≥ 30 years were screened at the Headache Center of Careggi University Hospital and, if diagnosed with RCM with continuous headache and MOH, were informed about the possibility of receiving prophylactic LDM. Only patients with refractory headache or with contraindications to the use of evidence-based interventions were eligible [11]. Patients were considered not eligible in case of contraindications to opioid treatment, including past addictive disease or serious mental illnesses [11]. Before starting the LDM, patients underwent a psychiatric evaluation in order to exclude lifetime diagnosis of schizophrenia or other psychiatric syndromes according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) [5] and clinical assessment, including electrocardiography (ECG) and urine drug screening. According to standard clinical practice, patients that resulted eligible after clinical screening were informed about possible drug-drug interactions related to methadone treatment. In order to avoid possible interactions and optimize treatment, an informative letter was sent to the general practitioner of each patient.
According to standard practice, patients should have their headache diary reporting data about their chronic migraine in the previous 3 months. Information reported in this diary included the number of rescue medications (including non-opioid analgesics, NSAIDs, and triptans) consumed per month, the number of days with headache per month, the number of headache exacerbations deserving pain relievers per month, and their intensity assessed every day by the visual analogue scale (VAS).
Data from the headache diaries were used as baseline values for study assessments. After signature of the informed consent, eligible patients were transferred to the Toxicology Unit, where all the clinical procedures and study follow-up visits were performed.
The baseline visit was conducted at T0 (i.e., day of LDM start). All treated patients were prescribed with standard prophylaxis (i.e., enriched fiber diet, physical activity, lactulose if needed) to prevent methadone-induced constipation. LDM started from 2 mg per day and was increased or administered in multiple daily doses according to clinical evaluation, since no dosing strategy for initiation of therapy and later uptitration have been validated. In our patients, maximal dose administered was 30 mg per day at T0. and 40 mg per day at T4.
Follow-up visits were planned at T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). The variability in the time interval between subsequent visits was due to the increased need of follow-up in the initial phases of the treatment, when titration of the methadone doses can still be critical.
Outcome evaluation
The primary outcome was headache exacerbations. The primary endpoint was the number of headache exacerbations per month requiring a pain reliever.
The secondary outcomes were the pain intensity and the need of rescue medications. The secondary endpoints were the changes in pain intensity, measured using the VAS, and the number of rescue medications consumed per month.
Safety outcomes included all ADRs occurred during LDM treatment. Namely, safety endpoints were the number and the grade of ADRs recorded. To this aim, ECG recordings were performed at T0, T1, and T4 in order to detect QTc changes possibly due to administration of LDM.
Statistical analysis
Data were reported as mean value ± standard deviation of the mean (SD) or as median value and related interquartile range (IQR), according to data distribution.
Effectiveness and safety endpoints were evaluated at T1, T2, T3, and T4 and compared with T0 using the Wilcoxon test for paired data. Furthermore, effectiveness and safety endpoints at T0 were compared with those obtained at last available follow-up, i.e., T1, T2, T3, or T4, according to patients’ data availability. Statistical significance was considered for p value < 0.05. An analysis was conducted using the software STATA version 14.
Results
Thirty patients were considered eligible for LDM and were further enrolled in the study. Of them, 24 were females (80.0%), with a median age of 48 years (41.2–54.2). Demographic and clinical characteristics of the enrolled cohort are detailed in Table 1.Table 1 Demographic and clinical data of patients treated with low-dose methadone (LDM)
Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48 (41.2–54.2)#
Female 24 (80.0)
Overused drug/s*
NSAIDs 28 (93.3)
Triptans 17 (56.7)
Opioids 17 (56.7)
Acetaminophen 11 (36.7)
Comorbidities
Anxiety 20 (66.7)
Arterial hypertension 9 (30.0)
Other pain conditions 7 (23.3)
*Some patients overused more than one drug
IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Focusing on the previous pharmacological treatment of headache, 93.3% of patients overused NSAIDs (n = 28), 17 (56.7%) overused triptans, and the other 17 overused opioids. Acetaminophen was overused by 11 patients (36.7%). Notably, patients assumed more than one drug class to treat headache exacerbations. Concerning failed prophylaxes, tricyclic antidepressants, calcium-channel blockers, and antiepileptics were reported as previous treatment by 73% of patients, while beta-blockers and onabotulinum toxin A by 67% of patients. Importantly, 40% of patients are reported to have been treated with at least four of the abovementioned drug classes, while 60% of patients have tried them all.
As for comorbidities, most patients suffered from anxiety (66.7%), whereas arterial hypertension and other pain conditions were reported in 30.0 and 23.3% of patients, respectively.
LDM was initiated during in-hospital stay (2–3 days) in 28 patients, while 2 patients started LDM in a day-hospital setting. An initial mean dose of methadone was 12 ± 4 mg (IQR 8–17 mg).
The demographic and clinical characteristics of patients are detailed in Table 2. Nineteen (63.3%) patients discontinued LDM. Specifically, five (16.7%) withdrew because of ineffectiveness, after a median time of 4.6 months (IQR 3.5–5.5). Although LDM treatment was effective, fourteen patients withdrew for other reasons. Among them, ten (33.3%) withdrew because of ADR; it is worth noting that all were female. Other three patients (10.0%) dropped out because of poor treatment confidence, while one patient moved to another country and was therefore lost to follow-up. Eleven patients (36.7%) were still on LDM treatment at the end of our study. The persistence on LDM treatment, distinguishing patients that developed an ADR (n = 10) from the others (n = 20), is shown in Fig. 1 (solid and dashed lines, respectively).Table 2 Demographic and clinical data of patients treated with low-dose methadone (LDM), grouped according to clinical outcomes
Patients with ongoing treatment Dropout
n = 11 Inefficacy
n = 5 ADRs
n = 10 Others
n = 4
Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48, 41–58 47, 28–64.5 49, 47.5–56.7 41.5, 39.5–51.7
Female 8 (72.7%) 3 (60%) 10 (100%) 3 (75%)
Prevalent headache type
Migraine 10 (90.9%) 4 (80%) 10 (100%) 2 (50%)
Tension-type headache 1 (9.1%) 0 (0%) 0 (0%) 2 (50%)
Cluster headache 0 (0%) 1 (20%) 0 (0%) 0 (0%)
Overused drug/s*
NSAIDs 10 (90.9%) 4 (80%) 10 (100%) 4 (100%)
Opioids 8 (72.7%) 1 (20%) 4 (40%) 4 (100%)
Acetaminophen 5 (45.4%) 1 (20%) 4 (40%) 1 (25%)
Serotonin receptor agonists 5 (45.4%) 4 (80%) 6 (60%) 2 (50%)
Comorbidities§
Anxiety 9 (81.8%) 2 (40%) 6 (60%) 3 (75%)
Arterial hypertension 3 (27.3%) 2 (40%) 4 (40%) 0 (0%)
Other pain conditions 3 (27.3%) 1 (20%) 2 (20%) 1 (25%)
*Some patients overused more than one drug.
§Some patients have more than one concomitant disease in addition to RCM
ADRs adverse drug reactions, IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Fig. 1 Time on treatment with low-dose methadone (LDM) of patients in 1 year of follow-up. Survival curves of patients that dropped out because of an ADR (continuous line) vs. all the other patients (still on treatment at month 12/dropouts for inefficacy/dropouts for personal reasons; dotted line). Importantly, most ADR patients dropped out early after LDM initiation (median time 14 days, IQ range 7–40). The curves are statistically different (log-rank Mantel-Cox test; P < 0.0001)
The effectiveness of LDM in terms of headache exacerbations, pain reduction, and use of rescue medications is described in Fig. 2. At time of start of LDM treatment (T0), the mean number of headache exacerbations per month requiring a pain reliever in the 30 enrolled patients was of 68.5 ± 60.4 (median 45, IQR 30–90) (Fig. 2A). At T1, the mean number of attacks requiring a pain reliever in the 25 observed patients significantly decreased to 15.9 ± 12.4 (median 9, IQR 5–30; p < 0.001). This significant reduction in the monthly number of headache exacerbations was confirmed also at the other time points of follow-up. Specifically, at T2, among the 19 patients for whom follow-up data were available, the mean number of attacks was of 24.8 ± 26.0 (median 30, IQR 7–30; p = 0.003). At T3, among the 15 observed patients, the mean of attacks was of 24.9 ± 29.2 (median 26, IQR 4–30; p = 0.002), and at T4, the mean number in the 11 observed patients was of 17.1 ± 11.4 (median 16, IQR 5–30; p = 0.003). At time of the last follow-up available for each patient (ranging from T1 to T4, n = 25), the mean number of headache attacks per month requiring a pain reliever was of 21.0 ± 23.6 (median 16, IQR 5–30, p < 0.001, data not shown).Fig. 2 Effectiveness of low-dose methadone (LDM) on headache attacks, pain intensity, and the use of rescue medications. LDM decreased the number of headache exacerbations deserving a pain reliever per month (A), pain intensity assessed by a visual analogue scale (VAS) (B), and the number of pills of rescue medications consumed per month (C) at different time points of follow-up (T0 (baseline), T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). Namely, the median number (interquartile range, IQR) of headache exacerbations per month was 45 (30–90) at T0, 9 (5–30) at T1, 30 (7–30) at T2, 26 (4–30) at T3, and 16 (5–30) at T4. The median VAS (IQR) was 8.5 (8–9) at T0, 5 (3–7) at T1, 5 (4–7) at T2, 7 (4–8) at T3, and 3 (2–6) at T4. The median number of pills of rescue medications (IQR) was 95 (34–240) at T0, 5 (3–30) at T1, 15 (5–60) at T2, 8 (4–20) at T3, and 10 (3–16) at T4
Considering pain intensity, the mean VAS score at T0 in the 30 enrolled patients was of 8.0 ± 2.0 (median 8.5, IQR 8–9) (Fig. 2B). At T1 (25 observed patients), the mean VAS score significantly decreased to 5.0 ± 2.4 (median 5.0, IQR 3–7; p < 0.001). This significant reduction in pain intensity was confirmed also at T2 (19 patients; mean VAS of 5.4 ± 2.3; median 5, IQR 4–7; p < 0.001), T3 (15 patients; mean VAS of 5.9 ± 2.7; median 7, IQR 4–8; p = 0.001), and T4 (11 patients; mean VAS of 3.6 ± 2.3; median 3, IQR 2–6; p = 0.004). At time of the last follow-up available for each patient, the mean pain intensity was of 4.8 ± 2.3 (median 5, IQR 3–6, p < 0.001, data not shown).
A similar trend in pain relief was observed also considering the use of rescue medications (Fig. 2C). At T0, the mean number of pills used per month was of 163.3 ± 156.3 (median 95, IQR 34–240). At T1, the use of rescue medications significantly decreased to a mean of 21.3 ± 29.6 pills per month (median 5, IQR 3–30, p < 0.001). Similarly, at T2, T3, and T4, the monthly intake of rescue medications was reduced to a mean of number of 36.4 ± 45.6 pills (median 15, IQR 5–60, p < 0.001), 30.3 ± 55.5 pills (median 8, IQR 4–20, p < 0.001), and 21.8 ± 34.3 pills (median 10, IQR 3–16, p = 0.003), respectively. At time of the last follow-up, the mean number of pills used per month was of 22.2 ± 29.2 (median 15, IQR 3–28, p < 0.001, data not shown).
Ten patients reported clinically relevant ADRs (from low to moderate grade), requiring LDM discontinuation. Specifically, five patients had nausea, three vomiting, and two had constipation. Nine patients who experienced an ADR dropped out early after LDM initiation (after a median time of 14 days, IQ 7–40), while one patient dropped out at month 11. All patients fully recovered after tapered interruption of LDM. No other ADRs were observed in our sample. No case of misuse or diversion was observed (data not shown).
Discussion
This is the first study evaluating the effectiveness and safety of LDM over a 12-month follow-up period, in patients affected by RCM with continuous headache and MOH in a real-world setting. As mentioned above, refractoriness may be diagnosed when a patient experiences ineffectiveness of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. Our results show that in patients affected by RCM, when tolerated, LDM is an effective option for the prevention of headache exacerbation, as well as for the reduction of pain intensity and consumption of rescue medications.
However, a significant portion of patients, despite an initial benefit from LDM, discontinued the treatment because of ADRs, although they were expected and non-serious. Even if the portion of patients developing nausea and vomiting was quite similar to that observed in other populations [20], our patients did not develop the expected tolerance to these ADRs. Accordingly, we cannot exclude that patients with migraine have a disease-related alteration (read as hypersensitivity) to these disturbances. This phenomenon, being nausea and vomiting the most frequent causes of LDM withdrawal in our population, deserves future investigation. Importantly, the median time to develop ADRs, being rather short (14 days) after therapy initiation, favored the safety profile as tapering of methadone was quick and easy. Altogether, our observations suggest that the optimization of the treatment, including either the association with or a formulation containing methylnaltrexone, which has been shown to be able to counteract the constipation [21], would relevantly increase the persistence on treatment, thus increasing the proportion of patients that might benefit from LDM. Another interesting result emerging from our population is that all patients experiencing ADR were female. An increased sensitivity to opioid-induced nausea and vomiting in women has been already reported [22–27], but the underlying mechanism is not known. In our study, the exclusive involvement of women may be due to the low number of participants that, however, per se discourages further subgroup analysis.
The impressive reduction of drug consumption observed in our study (from a median of 95 pills per month (IQR) (34–240) to 15 (3–28), p < 0.001) suggests that the initial medication overuse is mostly driven by the pain intensity. It is worth noting that this is at odds with the assumption that medication overuse in patients with migraine is mainly due to a genetic predisposition to substance abuse [28]. Indeed, when methadone is administered to patients with MOH according to a scheduled plan, it alleviates pain and drug consumption consequently falls. The fact that none of our patients misused methadone, notwithstanding its well-known abuse potential, further corroborates the hypothesis that RCM patients with MOH are not genetically predisposed drug abusers per se [28], but just deserve an efficacious pain treatment to defeat the vicious cycle that sustains medication overuse. However, as no conclusive evidence exists, it would be of paramount importance to dissect the mechanisms that drive the medication overuse in patients with migraine as this could significantly change the therapeutic approach to these patients.
It has been already reported that prescribing methadone for headache patients is neither glamorous nor lucrative and that it is a tedious process because of extensive patient education, controlled substance agreement, and meticulous record keeping [29]. However, the absence of suitable pharmacological alternatives for RCM associated with MOH is associated with an increased risk of ADRs due to overused medications and severe disability of patients who still seek medical attention after a number of therapeutic failures [29]. In this context, practitioners should consider LDM as a potential effective alternative for these patients. Currently, there are no restrictions for methadone prescriptions in Italy, since by the release of Law 38/2010 that specifically deals with the treatment of pain, it can be prescribed with the same modalities used for any other prescription drugs. Nonetheless, methadone prescription should still be reserved to specialists experienced in patients’ education and methadone handling. The opioid epidemics emerging in the United States, following to a well-meaning movement emerged in the United States 20 years ago to promote an adequate treatment of chronic pain with opioids and causing the death of almost half a million Americans from drug overdoses, suggests that more than caution is needed [30]. Despite the low rate of use of opioids in most European countries [31], the strict adherence to available guidelines that reserve opioids for headache patients only in selected cases [32] is both essential and mandatory to pursue an optimal management of LDM prophylaxis and to minimize the occurrence of overuse and ADRs.
Our results have several limitations. Unquestionably, the major limitation is the small sample size that is however due to the investigated condition. Considering the low frequency of the disease and the restrictedness of criteria that candidate a patient to the treatment, we had to deal with study premises resembling those of rare diseases, indeed. Although we planned a self-controlled study to maximize the internal validity of the study [33, 34], only initial evidence may emerge from observations in such a small population.
Another relevant drawback is the high rate of early treatment discontinuation, which significantly compromised the power of the study. It is worth noting that the study has a pragmatic approach and that the high portion of patients who discontinued the treatment represents the first valuable result of the study, indeed. On the one side, it suggests that only some weeks are needed to understand if patients will tolerate LDM. On the other side, as discontinuation was mainly due to gastrointestinal liability, we may hypothesize that innovative formulations of methadone will significantly decrease the number of patients who discontinue the treatment. Nevertheless, it is reasonable to consider that eligible enrolled patients were exclusively those non-responders to standard treatments, thus suggesting that LDM can represent a valid prophylactic approach in those refractory patients.
Conclusions
LDM may be an effective prophylactic alternative for patients affected by RCM with continuous headache associated with MOH refractory to standard treatments. In eligible patients, after a short initial trial to test tolerability, LDM may represent a simple and inexpensive way to bring relief and reduce headache medication overuse, although the frequency of early ADRs poses major safety concerns. Further research, including assessment of methadone plasma levels and pharmacogenetic profiling, are needed to understand factors that may influence the clinical response to LDM in RCM patients. In addition, randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open access funding provided by Università degli Studi di Firenze within the CRUI-CARE Agreement. The authors acknowledge Prof. Emanuela Masini, MD, for her expert advice, and Dr. Eleonora Rossi, MD, Headache Centre, Careggi University Hospital, Florence, as contributor (contributing participants). The authors are also grateful to Mary Lokken for her expert English language revision.
Authors’ contributions
SB and GM conceived and designed the study. SB, CL, FDC, VG, CP, and BO contributed to the acquisition of data. SB and AB contributed to the analysis of data. SB, CL, NL, AC, PG, and GM contributed to the interpretation of data. SB, NL, and AB drafted the manuscript. All authors critically revised and approved the manuscript.
Funding information
This study was not funded.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Ethics approval
The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA).
Consent to participate
An informed consent was obtained from all individual participants included in the study.
Consent for publication
Patients signed an informed consent regarding publishing their data, in an aggregated and anonymous form.
Code availability
Not applicable. | METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 32691178 | 18,727,749 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study.
OBJECTIVE
A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH.
METHODS
A prospective cohort study was performed between May 2012 and November 2015 at the Headache Center and Toxicology Unit of the Careggi University Hospital. Eligible patients were treated with prophylactic LDM and followed up for 12 months. Headache exacerbations, pain intensity, use of rescue medications, and occurrence of adverse drug reactions (ADRs) were recorded.
RESULTS
Thirty patients (24 females, median age 48 years) were enrolled. Nineteen (63%) patients dropped out, mainly because of early ADRs (n = 10), including nausea, vomiting, and constipation. At last available follow-up, LDM was associated with a significant decrease in the number of headache attacks/month (from a median of 45 (interquartile range 30-150) to 16 (5-30), p < 0.001), in pain intensity (from 8.5 (8-9) to 5 (3-6), p < 0.001), and in the number of rescue medications consumed per month (from 95 (34-240) to 15 (3-28), p < 0.001). No misuse or diversion cases were observed.
CONCLUSIONS
LDM could represent a valuable and effective option in selected patients affected by RCM with continuous headache and MOH, although the frequency of early ADRs poses major safety concerns. Randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Introduction
Chronic migraine is increasingly disabling, making patients with continuous headache the most disabled in the spectrum of chronic migraineurs [1]. Chronic migraine affects at least 1% of the general population [2], and refractoriness to treatments (RCM, refractory chronic migraine) [3] and medication-overuse headache (MOH) [1] often aggravate this condition. Even if there is no conclusive consensus on its definition, refractoriness is a clinically relevant phenomenon that refers to the failure of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. As the prophylaxis fails, the risk for the patient to experience medication overuse and, consequently, undergo MOH significantly increases. Importantly, even if the majority of patients who discontinued medication overuse substantially improve [5–8], drug discontinuation is not always sufficient for the reduction of headache attack frequency or intensity. In a considerable portion of patients, chronic pain and exposure to adverse drug reactions (ADRs), due to the intense consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and/or triptans, lead to a vicious cycle that progressively deteriorates patients’ health and quality of life.
Despite some drawbacks, including the potential for misuse and diversion and the risk of cognitive impairment, continuous opioid therapy represents a reasonable prophylactic option for patients affected by RCM with continuous headache and MOH [9]. In 2009, the American Pain Society proposed chronic headaches as one of the four chronic pain conditions where continuous opioid therapy might be taken into consideration [10]. According to the data from longitudinal studies and a long-standing experience with refractory patients and opioid schedules, guidelines for the selection of patients eligible to continuous opioid therapy have been proposed [11].
Little evidence is available regarding the preferred opioid schedules for RCM with continuous headache and MOH. Methadone, because of the peculiar pharmacological profile of its racemic mixture of (R)- and (S)-isomers, seems to be a better candidate compared with other opioids, in particular for its duration of action (long-acting opioid), with an analgesic effect that persists for 4–6 h [12]. Methadone has a mean bioavailability of about 80%, which is much higher than for the other opioid; in addition, it also has a long terminal half-life ranging from 7 to 65 h compared with other clinically used opioids [13]. Although metabolism and disposition are highly variable among subjects, the appropriate dosage tailoring allows to maximally benefit of the pharmacokinetic profile of methadone for patients’ treatment. Its primary analgesic effect is mediated by the agonism of the sole (R)-methadone on μ-opioid receptors. However, both isomers act as antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor [14], likely contributing to a reduced opioid tolerance [15] especially at low doses [16, 17]. The favorable profile of methadone in terms of reduced tolerance in comparison with other opioids is another key point for the administration of methadone for chronic pain therapy. Some preclinical evidence suggests it has an optimal profile regarding the ability to induce opioid receptor internalization that may explain this clinical phenomenon [18]. Despite its proven efficacy, methadone has a relevant potential for drug interactions and may be associated with serious ADRs, among which is the dose-independent prolongation of the QT interval [19] leading to rare but potentially fatal arrhythmias. Thus, the clinical use of methadone requires trained physicians, a careful education of patients, and a strict monitoring; nevertheless, the use of low dosages is recommended.
In this clinical context, the aim of the present study was to evaluate the effectiveness and safety, at 12 months of treatment, of low doses of methadone (LDM) in patients affected by RCM with continuous headache and MOH.
Methods
Study design and setting
A prospective cohort study was performed at the Headache Center and Toxicology Unit of the Careggi University Hospital. The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA). The study was performed following all the guidelines for observational studies with human subjects required by the institution with which all the authors are affiliated. A written informed consent for research was obtained from all participants.
Study population
Between May 2012 and November 2015, patients aged ≥ 30 years were screened at the Headache Center of Careggi University Hospital and, if diagnosed with RCM with continuous headache and MOH, were informed about the possibility of receiving prophylactic LDM. Only patients with refractory headache or with contraindications to the use of evidence-based interventions were eligible [11]. Patients were considered not eligible in case of contraindications to opioid treatment, including past addictive disease or serious mental illnesses [11]. Before starting the LDM, patients underwent a psychiatric evaluation in order to exclude lifetime diagnosis of schizophrenia or other psychiatric syndromes according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) [5] and clinical assessment, including electrocardiography (ECG) and urine drug screening. According to standard clinical practice, patients that resulted eligible after clinical screening were informed about possible drug-drug interactions related to methadone treatment. In order to avoid possible interactions and optimize treatment, an informative letter was sent to the general practitioner of each patient.
According to standard practice, patients should have their headache diary reporting data about their chronic migraine in the previous 3 months. Information reported in this diary included the number of rescue medications (including non-opioid analgesics, NSAIDs, and triptans) consumed per month, the number of days with headache per month, the number of headache exacerbations deserving pain relievers per month, and their intensity assessed every day by the visual analogue scale (VAS).
Data from the headache diaries were used as baseline values for study assessments. After signature of the informed consent, eligible patients were transferred to the Toxicology Unit, where all the clinical procedures and study follow-up visits were performed.
The baseline visit was conducted at T0 (i.e., day of LDM start). All treated patients were prescribed with standard prophylaxis (i.e., enriched fiber diet, physical activity, lactulose if needed) to prevent methadone-induced constipation. LDM started from 2 mg per day and was increased or administered in multiple daily doses according to clinical evaluation, since no dosing strategy for initiation of therapy and later uptitration have been validated. In our patients, maximal dose administered was 30 mg per day at T0. and 40 mg per day at T4.
Follow-up visits were planned at T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). The variability in the time interval between subsequent visits was due to the increased need of follow-up in the initial phases of the treatment, when titration of the methadone doses can still be critical.
Outcome evaluation
The primary outcome was headache exacerbations. The primary endpoint was the number of headache exacerbations per month requiring a pain reliever.
The secondary outcomes were the pain intensity and the need of rescue medications. The secondary endpoints were the changes in pain intensity, measured using the VAS, and the number of rescue medications consumed per month.
Safety outcomes included all ADRs occurred during LDM treatment. Namely, safety endpoints were the number and the grade of ADRs recorded. To this aim, ECG recordings were performed at T0, T1, and T4 in order to detect QTc changes possibly due to administration of LDM.
Statistical analysis
Data were reported as mean value ± standard deviation of the mean (SD) or as median value and related interquartile range (IQR), according to data distribution.
Effectiveness and safety endpoints were evaluated at T1, T2, T3, and T4 and compared with T0 using the Wilcoxon test for paired data. Furthermore, effectiveness and safety endpoints at T0 were compared with those obtained at last available follow-up, i.e., T1, T2, T3, or T4, according to patients’ data availability. Statistical significance was considered for p value < 0.05. An analysis was conducted using the software STATA version 14.
Results
Thirty patients were considered eligible for LDM and were further enrolled in the study. Of them, 24 were females (80.0%), with a median age of 48 years (41.2–54.2). Demographic and clinical characteristics of the enrolled cohort are detailed in Table 1.Table 1 Demographic and clinical data of patients treated with low-dose methadone (LDM)
Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48 (41.2–54.2)#
Female 24 (80.0)
Overused drug/s*
NSAIDs 28 (93.3)
Triptans 17 (56.7)
Opioids 17 (56.7)
Acetaminophen 11 (36.7)
Comorbidities
Anxiety 20 (66.7)
Arterial hypertension 9 (30.0)
Other pain conditions 7 (23.3)
*Some patients overused more than one drug
IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Focusing on the previous pharmacological treatment of headache, 93.3% of patients overused NSAIDs (n = 28), 17 (56.7%) overused triptans, and the other 17 overused opioids. Acetaminophen was overused by 11 patients (36.7%). Notably, patients assumed more than one drug class to treat headache exacerbations. Concerning failed prophylaxes, tricyclic antidepressants, calcium-channel blockers, and antiepileptics were reported as previous treatment by 73% of patients, while beta-blockers and onabotulinum toxin A by 67% of patients. Importantly, 40% of patients are reported to have been treated with at least four of the abovementioned drug classes, while 60% of patients have tried them all.
As for comorbidities, most patients suffered from anxiety (66.7%), whereas arterial hypertension and other pain conditions were reported in 30.0 and 23.3% of patients, respectively.
LDM was initiated during in-hospital stay (2–3 days) in 28 patients, while 2 patients started LDM in a day-hospital setting. An initial mean dose of methadone was 12 ± 4 mg (IQR 8–17 mg).
The demographic and clinical characteristics of patients are detailed in Table 2. Nineteen (63.3%) patients discontinued LDM. Specifically, five (16.7%) withdrew because of ineffectiveness, after a median time of 4.6 months (IQR 3.5–5.5). Although LDM treatment was effective, fourteen patients withdrew for other reasons. Among them, ten (33.3%) withdrew because of ADR; it is worth noting that all were female. Other three patients (10.0%) dropped out because of poor treatment confidence, while one patient moved to another country and was therefore lost to follow-up. Eleven patients (36.7%) were still on LDM treatment at the end of our study. The persistence on LDM treatment, distinguishing patients that developed an ADR (n = 10) from the others (n = 20), is shown in Fig. 1 (solid and dashed lines, respectively).Table 2 Demographic and clinical data of patients treated with low-dose methadone (LDM), grouped according to clinical outcomes
Patients with ongoing treatment Dropout
n = 11 Inefficacy
n = 5 ADRs
n = 10 Others
n = 4
Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48, 41–58 47, 28–64.5 49, 47.5–56.7 41.5, 39.5–51.7
Female 8 (72.7%) 3 (60%) 10 (100%) 3 (75%)
Prevalent headache type
Migraine 10 (90.9%) 4 (80%) 10 (100%) 2 (50%)
Tension-type headache 1 (9.1%) 0 (0%) 0 (0%) 2 (50%)
Cluster headache 0 (0%) 1 (20%) 0 (0%) 0 (0%)
Overused drug/s*
NSAIDs 10 (90.9%) 4 (80%) 10 (100%) 4 (100%)
Opioids 8 (72.7%) 1 (20%) 4 (40%) 4 (100%)
Acetaminophen 5 (45.4%) 1 (20%) 4 (40%) 1 (25%)
Serotonin receptor agonists 5 (45.4%) 4 (80%) 6 (60%) 2 (50%)
Comorbidities§
Anxiety 9 (81.8%) 2 (40%) 6 (60%) 3 (75%)
Arterial hypertension 3 (27.3%) 2 (40%) 4 (40%) 0 (0%)
Other pain conditions 3 (27.3%) 1 (20%) 2 (20%) 1 (25%)
*Some patients overused more than one drug.
§Some patients have more than one concomitant disease in addition to RCM
ADRs adverse drug reactions, IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Fig. 1 Time on treatment with low-dose methadone (LDM) of patients in 1 year of follow-up. Survival curves of patients that dropped out because of an ADR (continuous line) vs. all the other patients (still on treatment at month 12/dropouts for inefficacy/dropouts for personal reasons; dotted line). Importantly, most ADR patients dropped out early after LDM initiation (median time 14 days, IQ range 7–40). The curves are statistically different (log-rank Mantel-Cox test; P < 0.0001)
The effectiveness of LDM in terms of headache exacerbations, pain reduction, and use of rescue medications is described in Fig. 2. At time of start of LDM treatment (T0), the mean number of headache exacerbations per month requiring a pain reliever in the 30 enrolled patients was of 68.5 ± 60.4 (median 45, IQR 30–90) (Fig. 2A). At T1, the mean number of attacks requiring a pain reliever in the 25 observed patients significantly decreased to 15.9 ± 12.4 (median 9, IQR 5–30; p < 0.001). This significant reduction in the monthly number of headache exacerbations was confirmed also at the other time points of follow-up. Specifically, at T2, among the 19 patients for whom follow-up data were available, the mean number of attacks was of 24.8 ± 26.0 (median 30, IQR 7–30; p = 0.003). At T3, among the 15 observed patients, the mean of attacks was of 24.9 ± 29.2 (median 26, IQR 4–30; p = 0.002), and at T4, the mean number in the 11 observed patients was of 17.1 ± 11.4 (median 16, IQR 5–30; p = 0.003). At time of the last follow-up available for each patient (ranging from T1 to T4, n = 25), the mean number of headache attacks per month requiring a pain reliever was of 21.0 ± 23.6 (median 16, IQR 5–30, p < 0.001, data not shown).Fig. 2 Effectiveness of low-dose methadone (LDM) on headache attacks, pain intensity, and the use of rescue medications. LDM decreased the number of headache exacerbations deserving a pain reliever per month (A), pain intensity assessed by a visual analogue scale (VAS) (B), and the number of pills of rescue medications consumed per month (C) at different time points of follow-up (T0 (baseline), T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). Namely, the median number (interquartile range, IQR) of headache exacerbations per month was 45 (30–90) at T0, 9 (5–30) at T1, 30 (7–30) at T2, 26 (4–30) at T3, and 16 (5–30) at T4. The median VAS (IQR) was 8.5 (8–9) at T0, 5 (3–7) at T1, 5 (4–7) at T2, 7 (4–8) at T3, and 3 (2–6) at T4. The median number of pills of rescue medications (IQR) was 95 (34–240) at T0, 5 (3–30) at T1, 15 (5–60) at T2, 8 (4–20) at T3, and 10 (3–16) at T4
Considering pain intensity, the mean VAS score at T0 in the 30 enrolled patients was of 8.0 ± 2.0 (median 8.5, IQR 8–9) (Fig. 2B). At T1 (25 observed patients), the mean VAS score significantly decreased to 5.0 ± 2.4 (median 5.0, IQR 3–7; p < 0.001). This significant reduction in pain intensity was confirmed also at T2 (19 patients; mean VAS of 5.4 ± 2.3; median 5, IQR 4–7; p < 0.001), T3 (15 patients; mean VAS of 5.9 ± 2.7; median 7, IQR 4–8; p = 0.001), and T4 (11 patients; mean VAS of 3.6 ± 2.3; median 3, IQR 2–6; p = 0.004). At time of the last follow-up available for each patient, the mean pain intensity was of 4.8 ± 2.3 (median 5, IQR 3–6, p < 0.001, data not shown).
A similar trend in pain relief was observed also considering the use of rescue medications (Fig. 2C). At T0, the mean number of pills used per month was of 163.3 ± 156.3 (median 95, IQR 34–240). At T1, the use of rescue medications significantly decreased to a mean of 21.3 ± 29.6 pills per month (median 5, IQR 3–30, p < 0.001). Similarly, at T2, T3, and T4, the monthly intake of rescue medications was reduced to a mean of number of 36.4 ± 45.6 pills (median 15, IQR 5–60, p < 0.001), 30.3 ± 55.5 pills (median 8, IQR 4–20, p < 0.001), and 21.8 ± 34.3 pills (median 10, IQR 3–16, p = 0.003), respectively. At time of the last follow-up, the mean number of pills used per month was of 22.2 ± 29.2 (median 15, IQR 3–28, p < 0.001, data not shown).
Ten patients reported clinically relevant ADRs (from low to moderate grade), requiring LDM discontinuation. Specifically, five patients had nausea, three vomiting, and two had constipation. Nine patients who experienced an ADR dropped out early after LDM initiation (after a median time of 14 days, IQ 7–40), while one patient dropped out at month 11. All patients fully recovered after tapered interruption of LDM. No other ADRs were observed in our sample. No case of misuse or diversion was observed (data not shown).
Discussion
This is the first study evaluating the effectiveness and safety of LDM over a 12-month follow-up period, in patients affected by RCM with continuous headache and MOH in a real-world setting. As mentioned above, refractoriness may be diagnosed when a patient experiences ineffectiveness of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. Our results show that in patients affected by RCM, when tolerated, LDM is an effective option for the prevention of headache exacerbation, as well as for the reduction of pain intensity and consumption of rescue medications.
However, a significant portion of patients, despite an initial benefit from LDM, discontinued the treatment because of ADRs, although they were expected and non-serious. Even if the portion of patients developing nausea and vomiting was quite similar to that observed in other populations [20], our patients did not develop the expected tolerance to these ADRs. Accordingly, we cannot exclude that patients with migraine have a disease-related alteration (read as hypersensitivity) to these disturbances. This phenomenon, being nausea and vomiting the most frequent causes of LDM withdrawal in our population, deserves future investigation. Importantly, the median time to develop ADRs, being rather short (14 days) after therapy initiation, favored the safety profile as tapering of methadone was quick and easy. Altogether, our observations suggest that the optimization of the treatment, including either the association with or a formulation containing methylnaltrexone, which has been shown to be able to counteract the constipation [21], would relevantly increase the persistence on treatment, thus increasing the proportion of patients that might benefit from LDM. Another interesting result emerging from our population is that all patients experiencing ADR were female. An increased sensitivity to opioid-induced nausea and vomiting in women has been already reported [22–27], but the underlying mechanism is not known. In our study, the exclusive involvement of women may be due to the low number of participants that, however, per se discourages further subgroup analysis.
The impressive reduction of drug consumption observed in our study (from a median of 95 pills per month (IQR) (34–240) to 15 (3–28), p < 0.001) suggests that the initial medication overuse is mostly driven by the pain intensity. It is worth noting that this is at odds with the assumption that medication overuse in patients with migraine is mainly due to a genetic predisposition to substance abuse [28]. Indeed, when methadone is administered to patients with MOH according to a scheduled plan, it alleviates pain and drug consumption consequently falls. The fact that none of our patients misused methadone, notwithstanding its well-known abuse potential, further corroborates the hypothesis that RCM patients with MOH are not genetically predisposed drug abusers per se [28], but just deserve an efficacious pain treatment to defeat the vicious cycle that sustains medication overuse. However, as no conclusive evidence exists, it would be of paramount importance to dissect the mechanisms that drive the medication overuse in patients with migraine as this could significantly change the therapeutic approach to these patients.
It has been already reported that prescribing methadone for headache patients is neither glamorous nor lucrative and that it is a tedious process because of extensive patient education, controlled substance agreement, and meticulous record keeping [29]. However, the absence of suitable pharmacological alternatives for RCM associated with MOH is associated with an increased risk of ADRs due to overused medications and severe disability of patients who still seek medical attention after a number of therapeutic failures [29]. In this context, practitioners should consider LDM as a potential effective alternative for these patients. Currently, there are no restrictions for methadone prescriptions in Italy, since by the release of Law 38/2010 that specifically deals with the treatment of pain, it can be prescribed with the same modalities used for any other prescription drugs. Nonetheless, methadone prescription should still be reserved to specialists experienced in patients’ education and methadone handling. The opioid epidemics emerging in the United States, following to a well-meaning movement emerged in the United States 20 years ago to promote an adequate treatment of chronic pain with opioids and causing the death of almost half a million Americans from drug overdoses, suggests that more than caution is needed [30]. Despite the low rate of use of opioids in most European countries [31], the strict adherence to available guidelines that reserve opioids for headache patients only in selected cases [32] is both essential and mandatory to pursue an optimal management of LDM prophylaxis and to minimize the occurrence of overuse and ADRs.
Our results have several limitations. Unquestionably, the major limitation is the small sample size that is however due to the investigated condition. Considering the low frequency of the disease and the restrictedness of criteria that candidate a patient to the treatment, we had to deal with study premises resembling those of rare diseases, indeed. Although we planned a self-controlled study to maximize the internal validity of the study [33, 34], only initial evidence may emerge from observations in such a small population.
Another relevant drawback is the high rate of early treatment discontinuation, which significantly compromised the power of the study. It is worth noting that the study has a pragmatic approach and that the high portion of patients who discontinued the treatment represents the first valuable result of the study, indeed. On the one side, it suggests that only some weeks are needed to understand if patients will tolerate LDM. On the other side, as discontinuation was mainly due to gastrointestinal liability, we may hypothesize that innovative formulations of methadone will significantly decrease the number of patients who discontinue the treatment. Nevertheless, it is reasonable to consider that eligible enrolled patients were exclusively those non-responders to standard treatments, thus suggesting that LDM can represent a valid prophylactic approach in those refractory patients.
Conclusions
LDM may be an effective prophylactic alternative for patients affected by RCM with continuous headache associated with MOH refractory to standard treatments. In eligible patients, after a short initial trial to test tolerability, LDM may represent a simple and inexpensive way to bring relief and reduce headache medication overuse, although the frequency of early ADRs poses major safety concerns. Further research, including assessment of methadone plasma levels and pharmacogenetic profiling, are needed to understand factors that may influence the clinical response to LDM in RCM patients. In addition, randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open access funding provided by Università degli Studi di Firenze within the CRUI-CARE Agreement. The authors acknowledge Prof. Emanuela Masini, MD, for her expert advice, and Dr. Eleonora Rossi, MD, Headache Centre, Careggi University Hospital, Florence, as contributor (contributing participants). The authors are also grateful to Mary Lokken for her expert English language revision.
Authors’ contributions
SB and GM conceived and designed the study. SB, CL, FDC, VG, CP, and BO contributed to the acquisition of data. SB and AB contributed to the analysis of data. SB, CL, NL, AC, PG, and GM contributed to the interpretation of data. SB, NL, and AB drafted the manuscript. All authors critically revised and approved the manuscript.
Funding information
This study was not funded.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Ethics approval
The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA).
Consent to participate
An informed consent was obtained from all individual participants included in the study.
Consent for publication
Patients signed an informed consent regarding publishing their data, in an aggregated and anonymous form.
Code availability
Not applicable. | METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 32691178 | 18,722,654 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study.
OBJECTIVE
A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH.
METHODS
A prospective cohort study was performed between May 2012 and November 2015 at the Headache Center and Toxicology Unit of the Careggi University Hospital. Eligible patients were treated with prophylactic LDM and followed up for 12 months. Headache exacerbations, pain intensity, use of rescue medications, and occurrence of adverse drug reactions (ADRs) were recorded.
RESULTS
Thirty patients (24 females, median age 48 years) were enrolled. Nineteen (63%) patients dropped out, mainly because of early ADRs (n = 10), including nausea, vomiting, and constipation. At last available follow-up, LDM was associated with a significant decrease in the number of headache attacks/month (from a median of 45 (interquartile range 30-150) to 16 (5-30), p < 0.001), in pain intensity (from 8.5 (8-9) to 5 (3-6), p < 0.001), and in the number of rescue medications consumed per month (from 95 (34-240) to 15 (3-28), p < 0.001). No misuse or diversion cases were observed.
CONCLUSIONS
LDM could represent a valuable and effective option in selected patients affected by RCM with continuous headache and MOH, although the frequency of early ADRs poses major safety concerns. Randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Introduction
Chronic migraine is increasingly disabling, making patients with continuous headache the most disabled in the spectrum of chronic migraineurs [1]. Chronic migraine affects at least 1% of the general population [2], and refractoriness to treatments (RCM, refractory chronic migraine) [3] and medication-overuse headache (MOH) [1] often aggravate this condition. Even if there is no conclusive consensus on its definition, refractoriness is a clinically relevant phenomenon that refers to the failure of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. As the prophylaxis fails, the risk for the patient to experience medication overuse and, consequently, undergo MOH significantly increases. Importantly, even if the majority of patients who discontinued medication overuse substantially improve [5–8], drug discontinuation is not always sufficient for the reduction of headache attack frequency or intensity. In a considerable portion of patients, chronic pain and exposure to adverse drug reactions (ADRs), due to the intense consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and/or triptans, lead to a vicious cycle that progressively deteriorates patients’ health and quality of life.
Despite some drawbacks, including the potential for misuse and diversion and the risk of cognitive impairment, continuous opioid therapy represents a reasonable prophylactic option for patients affected by RCM with continuous headache and MOH [9]. In 2009, the American Pain Society proposed chronic headaches as one of the four chronic pain conditions where continuous opioid therapy might be taken into consideration [10]. According to the data from longitudinal studies and a long-standing experience with refractory patients and opioid schedules, guidelines for the selection of patients eligible to continuous opioid therapy have been proposed [11].
Little evidence is available regarding the preferred opioid schedules for RCM with continuous headache and MOH. Methadone, because of the peculiar pharmacological profile of its racemic mixture of (R)- and (S)-isomers, seems to be a better candidate compared with other opioids, in particular for its duration of action (long-acting opioid), with an analgesic effect that persists for 4–6 h [12]. Methadone has a mean bioavailability of about 80%, which is much higher than for the other opioid; in addition, it also has a long terminal half-life ranging from 7 to 65 h compared with other clinically used opioids [13]. Although metabolism and disposition are highly variable among subjects, the appropriate dosage tailoring allows to maximally benefit of the pharmacokinetic profile of methadone for patients’ treatment. Its primary analgesic effect is mediated by the agonism of the sole (R)-methadone on μ-opioid receptors. However, both isomers act as antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor [14], likely contributing to a reduced opioid tolerance [15] especially at low doses [16, 17]. The favorable profile of methadone in terms of reduced tolerance in comparison with other opioids is another key point for the administration of methadone for chronic pain therapy. Some preclinical evidence suggests it has an optimal profile regarding the ability to induce opioid receptor internalization that may explain this clinical phenomenon [18]. Despite its proven efficacy, methadone has a relevant potential for drug interactions and may be associated with serious ADRs, among which is the dose-independent prolongation of the QT interval [19] leading to rare but potentially fatal arrhythmias. Thus, the clinical use of methadone requires trained physicians, a careful education of patients, and a strict monitoring; nevertheless, the use of low dosages is recommended.
In this clinical context, the aim of the present study was to evaluate the effectiveness and safety, at 12 months of treatment, of low doses of methadone (LDM) in patients affected by RCM with continuous headache and MOH.
Methods
Study design and setting
A prospective cohort study was performed at the Headache Center and Toxicology Unit of the Careggi University Hospital. The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA). The study was performed following all the guidelines for observational studies with human subjects required by the institution with which all the authors are affiliated. A written informed consent for research was obtained from all participants.
Study population
Between May 2012 and November 2015, patients aged ≥ 30 years were screened at the Headache Center of Careggi University Hospital and, if diagnosed with RCM with continuous headache and MOH, were informed about the possibility of receiving prophylactic LDM. Only patients with refractory headache or with contraindications to the use of evidence-based interventions were eligible [11]. Patients were considered not eligible in case of contraindications to opioid treatment, including past addictive disease or serious mental illnesses [11]. Before starting the LDM, patients underwent a psychiatric evaluation in order to exclude lifetime diagnosis of schizophrenia or other psychiatric syndromes according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) [5] and clinical assessment, including electrocardiography (ECG) and urine drug screening. According to standard clinical practice, patients that resulted eligible after clinical screening were informed about possible drug-drug interactions related to methadone treatment. In order to avoid possible interactions and optimize treatment, an informative letter was sent to the general practitioner of each patient.
According to standard practice, patients should have their headache diary reporting data about their chronic migraine in the previous 3 months. Information reported in this diary included the number of rescue medications (including non-opioid analgesics, NSAIDs, and triptans) consumed per month, the number of days with headache per month, the number of headache exacerbations deserving pain relievers per month, and their intensity assessed every day by the visual analogue scale (VAS).
Data from the headache diaries were used as baseline values for study assessments. After signature of the informed consent, eligible patients were transferred to the Toxicology Unit, where all the clinical procedures and study follow-up visits were performed.
The baseline visit was conducted at T0 (i.e., day of LDM start). All treated patients were prescribed with standard prophylaxis (i.e., enriched fiber diet, physical activity, lactulose if needed) to prevent methadone-induced constipation. LDM started from 2 mg per day and was increased or administered in multiple daily doses according to clinical evaluation, since no dosing strategy for initiation of therapy and later uptitration have been validated. In our patients, maximal dose administered was 30 mg per day at T0. and 40 mg per day at T4.
Follow-up visits were planned at T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). The variability in the time interval between subsequent visits was due to the increased need of follow-up in the initial phases of the treatment, when titration of the methadone doses can still be critical.
Outcome evaluation
The primary outcome was headache exacerbations. The primary endpoint was the number of headache exacerbations per month requiring a pain reliever.
The secondary outcomes were the pain intensity and the need of rescue medications. The secondary endpoints were the changes in pain intensity, measured using the VAS, and the number of rescue medications consumed per month.
Safety outcomes included all ADRs occurred during LDM treatment. Namely, safety endpoints were the number and the grade of ADRs recorded. To this aim, ECG recordings were performed at T0, T1, and T4 in order to detect QTc changes possibly due to administration of LDM.
Statistical analysis
Data were reported as mean value ± standard deviation of the mean (SD) or as median value and related interquartile range (IQR), according to data distribution.
Effectiveness and safety endpoints were evaluated at T1, T2, T3, and T4 and compared with T0 using the Wilcoxon test for paired data. Furthermore, effectiveness and safety endpoints at T0 were compared with those obtained at last available follow-up, i.e., T1, T2, T3, or T4, according to patients’ data availability. Statistical significance was considered for p value < 0.05. An analysis was conducted using the software STATA version 14.
Results
Thirty patients were considered eligible for LDM and were further enrolled in the study. Of them, 24 were females (80.0%), with a median age of 48 years (41.2–54.2). Demographic and clinical characteristics of the enrolled cohort are detailed in Table 1.Table 1 Demographic and clinical data of patients treated with low-dose methadone (LDM)
Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48 (41.2–54.2)#
Female 24 (80.0)
Overused drug/s*
NSAIDs 28 (93.3)
Triptans 17 (56.7)
Opioids 17 (56.7)
Acetaminophen 11 (36.7)
Comorbidities
Anxiety 20 (66.7)
Arterial hypertension 9 (30.0)
Other pain conditions 7 (23.3)
*Some patients overused more than one drug
IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Focusing on the previous pharmacological treatment of headache, 93.3% of patients overused NSAIDs (n = 28), 17 (56.7%) overused triptans, and the other 17 overused opioids. Acetaminophen was overused by 11 patients (36.7%). Notably, patients assumed more than one drug class to treat headache exacerbations. Concerning failed prophylaxes, tricyclic antidepressants, calcium-channel blockers, and antiepileptics were reported as previous treatment by 73% of patients, while beta-blockers and onabotulinum toxin A by 67% of patients. Importantly, 40% of patients are reported to have been treated with at least four of the abovementioned drug classes, while 60% of patients have tried them all.
As for comorbidities, most patients suffered from anxiety (66.7%), whereas arterial hypertension and other pain conditions were reported in 30.0 and 23.3% of patients, respectively.
LDM was initiated during in-hospital stay (2–3 days) in 28 patients, while 2 patients started LDM in a day-hospital setting. An initial mean dose of methadone was 12 ± 4 mg (IQR 8–17 mg).
The demographic and clinical characteristics of patients are detailed in Table 2. Nineteen (63.3%) patients discontinued LDM. Specifically, five (16.7%) withdrew because of ineffectiveness, after a median time of 4.6 months (IQR 3.5–5.5). Although LDM treatment was effective, fourteen patients withdrew for other reasons. Among them, ten (33.3%) withdrew because of ADR; it is worth noting that all were female. Other three patients (10.0%) dropped out because of poor treatment confidence, while one patient moved to another country and was therefore lost to follow-up. Eleven patients (36.7%) were still on LDM treatment at the end of our study. The persistence on LDM treatment, distinguishing patients that developed an ADR (n = 10) from the others (n = 20), is shown in Fig. 1 (solid and dashed lines, respectively).Table 2 Demographic and clinical data of patients treated with low-dose methadone (LDM), grouped according to clinical outcomes
Patients with ongoing treatment Dropout
n = 11 Inefficacy
n = 5 ADRs
n = 10 Others
n = 4
Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48, 41–58 47, 28–64.5 49, 47.5–56.7 41.5, 39.5–51.7
Female 8 (72.7%) 3 (60%) 10 (100%) 3 (75%)
Prevalent headache type
Migraine 10 (90.9%) 4 (80%) 10 (100%) 2 (50%)
Tension-type headache 1 (9.1%) 0 (0%) 0 (0%) 2 (50%)
Cluster headache 0 (0%) 1 (20%) 0 (0%) 0 (0%)
Overused drug/s*
NSAIDs 10 (90.9%) 4 (80%) 10 (100%) 4 (100%)
Opioids 8 (72.7%) 1 (20%) 4 (40%) 4 (100%)
Acetaminophen 5 (45.4%) 1 (20%) 4 (40%) 1 (25%)
Serotonin receptor agonists 5 (45.4%) 4 (80%) 6 (60%) 2 (50%)
Comorbidities§
Anxiety 9 (81.8%) 2 (40%) 6 (60%) 3 (75%)
Arterial hypertension 3 (27.3%) 2 (40%) 4 (40%) 0 (0%)
Other pain conditions 3 (27.3%) 1 (20%) 2 (20%) 1 (25%)
*Some patients overused more than one drug.
§Some patients have more than one concomitant disease in addition to RCM
ADRs adverse drug reactions, IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Fig. 1 Time on treatment with low-dose methadone (LDM) of patients in 1 year of follow-up. Survival curves of patients that dropped out because of an ADR (continuous line) vs. all the other patients (still on treatment at month 12/dropouts for inefficacy/dropouts for personal reasons; dotted line). Importantly, most ADR patients dropped out early after LDM initiation (median time 14 days, IQ range 7–40). The curves are statistically different (log-rank Mantel-Cox test; P < 0.0001)
The effectiveness of LDM in terms of headache exacerbations, pain reduction, and use of rescue medications is described in Fig. 2. At time of start of LDM treatment (T0), the mean number of headache exacerbations per month requiring a pain reliever in the 30 enrolled patients was of 68.5 ± 60.4 (median 45, IQR 30–90) (Fig. 2A). At T1, the mean number of attacks requiring a pain reliever in the 25 observed patients significantly decreased to 15.9 ± 12.4 (median 9, IQR 5–30; p < 0.001). This significant reduction in the monthly number of headache exacerbations was confirmed also at the other time points of follow-up. Specifically, at T2, among the 19 patients for whom follow-up data were available, the mean number of attacks was of 24.8 ± 26.0 (median 30, IQR 7–30; p = 0.003). At T3, among the 15 observed patients, the mean of attacks was of 24.9 ± 29.2 (median 26, IQR 4–30; p = 0.002), and at T4, the mean number in the 11 observed patients was of 17.1 ± 11.4 (median 16, IQR 5–30; p = 0.003). At time of the last follow-up available for each patient (ranging from T1 to T4, n = 25), the mean number of headache attacks per month requiring a pain reliever was of 21.0 ± 23.6 (median 16, IQR 5–30, p < 0.001, data not shown).Fig. 2 Effectiveness of low-dose methadone (LDM) on headache attacks, pain intensity, and the use of rescue medications. LDM decreased the number of headache exacerbations deserving a pain reliever per month (A), pain intensity assessed by a visual analogue scale (VAS) (B), and the number of pills of rescue medications consumed per month (C) at different time points of follow-up (T0 (baseline), T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). Namely, the median number (interquartile range, IQR) of headache exacerbations per month was 45 (30–90) at T0, 9 (5–30) at T1, 30 (7–30) at T2, 26 (4–30) at T3, and 16 (5–30) at T4. The median VAS (IQR) was 8.5 (8–9) at T0, 5 (3–7) at T1, 5 (4–7) at T2, 7 (4–8) at T3, and 3 (2–6) at T4. The median number of pills of rescue medications (IQR) was 95 (34–240) at T0, 5 (3–30) at T1, 15 (5–60) at T2, 8 (4–20) at T3, and 10 (3–16) at T4
Considering pain intensity, the mean VAS score at T0 in the 30 enrolled patients was of 8.0 ± 2.0 (median 8.5, IQR 8–9) (Fig. 2B). At T1 (25 observed patients), the mean VAS score significantly decreased to 5.0 ± 2.4 (median 5.0, IQR 3–7; p < 0.001). This significant reduction in pain intensity was confirmed also at T2 (19 patients; mean VAS of 5.4 ± 2.3; median 5, IQR 4–7; p < 0.001), T3 (15 patients; mean VAS of 5.9 ± 2.7; median 7, IQR 4–8; p = 0.001), and T4 (11 patients; mean VAS of 3.6 ± 2.3; median 3, IQR 2–6; p = 0.004). At time of the last follow-up available for each patient, the mean pain intensity was of 4.8 ± 2.3 (median 5, IQR 3–6, p < 0.001, data not shown).
A similar trend in pain relief was observed also considering the use of rescue medications (Fig. 2C). At T0, the mean number of pills used per month was of 163.3 ± 156.3 (median 95, IQR 34–240). At T1, the use of rescue medications significantly decreased to a mean of 21.3 ± 29.6 pills per month (median 5, IQR 3–30, p < 0.001). Similarly, at T2, T3, and T4, the monthly intake of rescue medications was reduced to a mean of number of 36.4 ± 45.6 pills (median 15, IQR 5–60, p < 0.001), 30.3 ± 55.5 pills (median 8, IQR 4–20, p < 0.001), and 21.8 ± 34.3 pills (median 10, IQR 3–16, p = 0.003), respectively. At time of the last follow-up, the mean number of pills used per month was of 22.2 ± 29.2 (median 15, IQR 3–28, p < 0.001, data not shown).
Ten patients reported clinically relevant ADRs (from low to moderate grade), requiring LDM discontinuation. Specifically, five patients had nausea, three vomiting, and two had constipation. Nine patients who experienced an ADR dropped out early after LDM initiation (after a median time of 14 days, IQ 7–40), while one patient dropped out at month 11. All patients fully recovered after tapered interruption of LDM. No other ADRs were observed in our sample. No case of misuse or diversion was observed (data not shown).
Discussion
This is the first study evaluating the effectiveness and safety of LDM over a 12-month follow-up period, in patients affected by RCM with continuous headache and MOH in a real-world setting. As mentioned above, refractoriness may be diagnosed when a patient experiences ineffectiveness of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. Our results show that in patients affected by RCM, when tolerated, LDM is an effective option for the prevention of headache exacerbation, as well as for the reduction of pain intensity and consumption of rescue medications.
However, a significant portion of patients, despite an initial benefit from LDM, discontinued the treatment because of ADRs, although they were expected and non-serious. Even if the portion of patients developing nausea and vomiting was quite similar to that observed in other populations [20], our patients did not develop the expected tolerance to these ADRs. Accordingly, we cannot exclude that patients with migraine have a disease-related alteration (read as hypersensitivity) to these disturbances. This phenomenon, being nausea and vomiting the most frequent causes of LDM withdrawal in our population, deserves future investigation. Importantly, the median time to develop ADRs, being rather short (14 days) after therapy initiation, favored the safety profile as tapering of methadone was quick and easy. Altogether, our observations suggest that the optimization of the treatment, including either the association with or a formulation containing methylnaltrexone, which has been shown to be able to counteract the constipation [21], would relevantly increase the persistence on treatment, thus increasing the proportion of patients that might benefit from LDM. Another interesting result emerging from our population is that all patients experiencing ADR were female. An increased sensitivity to opioid-induced nausea and vomiting in women has been already reported [22–27], but the underlying mechanism is not known. In our study, the exclusive involvement of women may be due to the low number of participants that, however, per se discourages further subgroup analysis.
The impressive reduction of drug consumption observed in our study (from a median of 95 pills per month (IQR) (34–240) to 15 (3–28), p < 0.001) suggests that the initial medication overuse is mostly driven by the pain intensity. It is worth noting that this is at odds with the assumption that medication overuse in patients with migraine is mainly due to a genetic predisposition to substance abuse [28]. Indeed, when methadone is administered to patients with MOH according to a scheduled plan, it alleviates pain and drug consumption consequently falls. The fact that none of our patients misused methadone, notwithstanding its well-known abuse potential, further corroborates the hypothesis that RCM patients with MOH are not genetically predisposed drug abusers per se [28], but just deserve an efficacious pain treatment to defeat the vicious cycle that sustains medication overuse. However, as no conclusive evidence exists, it would be of paramount importance to dissect the mechanisms that drive the medication overuse in patients with migraine as this could significantly change the therapeutic approach to these patients.
It has been already reported that prescribing methadone for headache patients is neither glamorous nor lucrative and that it is a tedious process because of extensive patient education, controlled substance agreement, and meticulous record keeping [29]. However, the absence of suitable pharmacological alternatives for RCM associated with MOH is associated with an increased risk of ADRs due to overused medications and severe disability of patients who still seek medical attention after a number of therapeutic failures [29]. In this context, practitioners should consider LDM as a potential effective alternative for these patients. Currently, there are no restrictions for methadone prescriptions in Italy, since by the release of Law 38/2010 that specifically deals with the treatment of pain, it can be prescribed with the same modalities used for any other prescription drugs. Nonetheless, methadone prescription should still be reserved to specialists experienced in patients’ education and methadone handling. The opioid epidemics emerging in the United States, following to a well-meaning movement emerged in the United States 20 years ago to promote an adequate treatment of chronic pain with opioids and causing the death of almost half a million Americans from drug overdoses, suggests that more than caution is needed [30]. Despite the low rate of use of opioids in most European countries [31], the strict adherence to available guidelines that reserve opioids for headache patients only in selected cases [32] is both essential and mandatory to pursue an optimal management of LDM prophylaxis and to minimize the occurrence of overuse and ADRs.
Our results have several limitations. Unquestionably, the major limitation is the small sample size that is however due to the investigated condition. Considering the low frequency of the disease and the restrictedness of criteria that candidate a patient to the treatment, we had to deal with study premises resembling those of rare diseases, indeed. Although we planned a self-controlled study to maximize the internal validity of the study [33, 34], only initial evidence may emerge from observations in such a small population.
Another relevant drawback is the high rate of early treatment discontinuation, which significantly compromised the power of the study. It is worth noting that the study has a pragmatic approach and that the high portion of patients who discontinued the treatment represents the first valuable result of the study, indeed. On the one side, it suggests that only some weeks are needed to understand if patients will tolerate LDM. On the other side, as discontinuation was mainly due to gastrointestinal liability, we may hypothesize that innovative formulations of methadone will significantly decrease the number of patients who discontinue the treatment. Nevertheless, it is reasonable to consider that eligible enrolled patients were exclusively those non-responders to standard treatments, thus suggesting that LDM can represent a valid prophylactic approach in those refractory patients.
Conclusions
LDM may be an effective prophylactic alternative for patients affected by RCM with continuous headache associated with MOH refractory to standard treatments. In eligible patients, after a short initial trial to test tolerability, LDM may represent a simple and inexpensive way to bring relief and reduce headache medication overuse, although the frequency of early ADRs poses major safety concerns. Further research, including assessment of methadone plasma levels and pharmacogenetic profiling, are needed to understand factors that may influence the clinical response to LDM in RCM patients. In addition, randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open access funding provided by Università degli Studi di Firenze within the CRUI-CARE Agreement. The authors acknowledge Prof. Emanuela Masini, MD, for her expert advice, and Dr. Eleonora Rossi, MD, Headache Centre, Careggi University Hospital, Florence, as contributor (contributing participants). The authors are also grateful to Mary Lokken for her expert English language revision.
Authors’ contributions
SB and GM conceived and designed the study. SB, CL, FDC, VG, CP, and BO contributed to the acquisition of data. SB and AB contributed to the analysis of data. SB, CL, NL, AC, PG, and GM contributed to the interpretation of data. SB, NL, and AB drafted the manuscript. All authors critically revised and approved the manuscript.
Funding information
This study was not funded.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Ethics approval
The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA).
Consent to participate
An informed consent was obtained from all individual participants included in the study.
Consent for publication
Patients signed an informed consent regarding publishing their data, in an aggregated and anonymous form.
Code availability
Not applicable. | METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 32691178 | 18,722,657 | 2021-03 |
What was the outcome of reaction 'Constipation'? | Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study.
OBJECTIVE
A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH.
METHODS
A prospective cohort study was performed between May 2012 and November 2015 at the Headache Center and Toxicology Unit of the Careggi University Hospital. Eligible patients were treated with prophylactic LDM and followed up for 12 months. Headache exacerbations, pain intensity, use of rescue medications, and occurrence of adverse drug reactions (ADRs) were recorded.
RESULTS
Thirty patients (24 females, median age 48 years) were enrolled. Nineteen (63%) patients dropped out, mainly because of early ADRs (n = 10), including nausea, vomiting, and constipation. At last available follow-up, LDM was associated with a significant decrease in the number of headache attacks/month (from a median of 45 (interquartile range 30-150) to 16 (5-30), p < 0.001), in pain intensity (from 8.5 (8-9) to 5 (3-6), p < 0.001), and in the number of rescue medications consumed per month (from 95 (34-240) to 15 (3-28), p < 0.001). No misuse or diversion cases were observed.
CONCLUSIONS
LDM could represent a valuable and effective option in selected patients affected by RCM with continuous headache and MOH, although the frequency of early ADRs poses major safety concerns. Randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Introduction
Chronic migraine is increasingly disabling, making patients with continuous headache the most disabled in the spectrum of chronic migraineurs [1]. Chronic migraine affects at least 1% of the general population [2], and refractoriness to treatments (RCM, refractory chronic migraine) [3] and medication-overuse headache (MOH) [1] often aggravate this condition. Even if there is no conclusive consensus on its definition, refractoriness is a clinically relevant phenomenon that refers to the failure of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. As the prophylaxis fails, the risk for the patient to experience medication overuse and, consequently, undergo MOH significantly increases. Importantly, even if the majority of patients who discontinued medication overuse substantially improve [5–8], drug discontinuation is not always sufficient for the reduction of headache attack frequency or intensity. In a considerable portion of patients, chronic pain and exposure to adverse drug reactions (ADRs), due to the intense consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and/or triptans, lead to a vicious cycle that progressively deteriorates patients’ health and quality of life.
Despite some drawbacks, including the potential for misuse and diversion and the risk of cognitive impairment, continuous opioid therapy represents a reasonable prophylactic option for patients affected by RCM with continuous headache and MOH [9]. In 2009, the American Pain Society proposed chronic headaches as one of the four chronic pain conditions where continuous opioid therapy might be taken into consideration [10]. According to the data from longitudinal studies and a long-standing experience with refractory patients and opioid schedules, guidelines for the selection of patients eligible to continuous opioid therapy have been proposed [11].
Little evidence is available regarding the preferred opioid schedules for RCM with continuous headache and MOH. Methadone, because of the peculiar pharmacological profile of its racemic mixture of (R)- and (S)-isomers, seems to be a better candidate compared with other opioids, in particular for its duration of action (long-acting opioid), with an analgesic effect that persists for 4–6 h [12]. Methadone has a mean bioavailability of about 80%, which is much higher than for the other opioid; in addition, it also has a long terminal half-life ranging from 7 to 65 h compared with other clinically used opioids [13]. Although metabolism and disposition are highly variable among subjects, the appropriate dosage tailoring allows to maximally benefit of the pharmacokinetic profile of methadone for patients’ treatment. Its primary analgesic effect is mediated by the agonism of the sole (R)-methadone on μ-opioid receptors. However, both isomers act as antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor [14], likely contributing to a reduced opioid tolerance [15] especially at low doses [16, 17]. The favorable profile of methadone in terms of reduced tolerance in comparison with other opioids is another key point for the administration of methadone for chronic pain therapy. Some preclinical evidence suggests it has an optimal profile regarding the ability to induce opioid receptor internalization that may explain this clinical phenomenon [18]. Despite its proven efficacy, methadone has a relevant potential for drug interactions and may be associated with serious ADRs, among which is the dose-independent prolongation of the QT interval [19] leading to rare but potentially fatal arrhythmias. Thus, the clinical use of methadone requires trained physicians, a careful education of patients, and a strict monitoring; nevertheless, the use of low dosages is recommended.
In this clinical context, the aim of the present study was to evaluate the effectiveness and safety, at 12 months of treatment, of low doses of methadone (LDM) in patients affected by RCM with continuous headache and MOH.
Methods
Study design and setting
A prospective cohort study was performed at the Headache Center and Toxicology Unit of the Careggi University Hospital. The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA). The study was performed following all the guidelines for observational studies with human subjects required by the institution with which all the authors are affiliated. A written informed consent for research was obtained from all participants.
Study population
Between May 2012 and November 2015, patients aged ≥ 30 years were screened at the Headache Center of Careggi University Hospital and, if diagnosed with RCM with continuous headache and MOH, were informed about the possibility of receiving prophylactic LDM. Only patients with refractory headache or with contraindications to the use of evidence-based interventions were eligible [11]. Patients were considered not eligible in case of contraindications to opioid treatment, including past addictive disease or serious mental illnesses [11]. Before starting the LDM, patients underwent a psychiatric evaluation in order to exclude lifetime diagnosis of schizophrenia or other psychiatric syndromes according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) [5] and clinical assessment, including electrocardiography (ECG) and urine drug screening. According to standard clinical practice, patients that resulted eligible after clinical screening were informed about possible drug-drug interactions related to methadone treatment. In order to avoid possible interactions and optimize treatment, an informative letter was sent to the general practitioner of each patient.
According to standard practice, patients should have their headache diary reporting data about their chronic migraine in the previous 3 months. Information reported in this diary included the number of rescue medications (including non-opioid analgesics, NSAIDs, and triptans) consumed per month, the number of days with headache per month, the number of headache exacerbations deserving pain relievers per month, and their intensity assessed every day by the visual analogue scale (VAS).
Data from the headache diaries were used as baseline values for study assessments. After signature of the informed consent, eligible patients were transferred to the Toxicology Unit, where all the clinical procedures and study follow-up visits were performed.
The baseline visit was conducted at T0 (i.e., day of LDM start). All treated patients were prescribed with standard prophylaxis (i.e., enriched fiber diet, physical activity, lactulose if needed) to prevent methadone-induced constipation. LDM started from 2 mg per day and was increased or administered in multiple daily doses according to clinical evaluation, since no dosing strategy for initiation of therapy and later uptitration have been validated. In our patients, maximal dose administered was 30 mg per day at T0. and 40 mg per day at T4.
Follow-up visits were planned at T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). The variability in the time interval between subsequent visits was due to the increased need of follow-up in the initial phases of the treatment, when titration of the methadone doses can still be critical.
Outcome evaluation
The primary outcome was headache exacerbations. The primary endpoint was the number of headache exacerbations per month requiring a pain reliever.
The secondary outcomes were the pain intensity and the need of rescue medications. The secondary endpoints were the changes in pain intensity, measured using the VAS, and the number of rescue medications consumed per month.
Safety outcomes included all ADRs occurred during LDM treatment. Namely, safety endpoints were the number and the grade of ADRs recorded. To this aim, ECG recordings were performed at T0, T1, and T4 in order to detect QTc changes possibly due to administration of LDM.
Statistical analysis
Data were reported as mean value ± standard deviation of the mean (SD) or as median value and related interquartile range (IQR), according to data distribution.
Effectiveness and safety endpoints were evaluated at T1, T2, T3, and T4 and compared with T0 using the Wilcoxon test for paired data. Furthermore, effectiveness and safety endpoints at T0 were compared with those obtained at last available follow-up, i.e., T1, T2, T3, or T4, according to patients’ data availability. Statistical significance was considered for p value < 0.05. An analysis was conducted using the software STATA version 14.
Results
Thirty patients were considered eligible for LDM and were further enrolled in the study. Of them, 24 were females (80.0%), with a median age of 48 years (41.2–54.2). Demographic and clinical characteristics of the enrolled cohort are detailed in Table 1.Table 1 Demographic and clinical data of patients treated with low-dose methadone (LDM)
Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48 (41.2–54.2)#
Female 24 (80.0)
Overused drug/s*
NSAIDs 28 (93.3)
Triptans 17 (56.7)
Opioids 17 (56.7)
Acetaminophen 11 (36.7)
Comorbidities
Anxiety 20 (66.7)
Arterial hypertension 9 (30.0)
Other pain conditions 7 (23.3)
*Some patients overused more than one drug
IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Focusing on the previous pharmacological treatment of headache, 93.3% of patients overused NSAIDs (n = 28), 17 (56.7%) overused triptans, and the other 17 overused opioids. Acetaminophen was overused by 11 patients (36.7%). Notably, patients assumed more than one drug class to treat headache exacerbations. Concerning failed prophylaxes, tricyclic antidepressants, calcium-channel blockers, and antiepileptics were reported as previous treatment by 73% of patients, while beta-blockers and onabotulinum toxin A by 67% of patients. Importantly, 40% of patients are reported to have been treated with at least four of the abovementioned drug classes, while 60% of patients have tried them all.
As for comorbidities, most patients suffered from anxiety (66.7%), whereas arterial hypertension and other pain conditions were reported in 30.0 and 23.3% of patients, respectively.
LDM was initiated during in-hospital stay (2–3 days) in 28 patients, while 2 patients started LDM in a day-hospital setting. An initial mean dose of methadone was 12 ± 4 mg (IQR 8–17 mg).
The demographic and clinical characteristics of patients are detailed in Table 2. Nineteen (63.3%) patients discontinued LDM. Specifically, five (16.7%) withdrew because of ineffectiveness, after a median time of 4.6 months (IQR 3.5–5.5). Although LDM treatment was effective, fourteen patients withdrew for other reasons. Among them, ten (33.3%) withdrew because of ADR; it is worth noting that all were female. Other three patients (10.0%) dropped out because of poor treatment confidence, while one patient moved to another country and was therefore lost to follow-up. Eleven patients (36.7%) were still on LDM treatment at the end of our study. The persistence on LDM treatment, distinguishing patients that developed an ADR (n = 10) from the others (n = 20), is shown in Fig. 1 (solid and dashed lines, respectively).Table 2 Demographic and clinical data of patients treated with low-dose methadone (LDM), grouped according to clinical outcomes
Patients with ongoing treatment Dropout
n = 11 Inefficacy
n = 5 ADRs
n = 10 Others
n = 4
Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48, 41–58 47, 28–64.5 49, 47.5–56.7 41.5, 39.5–51.7
Female 8 (72.7%) 3 (60%) 10 (100%) 3 (75%)
Prevalent headache type
Migraine 10 (90.9%) 4 (80%) 10 (100%) 2 (50%)
Tension-type headache 1 (9.1%) 0 (0%) 0 (0%) 2 (50%)
Cluster headache 0 (0%) 1 (20%) 0 (0%) 0 (0%)
Overused drug/s*
NSAIDs 10 (90.9%) 4 (80%) 10 (100%) 4 (100%)
Opioids 8 (72.7%) 1 (20%) 4 (40%) 4 (100%)
Acetaminophen 5 (45.4%) 1 (20%) 4 (40%) 1 (25%)
Serotonin receptor agonists 5 (45.4%) 4 (80%) 6 (60%) 2 (50%)
Comorbidities§
Anxiety 9 (81.8%) 2 (40%) 6 (60%) 3 (75%)
Arterial hypertension 3 (27.3%) 2 (40%) 4 (40%) 0 (0%)
Other pain conditions 3 (27.3%) 1 (20%) 2 (20%) 1 (25%)
*Some patients overused more than one drug.
§Some patients have more than one concomitant disease in addition to RCM
ADRs adverse drug reactions, IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Fig. 1 Time on treatment with low-dose methadone (LDM) of patients in 1 year of follow-up. Survival curves of patients that dropped out because of an ADR (continuous line) vs. all the other patients (still on treatment at month 12/dropouts for inefficacy/dropouts for personal reasons; dotted line). Importantly, most ADR patients dropped out early after LDM initiation (median time 14 days, IQ range 7–40). The curves are statistically different (log-rank Mantel-Cox test; P < 0.0001)
The effectiveness of LDM in terms of headache exacerbations, pain reduction, and use of rescue medications is described in Fig. 2. At time of start of LDM treatment (T0), the mean number of headache exacerbations per month requiring a pain reliever in the 30 enrolled patients was of 68.5 ± 60.4 (median 45, IQR 30–90) (Fig. 2A). At T1, the mean number of attacks requiring a pain reliever in the 25 observed patients significantly decreased to 15.9 ± 12.4 (median 9, IQR 5–30; p < 0.001). This significant reduction in the monthly number of headache exacerbations was confirmed also at the other time points of follow-up. Specifically, at T2, among the 19 patients for whom follow-up data were available, the mean number of attacks was of 24.8 ± 26.0 (median 30, IQR 7–30; p = 0.003). At T3, among the 15 observed patients, the mean of attacks was of 24.9 ± 29.2 (median 26, IQR 4–30; p = 0.002), and at T4, the mean number in the 11 observed patients was of 17.1 ± 11.4 (median 16, IQR 5–30; p = 0.003). At time of the last follow-up available for each patient (ranging from T1 to T4, n = 25), the mean number of headache attacks per month requiring a pain reliever was of 21.0 ± 23.6 (median 16, IQR 5–30, p < 0.001, data not shown).Fig. 2 Effectiveness of low-dose methadone (LDM) on headache attacks, pain intensity, and the use of rescue medications. LDM decreased the number of headache exacerbations deserving a pain reliever per month (A), pain intensity assessed by a visual analogue scale (VAS) (B), and the number of pills of rescue medications consumed per month (C) at different time points of follow-up (T0 (baseline), T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). Namely, the median number (interquartile range, IQR) of headache exacerbations per month was 45 (30–90) at T0, 9 (5–30) at T1, 30 (7–30) at T2, 26 (4–30) at T3, and 16 (5–30) at T4. The median VAS (IQR) was 8.5 (8–9) at T0, 5 (3–7) at T1, 5 (4–7) at T2, 7 (4–8) at T3, and 3 (2–6) at T4. The median number of pills of rescue medications (IQR) was 95 (34–240) at T0, 5 (3–30) at T1, 15 (5–60) at T2, 8 (4–20) at T3, and 10 (3–16) at T4
Considering pain intensity, the mean VAS score at T0 in the 30 enrolled patients was of 8.0 ± 2.0 (median 8.5, IQR 8–9) (Fig. 2B). At T1 (25 observed patients), the mean VAS score significantly decreased to 5.0 ± 2.4 (median 5.0, IQR 3–7; p < 0.001). This significant reduction in pain intensity was confirmed also at T2 (19 patients; mean VAS of 5.4 ± 2.3; median 5, IQR 4–7; p < 0.001), T3 (15 patients; mean VAS of 5.9 ± 2.7; median 7, IQR 4–8; p = 0.001), and T4 (11 patients; mean VAS of 3.6 ± 2.3; median 3, IQR 2–6; p = 0.004). At time of the last follow-up available for each patient, the mean pain intensity was of 4.8 ± 2.3 (median 5, IQR 3–6, p < 0.001, data not shown).
A similar trend in pain relief was observed also considering the use of rescue medications (Fig. 2C). At T0, the mean number of pills used per month was of 163.3 ± 156.3 (median 95, IQR 34–240). At T1, the use of rescue medications significantly decreased to a mean of 21.3 ± 29.6 pills per month (median 5, IQR 3–30, p < 0.001). Similarly, at T2, T3, and T4, the monthly intake of rescue medications was reduced to a mean of number of 36.4 ± 45.6 pills (median 15, IQR 5–60, p < 0.001), 30.3 ± 55.5 pills (median 8, IQR 4–20, p < 0.001), and 21.8 ± 34.3 pills (median 10, IQR 3–16, p = 0.003), respectively. At time of the last follow-up, the mean number of pills used per month was of 22.2 ± 29.2 (median 15, IQR 3–28, p < 0.001, data not shown).
Ten patients reported clinically relevant ADRs (from low to moderate grade), requiring LDM discontinuation. Specifically, five patients had nausea, three vomiting, and two had constipation. Nine patients who experienced an ADR dropped out early after LDM initiation (after a median time of 14 days, IQ 7–40), while one patient dropped out at month 11. All patients fully recovered after tapered interruption of LDM. No other ADRs were observed in our sample. No case of misuse or diversion was observed (data not shown).
Discussion
This is the first study evaluating the effectiveness and safety of LDM over a 12-month follow-up period, in patients affected by RCM with continuous headache and MOH in a real-world setting. As mentioned above, refractoriness may be diagnosed when a patient experiences ineffectiveness of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. Our results show that in patients affected by RCM, when tolerated, LDM is an effective option for the prevention of headache exacerbation, as well as for the reduction of pain intensity and consumption of rescue medications.
However, a significant portion of patients, despite an initial benefit from LDM, discontinued the treatment because of ADRs, although they were expected and non-serious. Even if the portion of patients developing nausea and vomiting was quite similar to that observed in other populations [20], our patients did not develop the expected tolerance to these ADRs. Accordingly, we cannot exclude that patients with migraine have a disease-related alteration (read as hypersensitivity) to these disturbances. This phenomenon, being nausea and vomiting the most frequent causes of LDM withdrawal in our population, deserves future investigation. Importantly, the median time to develop ADRs, being rather short (14 days) after therapy initiation, favored the safety profile as tapering of methadone was quick and easy. Altogether, our observations suggest that the optimization of the treatment, including either the association with or a formulation containing methylnaltrexone, which has been shown to be able to counteract the constipation [21], would relevantly increase the persistence on treatment, thus increasing the proportion of patients that might benefit from LDM. Another interesting result emerging from our population is that all patients experiencing ADR were female. An increased sensitivity to opioid-induced nausea and vomiting in women has been already reported [22–27], but the underlying mechanism is not known. In our study, the exclusive involvement of women may be due to the low number of participants that, however, per se discourages further subgroup analysis.
The impressive reduction of drug consumption observed in our study (from a median of 95 pills per month (IQR) (34–240) to 15 (3–28), p < 0.001) suggests that the initial medication overuse is mostly driven by the pain intensity. It is worth noting that this is at odds with the assumption that medication overuse in patients with migraine is mainly due to a genetic predisposition to substance abuse [28]. Indeed, when methadone is administered to patients with MOH according to a scheduled plan, it alleviates pain and drug consumption consequently falls. The fact that none of our patients misused methadone, notwithstanding its well-known abuse potential, further corroborates the hypothesis that RCM patients with MOH are not genetically predisposed drug abusers per se [28], but just deserve an efficacious pain treatment to defeat the vicious cycle that sustains medication overuse. However, as no conclusive evidence exists, it would be of paramount importance to dissect the mechanisms that drive the medication overuse in patients with migraine as this could significantly change the therapeutic approach to these patients.
It has been already reported that prescribing methadone for headache patients is neither glamorous nor lucrative and that it is a tedious process because of extensive patient education, controlled substance agreement, and meticulous record keeping [29]. However, the absence of suitable pharmacological alternatives for RCM associated with MOH is associated with an increased risk of ADRs due to overused medications and severe disability of patients who still seek medical attention after a number of therapeutic failures [29]. In this context, practitioners should consider LDM as a potential effective alternative for these patients. Currently, there are no restrictions for methadone prescriptions in Italy, since by the release of Law 38/2010 that specifically deals with the treatment of pain, it can be prescribed with the same modalities used for any other prescription drugs. Nonetheless, methadone prescription should still be reserved to specialists experienced in patients’ education and methadone handling. The opioid epidemics emerging in the United States, following to a well-meaning movement emerged in the United States 20 years ago to promote an adequate treatment of chronic pain with opioids and causing the death of almost half a million Americans from drug overdoses, suggests that more than caution is needed [30]. Despite the low rate of use of opioids in most European countries [31], the strict adherence to available guidelines that reserve opioids for headache patients only in selected cases [32] is both essential and mandatory to pursue an optimal management of LDM prophylaxis and to minimize the occurrence of overuse and ADRs.
Our results have several limitations. Unquestionably, the major limitation is the small sample size that is however due to the investigated condition. Considering the low frequency of the disease and the restrictedness of criteria that candidate a patient to the treatment, we had to deal with study premises resembling those of rare diseases, indeed. Although we planned a self-controlled study to maximize the internal validity of the study [33, 34], only initial evidence may emerge from observations in such a small population.
Another relevant drawback is the high rate of early treatment discontinuation, which significantly compromised the power of the study. It is worth noting that the study has a pragmatic approach and that the high portion of patients who discontinued the treatment represents the first valuable result of the study, indeed. On the one side, it suggests that only some weeks are needed to understand if patients will tolerate LDM. On the other side, as discontinuation was mainly due to gastrointestinal liability, we may hypothesize that innovative formulations of methadone will significantly decrease the number of patients who discontinue the treatment. Nevertheless, it is reasonable to consider that eligible enrolled patients were exclusively those non-responders to standard treatments, thus suggesting that LDM can represent a valid prophylactic approach in those refractory patients.
Conclusions
LDM may be an effective prophylactic alternative for patients affected by RCM with continuous headache associated with MOH refractory to standard treatments. In eligible patients, after a short initial trial to test tolerability, LDM may represent a simple and inexpensive way to bring relief and reduce headache medication overuse, although the frequency of early ADRs poses major safety concerns. Further research, including assessment of methadone plasma levels and pharmacogenetic profiling, are needed to understand factors that may influence the clinical response to LDM in RCM patients. In addition, randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open access funding provided by Università degli Studi di Firenze within the CRUI-CARE Agreement. The authors acknowledge Prof. Emanuela Masini, MD, for her expert advice, and Dr. Eleonora Rossi, MD, Headache Centre, Careggi University Hospital, Florence, as contributor (contributing participants). The authors are also grateful to Mary Lokken for her expert English language revision.
Authors’ contributions
SB and GM conceived and designed the study. SB, CL, FDC, VG, CP, and BO contributed to the acquisition of data. SB and AB contributed to the analysis of data. SB, CL, NL, AC, PG, and GM contributed to the interpretation of data. SB, NL, and AB drafted the manuscript. All authors critically revised and approved the manuscript.
Funding information
This study was not funded.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Ethics approval
The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA).
Consent to participate
An informed consent was obtained from all individual participants included in the study.
Consent for publication
Patients signed an informed consent regarding publishing their data, in an aggregated and anonymous form.
Code availability
Not applicable. | Recovered | ReactionOutcome | CC BY | 32691178 | 18,727,749 | 2021-03 |
What was the outcome of reaction 'Nausea'? | Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study.
OBJECTIVE
A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH.
METHODS
A prospective cohort study was performed between May 2012 and November 2015 at the Headache Center and Toxicology Unit of the Careggi University Hospital. Eligible patients were treated with prophylactic LDM and followed up for 12 months. Headache exacerbations, pain intensity, use of rescue medications, and occurrence of adverse drug reactions (ADRs) were recorded.
RESULTS
Thirty patients (24 females, median age 48 years) were enrolled. Nineteen (63%) patients dropped out, mainly because of early ADRs (n = 10), including nausea, vomiting, and constipation. At last available follow-up, LDM was associated with a significant decrease in the number of headache attacks/month (from a median of 45 (interquartile range 30-150) to 16 (5-30), p < 0.001), in pain intensity (from 8.5 (8-9) to 5 (3-6), p < 0.001), and in the number of rescue medications consumed per month (from 95 (34-240) to 15 (3-28), p < 0.001). No misuse or diversion cases were observed.
CONCLUSIONS
LDM could represent a valuable and effective option in selected patients affected by RCM with continuous headache and MOH, although the frequency of early ADRs poses major safety concerns. Randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Introduction
Chronic migraine is increasingly disabling, making patients with continuous headache the most disabled in the spectrum of chronic migraineurs [1]. Chronic migraine affects at least 1% of the general population [2], and refractoriness to treatments (RCM, refractory chronic migraine) [3] and medication-overuse headache (MOH) [1] often aggravate this condition. Even if there is no conclusive consensus on its definition, refractoriness is a clinically relevant phenomenon that refers to the failure of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. As the prophylaxis fails, the risk for the patient to experience medication overuse and, consequently, undergo MOH significantly increases. Importantly, even if the majority of patients who discontinued medication overuse substantially improve [5–8], drug discontinuation is not always sufficient for the reduction of headache attack frequency or intensity. In a considerable portion of patients, chronic pain and exposure to adverse drug reactions (ADRs), due to the intense consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and/or triptans, lead to a vicious cycle that progressively deteriorates patients’ health and quality of life.
Despite some drawbacks, including the potential for misuse and diversion and the risk of cognitive impairment, continuous opioid therapy represents a reasonable prophylactic option for patients affected by RCM with continuous headache and MOH [9]. In 2009, the American Pain Society proposed chronic headaches as one of the four chronic pain conditions where continuous opioid therapy might be taken into consideration [10]. According to the data from longitudinal studies and a long-standing experience with refractory patients and opioid schedules, guidelines for the selection of patients eligible to continuous opioid therapy have been proposed [11].
Little evidence is available regarding the preferred opioid schedules for RCM with continuous headache and MOH. Methadone, because of the peculiar pharmacological profile of its racemic mixture of (R)- and (S)-isomers, seems to be a better candidate compared with other opioids, in particular for its duration of action (long-acting opioid), with an analgesic effect that persists for 4–6 h [12]. Methadone has a mean bioavailability of about 80%, which is much higher than for the other opioid; in addition, it also has a long terminal half-life ranging from 7 to 65 h compared with other clinically used opioids [13]. Although metabolism and disposition are highly variable among subjects, the appropriate dosage tailoring allows to maximally benefit of the pharmacokinetic profile of methadone for patients’ treatment. Its primary analgesic effect is mediated by the agonism of the sole (R)-methadone on μ-opioid receptors. However, both isomers act as antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor [14], likely contributing to a reduced opioid tolerance [15] especially at low doses [16, 17]. The favorable profile of methadone in terms of reduced tolerance in comparison with other opioids is another key point for the administration of methadone for chronic pain therapy. Some preclinical evidence suggests it has an optimal profile regarding the ability to induce opioid receptor internalization that may explain this clinical phenomenon [18]. Despite its proven efficacy, methadone has a relevant potential for drug interactions and may be associated with serious ADRs, among which is the dose-independent prolongation of the QT interval [19] leading to rare but potentially fatal arrhythmias. Thus, the clinical use of methadone requires trained physicians, a careful education of patients, and a strict monitoring; nevertheless, the use of low dosages is recommended.
In this clinical context, the aim of the present study was to evaluate the effectiveness and safety, at 12 months of treatment, of low doses of methadone (LDM) in patients affected by RCM with continuous headache and MOH.
Methods
Study design and setting
A prospective cohort study was performed at the Headache Center and Toxicology Unit of the Careggi University Hospital. The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA). The study was performed following all the guidelines for observational studies with human subjects required by the institution with which all the authors are affiliated. A written informed consent for research was obtained from all participants.
Study population
Between May 2012 and November 2015, patients aged ≥ 30 years were screened at the Headache Center of Careggi University Hospital and, if diagnosed with RCM with continuous headache and MOH, were informed about the possibility of receiving prophylactic LDM. Only patients with refractory headache or with contraindications to the use of evidence-based interventions were eligible [11]. Patients were considered not eligible in case of contraindications to opioid treatment, including past addictive disease or serious mental illnesses [11]. Before starting the LDM, patients underwent a psychiatric evaluation in order to exclude lifetime diagnosis of schizophrenia or other psychiatric syndromes according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) [5] and clinical assessment, including electrocardiography (ECG) and urine drug screening. According to standard clinical practice, patients that resulted eligible after clinical screening were informed about possible drug-drug interactions related to methadone treatment. In order to avoid possible interactions and optimize treatment, an informative letter was sent to the general practitioner of each patient.
According to standard practice, patients should have their headache diary reporting data about their chronic migraine in the previous 3 months. Information reported in this diary included the number of rescue medications (including non-opioid analgesics, NSAIDs, and triptans) consumed per month, the number of days with headache per month, the number of headache exacerbations deserving pain relievers per month, and their intensity assessed every day by the visual analogue scale (VAS).
Data from the headache diaries were used as baseline values for study assessments. After signature of the informed consent, eligible patients were transferred to the Toxicology Unit, where all the clinical procedures and study follow-up visits were performed.
The baseline visit was conducted at T0 (i.e., day of LDM start). All treated patients were prescribed with standard prophylaxis (i.e., enriched fiber diet, physical activity, lactulose if needed) to prevent methadone-induced constipation. LDM started from 2 mg per day and was increased or administered in multiple daily doses according to clinical evaluation, since no dosing strategy for initiation of therapy and later uptitration have been validated. In our patients, maximal dose administered was 30 mg per day at T0. and 40 mg per day at T4.
Follow-up visits were planned at T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). The variability in the time interval between subsequent visits was due to the increased need of follow-up in the initial phases of the treatment, when titration of the methadone doses can still be critical.
Outcome evaluation
The primary outcome was headache exacerbations. The primary endpoint was the number of headache exacerbations per month requiring a pain reliever.
The secondary outcomes were the pain intensity and the need of rescue medications. The secondary endpoints were the changes in pain intensity, measured using the VAS, and the number of rescue medications consumed per month.
Safety outcomes included all ADRs occurred during LDM treatment. Namely, safety endpoints were the number and the grade of ADRs recorded. To this aim, ECG recordings were performed at T0, T1, and T4 in order to detect QTc changes possibly due to administration of LDM.
Statistical analysis
Data were reported as mean value ± standard deviation of the mean (SD) or as median value and related interquartile range (IQR), according to data distribution.
Effectiveness and safety endpoints were evaluated at T1, T2, T3, and T4 and compared with T0 using the Wilcoxon test for paired data. Furthermore, effectiveness and safety endpoints at T0 were compared with those obtained at last available follow-up, i.e., T1, T2, T3, or T4, according to patients’ data availability. Statistical significance was considered for p value < 0.05. An analysis was conducted using the software STATA version 14.
Results
Thirty patients were considered eligible for LDM and were further enrolled in the study. Of them, 24 were females (80.0%), with a median age of 48 years (41.2–54.2). Demographic and clinical characteristics of the enrolled cohort are detailed in Table 1.Table 1 Demographic and clinical data of patients treated with low-dose methadone (LDM)
Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48 (41.2–54.2)#
Female 24 (80.0)
Overused drug/s*
NSAIDs 28 (93.3)
Triptans 17 (56.7)
Opioids 17 (56.7)
Acetaminophen 11 (36.7)
Comorbidities
Anxiety 20 (66.7)
Arterial hypertension 9 (30.0)
Other pain conditions 7 (23.3)
*Some patients overused more than one drug
IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Focusing on the previous pharmacological treatment of headache, 93.3% of patients overused NSAIDs (n = 28), 17 (56.7%) overused triptans, and the other 17 overused opioids. Acetaminophen was overused by 11 patients (36.7%). Notably, patients assumed more than one drug class to treat headache exacerbations. Concerning failed prophylaxes, tricyclic antidepressants, calcium-channel blockers, and antiepileptics were reported as previous treatment by 73% of patients, while beta-blockers and onabotulinum toxin A by 67% of patients. Importantly, 40% of patients are reported to have been treated with at least four of the abovementioned drug classes, while 60% of patients have tried them all.
As for comorbidities, most patients suffered from anxiety (66.7%), whereas arterial hypertension and other pain conditions were reported in 30.0 and 23.3% of patients, respectively.
LDM was initiated during in-hospital stay (2–3 days) in 28 patients, while 2 patients started LDM in a day-hospital setting. An initial mean dose of methadone was 12 ± 4 mg (IQR 8–17 mg).
The demographic and clinical characteristics of patients are detailed in Table 2. Nineteen (63.3%) patients discontinued LDM. Specifically, five (16.7%) withdrew because of ineffectiveness, after a median time of 4.6 months (IQR 3.5–5.5). Although LDM treatment was effective, fourteen patients withdrew for other reasons. Among them, ten (33.3%) withdrew because of ADR; it is worth noting that all were female. Other three patients (10.0%) dropped out because of poor treatment confidence, while one patient moved to another country and was therefore lost to follow-up. Eleven patients (36.7%) were still on LDM treatment at the end of our study. The persistence on LDM treatment, distinguishing patients that developed an ADR (n = 10) from the others (n = 20), is shown in Fig. 1 (solid and dashed lines, respectively).Table 2 Demographic and clinical data of patients treated with low-dose methadone (LDM), grouped according to clinical outcomes
Patients with ongoing treatment Dropout
n = 11 Inefficacy
n = 5 ADRs
n = 10 Others
n = 4
Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48, 41–58 47, 28–64.5 49, 47.5–56.7 41.5, 39.5–51.7
Female 8 (72.7%) 3 (60%) 10 (100%) 3 (75%)
Prevalent headache type
Migraine 10 (90.9%) 4 (80%) 10 (100%) 2 (50%)
Tension-type headache 1 (9.1%) 0 (0%) 0 (0%) 2 (50%)
Cluster headache 0 (0%) 1 (20%) 0 (0%) 0 (0%)
Overused drug/s*
NSAIDs 10 (90.9%) 4 (80%) 10 (100%) 4 (100%)
Opioids 8 (72.7%) 1 (20%) 4 (40%) 4 (100%)
Acetaminophen 5 (45.4%) 1 (20%) 4 (40%) 1 (25%)
Serotonin receptor agonists 5 (45.4%) 4 (80%) 6 (60%) 2 (50%)
Comorbidities§
Anxiety 9 (81.8%) 2 (40%) 6 (60%) 3 (75%)
Arterial hypertension 3 (27.3%) 2 (40%) 4 (40%) 0 (0%)
Other pain conditions 3 (27.3%) 1 (20%) 2 (20%) 1 (25%)
*Some patients overused more than one drug.
§Some patients have more than one concomitant disease in addition to RCM
ADRs adverse drug reactions, IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Fig. 1 Time on treatment with low-dose methadone (LDM) of patients in 1 year of follow-up. Survival curves of patients that dropped out because of an ADR (continuous line) vs. all the other patients (still on treatment at month 12/dropouts for inefficacy/dropouts for personal reasons; dotted line). Importantly, most ADR patients dropped out early after LDM initiation (median time 14 days, IQ range 7–40). The curves are statistically different (log-rank Mantel-Cox test; P < 0.0001)
The effectiveness of LDM in terms of headache exacerbations, pain reduction, and use of rescue medications is described in Fig. 2. At time of start of LDM treatment (T0), the mean number of headache exacerbations per month requiring a pain reliever in the 30 enrolled patients was of 68.5 ± 60.4 (median 45, IQR 30–90) (Fig. 2A). At T1, the mean number of attacks requiring a pain reliever in the 25 observed patients significantly decreased to 15.9 ± 12.4 (median 9, IQR 5–30; p < 0.001). This significant reduction in the monthly number of headache exacerbations was confirmed also at the other time points of follow-up. Specifically, at T2, among the 19 patients for whom follow-up data were available, the mean number of attacks was of 24.8 ± 26.0 (median 30, IQR 7–30; p = 0.003). At T3, among the 15 observed patients, the mean of attacks was of 24.9 ± 29.2 (median 26, IQR 4–30; p = 0.002), and at T4, the mean number in the 11 observed patients was of 17.1 ± 11.4 (median 16, IQR 5–30; p = 0.003). At time of the last follow-up available for each patient (ranging from T1 to T4, n = 25), the mean number of headache attacks per month requiring a pain reliever was of 21.0 ± 23.6 (median 16, IQR 5–30, p < 0.001, data not shown).Fig. 2 Effectiveness of low-dose methadone (LDM) on headache attacks, pain intensity, and the use of rescue medications. LDM decreased the number of headache exacerbations deserving a pain reliever per month (A), pain intensity assessed by a visual analogue scale (VAS) (B), and the number of pills of rescue medications consumed per month (C) at different time points of follow-up (T0 (baseline), T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). Namely, the median number (interquartile range, IQR) of headache exacerbations per month was 45 (30–90) at T0, 9 (5–30) at T1, 30 (7–30) at T2, 26 (4–30) at T3, and 16 (5–30) at T4. The median VAS (IQR) was 8.5 (8–9) at T0, 5 (3–7) at T1, 5 (4–7) at T2, 7 (4–8) at T3, and 3 (2–6) at T4. The median number of pills of rescue medications (IQR) was 95 (34–240) at T0, 5 (3–30) at T1, 15 (5–60) at T2, 8 (4–20) at T3, and 10 (3–16) at T4
Considering pain intensity, the mean VAS score at T0 in the 30 enrolled patients was of 8.0 ± 2.0 (median 8.5, IQR 8–9) (Fig. 2B). At T1 (25 observed patients), the mean VAS score significantly decreased to 5.0 ± 2.4 (median 5.0, IQR 3–7; p < 0.001). This significant reduction in pain intensity was confirmed also at T2 (19 patients; mean VAS of 5.4 ± 2.3; median 5, IQR 4–7; p < 0.001), T3 (15 patients; mean VAS of 5.9 ± 2.7; median 7, IQR 4–8; p = 0.001), and T4 (11 patients; mean VAS of 3.6 ± 2.3; median 3, IQR 2–6; p = 0.004). At time of the last follow-up available for each patient, the mean pain intensity was of 4.8 ± 2.3 (median 5, IQR 3–6, p < 0.001, data not shown).
A similar trend in pain relief was observed also considering the use of rescue medications (Fig. 2C). At T0, the mean number of pills used per month was of 163.3 ± 156.3 (median 95, IQR 34–240). At T1, the use of rescue medications significantly decreased to a mean of 21.3 ± 29.6 pills per month (median 5, IQR 3–30, p < 0.001). Similarly, at T2, T3, and T4, the monthly intake of rescue medications was reduced to a mean of number of 36.4 ± 45.6 pills (median 15, IQR 5–60, p < 0.001), 30.3 ± 55.5 pills (median 8, IQR 4–20, p < 0.001), and 21.8 ± 34.3 pills (median 10, IQR 3–16, p = 0.003), respectively. At time of the last follow-up, the mean number of pills used per month was of 22.2 ± 29.2 (median 15, IQR 3–28, p < 0.001, data not shown).
Ten patients reported clinically relevant ADRs (from low to moderate grade), requiring LDM discontinuation. Specifically, five patients had nausea, three vomiting, and two had constipation. Nine patients who experienced an ADR dropped out early after LDM initiation (after a median time of 14 days, IQ 7–40), while one patient dropped out at month 11. All patients fully recovered after tapered interruption of LDM. No other ADRs were observed in our sample. No case of misuse or diversion was observed (data not shown).
Discussion
This is the first study evaluating the effectiveness and safety of LDM over a 12-month follow-up period, in patients affected by RCM with continuous headache and MOH in a real-world setting. As mentioned above, refractoriness may be diagnosed when a patient experiences ineffectiveness of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. Our results show that in patients affected by RCM, when tolerated, LDM is an effective option for the prevention of headache exacerbation, as well as for the reduction of pain intensity and consumption of rescue medications.
However, a significant portion of patients, despite an initial benefit from LDM, discontinued the treatment because of ADRs, although they were expected and non-serious. Even if the portion of patients developing nausea and vomiting was quite similar to that observed in other populations [20], our patients did not develop the expected tolerance to these ADRs. Accordingly, we cannot exclude that patients with migraine have a disease-related alteration (read as hypersensitivity) to these disturbances. This phenomenon, being nausea and vomiting the most frequent causes of LDM withdrawal in our population, deserves future investigation. Importantly, the median time to develop ADRs, being rather short (14 days) after therapy initiation, favored the safety profile as tapering of methadone was quick and easy. Altogether, our observations suggest that the optimization of the treatment, including either the association with or a formulation containing methylnaltrexone, which has been shown to be able to counteract the constipation [21], would relevantly increase the persistence on treatment, thus increasing the proportion of patients that might benefit from LDM. Another interesting result emerging from our population is that all patients experiencing ADR were female. An increased sensitivity to opioid-induced nausea and vomiting in women has been already reported [22–27], but the underlying mechanism is not known. In our study, the exclusive involvement of women may be due to the low number of participants that, however, per se discourages further subgroup analysis.
The impressive reduction of drug consumption observed in our study (from a median of 95 pills per month (IQR) (34–240) to 15 (3–28), p < 0.001) suggests that the initial medication overuse is mostly driven by the pain intensity. It is worth noting that this is at odds with the assumption that medication overuse in patients with migraine is mainly due to a genetic predisposition to substance abuse [28]. Indeed, when methadone is administered to patients with MOH according to a scheduled plan, it alleviates pain and drug consumption consequently falls. The fact that none of our patients misused methadone, notwithstanding its well-known abuse potential, further corroborates the hypothesis that RCM patients with MOH are not genetically predisposed drug abusers per se [28], but just deserve an efficacious pain treatment to defeat the vicious cycle that sustains medication overuse. However, as no conclusive evidence exists, it would be of paramount importance to dissect the mechanisms that drive the medication overuse in patients with migraine as this could significantly change the therapeutic approach to these patients.
It has been already reported that prescribing methadone for headache patients is neither glamorous nor lucrative and that it is a tedious process because of extensive patient education, controlled substance agreement, and meticulous record keeping [29]. However, the absence of suitable pharmacological alternatives for RCM associated with MOH is associated with an increased risk of ADRs due to overused medications and severe disability of patients who still seek medical attention after a number of therapeutic failures [29]. In this context, practitioners should consider LDM as a potential effective alternative for these patients. Currently, there are no restrictions for methadone prescriptions in Italy, since by the release of Law 38/2010 that specifically deals with the treatment of pain, it can be prescribed with the same modalities used for any other prescription drugs. Nonetheless, methadone prescription should still be reserved to specialists experienced in patients’ education and methadone handling. The opioid epidemics emerging in the United States, following to a well-meaning movement emerged in the United States 20 years ago to promote an adequate treatment of chronic pain with opioids and causing the death of almost half a million Americans from drug overdoses, suggests that more than caution is needed [30]. Despite the low rate of use of opioids in most European countries [31], the strict adherence to available guidelines that reserve opioids for headache patients only in selected cases [32] is both essential and mandatory to pursue an optimal management of LDM prophylaxis and to minimize the occurrence of overuse and ADRs.
Our results have several limitations. Unquestionably, the major limitation is the small sample size that is however due to the investigated condition. Considering the low frequency of the disease and the restrictedness of criteria that candidate a patient to the treatment, we had to deal with study premises resembling those of rare diseases, indeed. Although we planned a self-controlled study to maximize the internal validity of the study [33, 34], only initial evidence may emerge from observations in such a small population.
Another relevant drawback is the high rate of early treatment discontinuation, which significantly compromised the power of the study. It is worth noting that the study has a pragmatic approach and that the high portion of patients who discontinued the treatment represents the first valuable result of the study, indeed. On the one side, it suggests that only some weeks are needed to understand if patients will tolerate LDM. On the other side, as discontinuation was mainly due to gastrointestinal liability, we may hypothesize that innovative formulations of methadone will significantly decrease the number of patients who discontinue the treatment. Nevertheless, it is reasonable to consider that eligible enrolled patients were exclusively those non-responders to standard treatments, thus suggesting that LDM can represent a valid prophylactic approach in those refractory patients.
Conclusions
LDM may be an effective prophylactic alternative for patients affected by RCM with continuous headache associated with MOH refractory to standard treatments. In eligible patients, after a short initial trial to test tolerability, LDM may represent a simple and inexpensive way to bring relief and reduce headache medication overuse, although the frequency of early ADRs poses major safety concerns. Further research, including assessment of methadone plasma levels and pharmacogenetic profiling, are needed to understand factors that may influence the clinical response to LDM in RCM patients. In addition, randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open access funding provided by Università degli Studi di Firenze within the CRUI-CARE Agreement. The authors acknowledge Prof. Emanuela Masini, MD, for her expert advice, and Dr. Eleonora Rossi, MD, Headache Centre, Careggi University Hospital, Florence, as contributor (contributing participants). The authors are also grateful to Mary Lokken for her expert English language revision.
Authors’ contributions
SB and GM conceived and designed the study. SB, CL, FDC, VG, CP, and BO contributed to the acquisition of data. SB and AB contributed to the analysis of data. SB, CL, NL, AC, PG, and GM contributed to the interpretation of data. SB, NL, and AB drafted the manuscript. All authors critically revised and approved the manuscript.
Funding information
This study was not funded.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Ethics approval
The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA).
Consent to participate
An informed consent was obtained from all individual participants included in the study.
Consent for publication
Patients signed an informed consent regarding publishing their data, in an aggregated and anonymous form.
Code availability
Not applicable. | Recovered | ReactionOutcome | CC BY | 32691178 | 18,722,654 | 2021-03 |
What was the outcome of reaction 'Vomiting'? | Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study.
OBJECTIVE
A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH.
METHODS
A prospective cohort study was performed between May 2012 and November 2015 at the Headache Center and Toxicology Unit of the Careggi University Hospital. Eligible patients were treated with prophylactic LDM and followed up for 12 months. Headache exacerbations, pain intensity, use of rescue medications, and occurrence of adverse drug reactions (ADRs) were recorded.
RESULTS
Thirty patients (24 females, median age 48 years) were enrolled. Nineteen (63%) patients dropped out, mainly because of early ADRs (n = 10), including nausea, vomiting, and constipation. At last available follow-up, LDM was associated with a significant decrease in the number of headache attacks/month (from a median of 45 (interquartile range 30-150) to 16 (5-30), p < 0.001), in pain intensity (from 8.5 (8-9) to 5 (3-6), p < 0.001), and in the number of rescue medications consumed per month (from 95 (34-240) to 15 (3-28), p < 0.001). No misuse or diversion cases were observed.
CONCLUSIONS
LDM could represent a valuable and effective option in selected patients affected by RCM with continuous headache and MOH, although the frequency of early ADRs poses major safety concerns. Randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Introduction
Chronic migraine is increasingly disabling, making patients with continuous headache the most disabled in the spectrum of chronic migraineurs [1]. Chronic migraine affects at least 1% of the general population [2], and refractoriness to treatments (RCM, refractory chronic migraine) [3] and medication-overuse headache (MOH) [1] often aggravate this condition. Even if there is no conclusive consensus on its definition, refractoriness is a clinically relevant phenomenon that refers to the failure of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. As the prophylaxis fails, the risk for the patient to experience medication overuse and, consequently, undergo MOH significantly increases. Importantly, even if the majority of patients who discontinued medication overuse substantially improve [5–8], drug discontinuation is not always sufficient for the reduction of headache attack frequency or intensity. In a considerable portion of patients, chronic pain and exposure to adverse drug reactions (ADRs), due to the intense consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and/or triptans, lead to a vicious cycle that progressively deteriorates patients’ health and quality of life.
Despite some drawbacks, including the potential for misuse and diversion and the risk of cognitive impairment, continuous opioid therapy represents a reasonable prophylactic option for patients affected by RCM with continuous headache and MOH [9]. In 2009, the American Pain Society proposed chronic headaches as one of the four chronic pain conditions where continuous opioid therapy might be taken into consideration [10]. According to the data from longitudinal studies and a long-standing experience with refractory patients and opioid schedules, guidelines for the selection of patients eligible to continuous opioid therapy have been proposed [11].
Little evidence is available regarding the preferred opioid schedules for RCM with continuous headache and MOH. Methadone, because of the peculiar pharmacological profile of its racemic mixture of (R)- and (S)-isomers, seems to be a better candidate compared with other opioids, in particular for its duration of action (long-acting opioid), with an analgesic effect that persists for 4–6 h [12]. Methadone has a mean bioavailability of about 80%, which is much higher than for the other opioid; in addition, it also has a long terminal half-life ranging from 7 to 65 h compared with other clinically used opioids [13]. Although metabolism and disposition are highly variable among subjects, the appropriate dosage tailoring allows to maximally benefit of the pharmacokinetic profile of methadone for patients’ treatment. Its primary analgesic effect is mediated by the agonism of the sole (R)-methadone on μ-opioid receptors. However, both isomers act as antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor [14], likely contributing to a reduced opioid tolerance [15] especially at low doses [16, 17]. The favorable profile of methadone in terms of reduced tolerance in comparison with other opioids is another key point for the administration of methadone for chronic pain therapy. Some preclinical evidence suggests it has an optimal profile regarding the ability to induce opioid receptor internalization that may explain this clinical phenomenon [18]. Despite its proven efficacy, methadone has a relevant potential for drug interactions and may be associated with serious ADRs, among which is the dose-independent prolongation of the QT interval [19] leading to rare but potentially fatal arrhythmias. Thus, the clinical use of methadone requires trained physicians, a careful education of patients, and a strict monitoring; nevertheless, the use of low dosages is recommended.
In this clinical context, the aim of the present study was to evaluate the effectiveness and safety, at 12 months of treatment, of low doses of methadone (LDM) in patients affected by RCM with continuous headache and MOH.
Methods
Study design and setting
A prospective cohort study was performed at the Headache Center and Toxicology Unit of the Careggi University Hospital. The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA). The study was performed following all the guidelines for observational studies with human subjects required by the institution with which all the authors are affiliated. A written informed consent for research was obtained from all participants.
Study population
Between May 2012 and November 2015, patients aged ≥ 30 years were screened at the Headache Center of Careggi University Hospital and, if diagnosed with RCM with continuous headache and MOH, were informed about the possibility of receiving prophylactic LDM. Only patients with refractory headache or with contraindications to the use of evidence-based interventions were eligible [11]. Patients were considered not eligible in case of contraindications to opioid treatment, including past addictive disease or serious mental illnesses [11]. Before starting the LDM, patients underwent a psychiatric evaluation in order to exclude lifetime diagnosis of schizophrenia or other psychiatric syndromes according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) [5] and clinical assessment, including electrocardiography (ECG) and urine drug screening. According to standard clinical practice, patients that resulted eligible after clinical screening were informed about possible drug-drug interactions related to methadone treatment. In order to avoid possible interactions and optimize treatment, an informative letter was sent to the general practitioner of each patient.
According to standard practice, patients should have their headache diary reporting data about their chronic migraine in the previous 3 months. Information reported in this diary included the number of rescue medications (including non-opioid analgesics, NSAIDs, and triptans) consumed per month, the number of days with headache per month, the number of headache exacerbations deserving pain relievers per month, and their intensity assessed every day by the visual analogue scale (VAS).
Data from the headache diaries were used as baseline values for study assessments. After signature of the informed consent, eligible patients were transferred to the Toxicology Unit, where all the clinical procedures and study follow-up visits were performed.
The baseline visit was conducted at T0 (i.e., day of LDM start). All treated patients were prescribed with standard prophylaxis (i.e., enriched fiber diet, physical activity, lactulose if needed) to prevent methadone-induced constipation. LDM started from 2 mg per day and was increased or administered in multiple daily doses according to clinical evaluation, since no dosing strategy for initiation of therapy and later uptitration have been validated. In our patients, maximal dose administered was 30 mg per day at T0. and 40 mg per day at T4.
Follow-up visits were planned at T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). The variability in the time interval between subsequent visits was due to the increased need of follow-up in the initial phases of the treatment, when titration of the methadone doses can still be critical.
Outcome evaluation
The primary outcome was headache exacerbations. The primary endpoint was the number of headache exacerbations per month requiring a pain reliever.
The secondary outcomes were the pain intensity and the need of rescue medications. The secondary endpoints were the changes in pain intensity, measured using the VAS, and the number of rescue medications consumed per month.
Safety outcomes included all ADRs occurred during LDM treatment. Namely, safety endpoints were the number and the grade of ADRs recorded. To this aim, ECG recordings were performed at T0, T1, and T4 in order to detect QTc changes possibly due to administration of LDM.
Statistical analysis
Data were reported as mean value ± standard deviation of the mean (SD) or as median value and related interquartile range (IQR), according to data distribution.
Effectiveness and safety endpoints were evaluated at T1, T2, T3, and T4 and compared with T0 using the Wilcoxon test for paired data. Furthermore, effectiveness and safety endpoints at T0 were compared with those obtained at last available follow-up, i.e., T1, T2, T3, or T4, according to patients’ data availability. Statistical significance was considered for p value < 0.05. An analysis was conducted using the software STATA version 14.
Results
Thirty patients were considered eligible for LDM and were further enrolled in the study. Of them, 24 were females (80.0%), with a median age of 48 years (41.2–54.2). Demographic and clinical characteristics of the enrolled cohort are detailed in Table 1.Table 1 Demographic and clinical data of patients treated with low-dose methadone (LDM)
Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48 (41.2–54.2)#
Female 24 (80.0)
Overused drug/s*
NSAIDs 28 (93.3)
Triptans 17 (56.7)
Opioids 17 (56.7)
Acetaminophen 11 (36.7)
Comorbidities
Anxiety 20 (66.7)
Arterial hypertension 9 (30.0)
Other pain conditions 7 (23.3)
*Some patients overused more than one drug
IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Focusing on the previous pharmacological treatment of headache, 93.3% of patients overused NSAIDs (n = 28), 17 (56.7%) overused triptans, and the other 17 overused opioids. Acetaminophen was overused by 11 patients (36.7%). Notably, patients assumed more than one drug class to treat headache exacerbations. Concerning failed prophylaxes, tricyclic antidepressants, calcium-channel blockers, and antiepileptics were reported as previous treatment by 73% of patients, while beta-blockers and onabotulinum toxin A by 67% of patients. Importantly, 40% of patients are reported to have been treated with at least four of the abovementioned drug classes, while 60% of patients have tried them all.
As for comorbidities, most patients suffered from anxiety (66.7%), whereas arterial hypertension and other pain conditions were reported in 30.0 and 23.3% of patients, respectively.
LDM was initiated during in-hospital stay (2–3 days) in 28 patients, while 2 patients started LDM in a day-hospital setting. An initial mean dose of methadone was 12 ± 4 mg (IQR 8–17 mg).
The demographic and clinical characteristics of patients are detailed in Table 2. Nineteen (63.3%) patients discontinued LDM. Specifically, five (16.7%) withdrew because of ineffectiveness, after a median time of 4.6 months (IQR 3.5–5.5). Although LDM treatment was effective, fourteen patients withdrew for other reasons. Among them, ten (33.3%) withdrew because of ADR; it is worth noting that all were female. Other three patients (10.0%) dropped out because of poor treatment confidence, while one patient moved to another country and was therefore lost to follow-up. Eleven patients (36.7%) were still on LDM treatment at the end of our study. The persistence on LDM treatment, distinguishing patients that developed an ADR (n = 10) from the others (n = 20), is shown in Fig. 1 (solid and dashed lines, respectively).Table 2 Demographic and clinical data of patients treated with low-dose methadone (LDM), grouped according to clinical outcomes
Patients with ongoing treatment Dropout
n = 11 Inefficacy
n = 5 ADRs
n = 10 Others
n = 4
Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%) Median (IQR) or n (%)
Demographic data
Age (median years, IQR) 48, 41–58 47, 28–64.5 49, 47.5–56.7 41.5, 39.5–51.7
Female 8 (72.7%) 3 (60%) 10 (100%) 3 (75%)
Prevalent headache type
Migraine 10 (90.9%) 4 (80%) 10 (100%) 2 (50%)
Tension-type headache 1 (9.1%) 0 (0%) 0 (0%) 2 (50%)
Cluster headache 0 (0%) 1 (20%) 0 (0%) 0 (0%)
Overused drug/s*
NSAIDs 10 (90.9%) 4 (80%) 10 (100%) 4 (100%)
Opioids 8 (72.7%) 1 (20%) 4 (40%) 4 (100%)
Acetaminophen 5 (45.4%) 1 (20%) 4 (40%) 1 (25%)
Serotonin receptor agonists 5 (45.4%) 4 (80%) 6 (60%) 2 (50%)
Comorbidities§
Anxiety 9 (81.8%) 2 (40%) 6 (60%) 3 (75%)
Arterial hypertension 3 (27.3%) 2 (40%) 4 (40%) 0 (0%)
Other pain conditions 3 (27.3%) 1 (20%) 2 (20%) 1 (25%)
*Some patients overused more than one drug.
§Some patients have more than one concomitant disease in addition to RCM
ADRs adverse drug reactions, IQR interquartile range, NSAIDs nonsteroidal anti-inflammatory drugs
Fig. 1 Time on treatment with low-dose methadone (LDM) of patients in 1 year of follow-up. Survival curves of patients that dropped out because of an ADR (continuous line) vs. all the other patients (still on treatment at month 12/dropouts for inefficacy/dropouts for personal reasons; dotted line). Importantly, most ADR patients dropped out early after LDM initiation (median time 14 days, IQ range 7–40). The curves are statistically different (log-rank Mantel-Cox test; P < 0.0001)
The effectiveness of LDM in terms of headache exacerbations, pain reduction, and use of rescue medications is described in Fig. 2. At time of start of LDM treatment (T0), the mean number of headache exacerbations per month requiring a pain reliever in the 30 enrolled patients was of 68.5 ± 60.4 (median 45, IQR 30–90) (Fig. 2A). At T1, the mean number of attacks requiring a pain reliever in the 25 observed patients significantly decreased to 15.9 ± 12.4 (median 9, IQR 5–30; p < 0.001). This significant reduction in the monthly number of headache exacerbations was confirmed also at the other time points of follow-up. Specifically, at T2, among the 19 patients for whom follow-up data were available, the mean number of attacks was of 24.8 ± 26.0 (median 30, IQR 7–30; p = 0.003). At T3, among the 15 observed patients, the mean of attacks was of 24.9 ± 29.2 (median 26, IQR 4–30; p = 0.002), and at T4, the mean number in the 11 observed patients was of 17.1 ± 11.4 (median 16, IQR 5–30; p = 0.003). At time of the last follow-up available for each patient (ranging from T1 to T4, n = 25), the mean number of headache attacks per month requiring a pain reliever was of 21.0 ± 23.6 (median 16, IQR 5–30, p < 0.001, data not shown).Fig. 2 Effectiveness of low-dose methadone (LDM) on headache attacks, pain intensity, and the use of rescue medications. LDM decreased the number of headache exacerbations deserving a pain reliever per month (A), pain intensity assessed by a visual analogue scale (VAS) (B), and the number of pills of rescue medications consumed per month (C) at different time points of follow-up (T0 (baseline), T1 (30 days following T0), T2 (3 months after T0), T3 (6 months after T0), and T4 (12 months after T0). Namely, the median number (interquartile range, IQR) of headache exacerbations per month was 45 (30–90) at T0, 9 (5–30) at T1, 30 (7–30) at T2, 26 (4–30) at T3, and 16 (5–30) at T4. The median VAS (IQR) was 8.5 (8–9) at T0, 5 (3–7) at T1, 5 (4–7) at T2, 7 (4–8) at T3, and 3 (2–6) at T4. The median number of pills of rescue medications (IQR) was 95 (34–240) at T0, 5 (3–30) at T1, 15 (5–60) at T2, 8 (4–20) at T3, and 10 (3–16) at T4
Considering pain intensity, the mean VAS score at T0 in the 30 enrolled patients was of 8.0 ± 2.0 (median 8.5, IQR 8–9) (Fig. 2B). At T1 (25 observed patients), the mean VAS score significantly decreased to 5.0 ± 2.4 (median 5.0, IQR 3–7; p < 0.001). This significant reduction in pain intensity was confirmed also at T2 (19 patients; mean VAS of 5.4 ± 2.3; median 5, IQR 4–7; p < 0.001), T3 (15 patients; mean VAS of 5.9 ± 2.7; median 7, IQR 4–8; p = 0.001), and T4 (11 patients; mean VAS of 3.6 ± 2.3; median 3, IQR 2–6; p = 0.004). At time of the last follow-up available for each patient, the mean pain intensity was of 4.8 ± 2.3 (median 5, IQR 3–6, p < 0.001, data not shown).
A similar trend in pain relief was observed also considering the use of rescue medications (Fig. 2C). At T0, the mean number of pills used per month was of 163.3 ± 156.3 (median 95, IQR 34–240). At T1, the use of rescue medications significantly decreased to a mean of 21.3 ± 29.6 pills per month (median 5, IQR 3–30, p < 0.001). Similarly, at T2, T3, and T4, the monthly intake of rescue medications was reduced to a mean of number of 36.4 ± 45.6 pills (median 15, IQR 5–60, p < 0.001), 30.3 ± 55.5 pills (median 8, IQR 4–20, p < 0.001), and 21.8 ± 34.3 pills (median 10, IQR 3–16, p = 0.003), respectively. At time of the last follow-up, the mean number of pills used per month was of 22.2 ± 29.2 (median 15, IQR 3–28, p < 0.001, data not shown).
Ten patients reported clinically relevant ADRs (from low to moderate grade), requiring LDM discontinuation. Specifically, five patients had nausea, three vomiting, and two had constipation. Nine patients who experienced an ADR dropped out early after LDM initiation (after a median time of 14 days, IQ 7–40), while one patient dropped out at month 11. All patients fully recovered after tapered interruption of LDM. No other ADRs were observed in our sample. No case of misuse or diversion was observed (data not shown).
Discussion
This is the first study evaluating the effectiveness and safety of LDM over a 12-month follow-up period, in patients affected by RCM with continuous headache and MOH in a real-world setting. As mentioned above, refractoriness may be diagnosed when a patient experiences ineffectiveness of at least 2 of 4 prophylactic treatments of different pharmacological classes [4]. Our results show that in patients affected by RCM, when tolerated, LDM is an effective option for the prevention of headache exacerbation, as well as for the reduction of pain intensity and consumption of rescue medications.
However, a significant portion of patients, despite an initial benefit from LDM, discontinued the treatment because of ADRs, although they were expected and non-serious. Even if the portion of patients developing nausea and vomiting was quite similar to that observed in other populations [20], our patients did not develop the expected tolerance to these ADRs. Accordingly, we cannot exclude that patients with migraine have a disease-related alteration (read as hypersensitivity) to these disturbances. This phenomenon, being nausea and vomiting the most frequent causes of LDM withdrawal in our population, deserves future investigation. Importantly, the median time to develop ADRs, being rather short (14 days) after therapy initiation, favored the safety profile as tapering of methadone was quick and easy. Altogether, our observations suggest that the optimization of the treatment, including either the association with or a formulation containing methylnaltrexone, which has been shown to be able to counteract the constipation [21], would relevantly increase the persistence on treatment, thus increasing the proportion of patients that might benefit from LDM. Another interesting result emerging from our population is that all patients experiencing ADR were female. An increased sensitivity to opioid-induced nausea and vomiting in women has been already reported [22–27], but the underlying mechanism is not known. In our study, the exclusive involvement of women may be due to the low number of participants that, however, per se discourages further subgroup analysis.
The impressive reduction of drug consumption observed in our study (from a median of 95 pills per month (IQR) (34–240) to 15 (3–28), p < 0.001) suggests that the initial medication overuse is mostly driven by the pain intensity. It is worth noting that this is at odds with the assumption that medication overuse in patients with migraine is mainly due to a genetic predisposition to substance abuse [28]. Indeed, when methadone is administered to patients with MOH according to a scheduled plan, it alleviates pain and drug consumption consequently falls. The fact that none of our patients misused methadone, notwithstanding its well-known abuse potential, further corroborates the hypothesis that RCM patients with MOH are not genetically predisposed drug abusers per se [28], but just deserve an efficacious pain treatment to defeat the vicious cycle that sustains medication overuse. However, as no conclusive evidence exists, it would be of paramount importance to dissect the mechanisms that drive the medication overuse in patients with migraine as this could significantly change the therapeutic approach to these patients.
It has been already reported that prescribing methadone for headache patients is neither glamorous nor lucrative and that it is a tedious process because of extensive patient education, controlled substance agreement, and meticulous record keeping [29]. However, the absence of suitable pharmacological alternatives for RCM associated with MOH is associated with an increased risk of ADRs due to overused medications and severe disability of patients who still seek medical attention after a number of therapeutic failures [29]. In this context, practitioners should consider LDM as a potential effective alternative for these patients. Currently, there are no restrictions for methadone prescriptions in Italy, since by the release of Law 38/2010 that specifically deals with the treatment of pain, it can be prescribed with the same modalities used for any other prescription drugs. Nonetheless, methadone prescription should still be reserved to specialists experienced in patients’ education and methadone handling. The opioid epidemics emerging in the United States, following to a well-meaning movement emerged in the United States 20 years ago to promote an adequate treatment of chronic pain with opioids and causing the death of almost half a million Americans from drug overdoses, suggests that more than caution is needed [30]. Despite the low rate of use of opioids in most European countries [31], the strict adherence to available guidelines that reserve opioids for headache patients only in selected cases [32] is both essential and mandatory to pursue an optimal management of LDM prophylaxis and to minimize the occurrence of overuse and ADRs.
Our results have several limitations. Unquestionably, the major limitation is the small sample size that is however due to the investigated condition. Considering the low frequency of the disease and the restrictedness of criteria that candidate a patient to the treatment, we had to deal with study premises resembling those of rare diseases, indeed. Although we planned a self-controlled study to maximize the internal validity of the study [33, 34], only initial evidence may emerge from observations in such a small population.
Another relevant drawback is the high rate of early treatment discontinuation, which significantly compromised the power of the study. It is worth noting that the study has a pragmatic approach and that the high portion of patients who discontinued the treatment represents the first valuable result of the study, indeed. On the one side, it suggests that only some weeks are needed to understand if patients will tolerate LDM. On the other side, as discontinuation was mainly due to gastrointestinal liability, we may hypothesize that innovative formulations of methadone will significantly decrease the number of patients who discontinue the treatment. Nevertheless, it is reasonable to consider that eligible enrolled patients were exclusively those non-responders to standard treatments, thus suggesting that LDM can represent a valid prophylactic approach in those refractory patients.
Conclusions
LDM may be an effective prophylactic alternative for patients affected by RCM with continuous headache associated with MOH refractory to standard treatments. In eligible patients, after a short initial trial to test tolerability, LDM may represent a simple and inexpensive way to bring relief and reduce headache medication overuse, although the frequency of early ADRs poses major safety concerns. Further research, including assessment of methadone plasma levels and pharmacogenetic profiling, are needed to understand factors that may influence the clinical response to LDM in RCM patients. In addition, randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open access funding provided by Università degli Studi di Firenze within the CRUI-CARE Agreement. The authors acknowledge Prof. Emanuela Masini, MD, for her expert advice, and Dr. Eleonora Rossi, MD, Headache Centre, Careggi University Hospital, Florence, as contributor (contributing participants). The authors are also grateful to Mary Lokken for her expert English language revision.
Authors’ contributions
SB and GM conceived and designed the study. SB, CL, FDC, VG, CP, and BO contributed to the acquisition of data. SB and AB contributed to the analysis of data. SB, CL, NL, AC, PG, and GM contributed to the interpretation of data. SB, NL, and AB drafted the manuscript. All authors critically revised and approved the manuscript.
Funding information
This study was not funded.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Ethics approval
The study was approved by the Ethics Committee on Clinical Research (Comitato Etico Regione Toscana, Sezione Area Vasta Centro; approval number 6078) and registered in the Italian Registry for Observational Studies held by the Italian Medicines Agency (AIFA).
Consent to participate
An informed consent was obtained from all individual participants included in the study.
Consent for publication
Patients signed an informed consent regarding publishing their data, in an aggregated and anonymous form.
Code availability
Not applicable. | Recovered | ReactionOutcome | CC BY | 32691178 | 18,722,657 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure'. | Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
OBJECTIVE
To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.
METHODS
In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.
RESULTS
Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.
CONCLUSIONS
In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.
BACKGROUND
Trial no. UMIN000009086.
Introduction
Bevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].
A meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].
The JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.
Although several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.
Patients and methods
Study design
In this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.
Patients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.
Written informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).
Study treatment
Because the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.
In cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.
Study assessment
At screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.
Regarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.
Analysis populations and endpoints
The eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.
The primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).
Statistical analyses
This was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.
Expected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.
For the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.
Safety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.
Results
Study population and baseline patient characteristics
A total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.
Baseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median age (range) (years) 58.0 (26–83) 58.0 (26–81) 58.0 (27–83) 59.0 (26–83) 57.0 (28–83)
Menopausal status
Premenopausal 198 26.3 133 24.7 65 30.2 127 26.6 71 25.7
Postmenopausal 532 70.6 385 71.4 147 68.4 337 70.5 195 70.7
Unknown 24 3.2 21 3.9 3 1.4 14 2.9 10 3.6
ECOG PS
0 522 69.2 371 68.8 151 70.2 345 72.2 177 64.1
1 172 22.8 122 22.6 50 23.3 96 20.1 76 27.5
2 43 5.7 34 6.3 9 4.2 29 6.1 14 5.1
3 17 2.3 12 2.2 5 2.3 8 1.7 9 3.3
ER status
Negative 208 27.6 8 1.5 200 93.0 125 26.2 83 30.1
Positive 544 72.1 529 98.1 15 7.0 351 73.4 193 69.9
Unknown 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
PgR status
Negative 332 44.0 122 22.6 210 97.7 203 42.5 129 46.7
Positive 419 55.6 414 76.8 5 2.3 272 56.9 147 53.3
Unknown 3 0.4 3 0.6 0 0.0 3 0.6 0 0.0
Nuclear grade
1 120 15.9 102 18.9 18 8.4 79 16.5 41 14.9
2 106 14.1 82 15.2 24 11.2 70 14.6 36 13.0
3 216 28.6 111 20.6 105 48.8 144 30.1 72 26.1
Unknown 312 41.4 244 45.3 68 31.6 185 38.7 127 46.0
Ki67 index
< 30 141 18.7 105 19.5 36 16.7 103 21.5 38 13.8
≥ 30 191 25.3 93 17.3 98 45.6 130 27.2 61 22.1
Unknown 422 56.0 341 63.3 81 37.7 245 51.3 177 64.1
Diagnosis
Locally advanced 34 4.5 20 3.7 14 6.5 29 6.1 5 1.8
Stage IV 199 26.4 149 27.6 50 23.3 130 27.2 69 25.0
Recurrence 521 69.1 370 68.6 151 70.2 319 66.7 202 73.2
Disease-free interval (months)
0 233 30.9 169 31.4 64 29.8 159 33.3 74 26.8
0–24 178 23.6 83 15.4 95 44.2 101 21.1 77 27.9
≥ 4 292 38.7 246 45.6 46 21.4 190 39.7 102 37.0
Unknown 51 6.8 41 7.6 10 4.7 28 5.9 23 8.3
Distant metastasis
No 81 10.7 47 8.7 34 15.8 34 7.1 47 17.0
Yes 649 86.1 476 88.3 173 80.5 422 88.3 227 82.2
Unknown 24 3.2 16 3.0 8 3.7 22 4.6 2 0.7
Metastatic sitec
Non-visceral 54 8.3 36 7.6 18 10.4 40 9.5 14 6.2
Visceral 595 91.7 440 92.4 155 89.6 382 90.5 213 93.8
No. of metastatic organsc
< 3 558 86.0 409 85.9 149 86.1 355 84.1 203 89.4
≥ 3 91 14.0 67 14.1 24 13.9 67 15.9 24 10.6
Cancer-related symptoms
No 315 41.8 230 42.7 85 39.5 200 41.8 115 41.7
Yes 434 57.6 305 56.6 129 60.0 275 57.5 159 57.6
Unknown 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Treatment line for locally advanced or metastatic breast cancer
First line 478 63.4 345 64.0 133 61.9
Second line 276 36.6 194 36.0 82 38.1
History of adjuvant therapyd
Chemotherapy 370 71.0 238 64.3 132 87.4 227 71.2 143 70.8
Anthracycline 297 57.0 188 50.8 109 72.2 186 58.3 111 55.0
Taxane 262 50.3 153 41.4 109 72.2 165 51.7 97 48.0
Endocrine therapy 336 64.5 324 87.6 12 7.9 205 64.3 131 64.9
Previous therapy for locally advanced or metastatic breast cancer
Chemotherapy 266 35.3 188 34.9 78 36.3 12 2.5 254 92.0
Anthracycline 80 10.6 63 11.7 17 7.9 4 0.8 76 27.5
Taxane 54 7.2 36 6.7 18 8.4 5 1.0 49 17.8
Endocrine therapy 356 47.2 348 64.6 8 3.7 195 40.8 161 58.3
Radiotherapy 140 18.6 111 20.6 29 13.5 62 13.0 78 28.3
ECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cNumber (%) of distant metastasis
dNumber (%) of patients with breast cancer recurrence
The proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).
Treatment exposure
Most patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median duration of study treatment (25th, 75th percentiles), months 5.1 (3.1, 8.7) 5.5 (3.3, 9.5) 4.0 (2.3, 6.5) 5.3 (3.0, 8.7) 4.8 (2.4, 8.8)
Median duration of bevacizumab (25th, 75th percentiles), months 5.1 (2.8, 8.5) 5.4 (3.3, 9.5) 3.7 (2.3, 6.2) 5.1 (2.8, 8.5) 4.6 (2.4, 8.7)
Median RDI of bevacizumab (25th, 75th percentiles), 97.5 (86.2, 100) 95.9 (86.5, 100) 100 (85.7, 100) 95.6 (87.2–100) 100 (84.8–100)
Discontinuations of bevacizumab, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of bevacizumab, n (%)
Disease progression 379 50.7 261 48.7 118 55.7 221 46.5 158 57.9
Adverse events 214 28.6 169 31.5 45 21.2 143 30.1 71 26.0
Other 152 20.3 105 19.6 47 22.2 109 22.9 43 15.8
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Bevacizumab dose reductions, n (T) 15 2.0 12 2.2 3 1.4 13 2.7 2 0.7
Reason for bevacizumab dose reduction, n (%)c
Hypertension 3 20.0 2 16.7 1 33.3 3 23.1 0 0.0
Proteinuria 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Bleeding 1 6.7 1 8.3 0 0.0 1 7.7 0 0.0
Neutropenia 1 6.7 1 8.3 0 0.0 0 0.0 1 50.0
Other adverse events 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Other 4 26.7 2 16.7 2 66.7 3 23.1 0 0.0
Bevacizumab dose interruptions or delays, n (%) 263 34.9 188 34.9 75 34.9 155 32.4 108 39.1
Reason for bevacizumab dose interruption or delay, n (%)c
Hypertension 18 6.8 15 8.0 3 4.0 16 10.3 2 1.9
Proteinuria 53 20.2 36 19.1 17 22.7 35 22.6 18 16.7
Bleeding 3 1.1 2 1.1 1 1.3 2 1.3 1 0.9
Neutropenia 77 29.3 61 32.4 16 21.3 38 24.5 39 36.1
Other adverse events 106 40.3 77 41.0 29 38.7 61 39.4 45 41.7
Other 114 43.3 79 42.0 35 46.7 63 40.6 51 47.2
Median duration of paclitaxel (25th, 75th percentiles), months 4.9 (2.8, 8.1) 5.3 (3.2, 9.0) 3.9 (2.3, 6.0) 5.1 (3.0, 8.1) 4.6 (2.4, 8.2)
Median RDI of paclitaxel (25th, 75th percentiles), 90.9 (70.6, 100) 88.9 (69.5, 100) 96.0 (75.6, 105) 91.7 (72.7, 100) 89.8 (68.6, 100)
Discontinuations of paclitaxel, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of paclitaxel, n (%)
Disease progression 363 48.5 245 45.7 118 55.7 216 45.5 147 53.8
Adverse events 246 32.9 198 36.9 48 22.6 158 33.3 88 32.2
Other 136 18.2 92 17.2 44 20.8 99 20.8 37 13.6
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Paclitaxel dose reductions, n (%) 276 36.6 208 38.6 68 31.6 185 38.7 91 33.0
Reason for paclitaxel dose reduction, n (%)c
Peripheral neutropenia 114 41.3 89 42.8 25 36.8 81 43.8 33 36.3
Neutropenia 117 42.4 88 42.3 29 42.6 67 36.2 50 54.9
Other adverse events 81 29.3 61 29.3 20 29.4 57 30.8 24 26.4
Other 28 10.1 20 9.6 8 11.8 19 10.3 9 9.9
Paclitaxel dose interruptions or delays, n () 351 46.6 259 48.1 92 42.8 207 43.3 144 52.2
Reason for paclitaxel dose interruption or delay, n (%)c
Peripheral neutropenia 65 18.5 52 20.1 13 14.1 39 18.8 26 18.1
Neutropenia 159 45.3 123 47.5 36 39.1 82 39.6 77 53.5
Other adverse events 168 47.9 118 45.6 50 54.3 94 45.4 74 51.4
Other 127 36.2 90 34.7 37 40.2 72 34.8 55 38.2
Median duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 1.4 (N = 79) 0.5, 3.9 1.4 (N = 65) 0.5, 3.9 0.6 (N = 14) 0.2, 3.0 1.4 (N = 52) 0.5, 3.9 0.8 (N = 27) 0.3, 3.7
Median duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 0.2 (N = 133) 0.2, 0.7 0.2 (N = 86) 0.2, 0.7 0.2 (N = 47) 0.2, 0.9 0.2 (N = 87) 0.2, 1.2 0.2 (N = 46) 0.2, 0.3
RDI relative dose intensity
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cMultiple items could be selected
Of the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).
The dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.
When the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.
Details of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.
Effectiveness
Overall survival
Median observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B
The results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival
(a) All eligible patients
Univariate analysis (N = 754) Multivariate analysis (N = 736)a
Variable N HR 95% CI p HR 95% CI p
Cohort A vs cohort B 754 1.63 1.35–1.97 < 0.0001 1.75 1.44–2.14 < 0.0001
First- vs second-line therapy 754 1.46 1.22–1.74 < 0.0001 1.35 1.13–1.63 0.0011
Age: < 50 years vs ≥ 50 years 754 0.92 0.77–1.10 0.3361
ECOG PS: 0 vs 1, 2, or 3 754 1.59 1.32–1.91 < 0.0001 1.28 1.04–1.57 0.0175
Visceral metastasis: yes vs no 754 0.55 0.44–0.70 < 0.0001 0.52 0.40–0.66 < 0.0001
Cancer-related symptoms: yes vs no 749 0.57 0.48–0.69 < 0.0001 0.56 0.46–0.68 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.63 0.53–0.75 < 0.0001 0.87 0.66–1.14 0.3139
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.60 0.50–0.72 < 0.0001 0.65 0.49–0.86 0.0026
History of taxane-based chemotherapy: yes vs no 754 0.90 0.64–1.26 0.5380
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.78–1.38 0.8108
History of hormone therapy: yes vs no 754 1.02 0.86–1.22 0.8031
Nuclear grade: ≤ 2 vs 3 442 1.31 1.05–1.64 0.0186
Ki-67 index: < 30 vs ≥ 30 332 1.64 1.25–2.16 0.0004
Disease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.02 0.92–1.13 0.7575
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 521 1.52 1.22–1.90 0.0002 1.27 0.94–1.71 0.1251
First- vs second-line therapy 521 1.33 1.08–1.64 0.0069 1.20 0.95–1.52 0.1210
Age: < 50 years vs ≥ 50 years 521 0.92 0.75–1.13 0.4072
ECOG PS: 0 vs 1, 2, or 3 521 1.65 1.32–2.06 < 0.0001 1.32 1.02–1.71 0.0333
Visceral metastasis: yes vs no 521 0.58 0.44–0.77 0.0001 0.53 0.39–0.72 0.0001
Cancer-related symptoms: yes vs no 518 0.50 0.41–0.62 < 0.0001 0.52 0.41–0.66 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.68 0.53–0.86 0.0016 1.08 0.76–1.54 0.6634
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.66 0.53–0.81 0.0001 0.70 0.51–0.95 0.0209
History of taxane-based chemotherapy: yes vs no 521 0.86 0.56–1.32 0.4944
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.57–1.36 0.5617
History of hormone therapy: yes vs no 521 1.28 1.04–1.57 0.0190 1.14 0.87–1.50 0.3367
Nuclear grade: ≤ 2 vs 3 299 1.17 0.90–1.52 0.2389
Ki-67 index: < 30 vs ≥ 30 178 1.81 1.27–2.57 0.0011
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.45 0.36–0.56 < 0.0001 0.50 0.39–0.63 < 0.0001
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
The results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.
The results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.
Progression-free survival and objective response rates
Median PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.
Multivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival
(a) All eligible patients
Univariate analysis (n = 754) Multivariate analysis (n = 687)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 754 1.33 1.13–1.58 0.0008 1.56 1.26–1.93 0.0001
First- vs second-line therapy 754 1.40 1.20–1.64 < 0.0001 1.19 0.99–1.42 0.0622
Age: < 50 years vs ≥ 50 years 754 1.00 0.86–1.16 0.9589
ECOG PS: 0 vs 1, 2, or 3 754 1.60 1.36–1.88 < 0.0001 1.36 1.13–1.64 0.0013
Visceral metastasis: yes vs no 754 0.63 0.52–0.76 < 0.0001 0.68 0.55–0.85 0.0005
Cancer-related symptoms: yes vs no 749 0.68 0.58–0.79 < 0.0001 0.72 0.60–0.86 0.0003
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.62 0.53–0.72 < 0.0001 0.71 0.53–0.95 0.0227
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.61 0.52–0.72 < 0.0001 0.69 0.54–0.89 0.0044
History of taxane-based chemotherapy: yes vs no 754 0.69 0.52–0.92 0.0113 0.82 0.58–1.14 0.2358
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.80–1.31 0.8458
History of endocrine therapy: yes vs no 754 0.85 0.73–0.99 0.0411 0.76 0.62–0.93 0.0075
Nuclear grade: ≤ 2 vs 3 442 1.18 0.97–1.44 0.0961
Ki-67 index: < 30 vs ≥ 30 332 1.54 1.22–1.96 0.0003
Disease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.07 0.99–1.17 0.1040 0.89 0.78–1.01 0.0663
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI p HR 95% CI p
Cohort A vs cohort B 521 1.31 1.08–1.60 0.0073 1.12 0.89–1.40 0.3505
First- vs second-line therapy 521 1.33 1.11–1.60 0.0021 1.16 0.94–1.43 0.1643
Age: < 50 years vs ≥ 50 years 521 1.01 0.84–1.20 0.9470
PS: 0 vs 1, 2, or 3 521 1.74 1.43–2.11 < 0.0001 1.49 1.19–1.88 0.0006
Visceral metastasis: yes vs no 521 0.74 0.59–0.93 0.0086 0.78 0.60–1.00 0.0518
Cancer-related symptoms: yes vs no 518 0.62 0.52–0.74 < 0.0001 0.67 0.55–0.83 0.0002
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.66 0.54–0.81 0.0001 0.85 0.63–1.14 0.2795
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.67 0.56–0.81 < 0.0001 0.78 0.60–1.01 0.0573
History of taxane-based chemotherapy: yes vs no 521 0.66 0.45–0.97 0.0361 0.75 0.47–1.21 0.2333
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.60–1.28 0.5067
History of hormone therapy: yes vs no 521 1.07 0.89–1.28 0.4891
Nuclear grade: ≤ 2 vs 3 299 1.05 0.83–1.33 0.6669
Ki-67 index: < 30 vs ≥ 30 178 1.46 1.07–2.00 0.0174
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.51 0.42–0.61 < 0.0001 0.54 0.44–0.67 < 0.0001
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Multivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.
In the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).
ORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions
(a) All eligible patients
All eligible patients Cohort Aa Cohort Bb P First-line therapy Second-line therapy p
No. of patients with target lesions 545 383 162 352 193
Best response, n (%)
CR 14 (2.6%) 8 (2.1%) 6 (3.7%) 0.0180 (W) 10 (2.8%) 4 (2.1%) 0.0001 (W)
PR 292 (53.6%) 219 (57.2%) 73 (45.1%) 209 (59.4%) 83 (43.0%)
SD 139 (25.5%) 104 (27.2%) 35 (21.6%) 77 (21.9%) 62 (32.1%)
PD 71 (13.0%) 36 (9.4%) 35 (21.6%) 35 (9.9%) 36 (18.7%)
NE 29 (5.3%) 16 (4.2%) 13 (8.0%) 21 (6.0%) 8 (4.1%)
Response rate, n (%)
CR plus PR 306 (56.1%) 227 (59.3%) 79 (48.8%) 0.0297 (F) 219 (62.2%) 87 (45.1%) 0.0001 (F)
95% CI 51.9–60.4 54.2–64.2 40.8–56.7 56.9–67.3 37.9–52.4
(b) Cohorts A and B
Cohort Aa First-line therapy Second-line therapy P Cohort Bb First-line therapy Second-line therapy p
No. of patients with target lesions 383 252 131 162 100 62
Best response
CR 8 (2.1%) 6 (2.4%) 2 (1.5%) 0.0048 (W) 6 (3.7%) 4 (4.0%) 2 (3.2%) 0.0011 (W)
PR 219 (57.2%) 155 (61.5%) 64 (48.9%) 73 (45.1%) 54 (54.0%) 19 (30.6%)
SD 104 (27.2%) 57 (22.6%) 47 (35.9%) 35 (21.6%) 20 (20.0%) 15 (24.2%)
PD 36 (9.4%) 21 (8.3%) 15 (11.5%) 35 (21.6%) 14 (14.0%) 21 (33.9%)
NE 16 (4.2%) 13 (5.2%) 3 (2.3%) 13 (8.0%) 8 (8.0%) 5 (8.1%)
Response rate
CR plus PR 227 (59.3%) 161 (63.9%) 66 (50.4%) 0.0119 (F) 79 (48.8%) 58 (58.0%) 21 (33.9%) 0.0036 (F)
95% CI 54.2–64.2 57.6–69.8 41.5–59.2 40.8–56.7 47.7–67.8 22.3–47.0
CR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Safety
The great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)
Treated patient population Cohort Aa Cohort Bb First-line therapy Second-line therapy
n (%) n (%) n (%) n (%) n (%)
(a) Selected AEs
No. of patients 750 100 538 100 212 100 475 100 275 100
Hypertension
All grades 602 80.3 429 79.7 173 81.6 383 80.6 219 79.6
Grade ≥ 3 268 35.7 190 35.3 78 36.8 167 35.2 101 36.7
Peripheral neuropathy
All grades 535 71.3 400 74.3 135 63.7 341 71.8 194 70.5
Grade ≥ 3 54 7.2 41 7.6 13 6.1 36 7.6 18 6.5
Neutropenia
All grades 347 46.3 256 47.6 91 42.9 203 42.7 144 52.4
Grade ≥ 3 204 27.2 151 28.1 53 25.0 115 24.2 89 32.4
Proteinuria
All grades 223 29.7 160 29.7 63 29.7 156 32.8 67 24.4
Grade ≥ 3 28 3.7 18 3.3 10 4.7 20 4.2 8 2.9
Bleeding
All grades 131 17.5 96 17.8 35 16.5 87 18.3 44 16.0
Grade ≥ 3 2 0.3 2 0.4 0 0.0 1 0.2 1 0.4
(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)
No. of patients 750 100 538 100 212 100 475 100 275 100
Congestive heart failure 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Gastrointestinal perforation 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
Thromboembolism 3 0.4 3 0.6 0 0.0 2 0.4 1 0.4
Wound dehiscence 2 0.3 1 0.2 1 0.5 0 0.0 2 0.7
(c) Other adverse events grade ≥ 3
No. of patients 750 100 538 100 212 100 475 100 275 100
Fatigue 12 1.6 6 1.1 6 2.8 4 0.8 8 2.9
Stomatitis 6 0.8 6 1.1 0 0.0 3 0.6 3 1.1
Febrile neutropenia 4 0.5 2 0.4 2 0.9 1 0.2 3 1.1
Other infections 23 3.1 18 3.3 5 2.4 15 3.2 8 2.9
Skin disorders 11 1.5 10 1.9 1 0.5 9 1.9 2 0.7
Anemia 10 1.3 8 1.5 2 0.9 5 1.1 5 1.8
AST/ALT elevation 10 1.3 6 1.1 4 1.9 8 1.7 2 0.7
Appetite loss 7 0.9 5 0.9 2 0.9 3 0.6 4 1.5
Diarrhea 5 0.7 3 0.6 2 0.9 5 1.1 0 0.0
Drug-induced pneumonitis 5 0.7 4 0.7 1 0.5 2 0.4 3 1.1
Pain 4 0.5 3 0.6 1 0.5 2 0.4 2 0.7
Others 31 4.1 24 4.5 7 3.3 13 2.7 18 6.5
ALT alanine aminotransferase, AST aspartate aminotransferase
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Serious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.
Discussion
The B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.
The 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.
The multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].
OS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.
As for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].
The multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].
Despite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).
No new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.
The present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.
In conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.
Electronic supplementary material
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Acknowledgements
The authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.
Funding
The study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Compliance with ethical standards
Conflict of interest
Yamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;
Ethical statement
The study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.
Informed consent
Written informed consent was obtained from all patients. | BEVACIZUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 32715420 | 18,780,431 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastroenteritis'. | Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
OBJECTIVE
To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.
METHODS
In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.
RESULTS
Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.
CONCLUSIONS
In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.
BACKGROUND
Trial no. UMIN000009086.
Introduction
Bevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].
A meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].
The JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.
Although several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.
Patients and methods
Study design
In this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.
Patients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.
Written informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).
Study treatment
Because the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.
In cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.
Study assessment
At screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.
Regarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.
Analysis populations and endpoints
The eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.
The primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).
Statistical analyses
This was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.
Expected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.
For the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.
Safety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.
Results
Study population and baseline patient characteristics
A total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.
Baseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median age (range) (years) 58.0 (26–83) 58.0 (26–81) 58.0 (27–83) 59.0 (26–83) 57.0 (28–83)
Menopausal status
Premenopausal 198 26.3 133 24.7 65 30.2 127 26.6 71 25.7
Postmenopausal 532 70.6 385 71.4 147 68.4 337 70.5 195 70.7
Unknown 24 3.2 21 3.9 3 1.4 14 2.9 10 3.6
ECOG PS
0 522 69.2 371 68.8 151 70.2 345 72.2 177 64.1
1 172 22.8 122 22.6 50 23.3 96 20.1 76 27.5
2 43 5.7 34 6.3 9 4.2 29 6.1 14 5.1
3 17 2.3 12 2.2 5 2.3 8 1.7 9 3.3
ER status
Negative 208 27.6 8 1.5 200 93.0 125 26.2 83 30.1
Positive 544 72.1 529 98.1 15 7.0 351 73.4 193 69.9
Unknown 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
PgR status
Negative 332 44.0 122 22.6 210 97.7 203 42.5 129 46.7
Positive 419 55.6 414 76.8 5 2.3 272 56.9 147 53.3
Unknown 3 0.4 3 0.6 0 0.0 3 0.6 0 0.0
Nuclear grade
1 120 15.9 102 18.9 18 8.4 79 16.5 41 14.9
2 106 14.1 82 15.2 24 11.2 70 14.6 36 13.0
3 216 28.6 111 20.6 105 48.8 144 30.1 72 26.1
Unknown 312 41.4 244 45.3 68 31.6 185 38.7 127 46.0
Ki67 index
< 30 141 18.7 105 19.5 36 16.7 103 21.5 38 13.8
≥ 30 191 25.3 93 17.3 98 45.6 130 27.2 61 22.1
Unknown 422 56.0 341 63.3 81 37.7 245 51.3 177 64.1
Diagnosis
Locally advanced 34 4.5 20 3.7 14 6.5 29 6.1 5 1.8
Stage IV 199 26.4 149 27.6 50 23.3 130 27.2 69 25.0
Recurrence 521 69.1 370 68.6 151 70.2 319 66.7 202 73.2
Disease-free interval (months)
0 233 30.9 169 31.4 64 29.8 159 33.3 74 26.8
0–24 178 23.6 83 15.4 95 44.2 101 21.1 77 27.9
≥ 4 292 38.7 246 45.6 46 21.4 190 39.7 102 37.0
Unknown 51 6.8 41 7.6 10 4.7 28 5.9 23 8.3
Distant metastasis
No 81 10.7 47 8.7 34 15.8 34 7.1 47 17.0
Yes 649 86.1 476 88.3 173 80.5 422 88.3 227 82.2
Unknown 24 3.2 16 3.0 8 3.7 22 4.6 2 0.7
Metastatic sitec
Non-visceral 54 8.3 36 7.6 18 10.4 40 9.5 14 6.2
Visceral 595 91.7 440 92.4 155 89.6 382 90.5 213 93.8
No. of metastatic organsc
< 3 558 86.0 409 85.9 149 86.1 355 84.1 203 89.4
≥ 3 91 14.0 67 14.1 24 13.9 67 15.9 24 10.6
Cancer-related symptoms
No 315 41.8 230 42.7 85 39.5 200 41.8 115 41.7
Yes 434 57.6 305 56.6 129 60.0 275 57.5 159 57.6
Unknown 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Treatment line for locally advanced or metastatic breast cancer
First line 478 63.4 345 64.0 133 61.9
Second line 276 36.6 194 36.0 82 38.1
History of adjuvant therapyd
Chemotherapy 370 71.0 238 64.3 132 87.4 227 71.2 143 70.8
Anthracycline 297 57.0 188 50.8 109 72.2 186 58.3 111 55.0
Taxane 262 50.3 153 41.4 109 72.2 165 51.7 97 48.0
Endocrine therapy 336 64.5 324 87.6 12 7.9 205 64.3 131 64.9
Previous therapy for locally advanced or metastatic breast cancer
Chemotherapy 266 35.3 188 34.9 78 36.3 12 2.5 254 92.0
Anthracycline 80 10.6 63 11.7 17 7.9 4 0.8 76 27.5
Taxane 54 7.2 36 6.7 18 8.4 5 1.0 49 17.8
Endocrine therapy 356 47.2 348 64.6 8 3.7 195 40.8 161 58.3
Radiotherapy 140 18.6 111 20.6 29 13.5 62 13.0 78 28.3
ECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cNumber (%) of distant metastasis
dNumber (%) of patients with breast cancer recurrence
The proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).
Treatment exposure
Most patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median duration of study treatment (25th, 75th percentiles), months 5.1 (3.1, 8.7) 5.5 (3.3, 9.5) 4.0 (2.3, 6.5) 5.3 (3.0, 8.7) 4.8 (2.4, 8.8)
Median duration of bevacizumab (25th, 75th percentiles), months 5.1 (2.8, 8.5) 5.4 (3.3, 9.5) 3.7 (2.3, 6.2) 5.1 (2.8, 8.5) 4.6 (2.4, 8.7)
Median RDI of bevacizumab (25th, 75th percentiles), 97.5 (86.2, 100) 95.9 (86.5, 100) 100 (85.7, 100) 95.6 (87.2–100) 100 (84.8–100)
Discontinuations of bevacizumab, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of bevacizumab, n (%)
Disease progression 379 50.7 261 48.7 118 55.7 221 46.5 158 57.9
Adverse events 214 28.6 169 31.5 45 21.2 143 30.1 71 26.0
Other 152 20.3 105 19.6 47 22.2 109 22.9 43 15.8
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Bevacizumab dose reductions, n (T) 15 2.0 12 2.2 3 1.4 13 2.7 2 0.7
Reason for bevacizumab dose reduction, n (%)c
Hypertension 3 20.0 2 16.7 1 33.3 3 23.1 0 0.0
Proteinuria 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Bleeding 1 6.7 1 8.3 0 0.0 1 7.7 0 0.0
Neutropenia 1 6.7 1 8.3 0 0.0 0 0.0 1 50.0
Other adverse events 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Other 4 26.7 2 16.7 2 66.7 3 23.1 0 0.0
Bevacizumab dose interruptions or delays, n (%) 263 34.9 188 34.9 75 34.9 155 32.4 108 39.1
Reason for bevacizumab dose interruption or delay, n (%)c
Hypertension 18 6.8 15 8.0 3 4.0 16 10.3 2 1.9
Proteinuria 53 20.2 36 19.1 17 22.7 35 22.6 18 16.7
Bleeding 3 1.1 2 1.1 1 1.3 2 1.3 1 0.9
Neutropenia 77 29.3 61 32.4 16 21.3 38 24.5 39 36.1
Other adverse events 106 40.3 77 41.0 29 38.7 61 39.4 45 41.7
Other 114 43.3 79 42.0 35 46.7 63 40.6 51 47.2
Median duration of paclitaxel (25th, 75th percentiles), months 4.9 (2.8, 8.1) 5.3 (3.2, 9.0) 3.9 (2.3, 6.0) 5.1 (3.0, 8.1) 4.6 (2.4, 8.2)
Median RDI of paclitaxel (25th, 75th percentiles), 90.9 (70.6, 100) 88.9 (69.5, 100) 96.0 (75.6, 105) 91.7 (72.7, 100) 89.8 (68.6, 100)
Discontinuations of paclitaxel, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of paclitaxel, n (%)
Disease progression 363 48.5 245 45.7 118 55.7 216 45.5 147 53.8
Adverse events 246 32.9 198 36.9 48 22.6 158 33.3 88 32.2
Other 136 18.2 92 17.2 44 20.8 99 20.8 37 13.6
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Paclitaxel dose reductions, n (%) 276 36.6 208 38.6 68 31.6 185 38.7 91 33.0
Reason for paclitaxel dose reduction, n (%)c
Peripheral neutropenia 114 41.3 89 42.8 25 36.8 81 43.8 33 36.3
Neutropenia 117 42.4 88 42.3 29 42.6 67 36.2 50 54.9
Other adverse events 81 29.3 61 29.3 20 29.4 57 30.8 24 26.4
Other 28 10.1 20 9.6 8 11.8 19 10.3 9 9.9
Paclitaxel dose interruptions or delays, n () 351 46.6 259 48.1 92 42.8 207 43.3 144 52.2
Reason for paclitaxel dose interruption or delay, n (%)c
Peripheral neutropenia 65 18.5 52 20.1 13 14.1 39 18.8 26 18.1
Neutropenia 159 45.3 123 47.5 36 39.1 82 39.6 77 53.5
Other adverse events 168 47.9 118 45.6 50 54.3 94 45.4 74 51.4
Other 127 36.2 90 34.7 37 40.2 72 34.8 55 38.2
Median duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 1.4 (N = 79) 0.5, 3.9 1.4 (N = 65) 0.5, 3.9 0.6 (N = 14) 0.2, 3.0 1.4 (N = 52) 0.5, 3.9 0.8 (N = 27) 0.3, 3.7
Median duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 0.2 (N = 133) 0.2, 0.7 0.2 (N = 86) 0.2, 0.7 0.2 (N = 47) 0.2, 0.9 0.2 (N = 87) 0.2, 1.2 0.2 (N = 46) 0.2, 0.3
RDI relative dose intensity
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cMultiple items could be selected
Of the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).
The dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.
When the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.
Details of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.
Effectiveness
Overall survival
Median observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B
The results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival
(a) All eligible patients
Univariate analysis (N = 754) Multivariate analysis (N = 736)a
Variable N HR 95% CI p HR 95% CI p
Cohort A vs cohort B 754 1.63 1.35–1.97 < 0.0001 1.75 1.44–2.14 < 0.0001
First- vs second-line therapy 754 1.46 1.22–1.74 < 0.0001 1.35 1.13–1.63 0.0011
Age: < 50 years vs ≥ 50 years 754 0.92 0.77–1.10 0.3361
ECOG PS: 0 vs 1, 2, or 3 754 1.59 1.32–1.91 < 0.0001 1.28 1.04–1.57 0.0175
Visceral metastasis: yes vs no 754 0.55 0.44–0.70 < 0.0001 0.52 0.40–0.66 < 0.0001
Cancer-related symptoms: yes vs no 749 0.57 0.48–0.69 < 0.0001 0.56 0.46–0.68 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.63 0.53–0.75 < 0.0001 0.87 0.66–1.14 0.3139
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.60 0.50–0.72 < 0.0001 0.65 0.49–0.86 0.0026
History of taxane-based chemotherapy: yes vs no 754 0.90 0.64–1.26 0.5380
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.78–1.38 0.8108
History of hormone therapy: yes vs no 754 1.02 0.86–1.22 0.8031
Nuclear grade: ≤ 2 vs 3 442 1.31 1.05–1.64 0.0186
Ki-67 index: < 30 vs ≥ 30 332 1.64 1.25–2.16 0.0004
Disease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.02 0.92–1.13 0.7575
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 521 1.52 1.22–1.90 0.0002 1.27 0.94–1.71 0.1251
First- vs second-line therapy 521 1.33 1.08–1.64 0.0069 1.20 0.95–1.52 0.1210
Age: < 50 years vs ≥ 50 years 521 0.92 0.75–1.13 0.4072
ECOG PS: 0 vs 1, 2, or 3 521 1.65 1.32–2.06 < 0.0001 1.32 1.02–1.71 0.0333
Visceral metastasis: yes vs no 521 0.58 0.44–0.77 0.0001 0.53 0.39–0.72 0.0001
Cancer-related symptoms: yes vs no 518 0.50 0.41–0.62 < 0.0001 0.52 0.41–0.66 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.68 0.53–0.86 0.0016 1.08 0.76–1.54 0.6634
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.66 0.53–0.81 0.0001 0.70 0.51–0.95 0.0209
History of taxane-based chemotherapy: yes vs no 521 0.86 0.56–1.32 0.4944
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.57–1.36 0.5617
History of hormone therapy: yes vs no 521 1.28 1.04–1.57 0.0190 1.14 0.87–1.50 0.3367
Nuclear grade: ≤ 2 vs 3 299 1.17 0.90–1.52 0.2389
Ki-67 index: < 30 vs ≥ 30 178 1.81 1.27–2.57 0.0011
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.45 0.36–0.56 < 0.0001 0.50 0.39–0.63 < 0.0001
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
The results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.
The results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.
Progression-free survival and objective response rates
Median PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.
Multivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival
(a) All eligible patients
Univariate analysis (n = 754) Multivariate analysis (n = 687)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 754 1.33 1.13–1.58 0.0008 1.56 1.26–1.93 0.0001
First- vs second-line therapy 754 1.40 1.20–1.64 < 0.0001 1.19 0.99–1.42 0.0622
Age: < 50 years vs ≥ 50 years 754 1.00 0.86–1.16 0.9589
ECOG PS: 0 vs 1, 2, or 3 754 1.60 1.36–1.88 < 0.0001 1.36 1.13–1.64 0.0013
Visceral metastasis: yes vs no 754 0.63 0.52–0.76 < 0.0001 0.68 0.55–0.85 0.0005
Cancer-related symptoms: yes vs no 749 0.68 0.58–0.79 < 0.0001 0.72 0.60–0.86 0.0003
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.62 0.53–0.72 < 0.0001 0.71 0.53–0.95 0.0227
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.61 0.52–0.72 < 0.0001 0.69 0.54–0.89 0.0044
History of taxane-based chemotherapy: yes vs no 754 0.69 0.52–0.92 0.0113 0.82 0.58–1.14 0.2358
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.80–1.31 0.8458
History of endocrine therapy: yes vs no 754 0.85 0.73–0.99 0.0411 0.76 0.62–0.93 0.0075
Nuclear grade: ≤ 2 vs 3 442 1.18 0.97–1.44 0.0961
Ki-67 index: < 30 vs ≥ 30 332 1.54 1.22–1.96 0.0003
Disease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.07 0.99–1.17 0.1040 0.89 0.78–1.01 0.0663
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI p HR 95% CI p
Cohort A vs cohort B 521 1.31 1.08–1.60 0.0073 1.12 0.89–1.40 0.3505
First- vs second-line therapy 521 1.33 1.11–1.60 0.0021 1.16 0.94–1.43 0.1643
Age: < 50 years vs ≥ 50 years 521 1.01 0.84–1.20 0.9470
PS: 0 vs 1, 2, or 3 521 1.74 1.43–2.11 < 0.0001 1.49 1.19–1.88 0.0006
Visceral metastasis: yes vs no 521 0.74 0.59–0.93 0.0086 0.78 0.60–1.00 0.0518
Cancer-related symptoms: yes vs no 518 0.62 0.52–0.74 < 0.0001 0.67 0.55–0.83 0.0002
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.66 0.54–0.81 0.0001 0.85 0.63–1.14 0.2795
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.67 0.56–0.81 < 0.0001 0.78 0.60–1.01 0.0573
History of taxane-based chemotherapy: yes vs no 521 0.66 0.45–0.97 0.0361 0.75 0.47–1.21 0.2333
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.60–1.28 0.5067
History of hormone therapy: yes vs no 521 1.07 0.89–1.28 0.4891
Nuclear grade: ≤ 2 vs 3 299 1.05 0.83–1.33 0.6669
Ki-67 index: < 30 vs ≥ 30 178 1.46 1.07–2.00 0.0174
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.51 0.42–0.61 < 0.0001 0.54 0.44–0.67 < 0.0001
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Multivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.
In the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).
ORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions
(a) All eligible patients
All eligible patients Cohort Aa Cohort Bb P First-line therapy Second-line therapy p
No. of patients with target lesions 545 383 162 352 193
Best response, n (%)
CR 14 (2.6%) 8 (2.1%) 6 (3.7%) 0.0180 (W) 10 (2.8%) 4 (2.1%) 0.0001 (W)
PR 292 (53.6%) 219 (57.2%) 73 (45.1%) 209 (59.4%) 83 (43.0%)
SD 139 (25.5%) 104 (27.2%) 35 (21.6%) 77 (21.9%) 62 (32.1%)
PD 71 (13.0%) 36 (9.4%) 35 (21.6%) 35 (9.9%) 36 (18.7%)
NE 29 (5.3%) 16 (4.2%) 13 (8.0%) 21 (6.0%) 8 (4.1%)
Response rate, n (%)
CR plus PR 306 (56.1%) 227 (59.3%) 79 (48.8%) 0.0297 (F) 219 (62.2%) 87 (45.1%) 0.0001 (F)
95% CI 51.9–60.4 54.2–64.2 40.8–56.7 56.9–67.3 37.9–52.4
(b) Cohorts A and B
Cohort Aa First-line therapy Second-line therapy P Cohort Bb First-line therapy Second-line therapy p
No. of patients with target lesions 383 252 131 162 100 62
Best response
CR 8 (2.1%) 6 (2.4%) 2 (1.5%) 0.0048 (W) 6 (3.7%) 4 (4.0%) 2 (3.2%) 0.0011 (W)
PR 219 (57.2%) 155 (61.5%) 64 (48.9%) 73 (45.1%) 54 (54.0%) 19 (30.6%)
SD 104 (27.2%) 57 (22.6%) 47 (35.9%) 35 (21.6%) 20 (20.0%) 15 (24.2%)
PD 36 (9.4%) 21 (8.3%) 15 (11.5%) 35 (21.6%) 14 (14.0%) 21 (33.9%)
NE 16 (4.2%) 13 (5.2%) 3 (2.3%) 13 (8.0%) 8 (8.0%) 5 (8.1%)
Response rate
CR plus PR 227 (59.3%) 161 (63.9%) 66 (50.4%) 0.0119 (F) 79 (48.8%) 58 (58.0%) 21 (33.9%) 0.0036 (F)
95% CI 54.2–64.2 57.6–69.8 41.5–59.2 40.8–56.7 47.7–67.8 22.3–47.0
CR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Safety
The great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)
Treated patient population Cohort Aa Cohort Bb First-line therapy Second-line therapy
n (%) n (%) n (%) n (%) n (%)
(a) Selected AEs
No. of patients 750 100 538 100 212 100 475 100 275 100
Hypertension
All grades 602 80.3 429 79.7 173 81.6 383 80.6 219 79.6
Grade ≥ 3 268 35.7 190 35.3 78 36.8 167 35.2 101 36.7
Peripheral neuropathy
All grades 535 71.3 400 74.3 135 63.7 341 71.8 194 70.5
Grade ≥ 3 54 7.2 41 7.6 13 6.1 36 7.6 18 6.5
Neutropenia
All grades 347 46.3 256 47.6 91 42.9 203 42.7 144 52.4
Grade ≥ 3 204 27.2 151 28.1 53 25.0 115 24.2 89 32.4
Proteinuria
All grades 223 29.7 160 29.7 63 29.7 156 32.8 67 24.4
Grade ≥ 3 28 3.7 18 3.3 10 4.7 20 4.2 8 2.9
Bleeding
All grades 131 17.5 96 17.8 35 16.5 87 18.3 44 16.0
Grade ≥ 3 2 0.3 2 0.4 0 0.0 1 0.2 1 0.4
(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)
No. of patients 750 100 538 100 212 100 475 100 275 100
Congestive heart failure 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Gastrointestinal perforation 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
Thromboembolism 3 0.4 3 0.6 0 0.0 2 0.4 1 0.4
Wound dehiscence 2 0.3 1 0.2 1 0.5 0 0.0 2 0.7
(c) Other adverse events grade ≥ 3
No. of patients 750 100 538 100 212 100 475 100 275 100
Fatigue 12 1.6 6 1.1 6 2.8 4 0.8 8 2.9
Stomatitis 6 0.8 6 1.1 0 0.0 3 0.6 3 1.1
Febrile neutropenia 4 0.5 2 0.4 2 0.9 1 0.2 3 1.1
Other infections 23 3.1 18 3.3 5 2.4 15 3.2 8 2.9
Skin disorders 11 1.5 10 1.9 1 0.5 9 1.9 2 0.7
Anemia 10 1.3 8 1.5 2 0.9 5 1.1 5 1.8
AST/ALT elevation 10 1.3 6 1.1 4 1.9 8 1.7 2 0.7
Appetite loss 7 0.9 5 0.9 2 0.9 3 0.6 4 1.5
Diarrhea 5 0.7 3 0.6 2 0.9 5 1.1 0 0.0
Drug-induced pneumonitis 5 0.7 4 0.7 1 0.5 2 0.4 3 1.1
Pain 4 0.5 3 0.6 1 0.5 2 0.4 2 0.7
Others 31 4.1 24 4.5 7 3.3 13 2.7 18 6.5
ALT alanine aminotransferase, AST aspartate aminotransferase
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Serious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.
Discussion
The B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.
The 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.
The multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].
OS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.
As for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].
The multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].
Despite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).
No new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.
The present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.
In conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (XLSX 85 kb)
Supplementary file2 (PDF 953 kb)
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Acknowledgements
The authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.
Funding
The study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Compliance with ethical standards
Conflict of interest
Yamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;
Ethical statement
The study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.
Informed consent
Written informed consent was obtained from all patients. | BEVACIZUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 32715420 | 18,780,431 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal perforation'. | Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
OBJECTIVE
To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.
METHODS
In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.
RESULTS
Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.
CONCLUSIONS
In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.
BACKGROUND
Trial no. UMIN000009086.
Introduction
Bevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].
A meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].
The JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.
Although several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.
Patients and methods
Study design
In this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.
Patients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.
Written informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).
Study treatment
Because the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.
In cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.
Study assessment
At screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.
Regarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.
Analysis populations and endpoints
The eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.
The primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).
Statistical analyses
This was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.
Expected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.
For the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.
Safety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.
Results
Study population and baseline patient characteristics
A total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.
Baseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median age (range) (years) 58.0 (26–83) 58.0 (26–81) 58.0 (27–83) 59.0 (26–83) 57.0 (28–83)
Menopausal status
Premenopausal 198 26.3 133 24.7 65 30.2 127 26.6 71 25.7
Postmenopausal 532 70.6 385 71.4 147 68.4 337 70.5 195 70.7
Unknown 24 3.2 21 3.9 3 1.4 14 2.9 10 3.6
ECOG PS
0 522 69.2 371 68.8 151 70.2 345 72.2 177 64.1
1 172 22.8 122 22.6 50 23.3 96 20.1 76 27.5
2 43 5.7 34 6.3 9 4.2 29 6.1 14 5.1
3 17 2.3 12 2.2 5 2.3 8 1.7 9 3.3
ER status
Negative 208 27.6 8 1.5 200 93.0 125 26.2 83 30.1
Positive 544 72.1 529 98.1 15 7.0 351 73.4 193 69.9
Unknown 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
PgR status
Negative 332 44.0 122 22.6 210 97.7 203 42.5 129 46.7
Positive 419 55.6 414 76.8 5 2.3 272 56.9 147 53.3
Unknown 3 0.4 3 0.6 0 0.0 3 0.6 0 0.0
Nuclear grade
1 120 15.9 102 18.9 18 8.4 79 16.5 41 14.9
2 106 14.1 82 15.2 24 11.2 70 14.6 36 13.0
3 216 28.6 111 20.6 105 48.8 144 30.1 72 26.1
Unknown 312 41.4 244 45.3 68 31.6 185 38.7 127 46.0
Ki67 index
< 30 141 18.7 105 19.5 36 16.7 103 21.5 38 13.8
≥ 30 191 25.3 93 17.3 98 45.6 130 27.2 61 22.1
Unknown 422 56.0 341 63.3 81 37.7 245 51.3 177 64.1
Diagnosis
Locally advanced 34 4.5 20 3.7 14 6.5 29 6.1 5 1.8
Stage IV 199 26.4 149 27.6 50 23.3 130 27.2 69 25.0
Recurrence 521 69.1 370 68.6 151 70.2 319 66.7 202 73.2
Disease-free interval (months)
0 233 30.9 169 31.4 64 29.8 159 33.3 74 26.8
0–24 178 23.6 83 15.4 95 44.2 101 21.1 77 27.9
≥ 4 292 38.7 246 45.6 46 21.4 190 39.7 102 37.0
Unknown 51 6.8 41 7.6 10 4.7 28 5.9 23 8.3
Distant metastasis
No 81 10.7 47 8.7 34 15.8 34 7.1 47 17.0
Yes 649 86.1 476 88.3 173 80.5 422 88.3 227 82.2
Unknown 24 3.2 16 3.0 8 3.7 22 4.6 2 0.7
Metastatic sitec
Non-visceral 54 8.3 36 7.6 18 10.4 40 9.5 14 6.2
Visceral 595 91.7 440 92.4 155 89.6 382 90.5 213 93.8
No. of metastatic organsc
< 3 558 86.0 409 85.9 149 86.1 355 84.1 203 89.4
≥ 3 91 14.0 67 14.1 24 13.9 67 15.9 24 10.6
Cancer-related symptoms
No 315 41.8 230 42.7 85 39.5 200 41.8 115 41.7
Yes 434 57.6 305 56.6 129 60.0 275 57.5 159 57.6
Unknown 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Treatment line for locally advanced or metastatic breast cancer
First line 478 63.4 345 64.0 133 61.9
Second line 276 36.6 194 36.0 82 38.1
History of adjuvant therapyd
Chemotherapy 370 71.0 238 64.3 132 87.4 227 71.2 143 70.8
Anthracycline 297 57.0 188 50.8 109 72.2 186 58.3 111 55.0
Taxane 262 50.3 153 41.4 109 72.2 165 51.7 97 48.0
Endocrine therapy 336 64.5 324 87.6 12 7.9 205 64.3 131 64.9
Previous therapy for locally advanced or metastatic breast cancer
Chemotherapy 266 35.3 188 34.9 78 36.3 12 2.5 254 92.0
Anthracycline 80 10.6 63 11.7 17 7.9 4 0.8 76 27.5
Taxane 54 7.2 36 6.7 18 8.4 5 1.0 49 17.8
Endocrine therapy 356 47.2 348 64.6 8 3.7 195 40.8 161 58.3
Radiotherapy 140 18.6 111 20.6 29 13.5 62 13.0 78 28.3
ECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cNumber (%) of distant metastasis
dNumber (%) of patients with breast cancer recurrence
The proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).
Treatment exposure
Most patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median duration of study treatment (25th, 75th percentiles), months 5.1 (3.1, 8.7) 5.5 (3.3, 9.5) 4.0 (2.3, 6.5) 5.3 (3.0, 8.7) 4.8 (2.4, 8.8)
Median duration of bevacizumab (25th, 75th percentiles), months 5.1 (2.8, 8.5) 5.4 (3.3, 9.5) 3.7 (2.3, 6.2) 5.1 (2.8, 8.5) 4.6 (2.4, 8.7)
Median RDI of bevacizumab (25th, 75th percentiles), 97.5 (86.2, 100) 95.9 (86.5, 100) 100 (85.7, 100) 95.6 (87.2–100) 100 (84.8–100)
Discontinuations of bevacizumab, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of bevacizumab, n (%)
Disease progression 379 50.7 261 48.7 118 55.7 221 46.5 158 57.9
Adverse events 214 28.6 169 31.5 45 21.2 143 30.1 71 26.0
Other 152 20.3 105 19.6 47 22.2 109 22.9 43 15.8
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Bevacizumab dose reductions, n (T) 15 2.0 12 2.2 3 1.4 13 2.7 2 0.7
Reason for bevacizumab dose reduction, n (%)c
Hypertension 3 20.0 2 16.7 1 33.3 3 23.1 0 0.0
Proteinuria 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Bleeding 1 6.7 1 8.3 0 0.0 1 7.7 0 0.0
Neutropenia 1 6.7 1 8.3 0 0.0 0 0.0 1 50.0
Other adverse events 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Other 4 26.7 2 16.7 2 66.7 3 23.1 0 0.0
Bevacizumab dose interruptions or delays, n (%) 263 34.9 188 34.9 75 34.9 155 32.4 108 39.1
Reason for bevacizumab dose interruption or delay, n (%)c
Hypertension 18 6.8 15 8.0 3 4.0 16 10.3 2 1.9
Proteinuria 53 20.2 36 19.1 17 22.7 35 22.6 18 16.7
Bleeding 3 1.1 2 1.1 1 1.3 2 1.3 1 0.9
Neutropenia 77 29.3 61 32.4 16 21.3 38 24.5 39 36.1
Other adverse events 106 40.3 77 41.0 29 38.7 61 39.4 45 41.7
Other 114 43.3 79 42.0 35 46.7 63 40.6 51 47.2
Median duration of paclitaxel (25th, 75th percentiles), months 4.9 (2.8, 8.1) 5.3 (3.2, 9.0) 3.9 (2.3, 6.0) 5.1 (3.0, 8.1) 4.6 (2.4, 8.2)
Median RDI of paclitaxel (25th, 75th percentiles), 90.9 (70.6, 100) 88.9 (69.5, 100) 96.0 (75.6, 105) 91.7 (72.7, 100) 89.8 (68.6, 100)
Discontinuations of paclitaxel, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of paclitaxel, n (%)
Disease progression 363 48.5 245 45.7 118 55.7 216 45.5 147 53.8
Adverse events 246 32.9 198 36.9 48 22.6 158 33.3 88 32.2
Other 136 18.2 92 17.2 44 20.8 99 20.8 37 13.6
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Paclitaxel dose reductions, n (%) 276 36.6 208 38.6 68 31.6 185 38.7 91 33.0
Reason for paclitaxel dose reduction, n (%)c
Peripheral neutropenia 114 41.3 89 42.8 25 36.8 81 43.8 33 36.3
Neutropenia 117 42.4 88 42.3 29 42.6 67 36.2 50 54.9
Other adverse events 81 29.3 61 29.3 20 29.4 57 30.8 24 26.4
Other 28 10.1 20 9.6 8 11.8 19 10.3 9 9.9
Paclitaxel dose interruptions or delays, n () 351 46.6 259 48.1 92 42.8 207 43.3 144 52.2
Reason for paclitaxel dose interruption or delay, n (%)c
Peripheral neutropenia 65 18.5 52 20.1 13 14.1 39 18.8 26 18.1
Neutropenia 159 45.3 123 47.5 36 39.1 82 39.6 77 53.5
Other adverse events 168 47.9 118 45.6 50 54.3 94 45.4 74 51.4
Other 127 36.2 90 34.7 37 40.2 72 34.8 55 38.2
Median duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 1.4 (N = 79) 0.5, 3.9 1.4 (N = 65) 0.5, 3.9 0.6 (N = 14) 0.2, 3.0 1.4 (N = 52) 0.5, 3.9 0.8 (N = 27) 0.3, 3.7
Median duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 0.2 (N = 133) 0.2, 0.7 0.2 (N = 86) 0.2, 0.7 0.2 (N = 47) 0.2, 0.9 0.2 (N = 87) 0.2, 1.2 0.2 (N = 46) 0.2, 0.3
RDI relative dose intensity
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cMultiple items could be selected
Of the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).
The dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.
When the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.
Details of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.
Effectiveness
Overall survival
Median observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B
The results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival
(a) All eligible patients
Univariate analysis (N = 754) Multivariate analysis (N = 736)a
Variable N HR 95% CI p HR 95% CI p
Cohort A vs cohort B 754 1.63 1.35–1.97 < 0.0001 1.75 1.44–2.14 < 0.0001
First- vs second-line therapy 754 1.46 1.22–1.74 < 0.0001 1.35 1.13–1.63 0.0011
Age: < 50 years vs ≥ 50 years 754 0.92 0.77–1.10 0.3361
ECOG PS: 0 vs 1, 2, or 3 754 1.59 1.32–1.91 < 0.0001 1.28 1.04–1.57 0.0175
Visceral metastasis: yes vs no 754 0.55 0.44–0.70 < 0.0001 0.52 0.40–0.66 < 0.0001
Cancer-related symptoms: yes vs no 749 0.57 0.48–0.69 < 0.0001 0.56 0.46–0.68 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.63 0.53–0.75 < 0.0001 0.87 0.66–1.14 0.3139
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.60 0.50–0.72 < 0.0001 0.65 0.49–0.86 0.0026
History of taxane-based chemotherapy: yes vs no 754 0.90 0.64–1.26 0.5380
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.78–1.38 0.8108
History of hormone therapy: yes vs no 754 1.02 0.86–1.22 0.8031
Nuclear grade: ≤ 2 vs 3 442 1.31 1.05–1.64 0.0186
Ki-67 index: < 30 vs ≥ 30 332 1.64 1.25–2.16 0.0004
Disease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.02 0.92–1.13 0.7575
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 521 1.52 1.22–1.90 0.0002 1.27 0.94–1.71 0.1251
First- vs second-line therapy 521 1.33 1.08–1.64 0.0069 1.20 0.95–1.52 0.1210
Age: < 50 years vs ≥ 50 years 521 0.92 0.75–1.13 0.4072
ECOG PS: 0 vs 1, 2, or 3 521 1.65 1.32–2.06 < 0.0001 1.32 1.02–1.71 0.0333
Visceral metastasis: yes vs no 521 0.58 0.44–0.77 0.0001 0.53 0.39–0.72 0.0001
Cancer-related symptoms: yes vs no 518 0.50 0.41–0.62 < 0.0001 0.52 0.41–0.66 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.68 0.53–0.86 0.0016 1.08 0.76–1.54 0.6634
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.66 0.53–0.81 0.0001 0.70 0.51–0.95 0.0209
History of taxane-based chemotherapy: yes vs no 521 0.86 0.56–1.32 0.4944
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.57–1.36 0.5617
History of hormone therapy: yes vs no 521 1.28 1.04–1.57 0.0190 1.14 0.87–1.50 0.3367
Nuclear grade: ≤ 2 vs 3 299 1.17 0.90–1.52 0.2389
Ki-67 index: < 30 vs ≥ 30 178 1.81 1.27–2.57 0.0011
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.45 0.36–0.56 < 0.0001 0.50 0.39–0.63 < 0.0001
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
The results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.
The results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.
Progression-free survival and objective response rates
Median PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.
Multivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival
(a) All eligible patients
Univariate analysis (n = 754) Multivariate analysis (n = 687)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 754 1.33 1.13–1.58 0.0008 1.56 1.26–1.93 0.0001
First- vs second-line therapy 754 1.40 1.20–1.64 < 0.0001 1.19 0.99–1.42 0.0622
Age: < 50 years vs ≥ 50 years 754 1.00 0.86–1.16 0.9589
ECOG PS: 0 vs 1, 2, or 3 754 1.60 1.36–1.88 < 0.0001 1.36 1.13–1.64 0.0013
Visceral metastasis: yes vs no 754 0.63 0.52–0.76 < 0.0001 0.68 0.55–0.85 0.0005
Cancer-related symptoms: yes vs no 749 0.68 0.58–0.79 < 0.0001 0.72 0.60–0.86 0.0003
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.62 0.53–0.72 < 0.0001 0.71 0.53–0.95 0.0227
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.61 0.52–0.72 < 0.0001 0.69 0.54–0.89 0.0044
History of taxane-based chemotherapy: yes vs no 754 0.69 0.52–0.92 0.0113 0.82 0.58–1.14 0.2358
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.80–1.31 0.8458
History of endocrine therapy: yes vs no 754 0.85 0.73–0.99 0.0411 0.76 0.62–0.93 0.0075
Nuclear grade: ≤ 2 vs 3 442 1.18 0.97–1.44 0.0961
Ki-67 index: < 30 vs ≥ 30 332 1.54 1.22–1.96 0.0003
Disease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.07 0.99–1.17 0.1040 0.89 0.78–1.01 0.0663
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI p HR 95% CI p
Cohort A vs cohort B 521 1.31 1.08–1.60 0.0073 1.12 0.89–1.40 0.3505
First- vs second-line therapy 521 1.33 1.11–1.60 0.0021 1.16 0.94–1.43 0.1643
Age: < 50 years vs ≥ 50 years 521 1.01 0.84–1.20 0.9470
PS: 0 vs 1, 2, or 3 521 1.74 1.43–2.11 < 0.0001 1.49 1.19–1.88 0.0006
Visceral metastasis: yes vs no 521 0.74 0.59–0.93 0.0086 0.78 0.60–1.00 0.0518
Cancer-related symptoms: yes vs no 518 0.62 0.52–0.74 < 0.0001 0.67 0.55–0.83 0.0002
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.66 0.54–0.81 0.0001 0.85 0.63–1.14 0.2795
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.67 0.56–0.81 < 0.0001 0.78 0.60–1.01 0.0573
History of taxane-based chemotherapy: yes vs no 521 0.66 0.45–0.97 0.0361 0.75 0.47–1.21 0.2333
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.60–1.28 0.5067
History of hormone therapy: yes vs no 521 1.07 0.89–1.28 0.4891
Nuclear grade: ≤ 2 vs 3 299 1.05 0.83–1.33 0.6669
Ki-67 index: < 30 vs ≥ 30 178 1.46 1.07–2.00 0.0174
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.51 0.42–0.61 < 0.0001 0.54 0.44–0.67 < 0.0001
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Multivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.
In the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).
ORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions
(a) All eligible patients
All eligible patients Cohort Aa Cohort Bb P First-line therapy Second-line therapy p
No. of patients with target lesions 545 383 162 352 193
Best response, n (%)
CR 14 (2.6%) 8 (2.1%) 6 (3.7%) 0.0180 (W) 10 (2.8%) 4 (2.1%) 0.0001 (W)
PR 292 (53.6%) 219 (57.2%) 73 (45.1%) 209 (59.4%) 83 (43.0%)
SD 139 (25.5%) 104 (27.2%) 35 (21.6%) 77 (21.9%) 62 (32.1%)
PD 71 (13.0%) 36 (9.4%) 35 (21.6%) 35 (9.9%) 36 (18.7%)
NE 29 (5.3%) 16 (4.2%) 13 (8.0%) 21 (6.0%) 8 (4.1%)
Response rate, n (%)
CR plus PR 306 (56.1%) 227 (59.3%) 79 (48.8%) 0.0297 (F) 219 (62.2%) 87 (45.1%) 0.0001 (F)
95% CI 51.9–60.4 54.2–64.2 40.8–56.7 56.9–67.3 37.9–52.4
(b) Cohorts A and B
Cohort Aa First-line therapy Second-line therapy P Cohort Bb First-line therapy Second-line therapy p
No. of patients with target lesions 383 252 131 162 100 62
Best response
CR 8 (2.1%) 6 (2.4%) 2 (1.5%) 0.0048 (W) 6 (3.7%) 4 (4.0%) 2 (3.2%) 0.0011 (W)
PR 219 (57.2%) 155 (61.5%) 64 (48.9%) 73 (45.1%) 54 (54.0%) 19 (30.6%)
SD 104 (27.2%) 57 (22.6%) 47 (35.9%) 35 (21.6%) 20 (20.0%) 15 (24.2%)
PD 36 (9.4%) 21 (8.3%) 15 (11.5%) 35 (21.6%) 14 (14.0%) 21 (33.9%)
NE 16 (4.2%) 13 (5.2%) 3 (2.3%) 13 (8.0%) 8 (8.0%) 5 (8.1%)
Response rate
CR plus PR 227 (59.3%) 161 (63.9%) 66 (50.4%) 0.0119 (F) 79 (48.8%) 58 (58.0%) 21 (33.9%) 0.0036 (F)
95% CI 54.2–64.2 57.6–69.8 41.5–59.2 40.8–56.7 47.7–67.8 22.3–47.0
CR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Safety
The great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)
Treated patient population Cohort Aa Cohort Bb First-line therapy Second-line therapy
n (%) n (%) n (%) n (%) n (%)
(a) Selected AEs
No. of patients 750 100 538 100 212 100 475 100 275 100
Hypertension
All grades 602 80.3 429 79.7 173 81.6 383 80.6 219 79.6
Grade ≥ 3 268 35.7 190 35.3 78 36.8 167 35.2 101 36.7
Peripheral neuropathy
All grades 535 71.3 400 74.3 135 63.7 341 71.8 194 70.5
Grade ≥ 3 54 7.2 41 7.6 13 6.1 36 7.6 18 6.5
Neutropenia
All grades 347 46.3 256 47.6 91 42.9 203 42.7 144 52.4
Grade ≥ 3 204 27.2 151 28.1 53 25.0 115 24.2 89 32.4
Proteinuria
All grades 223 29.7 160 29.7 63 29.7 156 32.8 67 24.4
Grade ≥ 3 28 3.7 18 3.3 10 4.7 20 4.2 8 2.9
Bleeding
All grades 131 17.5 96 17.8 35 16.5 87 18.3 44 16.0
Grade ≥ 3 2 0.3 2 0.4 0 0.0 1 0.2 1 0.4
(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)
No. of patients 750 100 538 100 212 100 475 100 275 100
Congestive heart failure 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Gastrointestinal perforation 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
Thromboembolism 3 0.4 3 0.6 0 0.0 2 0.4 1 0.4
Wound dehiscence 2 0.3 1 0.2 1 0.5 0 0.0 2 0.7
(c) Other adverse events grade ≥ 3
No. of patients 750 100 538 100 212 100 475 100 275 100
Fatigue 12 1.6 6 1.1 6 2.8 4 0.8 8 2.9
Stomatitis 6 0.8 6 1.1 0 0.0 3 0.6 3 1.1
Febrile neutropenia 4 0.5 2 0.4 2 0.9 1 0.2 3 1.1
Other infections 23 3.1 18 3.3 5 2.4 15 3.2 8 2.9
Skin disorders 11 1.5 10 1.9 1 0.5 9 1.9 2 0.7
Anemia 10 1.3 8 1.5 2 0.9 5 1.1 5 1.8
AST/ALT elevation 10 1.3 6 1.1 4 1.9 8 1.7 2 0.7
Appetite loss 7 0.9 5 0.9 2 0.9 3 0.6 4 1.5
Diarrhea 5 0.7 3 0.6 2 0.9 5 1.1 0 0.0
Drug-induced pneumonitis 5 0.7 4 0.7 1 0.5 2 0.4 3 1.1
Pain 4 0.5 3 0.6 1 0.5 2 0.4 2 0.7
Others 31 4.1 24 4.5 7 3.3 13 2.7 18 6.5
ALT alanine aminotransferase, AST aspartate aminotransferase
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Serious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.
Discussion
The B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.
The 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.
The multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].
OS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.
As for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].
The multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].
Despite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).
No new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.
The present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.
In conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.
Electronic supplementary material
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Acknowledgements
The authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.
Funding
The study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Compliance with ethical standards
Conflict of interest
Yamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;
Ethical statement
The study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.
Informed consent
Written informed consent was obtained from all patients. | BEVACIZUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 32715420 | 18,780,429 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic failure'. | Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
OBJECTIVE
To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.
METHODS
In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.
RESULTS
Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.
CONCLUSIONS
In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.
BACKGROUND
Trial no. UMIN000009086.
Introduction
Bevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].
A meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].
The JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.
Although several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.
Patients and methods
Study design
In this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.
Patients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.
Written informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).
Study treatment
Because the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.
In cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.
Study assessment
At screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.
Regarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.
Analysis populations and endpoints
The eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.
The primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).
Statistical analyses
This was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.
Expected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.
For the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.
Safety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.
Results
Study population and baseline patient characteristics
A total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.
Baseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median age (range) (years) 58.0 (26–83) 58.0 (26–81) 58.0 (27–83) 59.0 (26–83) 57.0 (28–83)
Menopausal status
Premenopausal 198 26.3 133 24.7 65 30.2 127 26.6 71 25.7
Postmenopausal 532 70.6 385 71.4 147 68.4 337 70.5 195 70.7
Unknown 24 3.2 21 3.9 3 1.4 14 2.9 10 3.6
ECOG PS
0 522 69.2 371 68.8 151 70.2 345 72.2 177 64.1
1 172 22.8 122 22.6 50 23.3 96 20.1 76 27.5
2 43 5.7 34 6.3 9 4.2 29 6.1 14 5.1
3 17 2.3 12 2.2 5 2.3 8 1.7 9 3.3
ER status
Negative 208 27.6 8 1.5 200 93.0 125 26.2 83 30.1
Positive 544 72.1 529 98.1 15 7.0 351 73.4 193 69.9
Unknown 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
PgR status
Negative 332 44.0 122 22.6 210 97.7 203 42.5 129 46.7
Positive 419 55.6 414 76.8 5 2.3 272 56.9 147 53.3
Unknown 3 0.4 3 0.6 0 0.0 3 0.6 0 0.0
Nuclear grade
1 120 15.9 102 18.9 18 8.4 79 16.5 41 14.9
2 106 14.1 82 15.2 24 11.2 70 14.6 36 13.0
3 216 28.6 111 20.6 105 48.8 144 30.1 72 26.1
Unknown 312 41.4 244 45.3 68 31.6 185 38.7 127 46.0
Ki67 index
< 30 141 18.7 105 19.5 36 16.7 103 21.5 38 13.8
≥ 30 191 25.3 93 17.3 98 45.6 130 27.2 61 22.1
Unknown 422 56.0 341 63.3 81 37.7 245 51.3 177 64.1
Diagnosis
Locally advanced 34 4.5 20 3.7 14 6.5 29 6.1 5 1.8
Stage IV 199 26.4 149 27.6 50 23.3 130 27.2 69 25.0
Recurrence 521 69.1 370 68.6 151 70.2 319 66.7 202 73.2
Disease-free interval (months)
0 233 30.9 169 31.4 64 29.8 159 33.3 74 26.8
0–24 178 23.6 83 15.4 95 44.2 101 21.1 77 27.9
≥ 4 292 38.7 246 45.6 46 21.4 190 39.7 102 37.0
Unknown 51 6.8 41 7.6 10 4.7 28 5.9 23 8.3
Distant metastasis
No 81 10.7 47 8.7 34 15.8 34 7.1 47 17.0
Yes 649 86.1 476 88.3 173 80.5 422 88.3 227 82.2
Unknown 24 3.2 16 3.0 8 3.7 22 4.6 2 0.7
Metastatic sitec
Non-visceral 54 8.3 36 7.6 18 10.4 40 9.5 14 6.2
Visceral 595 91.7 440 92.4 155 89.6 382 90.5 213 93.8
No. of metastatic organsc
< 3 558 86.0 409 85.9 149 86.1 355 84.1 203 89.4
≥ 3 91 14.0 67 14.1 24 13.9 67 15.9 24 10.6
Cancer-related symptoms
No 315 41.8 230 42.7 85 39.5 200 41.8 115 41.7
Yes 434 57.6 305 56.6 129 60.0 275 57.5 159 57.6
Unknown 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Treatment line for locally advanced or metastatic breast cancer
First line 478 63.4 345 64.0 133 61.9
Second line 276 36.6 194 36.0 82 38.1
History of adjuvant therapyd
Chemotherapy 370 71.0 238 64.3 132 87.4 227 71.2 143 70.8
Anthracycline 297 57.0 188 50.8 109 72.2 186 58.3 111 55.0
Taxane 262 50.3 153 41.4 109 72.2 165 51.7 97 48.0
Endocrine therapy 336 64.5 324 87.6 12 7.9 205 64.3 131 64.9
Previous therapy for locally advanced or metastatic breast cancer
Chemotherapy 266 35.3 188 34.9 78 36.3 12 2.5 254 92.0
Anthracycline 80 10.6 63 11.7 17 7.9 4 0.8 76 27.5
Taxane 54 7.2 36 6.7 18 8.4 5 1.0 49 17.8
Endocrine therapy 356 47.2 348 64.6 8 3.7 195 40.8 161 58.3
Radiotherapy 140 18.6 111 20.6 29 13.5 62 13.0 78 28.3
ECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cNumber (%) of distant metastasis
dNumber (%) of patients with breast cancer recurrence
The proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).
Treatment exposure
Most patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median duration of study treatment (25th, 75th percentiles), months 5.1 (3.1, 8.7) 5.5 (3.3, 9.5) 4.0 (2.3, 6.5) 5.3 (3.0, 8.7) 4.8 (2.4, 8.8)
Median duration of bevacizumab (25th, 75th percentiles), months 5.1 (2.8, 8.5) 5.4 (3.3, 9.5) 3.7 (2.3, 6.2) 5.1 (2.8, 8.5) 4.6 (2.4, 8.7)
Median RDI of bevacizumab (25th, 75th percentiles), 97.5 (86.2, 100) 95.9 (86.5, 100) 100 (85.7, 100) 95.6 (87.2–100) 100 (84.8–100)
Discontinuations of bevacizumab, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of bevacizumab, n (%)
Disease progression 379 50.7 261 48.7 118 55.7 221 46.5 158 57.9
Adverse events 214 28.6 169 31.5 45 21.2 143 30.1 71 26.0
Other 152 20.3 105 19.6 47 22.2 109 22.9 43 15.8
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Bevacizumab dose reductions, n (T) 15 2.0 12 2.2 3 1.4 13 2.7 2 0.7
Reason for bevacizumab dose reduction, n (%)c
Hypertension 3 20.0 2 16.7 1 33.3 3 23.1 0 0.0
Proteinuria 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Bleeding 1 6.7 1 8.3 0 0.0 1 7.7 0 0.0
Neutropenia 1 6.7 1 8.3 0 0.0 0 0.0 1 50.0
Other adverse events 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Other 4 26.7 2 16.7 2 66.7 3 23.1 0 0.0
Bevacizumab dose interruptions or delays, n (%) 263 34.9 188 34.9 75 34.9 155 32.4 108 39.1
Reason for bevacizumab dose interruption or delay, n (%)c
Hypertension 18 6.8 15 8.0 3 4.0 16 10.3 2 1.9
Proteinuria 53 20.2 36 19.1 17 22.7 35 22.6 18 16.7
Bleeding 3 1.1 2 1.1 1 1.3 2 1.3 1 0.9
Neutropenia 77 29.3 61 32.4 16 21.3 38 24.5 39 36.1
Other adverse events 106 40.3 77 41.0 29 38.7 61 39.4 45 41.7
Other 114 43.3 79 42.0 35 46.7 63 40.6 51 47.2
Median duration of paclitaxel (25th, 75th percentiles), months 4.9 (2.8, 8.1) 5.3 (3.2, 9.0) 3.9 (2.3, 6.0) 5.1 (3.0, 8.1) 4.6 (2.4, 8.2)
Median RDI of paclitaxel (25th, 75th percentiles), 90.9 (70.6, 100) 88.9 (69.5, 100) 96.0 (75.6, 105) 91.7 (72.7, 100) 89.8 (68.6, 100)
Discontinuations of paclitaxel, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of paclitaxel, n (%)
Disease progression 363 48.5 245 45.7 118 55.7 216 45.5 147 53.8
Adverse events 246 32.9 198 36.9 48 22.6 158 33.3 88 32.2
Other 136 18.2 92 17.2 44 20.8 99 20.8 37 13.6
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Paclitaxel dose reductions, n (%) 276 36.6 208 38.6 68 31.6 185 38.7 91 33.0
Reason for paclitaxel dose reduction, n (%)c
Peripheral neutropenia 114 41.3 89 42.8 25 36.8 81 43.8 33 36.3
Neutropenia 117 42.4 88 42.3 29 42.6 67 36.2 50 54.9
Other adverse events 81 29.3 61 29.3 20 29.4 57 30.8 24 26.4
Other 28 10.1 20 9.6 8 11.8 19 10.3 9 9.9
Paclitaxel dose interruptions or delays, n () 351 46.6 259 48.1 92 42.8 207 43.3 144 52.2
Reason for paclitaxel dose interruption or delay, n (%)c
Peripheral neutropenia 65 18.5 52 20.1 13 14.1 39 18.8 26 18.1
Neutropenia 159 45.3 123 47.5 36 39.1 82 39.6 77 53.5
Other adverse events 168 47.9 118 45.6 50 54.3 94 45.4 74 51.4
Other 127 36.2 90 34.7 37 40.2 72 34.8 55 38.2
Median duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 1.4 (N = 79) 0.5, 3.9 1.4 (N = 65) 0.5, 3.9 0.6 (N = 14) 0.2, 3.0 1.4 (N = 52) 0.5, 3.9 0.8 (N = 27) 0.3, 3.7
Median duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 0.2 (N = 133) 0.2, 0.7 0.2 (N = 86) 0.2, 0.7 0.2 (N = 47) 0.2, 0.9 0.2 (N = 87) 0.2, 1.2 0.2 (N = 46) 0.2, 0.3
RDI relative dose intensity
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cMultiple items could be selected
Of the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).
The dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.
When the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.
Details of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.
Effectiveness
Overall survival
Median observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B
The results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival
(a) All eligible patients
Univariate analysis (N = 754) Multivariate analysis (N = 736)a
Variable N HR 95% CI p HR 95% CI p
Cohort A vs cohort B 754 1.63 1.35–1.97 < 0.0001 1.75 1.44–2.14 < 0.0001
First- vs second-line therapy 754 1.46 1.22–1.74 < 0.0001 1.35 1.13–1.63 0.0011
Age: < 50 years vs ≥ 50 years 754 0.92 0.77–1.10 0.3361
ECOG PS: 0 vs 1, 2, or 3 754 1.59 1.32–1.91 < 0.0001 1.28 1.04–1.57 0.0175
Visceral metastasis: yes vs no 754 0.55 0.44–0.70 < 0.0001 0.52 0.40–0.66 < 0.0001
Cancer-related symptoms: yes vs no 749 0.57 0.48–0.69 < 0.0001 0.56 0.46–0.68 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.63 0.53–0.75 < 0.0001 0.87 0.66–1.14 0.3139
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.60 0.50–0.72 < 0.0001 0.65 0.49–0.86 0.0026
History of taxane-based chemotherapy: yes vs no 754 0.90 0.64–1.26 0.5380
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.78–1.38 0.8108
History of hormone therapy: yes vs no 754 1.02 0.86–1.22 0.8031
Nuclear grade: ≤ 2 vs 3 442 1.31 1.05–1.64 0.0186
Ki-67 index: < 30 vs ≥ 30 332 1.64 1.25–2.16 0.0004
Disease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.02 0.92–1.13 0.7575
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 521 1.52 1.22–1.90 0.0002 1.27 0.94–1.71 0.1251
First- vs second-line therapy 521 1.33 1.08–1.64 0.0069 1.20 0.95–1.52 0.1210
Age: < 50 years vs ≥ 50 years 521 0.92 0.75–1.13 0.4072
ECOG PS: 0 vs 1, 2, or 3 521 1.65 1.32–2.06 < 0.0001 1.32 1.02–1.71 0.0333
Visceral metastasis: yes vs no 521 0.58 0.44–0.77 0.0001 0.53 0.39–0.72 0.0001
Cancer-related symptoms: yes vs no 518 0.50 0.41–0.62 < 0.0001 0.52 0.41–0.66 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.68 0.53–0.86 0.0016 1.08 0.76–1.54 0.6634
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.66 0.53–0.81 0.0001 0.70 0.51–0.95 0.0209
History of taxane-based chemotherapy: yes vs no 521 0.86 0.56–1.32 0.4944
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.57–1.36 0.5617
History of hormone therapy: yes vs no 521 1.28 1.04–1.57 0.0190 1.14 0.87–1.50 0.3367
Nuclear grade: ≤ 2 vs 3 299 1.17 0.90–1.52 0.2389
Ki-67 index: < 30 vs ≥ 30 178 1.81 1.27–2.57 0.0011
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.45 0.36–0.56 < 0.0001 0.50 0.39–0.63 < 0.0001
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
The results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.
The results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.
Progression-free survival and objective response rates
Median PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.
Multivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival
(a) All eligible patients
Univariate analysis (n = 754) Multivariate analysis (n = 687)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 754 1.33 1.13–1.58 0.0008 1.56 1.26–1.93 0.0001
First- vs second-line therapy 754 1.40 1.20–1.64 < 0.0001 1.19 0.99–1.42 0.0622
Age: < 50 years vs ≥ 50 years 754 1.00 0.86–1.16 0.9589
ECOG PS: 0 vs 1, 2, or 3 754 1.60 1.36–1.88 < 0.0001 1.36 1.13–1.64 0.0013
Visceral metastasis: yes vs no 754 0.63 0.52–0.76 < 0.0001 0.68 0.55–0.85 0.0005
Cancer-related symptoms: yes vs no 749 0.68 0.58–0.79 < 0.0001 0.72 0.60–0.86 0.0003
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.62 0.53–0.72 < 0.0001 0.71 0.53–0.95 0.0227
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.61 0.52–0.72 < 0.0001 0.69 0.54–0.89 0.0044
History of taxane-based chemotherapy: yes vs no 754 0.69 0.52–0.92 0.0113 0.82 0.58–1.14 0.2358
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.80–1.31 0.8458
History of endocrine therapy: yes vs no 754 0.85 0.73–0.99 0.0411 0.76 0.62–0.93 0.0075
Nuclear grade: ≤ 2 vs 3 442 1.18 0.97–1.44 0.0961
Ki-67 index: < 30 vs ≥ 30 332 1.54 1.22–1.96 0.0003
Disease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.07 0.99–1.17 0.1040 0.89 0.78–1.01 0.0663
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI p HR 95% CI p
Cohort A vs cohort B 521 1.31 1.08–1.60 0.0073 1.12 0.89–1.40 0.3505
First- vs second-line therapy 521 1.33 1.11–1.60 0.0021 1.16 0.94–1.43 0.1643
Age: < 50 years vs ≥ 50 years 521 1.01 0.84–1.20 0.9470
PS: 0 vs 1, 2, or 3 521 1.74 1.43–2.11 < 0.0001 1.49 1.19–1.88 0.0006
Visceral metastasis: yes vs no 521 0.74 0.59–0.93 0.0086 0.78 0.60–1.00 0.0518
Cancer-related symptoms: yes vs no 518 0.62 0.52–0.74 < 0.0001 0.67 0.55–0.83 0.0002
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.66 0.54–0.81 0.0001 0.85 0.63–1.14 0.2795
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.67 0.56–0.81 < 0.0001 0.78 0.60–1.01 0.0573
History of taxane-based chemotherapy: yes vs no 521 0.66 0.45–0.97 0.0361 0.75 0.47–1.21 0.2333
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.60–1.28 0.5067
History of hormone therapy: yes vs no 521 1.07 0.89–1.28 0.4891
Nuclear grade: ≤ 2 vs 3 299 1.05 0.83–1.33 0.6669
Ki-67 index: < 30 vs ≥ 30 178 1.46 1.07–2.00 0.0174
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.51 0.42–0.61 < 0.0001 0.54 0.44–0.67 < 0.0001
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Multivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.
In the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).
ORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions
(a) All eligible patients
All eligible patients Cohort Aa Cohort Bb P First-line therapy Second-line therapy p
No. of patients with target lesions 545 383 162 352 193
Best response, n (%)
CR 14 (2.6%) 8 (2.1%) 6 (3.7%) 0.0180 (W) 10 (2.8%) 4 (2.1%) 0.0001 (W)
PR 292 (53.6%) 219 (57.2%) 73 (45.1%) 209 (59.4%) 83 (43.0%)
SD 139 (25.5%) 104 (27.2%) 35 (21.6%) 77 (21.9%) 62 (32.1%)
PD 71 (13.0%) 36 (9.4%) 35 (21.6%) 35 (9.9%) 36 (18.7%)
NE 29 (5.3%) 16 (4.2%) 13 (8.0%) 21 (6.0%) 8 (4.1%)
Response rate, n (%)
CR plus PR 306 (56.1%) 227 (59.3%) 79 (48.8%) 0.0297 (F) 219 (62.2%) 87 (45.1%) 0.0001 (F)
95% CI 51.9–60.4 54.2–64.2 40.8–56.7 56.9–67.3 37.9–52.4
(b) Cohorts A and B
Cohort Aa First-line therapy Second-line therapy P Cohort Bb First-line therapy Second-line therapy p
No. of patients with target lesions 383 252 131 162 100 62
Best response
CR 8 (2.1%) 6 (2.4%) 2 (1.5%) 0.0048 (W) 6 (3.7%) 4 (4.0%) 2 (3.2%) 0.0011 (W)
PR 219 (57.2%) 155 (61.5%) 64 (48.9%) 73 (45.1%) 54 (54.0%) 19 (30.6%)
SD 104 (27.2%) 57 (22.6%) 47 (35.9%) 35 (21.6%) 20 (20.0%) 15 (24.2%)
PD 36 (9.4%) 21 (8.3%) 15 (11.5%) 35 (21.6%) 14 (14.0%) 21 (33.9%)
NE 16 (4.2%) 13 (5.2%) 3 (2.3%) 13 (8.0%) 8 (8.0%) 5 (8.1%)
Response rate
CR plus PR 227 (59.3%) 161 (63.9%) 66 (50.4%) 0.0119 (F) 79 (48.8%) 58 (58.0%) 21 (33.9%) 0.0036 (F)
95% CI 54.2–64.2 57.6–69.8 41.5–59.2 40.8–56.7 47.7–67.8 22.3–47.0
CR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Safety
The great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)
Treated patient population Cohort Aa Cohort Bb First-line therapy Second-line therapy
n (%) n (%) n (%) n (%) n (%)
(a) Selected AEs
No. of patients 750 100 538 100 212 100 475 100 275 100
Hypertension
All grades 602 80.3 429 79.7 173 81.6 383 80.6 219 79.6
Grade ≥ 3 268 35.7 190 35.3 78 36.8 167 35.2 101 36.7
Peripheral neuropathy
All grades 535 71.3 400 74.3 135 63.7 341 71.8 194 70.5
Grade ≥ 3 54 7.2 41 7.6 13 6.1 36 7.6 18 6.5
Neutropenia
All grades 347 46.3 256 47.6 91 42.9 203 42.7 144 52.4
Grade ≥ 3 204 27.2 151 28.1 53 25.0 115 24.2 89 32.4
Proteinuria
All grades 223 29.7 160 29.7 63 29.7 156 32.8 67 24.4
Grade ≥ 3 28 3.7 18 3.3 10 4.7 20 4.2 8 2.9
Bleeding
All grades 131 17.5 96 17.8 35 16.5 87 18.3 44 16.0
Grade ≥ 3 2 0.3 2 0.4 0 0.0 1 0.2 1 0.4
(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)
No. of patients 750 100 538 100 212 100 475 100 275 100
Congestive heart failure 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Gastrointestinal perforation 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
Thromboembolism 3 0.4 3 0.6 0 0.0 2 0.4 1 0.4
Wound dehiscence 2 0.3 1 0.2 1 0.5 0 0.0 2 0.7
(c) Other adverse events grade ≥ 3
No. of patients 750 100 538 100 212 100 475 100 275 100
Fatigue 12 1.6 6 1.1 6 2.8 4 0.8 8 2.9
Stomatitis 6 0.8 6 1.1 0 0.0 3 0.6 3 1.1
Febrile neutropenia 4 0.5 2 0.4 2 0.9 1 0.2 3 1.1
Other infections 23 3.1 18 3.3 5 2.4 15 3.2 8 2.9
Skin disorders 11 1.5 10 1.9 1 0.5 9 1.9 2 0.7
Anemia 10 1.3 8 1.5 2 0.9 5 1.1 5 1.8
AST/ALT elevation 10 1.3 6 1.1 4 1.9 8 1.7 2 0.7
Appetite loss 7 0.9 5 0.9 2 0.9 3 0.6 4 1.5
Diarrhea 5 0.7 3 0.6 2 0.9 5 1.1 0 0.0
Drug-induced pneumonitis 5 0.7 4 0.7 1 0.5 2 0.4 3 1.1
Pain 4 0.5 3 0.6 1 0.5 2 0.4 2 0.7
Others 31 4.1 24 4.5 7 3.3 13 2.7 18 6.5
ALT alanine aminotransferase, AST aspartate aminotransferase
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Serious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.
Discussion
The B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.
The 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.
The multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].
OS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.
As for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].
The multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].
Despite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).
No new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.
The present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.
In conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.
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Acknowledgements
The authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.
Funding
The study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Compliance with ethical standards
Conflict of interest
Yamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;
Ethical statement
The study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.
Informed consent
Written informed consent was obtained from all patients. | BEVACIZUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 32715420 | 18,780,432 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pseudocirrhosis'. | Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
OBJECTIVE
To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.
METHODS
In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.
RESULTS
Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.
CONCLUSIONS
In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.
BACKGROUND
Trial no. UMIN000009086.
Introduction
Bevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].
A meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].
The JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.
Although several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.
Patients and methods
Study design
In this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.
Patients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.
Written informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).
Study treatment
Because the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.
In cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.
Study assessment
At screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.
Regarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.
Analysis populations and endpoints
The eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.
The primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).
Statistical analyses
This was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.
Expected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.
For the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.
Safety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.
Results
Study population and baseline patient characteristics
A total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.
Baseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median age (range) (years) 58.0 (26–83) 58.0 (26–81) 58.0 (27–83) 59.0 (26–83) 57.0 (28–83)
Menopausal status
Premenopausal 198 26.3 133 24.7 65 30.2 127 26.6 71 25.7
Postmenopausal 532 70.6 385 71.4 147 68.4 337 70.5 195 70.7
Unknown 24 3.2 21 3.9 3 1.4 14 2.9 10 3.6
ECOG PS
0 522 69.2 371 68.8 151 70.2 345 72.2 177 64.1
1 172 22.8 122 22.6 50 23.3 96 20.1 76 27.5
2 43 5.7 34 6.3 9 4.2 29 6.1 14 5.1
3 17 2.3 12 2.2 5 2.3 8 1.7 9 3.3
ER status
Negative 208 27.6 8 1.5 200 93.0 125 26.2 83 30.1
Positive 544 72.1 529 98.1 15 7.0 351 73.4 193 69.9
Unknown 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
PgR status
Negative 332 44.0 122 22.6 210 97.7 203 42.5 129 46.7
Positive 419 55.6 414 76.8 5 2.3 272 56.9 147 53.3
Unknown 3 0.4 3 0.6 0 0.0 3 0.6 0 0.0
Nuclear grade
1 120 15.9 102 18.9 18 8.4 79 16.5 41 14.9
2 106 14.1 82 15.2 24 11.2 70 14.6 36 13.0
3 216 28.6 111 20.6 105 48.8 144 30.1 72 26.1
Unknown 312 41.4 244 45.3 68 31.6 185 38.7 127 46.0
Ki67 index
< 30 141 18.7 105 19.5 36 16.7 103 21.5 38 13.8
≥ 30 191 25.3 93 17.3 98 45.6 130 27.2 61 22.1
Unknown 422 56.0 341 63.3 81 37.7 245 51.3 177 64.1
Diagnosis
Locally advanced 34 4.5 20 3.7 14 6.5 29 6.1 5 1.8
Stage IV 199 26.4 149 27.6 50 23.3 130 27.2 69 25.0
Recurrence 521 69.1 370 68.6 151 70.2 319 66.7 202 73.2
Disease-free interval (months)
0 233 30.9 169 31.4 64 29.8 159 33.3 74 26.8
0–24 178 23.6 83 15.4 95 44.2 101 21.1 77 27.9
≥ 4 292 38.7 246 45.6 46 21.4 190 39.7 102 37.0
Unknown 51 6.8 41 7.6 10 4.7 28 5.9 23 8.3
Distant metastasis
No 81 10.7 47 8.7 34 15.8 34 7.1 47 17.0
Yes 649 86.1 476 88.3 173 80.5 422 88.3 227 82.2
Unknown 24 3.2 16 3.0 8 3.7 22 4.6 2 0.7
Metastatic sitec
Non-visceral 54 8.3 36 7.6 18 10.4 40 9.5 14 6.2
Visceral 595 91.7 440 92.4 155 89.6 382 90.5 213 93.8
No. of metastatic organsc
< 3 558 86.0 409 85.9 149 86.1 355 84.1 203 89.4
≥ 3 91 14.0 67 14.1 24 13.9 67 15.9 24 10.6
Cancer-related symptoms
No 315 41.8 230 42.7 85 39.5 200 41.8 115 41.7
Yes 434 57.6 305 56.6 129 60.0 275 57.5 159 57.6
Unknown 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Treatment line for locally advanced or metastatic breast cancer
First line 478 63.4 345 64.0 133 61.9
Second line 276 36.6 194 36.0 82 38.1
History of adjuvant therapyd
Chemotherapy 370 71.0 238 64.3 132 87.4 227 71.2 143 70.8
Anthracycline 297 57.0 188 50.8 109 72.2 186 58.3 111 55.0
Taxane 262 50.3 153 41.4 109 72.2 165 51.7 97 48.0
Endocrine therapy 336 64.5 324 87.6 12 7.9 205 64.3 131 64.9
Previous therapy for locally advanced or metastatic breast cancer
Chemotherapy 266 35.3 188 34.9 78 36.3 12 2.5 254 92.0
Anthracycline 80 10.6 63 11.7 17 7.9 4 0.8 76 27.5
Taxane 54 7.2 36 6.7 18 8.4 5 1.0 49 17.8
Endocrine therapy 356 47.2 348 64.6 8 3.7 195 40.8 161 58.3
Radiotherapy 140 18.6 111 20.6 29 13.5 62 13.0 78 28.3
ECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cNumber (%) of distant metastasis
dNumber (%) of patients with breast cancer recurrence
The proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).
Treatment exposure
Most patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median duration of study treatment (25th, 75th percentiles), months 5.1 (3.1, 8.7) 5.5 (3.3, 9.5) 4.0 (2.3, 6.5) 5.3 (3.0, 8.7) 4.8 (2.4, 8.8)
Median duration of bevacizumab (25th, 75th percentiles), months 5.1 (2.8, 8.5) 5.4 (3.3, 9.5) 3.7 (2.3, 6.2) 5.1 (2.8, 8.5) 4.6 (2.4, 8.7)
Median RDI of bevacizumab (25th, 75th percentiles), 97.5 (86.2, 100) 95.9 (86.5, 100) 100 (85.7, 100) 95.6 (87.2–100) 100 (84.8–100)
Discontinuations of bevacizumab, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of bevacizumab, n (%)
Disease progression 379 50.7 261 48.7 118 55.7 221 46.5 158 57.9
Adverse events 214 28.6 169 31.5 45 21.2 143 30.1 71 26.0
Other 152 20.3 105 19.6 47 22.2 109 22.9 43 15.8
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Bevacizumab dose reductions, n (T) 15 2.0 12 2.2 3 1.4 13 2.7 2 0.7
Reason for bevacizumab dose reduction, n (%)c
Hypertension 3 20.0 2 16.7 1 33.3 3 23.1 0 0.0
Proteinuria 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Bleeding 1 6.7 1 8.3 0 0.0 1 7.7 0 0.0
Neutropenia 1 6.7 1 8.3 0 0.0 0 0.0 1 50.0
Other adverse events 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Other 4 26.7 2 16.7 2 66.7 3 23.1 0 0.0
Bevacizumab dose interruptions or delays, n (%) 263 34.9 188 34.9 75 34.9 155 32.4 108 39.1
Reason for bevacizumab dose interruption or delay, n (%)c
Hypertension 18 6.8 15 8.0 3 4.0 16 10.3 2 1.9
Proteinuria 53 20.2 36 19.1 17 22.7 35 22.6 18 16.7
Bleeding 3 1.1 2 1.1 1 1.3 2 1.3 1 0.9
Neutropenia 77 29.3 61 32.4 16 21.3 38 24.5 39 36.1
Other adverse events 106 40.3 77 41.0 29 38.7 61 39.4 45 41.7
Other 114 43.3 79 42.0 35 46.7 63 40.6 51 47.2
Median duration of paclitaxel (25th, 75th percentiles), months 4.9 (2.8, 8.1) 5.3 (3.2, 9.0) 3.9 (2.3, 6.0) 5.1 (3.0, 8.1) 4.6 (2.4, 8.2)
Median RDI of paclitaxel (25th, 75th percentiles), 90.9 (70.6, 100) 88.9 (69.5, 100) 96.0 (75.6, 105) 91.7 (72.7, 100) 89.8 (68.6, 100)
Discontinuations of paclitaxel, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of paclitaxel, n (%)
Disease progression 363 48.5 245 45.7 118 55.7 216 45.5 147 53.8
Adverse events 246 32.9 198 36.9 48 22.6 158 33.3 88 32.2
Other 136 18.2 92 17.2 44 20.8 99 20.8 37 13.6
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Paclitaxel dose reductions, n (%) 276 36.6 208 38.6 68 31.6 185 38.7 91 33.0
Reason for paclitaxel dose reduction, n (%)c
Peripheral neutropenia 114 41.3 89 42.8 25 36.8 81 43.8 33 36.3
Neutropenia 117 42.4 88 42.3 29 42.6 67 36.2 50 54.9
Other adverse events 81 29.3 61 29.3 20 29.4 57 30.8 24 26.4
Other 28 10.1 20 9.6 8 11.8 19 10.3 9 9.9
Paclitaxel dose interruptions or delays, n () 351 46.6 259 48.1 92 42.8 207 43.3 144 52.2
Reason for paclitaxel dose interruption or delay, n (%)c
Peripheral neutropenia 65 18.5 52 20.1 13 14.1 39 18.8 26 18.1
Neutropenia 159 45.3 123 47.5 36 39.1 82 39.6 77 53.5
Other adverse events 168 47.9 118 45.6 50 54.3 94 45.4 74 51.4
Other 127 36.2 90 34.7 37 40.2 72 34.8 55 38.2
Median duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 1.4 (N = 79) 0.5, 3.9 1.4 (N = 65) 0.5, 3.9 0.6 (N = 14) 0.2, 3.0 1.4 (N = 52) 0.5, 3.9 0.8 (N = 27) 0.3, 3.7
Median duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 0.2 (N = 133) 0.2, 0.7 0.2 (N = 86) 0.2, 0.7 0.2 (N = 47) 0.2, 0.9 0.2 (N = 87) 0.2, 1.2 0.2 (N = 46) 0.2, 0.3
RDI relative dose intensity
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cMultiple items could be selected
Of the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).
The dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.
When the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.
Details of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.
Effectiveness
Overall survival
Median observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B
The results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival
(a) All eligible patients
Univariate analysis (N = 754) Multivariate analysis (N = 736)a
Variable N HR 95% CI p HR 95% CI p
Cohort A vs cohort B 754 1.63 1.35–1.97 < 0.0001 1.75 1.44–2.14 < 0.0001
First- vs second-line therapy 754 1.46 1.22–1.74 < 0.0001 1.35 1.13–1.63 0.0011
Age: < 50 years vs ≥ 50 years 754 0.92 0.77–1.10 0.3361
ECOG PS: 0 vs 1, 2, or 3 754 1.59 1.32–1.91 < 0.0001 1.28 1.04–1.57 0.0175
Visceral metastasis: yes vs no 754 0.55 0.44–0.70 < 0.0001 0.52 0.40–0.66 < 0.0001
Cancer-related symptoms: yes vs no 749 0.57 0.48–0.69 < 0.0001 0.56 0.46–0.68 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.63 0.53–0.75 < 0.0001 0.87 0.66–1.14 0.3139
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.60 0.50–0.72 < 0.0001 0.65 0.49–0.86 0.0026
History of taxane-based chemotherapy: yes vs no 754 0.90 0.64–1.26 0.5380
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.78–1.38 0.8108
History of hormone therapy: yes vs no 754 1.02 0.86–1.22 0.8031
Nuclear grade: ≤ 2 vs 3 442 1.31 1.05–1.64 0.0186
Ki-67 index: < 30 vs ≥ 30 332 1.64 1.25–2.16 0.0004
Disease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.02 0.92–1.13 0.7575
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 521 1.52 1.22–1.90 0.0002 1.27 0.94–1.71 0.1251
First- vs second-line therapy 521 1.33 1.08–1.64 0.0069 1.20 0.95–1.52 0.1210
Age: < 50 years vs ≥ 50 years 521 0.92 0.75–1.13 0.4072
ECOG PS: 0 vs 1, 2, or 3 521 1.65 1.32–2.06 < 0.0001 1.32 1.02–1.71 0.0333
Visceral metastasis: yes vs no 521 0.58 0.44–0.77 0.0001 0.53 0.39–0.72 0.0001
Cancer-related symptoms: yes vs no 518 0.50 0.41–0.62 < 0.0001 0.52 0.41–0.66 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.68 0.53–0.86 0.0016 1.08 0.76–1.54 0.6634
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.66 0.53–0.81 0.0001 0.70 0.51–0.95 0.0209
History of taxane-based chemotherapy: yes vs no 521 0.86 0.56–1.32 0.4944
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.57–1.36 0.5617
History of hormone therapy: yes vs no 521 1.28 1.04–1.57 0.0190 1.14 0.87–1.50 0.3367
Nuclear grade: ≤ 2 vs 3 299 1.17 0.90–1.52 0.2389
Ki-67 index: < 30 vs ≥ 30 178 1.81 1.27–2.57 0.0011
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.45 0.36–0.56 < 0.0001 0.50 0.39–0.63 < 0.0001
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
The results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.
The results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.
Progression-free survival and objective response rates
Median PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.
Multivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival
(a) All eligible patients
Univariate analysis (n = 754) Multivariate analysis (n = 687)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 754 1.33 1.13–1.58 0.0008 1.56 1.26–1.93 0.0001
First- vs second-line therapy 754 1.40 1.20–1.64 < 0.0001 1.19 0.99–1.42 0.0622
Age: < 50 years vs ≥ 50 years 754 1.00 0.86–1.16 0.9589
ECOG PS: 0 vs 1, 2, or 3 754 1.60 1.36–1.88 < 0.0001 1.36 1.13–1.64 0.0013
Visceral metastasis: yes vs no 754 0.63 0.52–0.76 < 0.0001 0.68 0.55–0.85 0.0005
Cancer-related symptoms: yes vs no 749 0.68 0.58–0.79 < 0.0001 0.72 0.60–0.86 0.0003
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.62 0.53–0.72 < 0.0001 0.71 0.53–0.95 0.0227
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.61 0.52–0.72 < 0.0001 0.69 0.54–0.89 0.0044
History of taxane-based chemotherapy: yes vs no 754 0.69 0.52–0.92 0.0113 0.82 0.58–1.14 0.2358
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.80–1.31 0.8458
History of endocrine therapy: yes vs no 754 0.85 0.73–0.99 0.0411 0.76 0.62–0.93 0.0075
Nuclear grade: ≤ 2 vs 3 442 1.18 0.97–1.44 0.0961
Ki-67 index: < 30 vs ≥ 30 332 1.54 1.22–1.96 0.0003
Disease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.07 0.99–1.17 0.1040 0.89 0.78–1.01 0.0663
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI p HR 95% CI p
Cohort A vs cohort B 521 1.31 1.08–1.60 0.0073 1.12 0.89–1.40 0.3505
First- vs second-line therapy 521 1.33 1.11–1.60 0.0021 1.16 0.94–1.43 0.1643
Age: < 50 years vs ≥ 50 years 521 1.01 0.84–1.20 0.9470
PS: 0 vs 1, 2, or 3 521 1.74 1.43–2.11 < 0.0001 1.49 1.19–1.88 0.0006
Visceral metastasis: yes vs no 521 0.74 0.59–0.93 0.0086 0.78 0.60–1.00 0.0518
Cancer-related symptoms: yes vs no 518 0.62 0.52–0.74 < 0.0001 0.67 0.55–0.83 0.0002
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.66 0.54–0.81 0.0001 0.85 0.63–1.14 0.2795
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.67 0.56–0.81 < 0.0001 0.78 0.60–1.01 0.0573
History of taxane-based chemotherapy: yes vs no 521 0.66 0.45–0.97 0.0361 0.75 0.47–1.21 0.2333
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.60–1.28 0.5067
History of hormone therapy: yes vs no 521 1.07 0.89–1.28 0.4891
Nuclear grade: ≤ 2 vs 3 299 1.05 0.83–1.33 0.6669
Ki-67 index: < 30 vs ≥ 30 178 1.46 1.07–2.00 0.0174
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.51 0.42–0.61 < 0.0001 0.54 0.44–0.67 < 0.0001
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Multivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.
In the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).
ORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions
(a) All eligible patients
All eligible patients Cohort Aa Cohort Bb P First-line therapy Second-line therapy p
No. of patients with target lesions 545 383 162 352 193
Best response, n (%)
CR 14 (2.6%) 8 (2.1%) 6 (3.7%) 0.0180 (W) 10 (2.8%) 4 (2.1%) 0.0001 (W)
PR 292 (53.6%) 219 (57.2%) 73 (45.1%) 209 (59.4%) 83 (43.0%)
SD 139 (25.5%) 104 (27.2%) 35 (21.6%) 77 (21.9%) 62 (32.1%)
PD 71 (13.0%) 36 (9.4%) 35 (21.6%) 35 (9.9%) 36 (18.7%)
NE 29 (5.3%) 16 (4.2%) 13 (8.0%) 21 (6.0%) 8 (4.1%)
Response rate, n (%)
CR plus PR 306 (56.1%) 227 (59.3%) 79 (48.8%) 0.0297 (F) 219 (62.2%) 87 (45.1%) 0.0001 (F)
95% CI 51.9–60.4 54.2–64.2 40.8–56.7 56.9–67.3 37.9–52.4
(b) Cohorts A and B
Cohort Aa First-line therapy Second-line therapy P Cohort Bb First-line therapy Second-line therapy p
No. of patients with target lesions 383 252 131 162 100 62
Best response
CR 8 (2.1%) 6 (2.4%) 2 (1.5%) 0.0048 (W) 6 (3.7%) 4 (4.0%) 2 (3.2%) 0.0011 (W)
PR 219 (57.2%) 155 (61.5%) 64 (48.9%) 73 (45.1%) 54 (54.0%) 19 (30.6%)
SD 104 (27.2%) 57 (22.6%) 47 (35.9%) 35 (21.6%) 20 (20.0%) 15 (24.2%)
PD 36 (9.4%) 21 (8.3%) 15 (11.5%) 35 (21.6%) 14 (14.0%) 21 (33.9%)
NE 16 (4.2%) 13 (5.2%) 3 (2.3%) 13 (8.0%) 8 (8.0%) 5 (8.1%)
Response rate
CR plus PR 227 (59.3%) 161 (63.9%) 66 (50.4%) 0.0119 (F) 79 (48.8%) 58 (58.0%) 21 (33.9%) 0.0036 (F)
95% CI 54.2–64.2 57.6–69.8 41.5–59.2 40.8–56.7 47.7–67.8 22.3–47.0
CR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Safety
The great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)
Treated patient population Cohort Aa Cohort Bb First-line therapy Second-line therapy
n (%) n (%) n (%) n (%) n (%)
(a) Selected AEs
No. of patients 750 100 538 100 212 100 475 100 275 100
Hypertension
All grades 602 80.3 429 79.7 173 81.6 383 80.6 219 79.6
Grade ≥ 3 268 35.7 190 35.3 78 36.8 167 35.2 101 36.7
Peripheral neuropathy
All grades 535 71.3 400 74.3 135 63.7 341 71.8 194 70.5
Grade ≥ 3 54 7.2 41 7.6 13 6.1 36 7.6 18 6.5
Neutropenia
All grades 347 46.3 256 47.6 91 42.9 203 42.7 144 52.4
Grade ≥ 3 204 27.2 151 28.1 53 25.0 115 24.2 89 32.4
Proteinuria
All grades 223 29.7 160 29.7 63 29.7 156 32.8 67 24.4
Grade ≥ 3 28 3.7 18 3.3 10 4.7 20 4.2 8 2.9
Bleeding
All grades 131 17.5 96 17.8 35 16.5 87 18.3 44 16.0
Grade ≥ 3 2 0.3 2 0.4 0 0.0 1 0.2 1 0.4
(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)
No. of patients 750 100 538 100 212 100 475 100 275 100
Congestive heart failure 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Gastrointestinal perforation 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
Thromboembolism 3 0.4 3 0.6 0 0.0 2 0.4 1 0.4
Wound dehiscence 2 0.3 1 0.2 1 0.5 0 0.0 2 0.7
(c) Other adverse events grade ≥ 3
No. of patients 750 100 538 100 212 100 475 100 275 100
Fatigue 12 1.6 6 1.1 6 2.8 4 0.8 8 2.9
Stomatitis 6 0.8 6 1.1 0 0.0 3 0.6 3 1.1
Febrile neutropenia 4 0.5 2 0.4 2 0.9 1 0.2 3 1.1
Other infections 23 3.1 18 3.3 5 2.4 15 3.2 8 2.9
Skin disorders 11 1.5 10 1.9 1 0.5 9 1.9 2 0.7
Anemia 10 1.3 8 1.5 2 0.9 5 1.1 5 1.8
AST/ALT elevation 10 1.3 6 1.1 4 1.9 8 1.7 2 0.7
Appetite loss 7 0.9 5 0.9 2 0.9 3 0.6 4 1.5
Diarrhea 5 0.7 3 0.6 2 0.9 5 1.1 0 0.0
Drug-induced pneumonitis 5 0.7 4 0.7 1 0.5 2 0.4 3 1.1
Pain 4 0.5 3 0.6 1 0.5 2 0.4 2 0.7
Others 31 4.1 24 4.5 7 3.3 13 2.7 18 6.5
ALT alanine aminotransferase, AST aspartate aminotransferase
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Serious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.
Discussion
The B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.
The 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.
The multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].
OS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.
As for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].
The multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].
Despite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).
No new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.
The present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.
In conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.
Electronic supplementary material
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Acknowledgements
The authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.
Funding
The study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Compliance with ethical standards
Conflict of interest
Yamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;
Ethical statement
The study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.
Informed consent
Written informed consent was obtained from all patients. | BEVACIZUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 32715420 | 18,780,432 | 2021-01 |
What was the outcome of reaction 'Cardiac failure'? | Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
OBJECTIVE
To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.
METHODS
In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.
RESULTS
Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.
CONCLUSIONS
In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.
BACKGROUND
Trial no. UMIN000009086.
Introduction
Bevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].
A meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].
The JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.
Although several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.
Patients and methods
Study design
In this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.
Patients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.
Written informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).
Study treatment
Because the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.
In cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.
Study assessment
At screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.
Regarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.
Analysis populations and endpoints
The eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.
The primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).
Statistical analyses
This was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.
Expected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.
For the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.
Safety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.
Results
Study population and baseline patient characteristics
A total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.
Baseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median age (range) (years) 58.0 (26–83) 58.0 (26–81) 58.0 (27–83) 59.0 (26–83) 57.0 (28–83)
Menopausal status
Premenopausal 198 26.3 133 24.7 65 30.2 127 26.6 71 25.7
Postmenopausal 532 70.6 385 71.4 147 68.4 337 70.5 195 70.7
Unknown 24 3.2 21 3.9 3 1.4 14 2.9 10 3.6
ECOG PS
0 522 69.2 371 68.8 151 70.2 345 72.2 177 64.1
1 172 22.8 122 22.6 50 23.3 96 20.1 76 27.5
2 43 5.7 34 6.3 9 4.2 29 6.1 14 5.1
3 17 2.3 12 2.2 5 2.3 8 1.7 9 3.3
ER status
Negative 208 27.6 8 1.5 200 93.0 125 26.2 83 30.1
Positive 544 72.1 529 98.1 15 7.0 351 73.4 193 69.9
Unknown 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
PgR status
Negative 332 44.0 122 22.6 210 97.7 203 42.5 129 46.7
Positive 419 55.6 414 76.8 5 2.3 272 56.9 147 53.3
Unknown 3 0.4 3 0.6 0 0.0 3 0.6 0 0.0
Nuclear grade
1 120 15.9 102 18.9 18 8.4 79 16.5 41 14.9
2 106 14.1 82 15.2 24 11.2 70 14.6 36 13.0
3 216 28.6 111 20.6 105 48.8 144 30.1 72 26.1
Unknown 312 41.4 244 45.3 68 31.6 185 38.7 127 46.0
Ki67 index
< 30 141 18.7 105 19.5 36 16.7 103 21.5 38 13.8
≥ 30 191 25.3 93 17.3 98 45.6 130 27.2 61 22.1
Unknown 422 56.0 341 63.3 81 37.7 245 51.3 177 64.1
Diagnosis
Locally advanced 34 4.5 20 3.7 14 6.5 29 6.1 5 1.8
Stage IV 199 26.4 149 27.6 50 23.3 130 27.2 69 25.0
Recurrence 521 69.1 370 68.6 151 70.2 319 66.7 202 73.2
Disease-free interval (months)
0 233 30.9 169 31.4 64 29.8 159 33.3 74 26.8
0–24 178 23.6 83 15.4 95 44.2 101 21.1 77 27.9
≥ 4 292 38.7 246 45.6 46 21.4 190 39.7 102 37.0
Unknown 51 6.8 41 7.6 10 4.7 28 5.9 23 8.3
Distant metastasis
No 81 10.7 47 8.7 34 15.8 34 7.1 47 17.0
Yes 649 86.1 476 88.3 173 80.5 422 88.3 227 82.2
Unknown 24 3.2 16 3.0 8 3.7 22 4.6 2 0.7
Metastatic sitec
Non-visceral 54 8.3 36 7.6 18 10.4 40 9.5 14 6.2
Visceral 595 91.7 440 92.4 155 89.6 382 90.5 213 93.8
No. of metastatic organsc
< 3 558 86.0 409 85.9 149 86.1 355 84.1 203 89.4
≥ 3 91 14.0 67 14.1 24 13.9 67 15.9 24 10.6
Cancer-related symptoms
No 315 41.8 230 42.7 85 39.5 200 41.8 115 41.7
Yes 434 57.6 305 56.6 129 60.0 275 57.5 159 57.6
Unknown 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Treatment line for locally advanced or metastatic breast cancer
First line 478 63.4 345 64.0 133 61.9
Second line 276 36.6 194 36.0 82 38.1
History of adjuvant therapyd
Chemotherapy 370 71.0 238 64.3 132 87.4 227 71.2 143 70.8
Anthracycline 297 57.0 188 50.8 109 72.2 186 58.3 111 55.0
Taxane 262 50.3 153 41.4 109 72.2 165 51.7 97 48.0
Endocrine therapy 336 64.5 324 87.6 12 7.9 205 64.3 131 64.9
Previous therapy for locally advanced or metastatic breast cancer
Chemotherapy 266 35.3 188 34.9 78 36.3 12 2.5 254 92.0
Anthracycline 80 10.6 63 11.7 17 7.9 4 0.8 76 27.5
Taxane 54 7.2 36 6.7 18 8.4 5 1.0 49 17.8
Endocrine therapy 356 47.2 348 64.6 8 3.7 195 40.8 161 58.3
Radiotherapy 140 18.6 111 20.6 29 13.5 62 13.0 78 28.3
ECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cNumber (%) of distant metastasis
dNumber (%) of patients with breast cancer recurrence
The proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).
Treatment exposure
Most patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median duration of study treatment (25th, 75th percentiles), months 5.1 (3.1, 8.7) 5.5 (3.3, 9.5) 4.0 (2.3, 6.5) 5.3 (3.0, 8.7) 4.8 (2.4, 8.8)
Median duration of bevacizumab (25th, 75th percentiles), months 5.1 (2.8, 8.5) 5.4 (3.3, 9.5) 3.7 (2.3, 6.2) 5.1 (2.8, 8.5) 4.6 (2.4, 8.7)
Median RDI of bevacizumab (25th, 75th percentiles), 97.5 (86.2, 100) 95.9 (86.5, 100) 100 (85.7, 100) 95.6 (87.2–100) 100 (84.8–100)
Discontinuations of bevacizumab, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of bevacizumab, n (%)
Disease progression 379 50.7 261 48.7 118 55.7 221 46.5 158 57.9
Adverse events 214 28.6 169 31.5 45 21.2 143 30.1 71 26.0
Other 152 20.3 105 19.6 47 22.2 109 22.9 43 15.8
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Bevacizumab dose reductions, n (T) 15 2.0 12 2.2 3 1.4 13 2.7 2 0.7
Reason for bevacizumab dose reduction, n (%)c
Hypertension 3 20.0 2 16.7 1 33.3 3 23.1 0 0.0
Proteinuria 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Bleeding 1 6.7 1 8.3 0 0.0 1 7.7 0 0.0
Neutropenia 1 6.7 1 8.3 0 0.0 0 0.0 1 50.0
Other adverse events 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Other 4 26.7 2 16.7 2 66.7 3 23.1 0 0.0
Bevacizumab dose interruptions or delays, n (%) 263 34.9 188 34.9 75 34.9 155 32.4 108 39.1
Reason for bevacizumab dose interruption or delay, n (%)c
Hypertension 18 6.8 15 8.0 3 4.0 16 10.3 2 1.9
Proteinuria 53 20.2 36 19.1 17 22.7 35 22.6 18 16.7
Bleeding 3 1.1 2 1.1 1 1.3 2 1.3 1 0.9
Neutropenia 77 29.3 61 32.4 16 21.3 38 24.5 39 36.1
Other adverse events 106 40.3 77 41.0 29 38.7 61 39.4 45 41.7
Other 114 43.3 79 42.0 35 46.7 63 40.6 51 47.2
Median duration of paclitaxel (25th, 75th percentiles), months 4.9 (2.8, 8.1) 5.3 (3.2, 9.0) 3.9 (2.3, 6.0) 5.1 (3.0, 8.1) 4.6 (2.4, 8.2)
Median RDI of paclitaxel (25th, 75th percentiles), 90.9 (70.6, 100) 88.9 (69.5, 100) 96.0 (75.6, 105) 91.7 (72.7, 100) 89.8 (68.6, 100)
Discontinuations of paclitaxel, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of paclitaxel, n (%)
Disease progression 363 48.5 245 45.7 118 55.7 216 45.5 147 53.8
Adverse events 246 32.9 198 36.9 48 22.6 158 33.3 88 32.2
Other 136 18.2 92 17.2 44 20.8 99 20.8 37 13.6
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Paclitaxel dose reductions, n (%) 276 36.6 208 38.6 68 31.6 185 38.7 91 33.0
Reason for paclitaxel dose reduction, n (%)c
Peripheral neutropenia 114 41.3 89 42.8 25 36.8 81 43.8 33 36.3
Neutropenia 117 42.4 88 42.3 29 42.6 67 36.2 50 54.9
Other adverse events 81 29.3 61 29.3 20 29.4 57 30.8 24 26.4
Other 28 10.1 20 9.6 8 11.8 19 10.3 9 9.9
Paclitaxel dose interruptions or delays, n () 351 46.6 259 48.1 92 42.8 207 43.3 144 52.2
Reason for paclitaxel dose interruption or delay, n (%)c
Peripheral neutropenia 65 18.5 52 20.1 13 14.1 39 18.8 26 18.1
Neutropenia 159 45.3 123 47.5 36 39.1 82 39.6 77 53.5
Other adverse events 168 47.9 118 45.6 50 54.3 94 45.4 74 51.4
Other 127 36.2 90 34.7 37 40.2 72 34.8 55 38.2
Median duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 1.4 (N = 79) 0.5, 3.9 1.4 (N = 65) 0.5, 3.9 0.6 (N = 14) 0.2, 3.0 1.4 (N = 52) 0.5, 3.9 0.8 (N = 27) 0.3, 3.7
Median duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 0.2 (N = 133) 0.2, 0.7 0.2 (N = 86) 0.2, 0.7 0.2 (N = 47) 0.2, 0.9 0.2 (N = 87) 0.2, 1.2 0.2 (N = 46) 0.2, 0.3
RDI relative dose intensity
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cMultiple items could be selected
Of the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).
The dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.
When the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.
Details of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.
Effectiveness
Overall survival
Median observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B
The results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival
(a) All eligible patients
Univariate analysis (N = 754) Multivariate analysis (N = 736)a
Variable N HR 95% CI p HR 95% CI p
Cohort A vs cohort B 754 1.63 1.35–1.97 < 0.0001 1.75 1.44–2.14 < 0.0001
First- vs second-line therapy 754 1.46 1.22–1.74 < 0.0001 1.35 1.13–1.63 0.0011
Age: < 50 years vs ≥ 50 years 754 0.92 0.77–1.10 0.3361
ECOG PS: 0 vs 1, 2, or 3 754 1.59 1.32–1.91 < 0.0001 1.28 1.04–1.57 0.0175
Visceral metastasis: yes vs no 754 0.55 0.44–0.70 < 0.0001 0.52 0.40–0.66 < 0.0001
Cancer-related symptoms: yes vs no 749 0.57 0.48–0.69 < 0.0001 0.56 0.46–0.68 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.63 0.53–0.75 < 0.0001 0.87 0.66–1.14 0.3139
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.60 0.50–0.72 < 0.0001 0.65 0.49–0.86 0.0026
History of taxane-based chemotherapy: yes vs no 754 0.90 0.64–1.26 0.5380
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.78–1.38 0.8108
History of hormone therapy: yes vs no 754 1.02 0.86–1.22 0.8031
Nuclear grade: ≤ 2 vs 3 442 1.31 1.05–1.64 0.0186
Ki-67 index: < 30 vs ≥ 30 332 1.64 1.25–2.16 0.0004
Disease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.02 0.92–1.13 0.7575
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 521 1.52 1.22–1.90 0.0002 1.27 0.94–1.71 0.1251
First- vs second-line therapy 521 1.33 1.08–1.64 0.0069 1.20 0.95–1.52 0.1210
Age: < 50 years vs ≥ 50 years 521 0.92 0.75–1.13 0.4072
ECOG PS: 0 vs 1, 2, or 3 521 1.65 1.32–2.06 < 0.0001 1.32 1.02–1.71 0.0333
Visceral metastasis: yes vs no 521 0.58 0.44–0.77 0.0001 0.53 0.39–0.72 0.0001
Cancer-related symptoms: yes vs no 518 0.50 0.41–0.62 < 0.0001 0.52 0.41–0.66 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.68 0.53–0.86 0.0016 1.08 0.76–1.54 0.6634
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.66 0.53–0.81 0.0001 0.70 0.51–0.95 0.0209
History of taxane-based chemotherapy: yes vs no 521 0.86 0.56–1.32 0.4944
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.57–1.36 0.5617
History of hormone therapy: yes vs no 521 1.28 1.04–1.57 0.0190 1.14 0.87–1.50 0.3367
Nuclear grade: ≤ 2 vs 3 299 1.17 0.90–1.52 0.2389
Ki-67 index: < 30 vs ≥ 30 178 1.81 1.27–2.57 0.0011
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.45 0.36–0.56 < 0.0001 0.50 0.39–0.63 < 0.0001
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
The results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.
The results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.
Progression-free survival and objective response rates
Median PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.
Multivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival
(a) All eligible patients
Univariate analysis (n = 754) Multivariate analysis (n = 687)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 754 1.33 1.13–1.58 0.0008 1.56 1.26–1.93 0.0001
First- vs second-line therapy 754 1.40 1.20–1.64 < 0.0001 1.19 0.99–1.42 0.0622
Age: < 50 years vs ≥ 50 years 754 1.00 0.86–1.16 0.9589
ECOG PS: 0 vs 1, 2, or 3 754 1.60 1.36–1.88 < 0.0001 1.36 1.13–1.64 0.0013
Visceral metastasis: yes vs no 754 0.63 0.52–0.76 < 0.0001 0.68 0.55–0.85 0.0005
Cancer-related symptoms: yes vs no 749 0.68 0.58–0.79 < 0.0001 0.72 0.60–0.86 0.0003
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.62 0.53–0.72 < 0.0001 0.71 0.53–0.95 0.0227
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.61 0.52–0.72 < 0.0001 0.69 0.54–0.89 0.0044
History of taxane-based chemotherapy: yes vs no 754 0.69 0.52–0.92 0.0113 0.82 0.58–1.14 0.2358
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.80–1.31 0.8458
History of endocrine therapy: yes vs no 754 0.85 0.73–0.99 0.0411 0.76 0.62–0.93 0.0075
Nuclear grade: ≤ 2 vs 3 442 1.18 0.97–1.44 0.0961
Ki-67 index: < 30 vs ≥ 30 332 1.54 1.22–1.96 0.0003
Disease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.07 0.99–1.17 0.1040 0.89 0.78–1.01 0.0663
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI p HR 95% CI p
Cohort A vs cohort B 521 1.31 1.08–1.60 0.0073 1.12 0.89–1.40 0.3505
First- vs second-line therapy 521 1.33 1.11–1.60 0.0021 1.16 0.94–1.43 0.1643
Age: < 50 years vs ≥ 50 years 521 1.01 0.84–1.20 0.9470
PS: 0 vs 1, 2, or 3 521 1.74 1.43–2.11 < 0.0001 1.49 1.19–1.88 0.0006
Visceral metastasis: yes vs no 521 0.74 0.59–0.93 0.0086 0.78 0.60–1.00 0.0518
Cancer-related symptoms: yes vs no 518 0.62 0.52–0.74 < 0.0001 0.67 0.55–0.83 0.0002
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.66 0.54–0.81 0.0001 0.85 0.63–1.14 0.2795
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.67 0.56–0.81 < 0.0001 0.78 0.60–1.01 0.0573
History of taxane-based chemotherapy: yes vs no 521 0.66 0.45–0.97 0.0361 0.75 0.47–1.21 0.2333
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.60–1.28 0.5067
History of hormone therapy: yes vs no 521 1.07 0.89–1.28 0.4891
Nuclear grade: ≤ 2 vs 3 299 1.05 0.83–1.33 0.6669
Ki-67 index: < 30 vs ≥ 30 178 1.46 1.07–2.00 0.0174
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.51 0.42–0.61 < 0.0001 0.54 0.44–0.67 < 0.0001
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Multivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.
In the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).
ORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions
(a) All eligible patients
All eligible patients Cohort Aa Cohort Bb P First-line therapy Second-line therapy p
No. of patients with target lesions 545 383 162 352 193
Best response, n (%)
CR 14 (2.6%) 8 (2.1%) 6 (3.7%) 0.0180 (W) 10 (2.8%) 4 (2.1%) 0.0001 (W)
PR 292 (53.6%) 219 (57.2%) 73 (45.1%) 209 (59.4%) 83 (43.0%)
SD 139 (25.5%) 104 (27.2%) 35 (21.6%) 77 (21.9%) 62 (32.1%)
PD 71 (13.0%) 36 (9.4%) 35 (21.6%) 35 (9.9%) 36 (18.7%)
NE 29 (5.3%) 16 (4.2%) 13 (8.0%) 21 (6.0%) 8 (4.1%)
Response rate, n (%)
CR plus PR 306 (56.1%) 227 (59.3%) 79 (48.8%) 0.0297 (F) 219 (62.2%) 87 (45.1%) 0.0001 (F)
95% CI 51.9–60.4 54.2–64.2 40.8–56.7 56.9–67.3 37.9–52.4
(b) Cohorts A and B
Cohort Aa First-line therapy Second-line therapy P Cohort Bb First-line therapy Second-line therapy p
No. of patients with target lesions 383 252 131 162 100 62
Best response
CR 8 (2.1%) 6 (2.4%) 2 (1.5%) 0.0048 (W) 6 (3.7%) 4 (4.0%) 2 (3.2%) 0.0011 (W)
PR 219 (57.2%) 155 (61.5%) 64 (48.9%) 73 (45.1%) 54 (54.0%) 19 (30.6%)
SD 104 (27.2%) 57 (22.6%) 47 (35.9%) 35 (21.6%) 20 (20.0%) 15 (24.2%)
PD 36 (9.4%) 21 (8.3%) 15 (11.5%) 35 (21.6%) 14 (14.0%) 21 (33.9%)
NE 16 (4.2%) 13 (5.2%) 3 (2.3%) 13 (8.0%) 8 (8.0%) 5 (8.1%)
Response rate
CR plus PR 227 (59.3%) 161 (63.9%) 66 (50.4%) 0.0119 (F) 79 (48.8%) 58 (58.0%) 21 (33.9%) 0.0036 (F)
95% CI 54.2–64.2 57.6–69.8 41.5–59.2 40.8–56.7 47.7–67.8 22.3–47.0
CR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Safety
The great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)
Treated patient population Cohort Aa Cohort Bb First-line therapy Second-line therapy
n (%) n (%) n (%) n (%) n (%)
(a) Selected AEs
No. of patients 750 100 538 100 212 100 475 100 275 100
Hypertension
All grades 602 80.3 429 79.7 173 81.6 383 80.6 219 79.6
Grade ≥ 3 268 35.7 190 35.3 78 36.8 167 35.2 101 36.7
Peripheral neuropathy
All grades 535 71.3 400 74.3 135 63.7 341 71.8 194 70.5
Grade ≥ 3 54 7.2 41 7.6 13 6.1 36 7.6 18 6.5
Neutropenia
All grades 347 46.3 256 47.6 91 42.9 203 42.7 144 52.4
Grade ≥ 3 204 27.2 151 28.1 53 25.0 115 24.2 89 32.4
Proteinuria
All grades 223 29.7 160 29.7 63 29.7 156 32.8 67 24.4
Grade ≥ 3 28 3.7 18 3.3 10 4.7 20 4.2 8 2.9
Bleeding
All grades 131 17.5 96 17.8 35 16.5 87 18.3 44 16.0
Grade ≥ 3 2 0.3 2 0.4 0 0.0 1 0.2 1 0.4
(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)
No. of patients 750 100 538 100 212 100 475 100 275 100
Congestive heart failure 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Gastrointestinal perforation 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
Thromboembolism 3 0.4 3 0.6 0 0.0 2 0.4 1 0.4
Wound dehiscence 2 0.3 1 0.2 1 0.5 0 0.0 2 0.7
(c) Other adverse events grade ≥ 3
No. of patients 750 100 538 100 212 100 475 100 275 100
Fatigue 12 1.6 6 1.1 6 2.8 4 0.8 8 2.9
Stomatitis 6 0.8 6 1.1 0 0.0 3 0.6 3 1.1
Febrile neutropenia 4 0.5 2 0.4 2 0.9 1 0.2 3 1.1
Other infections 23 3.1 18 3.3 5 2.4 15 3.2 8 2.9
Skin disorders 11 1.5 10 1.9 1 0.5 9 1.9 2 0.7
Anemia 10 1.3 8 1.5 2 0.9 5 1.1 5 1.8
AST/ALT elevation 10 1.3 6 1.1 4 1.9 8 1.7 2 0.7
Appetite loss 7 0.9 5 0.9 2 0.9 3 0.6 4 1.5
Diarrhea 5 0.7 3 0.6 2 0.9 5 1.1 0 0.0
Drug-induced pneumonitis 5 0.7 4 0.7 1 0.5 2 0.4 3 1.1
Pain 4 0.5 3 0.6 1 0.5 2 0.4 2 0.7
Others 31 4.1 24 4.5 7 3.3 13 2.7 18 6.5
ALT alanine aminotransferase, AST aspartate aminotransferase
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Serious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.
Discussion
The B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.
The 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.
The multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].
OS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.
As for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].
The multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].
Despite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).
No new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.
The present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.
In conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.
Electronic supplementary material
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Acknowledgements
The authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.
Funding
The study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Compliance with ethical standards
Conflict of interest
Yamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;
Ethical statement
The study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.
Informed consent
Written informed consent was obtained from all patients. | Fatal | ReactionOutcome | CC BY | 32715420 | 18,780,431 | 2021-01 |
What was the outcome of reaction 'Gastroenteritis'? | Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
OBJECTIVE
To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.
METHODS
In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.
RESULTS
Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.
CONCLUSIONS
In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.
BACKGROUND
Trial no. UMIN000009086.
Introduction
Bevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].
A meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].
The JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.
Although several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.
Patients and methods
Study design
In this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.
Patients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.
Written informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).
Study treatment
Because the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.
In cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.
Study assessment
At screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.
Regarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.
Analysis populations and endpoints
The eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.
The primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).
Statistical analyses
This was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.
Expected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.
For the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.
Safety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.
Results
Study population and baseline patient characteristics
A total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.
Baseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median age (range) (years) 58.0 (26–83) 58.0 (26–81) 58.0 (27–83) 59.0 (26–83) 57.0 (28–83)
Menopausal status
Premenopausal 198 26.3 133 24.7 65 30.2 127 26.6 71 25.7
Postmenopausal 532 70.6 385 71.4 147 68.4 337 70.5 195 70.7
Unknown 24 3.2 21 3.9 3 1.4 14 2.9 10 3.6
ECOG PS
0 522 69.2 371 68.8 151 70.2 345 72.2 177 64.1
1 172 22.8 122 22.6 50 23.3 96 20.1 76 27.5
2 43 5.7 34 6.3 9 4.2 29 6.1 14 5.1
3 17 2.3 12 2.2 5 2.3 8 1.7 9 3.3
ER status
Negative 208 27.6 8 1.5 200 93.0 125 26.2 83 30.1
Positive 544 72.1 529 98.1 15 7.0 351 73.4 193 69.9
Unknown 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
PgR status
Negative 332 44.0 122 22.6 210 97.7 203 42.5 129 46.7
Positive 419 55.6 414 76.8 5 2.3 272 56.9 147 53.3
Unknown 3 0.4 3 0.6 0 0.0 3 0.6 0 0.0
Nuclear grade
1 120 15.9 102 18.9 18 8.4 79 16.5 41 14.9
2 106 14.1 82 15.2 24 11.2 70 14.6 36 13.0
3 216 28.6 111 20.6 105 48.8 144 30.1 72 26.1
Unknown 312 41.4 244 45.3 68 31.6 185 38.7 127 46.0
Ki67 index
< 30 141 18.7 105 19.5 36 16.7 103 21.5 38 13.8
≥ 30 191 25.3 93 17.3 98 45.6 130 27.2 61 22.1
Unknown 422 56.0 341 63.3 81 37.7 245 51.3 177 64.1
Diagnosis
Locally advanced 34 4.5 20 3.7 14 6.5 29 6.1 5 1.8
Stage IV 199 26.4 149 27.6 50 23.3 130 27.2 69 25.0
Recurrence 521 69.1 370 68.6 151 70.2 319 66.7 202 73.2
Disease-free interval (months)
0 233 30.9 169 31.4 64 29.8 159 33.3 74 26.8
0–24 178 23.6 83 15.4 95 44.2 101 21.1 77 27.9
≥ 4 292 38.7 246 45.6 46 21.4 190 39.7 102 37.0
Unknown 51 6.8 41 7.6 10 4.7 28 5.9 23 8.3
Distant metastasis
No 81 10.7 47 8.7 34 15.8 34 7.1 47 17.0
Yes 649 86.1 476 88.3 173 80.5 422 88.3 227 82.2
Unknown 24 3.2 16 3.0 8 3.7 22 4.6 2 0.7
Metastatic sitec
Non-visceral 54 8.3 36 7.6 18 10.4 40 9.5 14 6.2
Visceral 595 91.7 440 92.4 155 89.6 382 90.5 213 93.8
No. of metastatic organsc
< 3 558 86.0 409 85.9 149 86.1 355 84.1 203 89.4
≥ 3 91 14.0 67 14.1 24 13.9 67 15.9 24 10.6
Cancer-related symptoms
No 315 41.8 230 42.7 85 39.5 200 41.8 115 41.7
Yes 434 57.6 305 56.6 129 60.0 275 57.5 159 57.6
Unknown 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Treatment line for locally advanced or metastatic breast cancer
First line 478 63.4 345 64.0 133 61.9
Second line 276 36.6 194 36.0 82 38.1
History of adjuvant therapyd
Chemotherapy 370 71.0 238 64.3 132 87.4 227 71.2 143 70.8
Anthracycline 297 57.0 188 50.8 109 72.2 186 58.3 111 55.0
Taxane 262 50.3 153 41.4 109 72.2 165 51.7 97 48.0
Endocrine therapy 336 64.5 324 87.6 12 7.9 205 64.3 131 64.9
Previous therapy for locally advanced or metastatic breast cancer
Chemotherapy 266 35.3 188 34.9 78 36.3 12 2.5 254 92.0
Anthracycline 80 10.6 63 11.7 17 7.9 4 0.8 76 27.5
Taxane 54 7.2 36 6.7 18 8.4 5 1.0 49 17.8
Endocrine therapy 356 47.2 348 64.6 8 3.7 195 40.8 161 58.3
Radiotherapy 140 18.6 111 20.6 29 13.5 62 13.0 78 28.3
ECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cNumber (%) of distant metastasis
dNumber (%) of patients with breast cancer recurrence
The proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).
Treatment exposure
Most patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median duration of study treatment (25th, 75th percentiles), months 5.1 (3.1, 8.7) 5.5 (3.3, 9.5) 4.0 (2.3, 6.5) 5.3 (3.0, 8.7) 4.8 (2.4, 8.8)
Median duration of bevacizumab (25th, 75th percentiles), months 5.1 (2.8, 8.5) 5.4 (3.3, 9.5) 3.7 (2.3, 6.2) 5.1 (2.8, 8.5) 4.6 (2.4, 8.7)
Median RDI of bevacizumab (25th, 75th percentiles), 97.5 (86.2, 100) 95.9 (86.5, 100) 100 (85.7, 100) 95.6 (87.2–100) 100 (84.8–100)
Discontinuations of bevacizumab, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of bevacizumab, n (%)
Disease progression 379 50.7 261 48.7 118 55.7 221 46.5 158 57.9
Adverse events 214 28.6 169 31.5 45 21.2 143 30.1 71 26.0
Other 152 20.3 105 19.6 47 22.2 109 22.9 43 15.8
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Bevacizumab dose reductions, n (T) 15 2.0 12 2.2 3 1.4 13 2.7 2 0.7
Reason for bevacizumab dose reduction, n (%)c
Hypertension 3 20.0 2 16.7 1 33.3 3 23.1 0 0.0
Proteinuria 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Bleeding 1 6.7 1 8.3 0 0.0 1 7.7 0 0.0
Neutropenia 1 6.7 1 8.3 0 0.0 0 0.0 1 50.0
Other adverse events 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Other 4 26.7 2 16.7 2 66.7 3 23.1 0 0.0
Bevacizumab dose interruptions or delays, n (%) 263 34.9 188 34.9 75 34.9 155 32.4 108 39.1
Reason for bevacizumab dose interruption or delay, n (%)c
Hypertension 18 6.8 15 8.0 3 4.0 16 10.3 2 1.9
Proteinuria 53 20.2 36 19.1 17 22.7 35 22.6 18 16.7
Bleeding 3 1.1 2 1.1 1 1.3 2 1.3 1 0.9
Neutropenia 77 29.3 61 32.4 16 21.3 38 24.5 39 36.1
Other adverse events 106 40.3 77 41.0 29 38.7 61 39.4 45 41.7
Other 114 43.3 79 42.0 35 46.7 63 40.6 51 47.2
Median duration of paclitaxel (25th, 75th percentiles), months 4.9 (2.8, 8.1) 5.3 (3.2, 9.0) 3.9 (2.3, 6.0) 5.1 (3.0, 8.1) 4.6 (2.4, 8.2)
Median RDI of paclitaxel (25th, 75th percentiles), 90.9 (70.6, 100) 88.9 (69.5, 100) 96.0 (75.6, 105) 91.7 (72.7, 100) 89.8 (68.6, 100)
Discontinuations of paclitaxel, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of paclitaxel, n (%)
Disease progression 363 48.5 245 45.7 118 55.7 216 45.5 147 53.8
Adverse events 246 32.9 198 36.9 48 22.6 158 33.3 88 32.2
Other 136 18.2 92 17.2 44 20.8 99 20.8 37 13.6
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Paclitaxel dose reductions, n (%) 276 36.6 208 38.6 68 31.6 185 38.7 91 33.0
Reason for paclitaxel dose reduction, n (%)c
Peripheral neutropenia 114 41.3 89 42.8 25 36.8 81 43.8 33 36.3
Neutropenia 117 42.4 88 42.3 29 42.6 67 36.2 50 54.9
Other adverse events 81 29.3 61 29.3 20 29.4 57 30.8 24 26.4
Other 28 10.1 20 9.6 8 11.8 19 10.3 9 9.9
Paclitaxel dose interruptions or delays, n () 351 46.6 259 48.1 92 42.8 207 43.3 144 52.2
Reason for paclitaxel dose interruption or delay, n (%)c
Peripheral neutropenia 65 18.5 52 20.1 13 14.1 39 18.8 26 18.1
Neutropenia 159 45.3 123 47.5 36 39.1 82 39.6 77 53.5
Other adverse events 168 47.9 118 45.6 50 54.3 94 45.4 74 51.4
Other 127 36.2 90 34.7 37 40.2 72 34.8 55 38.2
Median duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 1.4 (N = 79) 0.5, 3.9 1.4 (N = 65) 0.5, 3.9 0.6 (N = 14) 0.2, 3.0 1.4 (N = 52) 0.5, 3.9 0.8 (N = 27) 0.3, 3.7
Median duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 0.2 (N = 133) 0.2, 0.7 0.2 (N = 86) 0.2, 0.7 0.2 (N = 47) 0.2, 0.9 0.2 (N = 87) 0.2, 1.2 0.2 (N = 46) 0.2, 0.3
RDI relative dose intensity
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cMultiple items could be selected
Of the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).
The dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.
When the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.
Details of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.
Effectiveness
Overall survival
Median observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B
The results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival
(a) All eligible patients
Univariate analysis (N = 754) Multivariate analysis (N = 736)a
Variable N HR 95% CI p HR 95% CI p
Cohort A vs cohort B 754 1.63 1.35–1.97 < 0.0001 1.75 1.44–2.14 < 0.0001
First- vs second-line therapy 754 1.46 1.22–1.74 < 0.0001 1.35 1.13–1.63 0.0011
Age: < 50 years vs ≥ 50 years 754 0.92 0.77–1.10 0.3361
ECOG PS: 0 vs 1, 2, or 3 754 1.59 1.32–1.91 < 0.0001 1.28 1.04–1.57 0.0175
Visceral metastasis: yes vs no 754 0.55 0.44–0.70 < 0.0001 0.52 0.40–0.66 < 0.0001
Cancer-related symptoms: yes vs no 749 0.57 0.48–0.69 < 0.0001 0.56 0.46–0.68 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.63 0.53–0.75 < 0.0001 0.87 0.66–1.14 0.3139
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.60 0.50–0.72 < 0.0001 0.65 0.49–0.86 0.0026
History of taxane-based chemotherapy: yes vs no 754 0.90 0.64–1.26 0.5380
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.78–1.38 0.8108
History of hormone therapy: yes vs no 754 1.02 0.86–1.22 0.8031
Nuclear grade: ≤ 2 vs 3 442 1.31 1.05–1.64 0.0186
Ki-67 index: < 30 vs ≥ 30 332 1.64 1.25–2.16 0.0004
Disease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.02 0.92–1.13 0.7575
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 521 1.52 1.22–1.90 0.0002 1.27 0.94–1.71 0.1251
First- vs second-line therapy 521 1.33 1.08–1.64 0.0069 1.20 0.95–1.52 0.1210
Age: < 50 years vs ≥ 50 years 521 0.92 0.75–1.13 0.4072
ECOG PS: 0 vs 1, 2, or 3 521 1.65 1.32–2.06 < 0.0001 1.32 1.02–1.71 0.0333
Visceral metastasis: yes vs no 521 0.58 0.44–0.77 0.0001 0.53 0.39–0.72 0.0001
Cancer-related symptoms: yes vs no 518 0.50 0.41–0.62 < 0.0001 0.52 0.41–0.66 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.68 0.53–0.86 0.0016 1.08 0.76–1.54 0.6634
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.66 0.53–0.81 0.0001 0.70 0.51–0.95 0.0209
History of taxane-based chemotherapy: yes vs no 521 0.86 0.56–1.32 0.4944
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.57–1.36 0.5617
History of hormone therapy: yes vs no 521 1.28 1.04–1.57 0.0190 1.14 0.87–1.50 0.3367
Nuclear grade: ≤ 2 vs 3 299 1.17 0.90–1.52 0.2389
Ki-67 index: < 30 vs ≥ 30 178 1.81 1.27–2.57 0.0011
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.45 0.36–0.56 < 0.0001 0.50 0.39–0.63 < 0.0001
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
The results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.
The results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.
Progression-free survival and objective response rates
Median PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.
Multivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival
(a) All eligible patients
Univariate analysis (n = 754) Multivariate analysis (n = 687)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 754 1.33 1.13–1.58 0.0008 1.56 1.26–1.93 0.0001
First- vs second-line therapy 754 1.40 1.20–1.64 < 0.0001 1.19 0.99–1.42 0.0622
Age: < 50 years vs ≥ 50 years 754 1.00 0.86–1.16 0.9589
ECOG PS: 0 vs 1, 2, or 3 754 1.60 1.36–1.88 < 0.0001 1.36 1.13–1.64 0.0013
Visceral metastasis: yes vs no 754 0.63 0.52–0.76 < 0.0001 0.68 0.55–0.85 0.0005
Cancer-related symptoms: yes vs no 749 0.68 0.58–0.79 < 0.0001 0.72 0.60–0.86 0.0003
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.62 0.53–0.72 < 0.0001 0.71 0.53–0.95 0.0227
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.61 0.52–0.72 < 0.0001 0.69 0.54–0.89 0.0044
History of taxane-based chemotherapy: yes vs no 754 0.69 0.52–0.92 0.0113 0.82 0.58–1.14 0.2358
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.80–1.31 0.8458
History of endocrine therapy: yes vs no 754 0.85 0.73–0.99 0.0411 0.76 0.62–0.93 0.0075
Nuclear grade: ≤ 2 vs 3 442 1.18 0.97–1.44 0.0961
Ki-67 index: < 30 vs ≥ 30 332 1.54 1.22–1.96 0.0003
Disease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.07 0.99–1.17 0.1040 0.89 0.78–1.01 0.0663
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI p HR 95% CI p
Cohort A vs cohort B 521 1.31 1.08–1.60 0.0073 1.12 0.89–1.40 0.3505
First- vs second-line therapy 521 1.33 1.11–1.60 0.0021 1.16 0.94–1.43 0.1643
Age: < 50 years vs ≥ 50 years 521 1.01 0.84–1.20 0.9470
PS: 0 vs 1, 2, or 3 521 1.74 1.43–2.11 < 0.0001 1.49 1.19–1.88 0.0006
Visceral metastasis: yes vs no 521 0.74 0.59–0.93 0.0086 0.78 0.60–1.00 0.0518
Cancer-related symptoms: yes vs no 518 0.62 0.52–0.74 < 0.0001 0.67 0.55–0.83 0.0002
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.66 0.54–0.81 0.0001 0.85 0.63–1.14 0.2795
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.67 0.56–0.81 < 0.0001 0.78 0.60–1.01 0.0573
History of taxane-based chemotherapy: yes vs no 521 0.66 0.45–0.97 0.0361 0.75 0.47–1.21 0.2333
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.60–1.28 0.5067
History of hormone therapy: yes vs no 521 1.07 0.89–1.28 0.4891
Nuclear grade: ≤ 2 vs 3 299 1.05 0.83–1.33 0.6669
Ki-67 index: < 30 vs ≥ 30 178 1.46 1.07–2.00 0.0174
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.51 0.42–0.61 < 0.0001 0.54 0.44–0.67 < 0.0001
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Multivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.
In the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).
ORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions
(a) All eligible patients
All eligible patients Cohort Aa Cohort Bb P First-line therapy Second-line therapy p
No. of patients with target lesions 545 383 162 352 193
Best response, n (%)
CR 14 (2.6%) 8 (2.1%) 6 (3.7%) 0.0180 (W) 10 (2.8%) 4 (2.1%) 0.0001 (W)
PR 292 (53.6%) 219 (57.2%) 73 (45.1%) 209 (59.4%) 83 (43.0%)
SD 139 (25.5%) 104 (27.2%) 35 (21.6%) 77 (21.9%) 62 (32.1%)
PD 71 (13.0%) 36 (9.4%) 35 (21.6%) 35 (9.9%) 36 (18.7%)
NE 29 (5.3%) 16 (4.2%) 13 (8.0%) 21 (6.0%) 8 (4.1%)
Response rate, n (%)
CR plus PR 306 (56.1%) 227 (59.3%) 79 (48.8%) 0.0297 (F) 219 (62.2%) 87 (45.1%) 0.0001 (F)
95% CI 51.9–60.4 54.2–64.2 40.8–56.7 56.9–67.3 37.9–52.4
(b) Cohorts A and B
Cohort Aa First-line therapy Second-line therapy P Cohort Bb First-line therapy Second-line therapy p
No. of patients with target lesions 383 252 131 162 100 62
Best response
CR 8 (2.1%) 6 (2.4%) 2 (1.5%) 0.0048 (W) 6 (3.7%) 4 (4.0%) 2 (3.2%) 0.0011 (W)
PR 219 (57.2%) 155 (61.5%) 64 (48.9%) 73 (45.1%) 54 (54.0%) 19 (30.6%)
SD 104 (27.2%) 57 (22.6%) 47 (35.9%) 35 (21.6%) 20 (20.0%) 15 (24.2%)
PD 36 (9.4%) 21 (8.3%) 15 (11.5%) 35 (21.6%) 14 (14.0%) 21 (33.9%)
NE 16 (4.2%) 13 (5.2%) 3 (2.3%) 13 (8.0%) 8 (8.0%) 5 (8.1%)
Response rate
CR plus PR 227 (59.3%) 161 (63.9%) 66 (50.4%) 0.0119 (F) 79 (48.8%) 58 (58.0%) 21 (33.9%) 0.0036 (F)
95% CI 54.2–64.2 57.6–69.8 41.5–59.2 40.8–56.7 47.7–67.8 22.3–47.0
CR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Safety
The great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)
Treated patient population Cohort Aa Cohort Bb First-line therapy Second-line therapy
n (%) n (%) n (%) n (%) n (%)
(a) Selected AEs
No. of patients 750 100 538 100 212 100 475 100 275 100
Hypertension
All grades 602 80.3 429 79.7 173 81.6 383 80.6 219 79.6
Grade ≥ 3 268 35.7 190 35.3 78 36.8 167 35.2 101 36.7
Peripheral neuropathy
All grades 535 71.3 400 74.3 135 63.7 341 71.8 194 70.5
Grade ≥ 3 54 7.2 41 7.6 13 6.1 36 7.6 18 6.5
Neutropenia
All grades 347 46.3 256 47.6 91 42.9 203 42.7 144 52.4
Grade ≥ 3 204 27.2 151 28.1 53 25.0 115 24.2 89 32.4
Proteinuria
All grades 223 29.7 160 29.7 63 29.7 156 32.8 67 24.4
Grade ≥ 3 28 3.7 18 3.3 10 4.7 20 4.2 8 2.9
Bleeding
All grades 131 17.5 96 17.8 35 16.5 87 18.3 44 16.0
Grade ≥ 3 2 0.3 2 0.4 0 0.0 1 0.2 1 0.4
(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)
No. of patients 750 100 538 100 212 100 475 100 275 100
Congestive heart failure 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Gastrointestinal perforation 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
Thromboembolism 3 0.4 3 0.6 0 0.0 2 0.4 1 0.4
Wound dehiscence 2 0.3 1 0.2 1 0.5 0 0.0 2 0.7
(c) Other adverse events grade ≥ 3
No. of patients 750 100 538 100 212 100 475 100 275 100
Fatigue 12 1.6 6 1.1 6 2.8 4 0.8 8 2.9
Stomatitis 6 0.8 6 1.1 0 0.0 3 0.6 3 1.1
Febrile neutropenia 4 0.5 2 0.4 2 0.9 1 0.2 3 1.1
Other infections 23 3.1 18 3.3 5 2.4 15 3.2 8 2.9
Skin disorders 11 1.5 10 1.9 1 0.5 9 1.9 2 0.7
Anemia 10 1.3 8 1.5 2 0.9 5 1.1 5 1.8
AST/ALT elevation 10 1.3 6 1.1 4 1.9 8 1.7 2 0.7
Appetite loss 7 0.9 5 0.9 2 0.9 3 0.6 4 1.5
Diarrhea 5 0.7 3 0.6 2 0.9 5 1.1 0 0.0
Drug-induced pneumonitis 5 0.7 4 0.7 1 0.5 2 0.4 3 1.1
Pain 4 0.5 3 0.6 1 0.5 2 0.4 2 0.7
Others 31 4.1 24 4.5 7 3.3 13 2.7 18 6.5
ALT alanine aminotransferase, AST aspartate aminotransferase
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Serious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.
Discussion
The B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.
The 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.
The multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].
OS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.
As for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].
The multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].
Despite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).
No new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.
The present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.
In conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.
Electronic supplementary material
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Supplementary file2 (PDF 953 kb)
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Acknowledgements
The authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.
Funding
The study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Compliance with ethical standards
Conflict of interest
Yamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;
Ethical statement
The study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.
Informed consent
Written informed consent was obtained from all patients. | Fatal | ReactionOutcome | CC BY | 32715420 | 18,780,431 | 2021-01 |
What was the outcome of reaction 'Gastrointestinal perforation'? | Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
OBJECTIVE
To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.
METHODS
In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.
RESULTS
Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.
CONCLUSIONS
In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.
BACKGROUND
Trial no. UMIN000009086.
Introduction
Bevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].
A meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].
The JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.
Although several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.
Patients and methods
Study design
In this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.
Patients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.
Written informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).
Study treatment
Because the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.
In cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.
Study assessment
At screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.
Regarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.
Analysis populations and endpoints
The eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.
The primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).
Statistical analyses
This was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.
Expected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.
For the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.
Safety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.
Results
Study population and baseline patient characteristics
A total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.
Baseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median age (range) (years) 58.0 (26–83) 58.0 (26–81) 58.0 (27–83) 59.0 (26–83) 57.0 (28–83)
Menopausal status
Premenopausal 198 26.3 133 24.7 65 30.2 127 26.6 71 25.7
Postmenopausal 532 70.6 385 71.4 147 68.4 337 70.5 195 70.7
Unknown 24 3.2 21 3.9 3 1.4 14 2.9 10 3.6
ECOG PS
0 522 69.2 371 68.8 151 70.2 345 72.2 177 64.1
1 172 22.8 122 22.6 50 23.3 96 20.1 76 27.5
2 43 5.7 34 6.3 9 4.2 29 6.1 14 5.1
3 17 2.3 12 2.2 5 2.3 8 1.7 9 3.3
ER status
Negative 208 27.6 8 1.5 200 93.0 125 26.2 83 30.1
Positive 544 72.1 529 98.1 15 7.0 351 73.4 193 69.9
Unknown 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
PgR status
Negative 332 44.0 122 22.6 210 97.7 203 42.5 129 46.7
Positive 419 55.6 414 76.8 5 2.3 272 56.9 147 53.3
Unknown 3 0.4 3 0.6 0 0.0 3 0.6 0 0.0
Nuclear grade
1 120 15.9 102 18.9 18 8.4 79 16.5 41 14.9
2 106 14.1 82 15.2 24 11.2 70 14.6 36 13.0
3 216 28.6 111 20.6 105 48.8 144 30.1 72 26.1
Unknown 312 41.4 244 45.3 68 31.6 185 38.7 127 46.0
Ki67 index
< 30 141 18.7 105 19.5 36 16.7 103 21.5 38 13.8
≥ 30 191 25.3 93 17.3 98 45.6 130 27.2 61 22.1
Unknown 422 56.0 341 63.3 81 37.7 245 51.3 177 64.1
Diagnosis
Locally advanced 34 4.5 20 3.7 14 6.5 29 6.1 5 1.8
Stage IV 199 26.4 149 27.6 50 23.3 130 27.2 69 25.0
Recurrence 521 69.1 370 68.6 151 70.2 319 66.7 202 73.2
Disease-free interval (months)
0 233 30.9 169 31.4 64 29.8 159 33.3 74 26.8
0–24 178 23.6 83 15.4 95 44.2 101 21.1 77 27.9
≥ 4 292 38.7 246 45.6 46 21.4 190 39.7 102 37.0
Unknown 51 6.8 41 7.6 10 4.7 28 5.9 23 8.3
Distant metastasis
No 81 10.7 47 8.7 34 15.8 34 7.1 47 17.0
Yes 649 86.1 476 88.3 173 80.5 422 88.3 227 82.2
Unknown 24 3.2 16 3.0 8 3.7 22 4.6 2 0.7
Metastatic sitec
Non-visceral 54 8.3 36 7.6 18 10.4 40 9.5 14 6.2
Visceral 595 91.7 440 92.4 155 89.6 382 90.5 213 93.8
No. of metastatic organsc
< 3 558 86.0 409 85.9 149 86.1 355 84.1 203 89.4
≥ 3 91 14.0 67 14.1 24 13.9 67 15.9 24 10.6
Cancer-related symptoms
No 315 41.8 230 42.7 85 39.5 200 41.8 115 41.7
Yes 434 57.6 305 56.6 129 60.0 275 57.5 159 57.6
Unknown 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Treatment line for locally advanced or metastatic breast cancer
First line 478 63.4 345 64.0 133 61.9
Second line 276 36.6 194 36.0 82 38.1
History of adjuvant therapyd
Chemotherapy 370 71.0 238 64.3 132 87.4 227 71.2 143 70.8
Anthracycline 297 57.0 188 50.8 109 72.2 186 58.3 111 55.0
Taxane 262 50.3 153 41.4 109 72.2 165 51.7 97 48.0
Endocrine therapy 336 64.5 324 87.6 12 7.9 205 64.3 131 64.9
Previous therapy for locally advanced or metastatic breast cancer
Chemotherapy 266 35.3 188 34.9 78 36.3 12 2.5 254 92.0
Anthracycline 80 10.6 63 11.7 17 7.9 4 0.8 76 27.5
Taxane 54 7.2 36 6.7 18 8.4 5 1.0 49 17.8
Endocrine therapy 356 47.2 348 64.6 8 3.7 195 40.8 161 58.3
Radiotherapy 140 18.6 111 20.6 29 13.5 62 13.0 78 28.3
ECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cNumber (%) of distant metastasis
dNumber (%) of patients with breast cancer recurrence
The proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).
Treatment exposure
Most patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median duration of study treatment (25th, 75th percentiles), months 5.1 (3.1, 8.7) 5.5 (3.3, 9.5) 4.0 (2.3, 6.5) 5.3 (3.0, 8.7) 4.8 (2.4, 8.8)
Median duration of bevacizumab (25th, 75th percentiles), months 5.1 (2.8, 8.5) 5.4 (3.3, 9.5) 3.7 (2.3, 6.2) 5.1 (2.8, 8.5) 4.6 (2.4, 8.7)
Median RDI of bevacizumab (25th, 75th percentiles), 97.5 (86.2, 100) 95.9 (86.5, 100) 100 (85.7, 100) 95.6 (87.2–100) 100 (84.8–100)
Discontinuations of bevacizumab, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of bevacizumab, n (%)
Disease progression 379 50.7 261 48.7 118 55.7 221 46.5 158 57.9
Adverse events 214 28.6 169 31.5 45 21.2 143 30.1 71 26.0
Other 152 20.3 105 19.6 47 22.2 109 22.9 43 15.8
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Bevacizumab dose reductions, n (T) 15 2.0 12 2.2 3 1.4 13 2.7 2 0.7
Reason for bevacizumab dose reduction, n (%)c
Hypertension 3 20.0 2 16.7 1 33.3 3 23.1 0 0.0
Proteinuria 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Bleeding 1 6.7 1 8.3 0 0.0 1 7.7 0 0.0
Neutropenia 1 6.7 1 8.3 0 0.0 0 0.0 1 50.0
Other adverse events 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Other 4 26.7 2 16.7 2 66.7 3 23.1 0 0.0
Bevacizumab dose interruptions or delays, n (%) 263 34.9 188 34.9 75 34.9 155 32.4 108 39.1
Reason for bevacizumab dose interruption or delay, n (%)c
Hypertension 18 6.8 15 8.0 3 4.0 16 10.3 2 1.9
Proteinuria 53 20.2 36 19.1 17 22.7 35 22.6 18 16.7
Bleeding 3 1.1 2 1.1 1 1.3 2 1.3 1 0.9
Neutropenia 77 29.3 61 32.4 16 21.3 38 24.5 39 36.1
Other adverse events 106 40.3 77 41.0 29 38.7 61 39.4 45 41.7
Other 114 43.3 79 42.0 35 46.7 63 40.6 51 47.2
Median duration of paclitaxel (25th, 75th percentiles), months 4.9 (2.8, 8.1) 5.3 (3.2, 9.0) 3.9 (2.3, 6.0) 5.1 (3.0, 8.1) 4.6 (2.4, 8.2)
Median RDI of paclitaxel (25th, 75th percentiles), 90.9 (70.6, 100) 88.9 (69.5, 100) 96.0 (75.6, 105) 91.7 (72.7, 100) 89.8 (68.6, 100)
Discontinuations of paclitaxel, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of paclitaxel, n (%)
Disease progression 363 48.5 245 45.7 118 55.7 216 45.5 147 53.8
Adverse events 246 32.9 198 36.9 48 22.6 158 33.3 88 32.2
Other 136 18.2 92 17.2 44 20.8 99 20.8 37 13.6
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Paclitaxel dose reductions, n (%) 276 36.6 208 38.6 68 31.6 185 38.7 91 33.0
Reason for paclitaxel dose reduction, n (%)c
Peripheral neutropenia 114 41.3 89 42.8 25 36.8 81 43.8 33 36.3
Neutropenia 117 42.4 88 42.3 29 42.6 67 36.2 50 54.9
Other adverse events 81 29.3 61 29.3 20 29.4 57 30.8 24 26.4
Other 28 10.1 20 9.6 8 11.8 19 10.3 9 9.9
Paclitaxel dose interruptions or delays, n () 351 46.6 259 48.1 92 42.8 207 43.3 144 52.2
Reason for paclitaxel dose interruption or delay, n (%)c
Peripheral neutropenia 65 18.5 52 20.1 13 14.1 39 18.8 26 18.1
Neutropenia 159 45.3 123 47.5 36 39.1 82 39.6 77 53.5
Other adverse events 168 47.9 118 45.6 50 54.3 94 45.4 74 51.4
Other 127 36.2 90 34.7 37 40.2 72 34.8 55 38.2
Median duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 1.4 (N = 79) 0.5, 3.9 1.4 (N = 65) 0.5, 3.9 0.6 (N = 14) 0.2, 3.0 1.4 (N = 52) 0.5, 3.9 0.8 (N = 27) 0.3, 3.7
Median duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 0.2 (N = 133) 0.2, 0.7 0.2 (N = 86) 0.2, 0.7 0.2 (N = 47) 0.2, 0.9 0.2 (N = 87) 0.2, 1.2 0.2 (N = 46) 0.2, 0.3
RDI relative dose intensity
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cMultiple items could be selected
Of the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).
The dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.
When the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.
Details of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.
Effectiveness
Overall survival
Median observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B
The results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival
(a) All eligible patients
Univariate analysis (N = 754) Multivariate analysis (N = 736)a
Variable N HR 95% CI p HR 95% CI p
Cohort A vs cohort B 754 1.63 1.35–1.97 < 0.0001 1.75 1.44–2.14 < 0.0001
First- vs second-line therapy 754 1.46 1.22–1.74 < 0.0001 1.35 1.13–1.63 0.0011
Age: < 50 years vs ≥ 50 years 754 0.92 0.77–1.10 0.3361
ECOG PS: 0 vs 1, 2, or 3 754 1.59 1.32–1.91 < 0.0001 1.28 1.04–1.57 0.0175
Visceral metastasis: yes vs no 754 0.55 0.44–0.70 < 0.0001 0.52 0.40–0.66 < 0.0001
Cancer-related symptoms: yes vs no 749 0.57 0.48–0.69 < 0.0001 0.56 0.46–0.68 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.63 0.53–0.75 < 0.0001 0.87 0.66–1.14 0.3139
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.60 0.50–0.72 < 0.0001 0.65 0.49–0.86 0.0026
History of taxane-based chemotherapy: yes vs no 754 0.90 0.64–1.26 0.5380
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.78–1.38 0.8108
History of hormone therapy: yes vs no 754 1.02 0.86–1.22 0.8031
Nuclear grade: ≤ 2 vs 3 442 1.31 1.05–1.64 0.0186
Ki-67 index: < 30 vs ≥ 30 332 1.64 1.25–2.16 0.0004
Disease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.02 0.92–1.13 0.7575
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 521 1.52 1.22–1.90 0.0002 1.27 0.94–1.71 0.1251
First- vs second-line therapy 521 1.33 1.08–1.64 0.0069 1.20 0.95–1.52 0.1210
Age: < 50 years vs ≥ 50 years 521 0.92 0.75–1.13 0.4072
ECOG PS: 0 vs 1, 2, or 3 521 1.65 1.32–2.06 < 0.0001 1.32 1.02–1.71 0.0333
Visceral metastasis: yes vs no 521 0.58 0.44–0.77 0.0001 0.53 0.39–0.72 0.0001
Cancer-related symptoms: yes vs no 518 0.50 0.41–0.62 < 0.0001 0.52 0.41–0.66 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.68 0.53–0.86 0.0016 1.08 0.76–1.54 0.6634
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.66 0.53–0.81 0.0001 0.70 0.51–0.95 0.0209
History of taxane-based chemotherapy: yes vs no 521 0.86 0.56–1.32 0.4944
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.57–1.36 0.5617
History of hormone therapy: yes vs no 521 1.28 1.04–1.57 0.0190 1.14 0.87–1.50 0.3367
Nuclear grade: ≤ 2 vs 3 299 1.17 0.90–1.52 0.2389
Ki-67 index: < 30 vs ≥ 30 178 1.81 1.27–2.57 0.0011
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.45 0.36–0.56 < 0.0001 0.50 0.39–0.63 < 0.0001
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
The results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.
The results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.
Progression-free survival and objective response rates
Median PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.
Multivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival
(a) All eligible patients
Univariate analysis (n = 754) Multivariate analysis (n = 687)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 754 1.33 1.13–1.58 0.0008 1.56 1.26–1.93 0.0001
First- vs second-line therapy 754 1.40 1.20–1.64 < 0.0001 1.19 0.99–1.42 0.0622
Age: < 50 years vs ≥ 50 years 754 1.00 0.86–1.16 0.9589
ECOG PS: 0 vs 1, 2, or 3 754 1.60 1.36–1.88 < 0.0001 1.36 1.13–1.64 0.0013
Visceral metastasis: yes vs no 754 0.63 0.52–0.76 < 0.0001 0.68 0.55–0.85 0.0005
Cancer-related symptoms: yes vs no 749 0.68 0.58–0.79 < 0.0001 0.72 0.60–0.86 0.0003
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.62 0.53–0.72 < 0.0001 0.71 0.53–0.95 0.0227
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.61 0.52–0.72 < 0.0001 0.69 0.54–0.89 0.0044
History of taxane-based chemotherapy: yes vs no 754 0.69 0.52–0.92 0.0113 0.82 0.58–1.14 0.2358
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.80–1.31 0.8458
History of endocrine therapy: yes vs no 754 0.85 0.73–0.99 0.0411 0.76 0.62–0.93 0.0075
Nuclear grade: ≤ 2 vs 3 442 1.18 0.97–1.44 0.0961
Ki-67 index: < 30 vs ≥ 30 332 1.54 1.22–1.96 0.0003
Disease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.07 0.99–1.17 0.1040 0.89 0.78–1.01 0.0663
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI p HR 95% CI p
Cohort A vs cohort B 521 1.31 1.08–1.60 0.0073 1.12 0.89–1.40 0.3505
First- vs second-line therapy 521 1.33 1.11–1.60 0.0021 1.16 0.94–1.43 0.1643
Age: < 50 years vs ≥ 50 years 521 1.01 0.84–1.20 0.9470
PS: 0 vs 1, 2, or 3 521 1.74 1.43–2.11 < 0.0001 1.49 1.19–1.88 0.0006
Visceral metastasis: yes vs no 521 0.74 0.59–0.93 0.0086 0.78 0.60–1.00 0.0518
Cancer-related symptoms: yes vs no 518 0.62 0.52–0.74 < 0.0001 0.67 0.55–0.83 0.0002
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.66 0.54–0.81 0.0001 0.85 0.63–1.14 0.2795
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.67 0.56–0.81 < 0.0001 0.78 0.60–1.01 0.0573
History of taxane-based chemotherapy: yes vs no 521 0.66 0.45–0.97 0.0361 0.75 0.47–1.21 0.2333
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.60–1.28 0.5067
History of hormone therapy: yes vs no 521 1.07 0.89–1.28 0.4891
Nuclear grade: ≤ 2 vs 3 299 1.05 0.83–1.33 0.6669
Ki-67 index: < 30 vs ≥ 30 178 1.46 1.07–2.00 0.0174
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.51 0.42–0.61 < 0.0001 0.54 0.44–0.67 < 0.0001
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Multivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.
In the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).
ORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions
(a) All eligible patients
All eligible patients Cohort Aa Cohort Bb P First-line therapy Second-line therapy p
No. of patients with target lesions 545 383 162 352 193
Best response, n (%)
CR 14 (2.6%) 8 (2.1%) 6 (3.7%) 0.0180 (W) 10 (2.8%) 4 (2.1%) 0.0001 (W)
PR 292 (53.6%) 219 (57.2%) 73 (45.1%) 209 (59.4%) 83 (43.0%)
SD 139 (25.5%) 104 (27.2%) 35 (21.6%) 77 (21.9%) 62 (32.1%)
PD 71 (13.0%) 36 (9.4%) 35 (21.6%) 35 (9.9%) 36 (18.7%)
NE 29 (5.3%) 16 (4.2%) 13 (8.0%) 21 (6.0%) 8 (4.1%)
Response rate, n (%)
CR plus PR 306 (56.1%) 227 (59.3%) 79 (48.8%) 0.0297 (F) 219 (62.2%) 87 (45.1%) 0.0001 (F)
95% CI 51.9–60.4 54.2–64.2 40.8–56.7 56.9–67.3 37.9–52.4
(b) Cohorts A and B
Cohort Aa First-line therapy Second-line therapy P Cohort Bb First-line therapy Second-line therapy p
No. of patients with target lesions 383 252 131 162 100 62
Best response
CR 8 (2.1%) 6 (2.4%) 2 (1.5%) 0.0048 (W) 6 (3.7%) 4 (4.0%) 2 (3.2%) 0.0011 (W)
PR 219 (57.2%) 155 (61.5%) 64 (48.9%) 73 (45.1%) 54 (54.0%) 19 (30.6%)
SD 104 (27.2%) 57 (22.6%) 47 (35.9%) 35 (21.6%) 20 (20.0%) 15 (24.2%)
PD 36 (9.4%) 21 (8.3%) 15 (11.5%) 35 (21.6%) 14 (14.0%) 21 (33.9%)
NE 16 (4.2%) 13 (5.2%) 3 (2.3%) 13 (8.0%) 8 (8.0%) 5 (8.1%)
Response rate
CR plus PR 227 (59.3%) 161 (63.9%) 66 (50.4%) 0.0119 (F) 79 (48.8%) 58 (58.0%) 21 (33.9%) 0.0036 (F)
95% CI 54.2–64.2 57.6–69.8 41.5–59.2 40.8–56.7 47.7–67.8 22.3–47.0
CR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Safety
The great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)
Treated patient population Cohort Aa Cohort Bb First-line therapy Second-line therapy
n (%) n (%) n (%) n (%) n (%)
(a) Selected AEs
No. of patients 750 100 538 100 212 100 475 100 275 100
Hypertension
All grades 602 80.3 429 79.7 173 81.6 383 80.6 219 79.6
Grade ≥ 3 268 35.7 190 35.3 78 36.8 167 35.2 101 36.7
Peripheral neuropathy
All grades 535 71.3 400 74.3 135 63.7 341 71.8 194 70.5
Grade ≥ 3 54 7.2 41 7.6 13 6.1 36 7.6 18 6.5
Neutropenia
All grades 347 46.3 256 47.6 91 42.9 203 42.7 144 52.4
Grade ≥ 3 204 27.2 151 28.1 53 25.0 115 24.2 89 32.4
Proteinuria
All grades 223 29.7 160 29.7 63 29.7 156 32.8 67 24.4
Grade ≥ 3 28 3.7 18 3.3 10 4.7 20 4.2 8 2.9
Bleeding
All grades 131 17.5 96 17.8 35 16.5 87 18.3 44 16.0
Grade ≥ 3 2 0.3 2 0.4 0 0.0 1 0.2 1 0.4
(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)
No. of patients 750 100 538 100 212 100 475 100 275 100
Congestive heart failure 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Gastrointestinal perforation 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
Thromboembolism 3 0.4 3 0.6 0 0.0 2 0.4 1 0.4
Wound dehiscence 2 0.3 1 0.2 1 0.5 0 0.0 2 0.7
(c) Other adverse events grade ≥ 3
No. of patients 750 100 538 100 212 100 475 100 275 100
Fatigue 12 1.6 6 1.1 6 2.8 4 0.8 8 2.9
Stomatitis 6 0.8 6 1.1 0 0.0 3 0.6 3 1.1
Febrile neutropenia 4 0.5 2 0.4 2 0.9 1 0.2 3 1.1
Other infections 23 3.1 18 3.3 5 2.4 15 3.2 8 2.9
Skin disorders 11 1.5 10 1.9 1 0.5 9 1.9 2 0.7
Anemia 10 1.3 8 1.5 2 0.9 5 1.1 5 1.8
AST/ALT elevation 10 1.3 6 1.1 4 1.9 8 1.7 2 0.7
Appetite loss 7 0.9 5 0.9 2 0.9 3 0.6 4 1.5
Diarrhea 5 0.7 3 0.6 2 0.9 5 1.1 0 0.0
Drug-induced pneumonitis 5 0.7 4 0.7 1 0.5 2 0.4 3 1.1
Pain 4 0.5 3 0.6 1 0.5 2 0.4 2 0.7
Others 31 4.1 24 4.5 7 3.3 13 2.7 18 6.5
ALT alanine aminotransferase, AST aspartate aminotransferase
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Serious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.
Discussion
The B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.
The 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.
The multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].
OS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.
As for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].
The multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].
Despite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).
No new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.
The present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.
In conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (XLSX 85 kb)
Supplementary file2 (PDF 953 kb)
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Acknowledgements
The authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.
Funding
The study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Compliance with ethical standards
Conflict of interest
Yamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;
Ethical statement
The study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.
Informed consent
Written informed consent was obtained from all patients. | Fatal | ReactionOutcome | CC BY | 32715420 | 18,780,429 | 2021-01 |
What was the outcome of reaction 'Hepatic failure'? | Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
OBJECTIVE
To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.
METHODS
In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.
RESULTS
Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.
CONCLUSIONS
In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.
BACKGROUND
Trial no. UMIN000009086.
Introduction
Bevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].
A meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].
The JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.
Although several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.
Patients and methods
Study design
In this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.
Patients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.
Written informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).
Study treatment
Because the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.
In cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.
Study assessment
At screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.
Regarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.
Analysis populations and endpoints
The eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.
The primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).
Statistical analyses
This was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.
Expected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.
For the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.
Safety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.
Results
Study population and baseline patient characteristics
A total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.
Baseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median age (range) (years) 58.0 (26–83) 58.0 (26–81) 58.0 (27–83) 59.0 (26–83) 57.0 (28–83)
Menopausal status
Premenopausal 198 26.3 133 24.7 65 30.2 127 26.6 71 25.7
Postmenopausal 532 70.6 385 71.4 147 68.4 337 70.5 195 70.7
Unknown 24 3.2 21 3.9 3 1.4 14 2.9 10 3.6
ECOG PS
0 522 69.2 371 68.8 151 70.2 345 72.2 177 64.1
1 172 22.8 122 22.6 50 23.3 96 20.1 76 27.5
2 43 5.7 34 6.3 9 4.2 29 6.1 14 5.1
3 17 2.3 12 2.2 5 2.3 8 1.7 9 3.3
ER status
Negative 208 27.6 8 1.5 200 93.0 125 26.2 83 30.1
Positive 544 72.1 529 98.1 15 7.0 351 73.4 193 69.9
Unknown 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
PgR status
Negative 332 44.0 122 22.6 210 97.7 203 42.5 129 46.7
Positive 419 55.6 414 76.8 5 2.3 272 56.9 147 53.3
Unknown 3 0.4 3 0.6 0 0.0 3 0.6 0 0.0
Nuclear grade
1 120 15.9 102 18.9 18 8.4 79 16.5 41 14.9
2 106 14.1 82 15.2 24 11.2 70 14.6 36 13.0
3 216 28.6 111 20.6 105 48.8 144 30.1 72 26.1
Unknown 312 41.4 244 45.3 68 31.6 185 38.7 127 46.0
Ki67 index
< 30 141 18.7 105 19.5 36 16.7 103 21.5 38 13.8
≥ 30 191 25.3 93 17.3 98 45.6 130 27.2 61 22.1
Unknown 422 56.0 341 63.3 81 37.7 245 51.3 177 64.1
Diagnosis
Locally advanced 34 4.5 20 3.7 14 6.5 29 6.1 5 1.8
Stage IV 199 26.4 149 27.6 50 23.3 130 27.2 69 25.0
Recurrence 521 69.1 370 68.6 151 70.2 319 66.7 202 73.2
Disease-free interval (months)
0 233 30.9 169 31.4 64 29.8 159 33.3 74 26.8
0–24 178 23.6 83 15.4 95 44.2 101 21.1 77 27.9
≥ 4 292 38.7 246 45.6 46 21.4 190 39.7 102 37.0
Unknown 51 6.8 41 7.6 10 4.7 28 5.9 23 8.3
Distant metastasis
No 81 10.7 47 8.7 34 15.8 34 7.1 47 17.0
Yes 649 86.1 476 88.3 173 80.5 422 88.3 227 82.2
Unknown 24 3.2 16 3.0 8 3.7 22 4.6 2 0.7
Metastatic sitec
Non-visceral 54 8.3 36 7.6 18 10.4 40 9.5 14 6.2
Visceral 595 91.7 440 92.4 155 89.6 382 90.5 213 93.8
No. of metastatic organsc
< 3 558 86.0 409 85.9 149 86.1 355 84.1 203 89.4
≥ 3 91 14.0 67 14.1 24 13.9 67 15.9 24 10.6
Cancer-related symptoms
No 315 41.8 230 42.7 85 39.5 200 41.8 115 41.7
Yes 434 57.6 305 56.6 129 60.0 275 57.5 159 57.6
Unknown 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Treatment line for locally advanced or metastatic breast cancer
First line 478 63.4 345 64.0 133 61.9
Second line 276 36.6 194 36.0 82 38.1
History of adjuvant therapyd
Chemotherapy 370 71.0 238 64.3 132 87.4 227 71.2 143 70.8
Anthracycline 297 57.0 188 50.8 109 72.2 186 58.3 111 55.0
Taxane 262 50.3 153 41.4 109 72.2 165 51.7 97 48.0
Endocrine therapy 336 64.5 324 87.6 12 7.9 205 64.3 131 64.9
Previous therapy for locally advanced or metastatic breast cancer
Chemotherapy 266 35.3 188 34.9 78 36.3 12 2.5 254 92.0
Anthracycline 80 10.6 63 11.7 17 7.9 4 0.8 76 27.5
Taxane 54 7.2 36 6.7 18 8.4 5 1.0 49 17.8
Endocrine therapy 356 47.2 348 64.6 8 3.7 195 40.8 161 58.3
Radiotherapy 140 18.6 111 20.6 29 13.5 62 13.0 78 28.3
ECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cNumber (%) of distant metastasis
dNumber (%) of patients with breast cancer recurrence
The proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).
Treatment exposure
Most patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median duration of study treatment (25th, 75th percentiles), months 5.1 (3.1, 8.7) 5.5 (3.3, 9.5) 4.0 (2.3, 6.5) 5.3 (3.0, 8.7) 4.8 (2.4, 8.8)
Median duration of bevacizumab (25th, 75th percentiles), months 5.1 (2.8, 8.5) 5.4 (3.3, 9.5) 3.7 (2.3, 6.2) 5.1 (2.8, 8.5) 4.6 (2.4, 8.7)
Median RDI of bevacizumab (25th, 75th percentiles), 97.5 (86.2, 100) 95.9 (86.5, 100) 100 (85.7, 100) 95.6 (87.2–100) 100 (84.8–100)
Discontinuations of bevacizumab, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of bevacizumab, n (%)
Disease progression 379 50.7 261 48.7 118 55.7 221 46.5 158 57.9
Adverse events 214 28.6 169 31.5 45 21.2 143 30.1 71 26.0
Other 152 20.3 105 19.6 47 22.2 109 22.9 43 15.8
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Bevacizumab dose reductions, n (T) 15 2.0 12 2.2 3 1.4 13 2.7 2 0.7
Reason for bevacizumab dose reduction, n (%)c
Hypertension 3 20.0 2 16.7 1 33.3 3 23.1 0 0.0
Proteinuria 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Bleeding 1 6.7 1 8.3 0 0.0 1 7.7 0 0.0
Neutropenia 1 6.7 1 8.3 0 0.0 0 0.0 1 50.0
Other adverse events 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Other 4 26.7 2 16.7 2 66.7 3 23.1 0 0.0
Bevacizumab dose interruptions or delays, n (%) 263 34.9 188 34.9 75 34.9 155 32.4 108 39.1
Reason for bevacizumab dose interruption or delay, n (%)c
Hypertension 18 6.8 15 8.0 3 4.0 16 10.3 2 1.9
Proteinuria 53 20.2 36 19.1 17 22.7 35 22.6 18 16.7
Bleeding 3 1.1 2 1.1 1 1.3 2 1.3 1 0.9
Neutropenia 77 29.3 61 32.4 16 21.3 38 24.5 39 36.1
Other adverse events 106 40.3 77 41.0 29 38.7 61 39.4 45 41.7
Other 114 43.3 79 42.0 35 46.7 63 40.6 51 47.2
Median duration of paclitaxel (25th, 75th percentiles), months 4.9 (2.8, 8.1) 5.3 (3.2, 9.0) 3.9 (2.3, 6.0) 5.1 (3.0, 8.1) 4.6 (2.4, 8.2)
Median RDI of paclitaxel (25th, 75th percentiles), 90.9 (70.6, 100) 88.9 (69.5, 100) 96.0 (75.6, 105) 91.7 (72.7, 100) 89.8 (68.6, 100)
Discontinuations of paclitaxel, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of paclitaxel, n (%)
Disease progression 363 48.5 245 45.7 118 55.7 216 45.5 147 53.8
Adverse events 246 32.9 198 36.9 48 22.6 158 33.3 88 32.2
Other 136 18.2 92 17.2 44 20.8 99 20.8 37 13.6
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Paclitaxel dose reductions, n (%) 276 36.6 208 38.6 68 31.6 185 38.7 91 33.0
Reason for paclitaxel dose reduction, n (%)c
Peripheral neutropenia 114 41.3 89 42.8 25 36.8 81 43.8 33 36.3
Neutropenia 117 42.4 88 42.3 29 42.6 67 36.2 50 54.9
Other adverse events 81 29.3 61 29.3 20 29.4 57 30.8 24 26.4
Other 28 10.1 20 9.6 8 11.8 19 10.3 9 9.9
Paclitaxel dose interruptions or delays, n () 351 46.6 259 48.1 92 42.8 207 43.3 144 52.2
Reason for paclitaxel dose interruption or delay, n (%)c
Peripheral neutropenia 65 18.5 52 20.1 13 14.1 39 18.8 26 18.1
Neutropenia 159 45.3 123 47.5 36 39.1 82 39.6 77 53.5
Other adverse events 168 47.9 118 45.6 50 54.3 94 45.4 74 51.4
Other 127 36.2 90 34.7 37 40.2 72 34.8 55 38.2
Median duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 1.4 (N = 79) 0.5, 3.9 1.4 (N = 65) 0.5, 3.9 0.6 (N = 14) 0.2, 3.0 1.4 (N = 52) 0.5, 3.9 0.8 (N = 27) 0.3, 3.7
Median duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 0.2 (N = 133) 0.2, 0.7 0.2 (N = 86) 0.2, 0.7 0.2 (N = 47) 0.2, 0.9 0.2 (N = 87) 0.2, 1.2 0.2 (N = 46) 0.2, 0.3
RDI relative dose intensity
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cMultiple items could be selected
Of the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).
The dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.
When the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.
Details of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.
Effectiveness
Overall survival
Median observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B
The results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival
(a) All eligible patients
Univariate analysis (N = 754) Multivariate analysis (N = 736)a
Variable N HR 95% CI p HR 95% CI p
Cohort A vs cohort B 754 1.63 1.35–1.97 < 0.0001 1.75 1.44–2.14 < 0.0001
First- vs second-line therapy 754 1.46 1.22–1.74 < 0.0001 1.35 1.13–1.63 0.0011
Age: < 50 years vs ≥ 50 years 754 0.92 0.77–1.10 0.3361
ECOG PS: 0 vs 1, 2, or 3 754 1.59 1.32–1.91 < 0.0001 1.28 1.04–1.57 0.0175
Visceral metastasis: yes vs no 754 0.55 0.44–0.70 < 0.0001 0.52 0.40–0.66 < 0.0001
Cancer-related symptoms: yes vs no 749 0.57 0.48–0.69 < 0.0001 0.56 0.46–0.68 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.63 0.53–0.75 < 0.0001 0.87 0.66–1.14 0.3139
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.60 0.50–0.72 < 0.0001 0.65 0.49–0.86 0.0026
History of taxane-based chemotherapy: yes vs no 754 0.90 0.64–1.26 0.5380
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.78–1.38 0.8108
History of hormone therapy: yes vs no 754 1.02 0.86–1.22 0.8031
Nuclear grade: ≤ 2 vs 3 442 1.31 1.05–1.64 0.0186
Ki-67 index: < 30 vs ≥ 30 332 1.64 1.25–2.16 0.0004
Disease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.02 0.92–1.13 0.7575
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 521 1.52 1.22–1.90 0.0002 1.27 0.94–1.71 0.1251
First- vs second-line therapy 521 1.33 1.08–1.64 0.0069 1.20 0.95–1.52 0.1210
Age: < 50 years vs ≥ 50 years 521 0.92 0.75–1.13 0.4072
ECOG PS: 0 vs 1, 2, or 3 521 1.65 1.32–2.06 < 0.0001 1.32 1.02–1.71 0.0333
Visceral metastasis: yes vs no 521 0.58 0.44–0.77 0.0001 0.53 0.39–0.72 0.0001
Cancer-related symptoms: yes vs no 518 0.50 0.41–0.62 < 0.0001 0.52 0.41–0.66 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.68 0.53–0.86 0.0016 1.08 0.76–1.54 0.6634
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.66 0.53–0.81 0.0001 0.70 0.51–0.95 0.0209
History of taxane-based chemotherapy: yes vs no 521 0.86 0.56–1.32 0.4944
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.57–1.36 0.5617
History of hormone therapy: yes vs no 521 1.28 1.04–1.57 0.0190 1.14 0.87–1.50 0.3367
Nuclear grade: ≤ 2 vs 3 299 1.17 0.90–1.52 0.2389
Ki-67 index: < 30 vs ≥ 30 178 1.81 1.27–2.57 0.0011
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.45 0.36–0.56 < 0.0001 0.50 0.39–0.63 < 0.0001
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
The results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.
The results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.
Progression-free survival and objective response rates
Median PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.
Multivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival
(a) All eligible patients
Univariate analysis (n = 754) Multivariate analysis (n = 687)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 754 1.33 1.13–1.58 0.0008 1.56 1.26–1.93 0.0001
First- vs second-line therapy 754 1.40 1.20–1.64 < 0.0001 1.19 0.99–1.42 0.0622
Age: < 50 years vs ≥ 50 years 754 1.00 0.86–1.16 0.9589
ECOG PS: 0 vs 1, 2, or 3 754 1.60 1.36–1.88 < 0.0001 1.36 1.13–1.64 0.0013
Visceral metastasis: yes vs no 754 0.63 0.52–0.76 < 0.0001 0.68 0.55–0.85 0.0005
Cancer-related symptoms: yes vs no 749 0.68 0.58–0.79 < 0.0001 0.72 0.60–0.86 0.0003
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.62 0.53–0.72 < 0.0001 0.71 0.53–0.95 0.0227
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.61 0.52–0.72 < 0.0001 0.69 0.54–0.89 0.0044
History of taxane-based chemotherapy: yes vs no 754 0.69 0.52–0.92 0.0113 0.82 0.58–1.14 0.2358
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.80–1.31 0.8458
History of endocrine therapy: yes vs no 754 0.85 0.73–0.99 0.0411 0.76 0.62–0.93 0.0075
Nuclear grade: ≤ 2 vs 3 442 1.18 0.97–1.44 0.0961
Ki-67 index: < 30 vs ≥ 30 332 1.54 1.22–1.96 0.0003
Disease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.07 0.99–1.17 0.1040 0.89 0.78–1.01 0.0663
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI p HR 95% CI p
Cohort A vs cohort B 521 1.31 1.08–1.60 0.0073 1.12 0.89–1.40 0.3505
First- vs second-line therapy 521 1.33 1.11–1.60 0.0021 1.16 0.94–1.43 0.1643
Age: < 50 years vs ≥ 50 years 521 1.01 0.84–1.20 0.9470
PS: 0 vs 1, 2, or 3 521 1.74 1.43–2.11 < 0.0001 1.49 1.19–1.88 0.0006
Visceral metastasis: yes vs no 521 0.74 0.59–0.93 0.0086 0.78 0.60–1.00 0.0518
Cancer-related symptoms: yes vs no 518 0.62 0.52–0.74 < 0.0001 0.67 0.55–0.83 0.0002
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.66 0.54–0.81 0.0001 0.85 0.63–1.14 0.2795
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.67 0.56–0.81 < 0.0001 0.78 0.60–1.01 0.0573
History of taxane-based chemotherapy: yes vs no 521 0.66 0.45–0.97 0.0361 0.75 0.47–1.21 0.2333
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.60–1.28 0.5067
History of hormone therapy: yes vs no 521 1.07 0.89–1.28 0.4891
Nuclear grade: ≤ 2 vs 3 299 1.05 0.83–1.33 0.6669
Ki-67 index: < 30 vs ≥ 30 178 1.46 1.07–2.00 0.0174
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.51 0.42–0.61 < 0.0001 0.54 0.44–0.67 < 0.0001
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Multivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.
In the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).
ORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions
(a) All eligible patients
All eligible patients Cohort Aa Cohort Bb P First-line therapy Second-line therapy p
No. of patients with target lesions 545 383 162 352 193
Best response, n (%)
CR 14 (2.6%) 8 (2.1%) 6 (3.7%) 0.0180 (W) 10 (2.8%) 4 (2.1%) 0.0001 (W)
PR 292 (53.6%) 219 (57.2%) 73 (45.1%) 209 (59.4%) 83 (43.0%)
SD 139 (25.5%) 104 (27.2%) 35 (21.6%) 77 (21.9%) 62 (32.1%)
PD 71 (13.0%) 36 (9.4%) 35 (21.6%) 35 (9.9%) 36 (18.7%)
NE 29 (5.3%) 16 (4.2%) 13 (8.0%) 21 (6.0%) 8 (4.1%)
Response rate, n (%)
CR plus PR 306 (56.1%) 227 (59.3%) 79 (48.8%) 0.0297 (F) 219 (62.2%) 87 (45.1%) 0.0001 (F)
95% CI 51.9–60.4 54.2–64.2 40.8–56.7 56.9–67.3 37.9–52.4
(b) Cohorts A and B
Cohort Aa First-line therapy Second-line therapy P Cohort Bb First-line therapy Second-line therapy p
No. of patients with target lesions 383 252 131 162 100 62
Best response
CR 8 (2.1%) 6 (2.4%) 2 (1.5%) 0.0048 (W) 6 (3.7%) 4 (4.0%) 2 (3.2%) 0.0011 (W)
PR 219 (57.2%) 155 (61.5%) 64 (48.9%) 73 (45.1%) 54 (54.0%) 19 (30.6%)
SD 104 (27.2%) 57 (22.6%) 47 (35.9%) 35 (21.6%) 20 (20.0%) 15 (24.2%)
PD 36 (9.4%) 21 (8.3%) 15 (11.5%) 35 (21.6%) 14 (14.0%) 21 (33.9%)
NE 16 (4.2%) 13 (5.2%) 3 (2.3%) 13 (8.0%) 8 (8.0%) 5 (8.1%)
Response rate
CR plus PR 227 (59.3%) 161 (63.9%) 66 (50.4%) 0.0119 (F) 79 (48.8%) 58 (58.0%) 21 (33.9%) 0.0036 (F)
95% CI 54.2–64.2 57.6–69.8 41.5–59.2 40.8–56.7 47.7–67.8 22.3–47.0
CR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Safety
The great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)
Treated patient population Cohort Aa Cohort Bb First-line therapy Second-line therapy
n (%) n (%) n (%) n (%) n (%)
(a) Selected AEs
No. of patients 750 100 538 100 212 100 475 100 275 100
Hypertension
All grades 602 80.3 429 79.7 173 81.6 383 80.6 219 79.6
Grade ≥ 3 268 35.7 190 35.3 78 36.8 167 35.2 101 36.7
Peripheral neuropathy
All grades 535 71.3 400 74.3 135 63.7 341 71.8 194 70.5
Grade ≥ 3 54 7.2 41 7.6 13 6.1 36 7.6 18 6.5
Neutropenia
All grades 347 46.3 256 47.6 91 42.9 203 42.7 144 52.4
Grade ≥ 3 204 27.2 151 28.1 53 25.0 115 24.2 89 32.4
Proteinuria
All grades 223 29.7 160 29.7 63 29.7 156 32.8 67 24.4
Grade ≥ 3 28 3.7 18 3.3 10 4.7 20 4.2 8 2.9
Bleeding
All grades 131 17.5 96 17.8 35 16.5 87 18.3 44 16.0
Grade ≥ 3 2 0.3 2 0.4 0 0.0 1 0.2 1 0.4
(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)
No. of patients 750 100 538 100 212 100 475 100 275 100
Congestive heart failure 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Gastrointestinal perforation 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
Thromboembolism 3 0.4 3 0.6 0 0.0 2 0.4 1 0.4
Wound dehiscence 2 0.3 1 0.2 1 0.5 0 0.0 2 0.7
(c) Other adverse events grade ≥ 3
No. of patients 750 100 538 100 212 100 475 100 275 100
Fatigue 12 1.6 6 1.1 6 2.8 4 0.8 8 2.9
Stomatitis 6 0.8 6 1.1 0 0.0 3 0.6 3 1.1
Febrile neutropenia 4 0.5 2 0.4 2 0.9 1 0.2 3 1.1
Other infections 23 3.1 18 3.3 5 2.4 15 3.2 8 2.9
Skin disorders 11 1.5 10 1.9 1 0.5 9 1.9 2 0.7
Anemia 10 1.3 8 1.5 2 0.9 5 1.1 5 1.8
AST/ALT elevation 10 1.3 6 1.1 4 1.9 8 1.7 2 0.7
Appetite loss 7 0.9 5 0.9 2 0.9 3 0.6 4 1.5
Diarrhea 5 0.7 3 0.6 2 0.9 5 1.1 0 0.0
Drug-induced pneumonitis 5 0.7 4 0.7 1 0.5 2 0.4 3 1.1
Pain 4 0.5 3 0.6 1 0.5 2 0.4 2 0.7
Others 31 4.1 24 4.5 7 3.3 13 2.7 18 6.5
ALT alanine aminotransferase, AST aspartate aminotransferase
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Serious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.
Discussion
The B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.
The 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.
The multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].
OS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.
As for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].
The multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].
Despite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).
No new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.
The present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.
In conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.
Electronic supplementary material
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Acknowledgements
The authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.
Funding
The study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Compliance with ethical standards
Conflict of interest
Yamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;
Ethical statement
The study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.
Informed consent
Written informed consent was obtained from all patients. | Fatal | ReactionOutcome | CC BY | 32715420 | 18,780,432 | 2021-01 |
What was the outcome of reaction 'Pseudocirrhosis'? | Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
OBJECTIVE
To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice.
METHODS
In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors.
RESULTS
Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.
CONCLUSIONS
In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously.
BACKGROUND
Trial no. UMIN000009086.
Introduction
Bevacizumab is a humanized monoclonal antibody for vascular endothelial growth factor (VEGF), which is the most important regulator for angiogenesis in both healthy and pathological states [1]. Its enhanced expression is observed in many types of tumors and promotes tumor growth and metastasis [2]. Bevacizumab binds to VEGF, thereby inhibiting VEGF binding to VEGF receptors 1 and 2 on endothelial cells. The consequent inhibition of tumor angiogenesis at the tumor site is understood to suppress the growth of cancer cells [3]. Additionally, normalization of abnormal vessels in the tumor tissue reduces its interstitial pressure, thereby facilitating penetration by anticancer agents in combination with bevacizumab [4].
A meta-analysis on addition of bevacizumab to chemotherapy for patients with locally advanced or metastatic breast cancer (LA/mBC) showed that addition of bevacizumab to first- or second-line chemotherapy significantly prolongs progression-free survival (PFS) and overall response rate (ORR) but not overall survival (OS) [5]. However, another meta-analysis of factors indicating poor prognosis in patients with LA/mBC showed that addition of bevacizumab to first-line chemotherapy improves 1-year OS and OS in patients with poor prognostic factors, as compared with chemotherapy alone [6]. Regarding adverse events (AEs), addition of bevacizumab increases the incidence of hypertension, proteinuria, and bleeding; however, the incidence of thromboembolism or gastrointestinal perforation is unchanged and that of treatment-related deaths is low [5].
The JO19901 study, carried out in Japan, was a phase II study of bevacizumab plus paclitaxel in chemotherapy-naive patients with HER2-negative LA/mBC [7]. The primary efficacy endpoint, median PFS, was 12.9 months. Regarding secondary endpoints, ORR was 74% and median OS was 35.8 months. Regarding safety, no new serious AEs were detected. Thus, the study confirmed the reproducibility in Japanese patients of the efficacy and safety results achieved for bevacizumab plus paclitaxel combination therapy in studies conducted outside Japan.
Although several cohort studies have been carried out in other countries [8–11], clinical experience of bevacizumab plus paclitaxel combination therapy in Japan has been limited to the small number of patients in the JO19901 study, which enrolled 120 patients [7]. Therefore, we conducted a prospective multicenter observational study to investigate the effectiveness and safety of this combination as first- or second-line therapy for LA/mBC in daily clinical practice. Two cohorts, one comprising patients with hormone receptor-positive breast cancer and the other comprising those with triple-negative breast cancer, were established to enable comparison of prognostic factors in patients with each of these cancer subtypes and in patients receiving first- or second-line therapy.
Patients and methods
Study design
In this multicenter prospective observational cohort study, patients who met the following inclusion criteria were enrolled: histologically confirmed HER2-negative LA/mBC with confirmed HR status; Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0–3; no history of second-line chemotherapy for LA/mBC; and sufficient bone marrow and major organ functions determined by the attending physician. Exclusion criteria included history of hypersensitivity to the ingredients of bevacizumab or paclitaxel, history of hemoptysis, uncontrolled hypertension, thromboembolism, positive urinary protein test result (≥ 2 +), gastrointestinal perforation, and severe fistula.
Patients were enrolled through central registration and classified by HR status: cohort A comprised patients with HR-positive breast cancer, and cohort B, those with triple-negative breast cancer (TNBC). First-line therapy was defined as treatment for patients who had not previously received chemotherapy for LA/mBC. Second-line therapy was defined as treatment for disease progression after or during receipt of first-line chemotherapy for LA/mBC. In cases of relapse during adjuvant chemotherapy, the first treatment after the relapse was considered the second-line therapy.
Written informed consent was obtained from all patients. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm; trial no. UMIN000009086).
Study treatment
Because the study was an observational study conducted in a clinical setting, dosage, treatment schedule, and criteria for dose reduction, interruption, and discontinuation were not specified. However, the study protocol recommended the following standard treatment regimen, which was used in the JO19901 study [7]: bevacizumab 10 mg/kg given every 2 weeks, and paclitaxel 90 mg/m2 given every week for 3 weeks, followed by a 1-week rest. Each combination of bevacizumab and paclitaxel administered as above for 4 weeks was deemed one cycle.
In cases of discontinuation of either drug due to AEs, the other drug could be continued as monotherapy. The protocol did not specify any treatment after discontinuation.
Study assessment
At screening on registration, medical history, symptoms of cancer, physical findings, pathological findings relating to the primary and metastatic lesions, presence or absence of measurable lesions, and previous treatments were recorded. During the treatment period, treatment schedule, treatment discontinuations, dose reductions, treatment interruption, concomitant drugs, and the last dosing date were recorded by electronic data capture.
Regarding safety, the incidence of five selected AEs of bevacizumab plus paclitaxel (i.e. neutropenia, hypertension, proteinuria, bleeding, and peripheral neuropathy), of any grade, was recorded. For other AEs, only those of grade ≥ 3 were recorded. AEs were evaluated based on CTCAE version 4.0 (Japanese Clinical Oncology Group edition) [12]. Effectiveness was evaluated and recorded in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Japanese Clinical Oncology Group edition) [13]. At the end of the observational period, patients’ disease progression, death, and post-treatment status were recorded.
Analysis populations and endpoints
The eligible patient population (used for the effectiveness analysis) was defined as patients who were registered according to the registration procedure, excluding those with ineligible cases or registration error. The treated patient population (used for the safety analysis and the sensitive analysis) was defined as patients who received bevacizumab plus paclitaxel combination therapy at least once. All evaluations were done by attending physicians.
The primary endpoint was OS, defined as the period between date of registration and death from any cause. Secondary endpoints were PFS, ORR, and safety. PFS was defined as the period between the registration date and the day when disease progression was determined (if that occurred first) or death (all causes).
Statistical analyses
This was an observational study conducted in the setting of daily clinical practice; therefore, the sample size was determined based on feasibility, considering the number of participating institutions, length of the registration period, and epidemiology of patients with HER2-negative LA/mBC. Consequently, the target numbers of patients were determined as 500 for cohort A and 250 for cohort B.
Expected median OS in each cohort according to treatment line (i.e. first- or second-line therapy) was estimated based on data from the prospective studies [7, 8, 14, 15, 17, 18]. Consequently, the expected median OS was 29.0 months and 18.0 months in patients receiving the study treatment as first-line and second-line therapy, respectively, in cohort A, and 17.0 months and 13.0 months in those receiving it as first-line and second-line therapy, respectively, in cohort B. Because the present study included patients who received the study treatment as both first- and second-line therapy, the ratio of first-line therapy patients to second-line therapy patients was assumed to be 5:5–7:3. Therefore, median OS was estimated to be 23.8 months in cohort A patients and 15.2 months in cohort B patients.
For the eligible patient population, cumulative survival curves for OS, median OS, and survival rate in each year were estimated using the Kaplan–Meier method, and Greenwood’s formula was used to construct 95% confidential intervals (CIs). Subgroup analysis was performed by Cox regression analysis to identify important prognostic factors. Sensitivity analysis was also performed, using data from the treated patient population. The same analyses were performed for PFS as those for OS. ORR was calculated as the proportion of patients achieving complete or partial response as the best overall response in patients with measurable lesions. CIs were calculated using the Clopper–Pearson method.
Safety was assessed using data from the treated patient population. The numbers of AEs, their grades, and their causal relation with the study drug were tabulated.
Results
Study population and baseline patient characteristics
A total of 767 patients were enrolled from 155 institutions across Japan between November 2012 and October 2014. Patient disposition is shown in Supplementary Fig. 1. Of these, the eligible patient population comprised 754 patients after exclusion of ineligible cases. Within this group, 539 (71.5%) were in cohort A and 215 (28.5%) in cohort B. The numbers of patients receiving the study treatment as first- and second-line therapy were 478 (63.4%) and 276 (36.6%), respectively. The treated patient population, that is, those who received the study treatment at least once, comprised 750 patients.
Baseline characteristics of the eligible patient population are shown in Table 1 and Supplementary Table 1a. Median age was 58 years. Most patients had distant metastasis (86.1%). Of these patients, most had visceral metastasis (91.7%), with ≥ 3 organs affected in a minority of cases (14.0%). Symptoms related to cancer (e.g. pain, dyspnea, pleural effusion, ascites, skin ulcer, and tumor fever) were experienced by 57.6% of eligible patients. Baseline characteristics of the treated patient population are shown in Supplementary Table 1c and are similar to those of the eligible patient population.Table 1 Baseline characteristics (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median age (range) (years) 58.0 (26–83) 58.0 (26–81) 58.0 (27–83) 59.0 (26–83) 57.0 (28–83)
Menopausal status
Premenopausal 198 26.3 133 24.7 65 30.2 127 26.6 71 25.7
Postmenopausal 532 70.6 385 71.4 147 68.4 337 70.5 195 70.7
Unknown 24 3.2 21 3.9 3 1.4 14 2.9 10 3.6
ECOG PS
0 522 69.2 371 68.8 151 70.2 345 72.2 177 64.1
1 172 22.8 122 22.6 50 23.3 96 20.1 76 27.5
2 43 5.7 34 6.3 9 4.2 29 6.1 14 5.1
3 17 2.3 12 2.2 5 2.3 8 1.7 9 3.3
ER status
Negative 208 27.6 8 1.5 200 93.0 125 26.2 83 30.1
Positive 544 72.1 529 98.1 15 7.0 351 73.4 193 69.9
Unknown 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
PgR status
Negative 332 44.0 122 22.6 210 97.7 203 42.5 129 46.7
Positive 419 55.6 414 76.8 5 2.3 272 56.9 147 53.3
Unknown 3 0.4 3 0.6 0 0.0 3 0.6 0 0.0
Nuclear grade
1 120 15.9 102 18.9 18 8.4 79 16.5 41 14.9
2 106 14.1 82 15.2 24 11.2 70 14.6 36 13.0
3 216 28.6 111 20.6 105 48.8 144 30.1 72 26.1
Unknown 312 41.4 244 45.3 68 31.6 185 38.7 127 46.0
Ki67 index
< 30 141 18.7 105 19.5 36 16.7 103 21.5 38 13.8
≥ 30 191 25.3 93 17.3 98 45.6 130 27.2 61 22.1
Unknown 422 56.0 341 63.3 81 37.7 245 51.3 177 64.1
Diagnosis
Locally advanced 34 4.5 20 3.7 14 6.5 29 6.1 5 1.8
Stage IV 199 26.4 149 27.6 50 23.3 130 27.2 69 25.0
Recurrence 521 69.1 370 68.6 151 70.2 319 66.7 202 73.2
Disease-free interval (months)
0 233 30.9 169 31.4 64 29.8 159 33.3 74 26.8
0–24 178 23.6 83 15.4 95 44.2 101 21.1 77 27.9
≥ 4 292 38.7 246 45.6 46 21.4 190 39.7 102 37.0
Unknown 51 6.8 41 7.6 10 4.7 28 5.9 23 8.3
Distant metastasis
No 81 10.7 47 8.7 34 15.8 34 7.1 47 17.0
Yes 649 86.1 476 88.3 173 80.5 422 88.3 227 82.2
Unknown 24 3.2 16 3.0 8 3.7 22 4.6 2 0.7
Metastatic sitec
Non-visceral 54 8.3 36 7.6 18 10.4 40 9.5 14 6.2
Visceral 595 91.7 440 92.4 155 89.6 382 90.5 213 93.8
No. of metastatic organsc
< 3 558 86.0 409 85.9 149 86.1 355 84.1 203 89.4
≥ 3 91 14.0 67 14.1 24 13.9 67 15.9 24 10.6
Cancer-related symptoms
No 315 41.8 230 42.7 85 39.5 200 41.8 115 41.7
Yes 434 57.6 305 56.6 129 60.0 275 57.5 159 57.6
Unknown 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Treatment line for locally advanced or metastatic breast cancer
First line 478 63.4 345 64.0 133 61.9
Second line 276 36.6 194 36.0 82 38.1
History of adjuvant therapyd
Chemotherapy 370 71.0 238 64.3 132 87.4 227 71.2 143 70.8
Anthracycline 297 57.0 188 50.8 109 72.2 186 58.3 111 55.0
Taxane 262 50.3 153 41.4 109 72.2 165 51.7 97 48.0
Endocrine therapy 336 64.5 324 87.6 12 7.9 205 64.3 131 64.9
Previous therapy for locally advanced or metastatic breast cancer
Chemotherapy 266 35.3 188 34.9 78 36.3 12 2.5 254 92.0
Anthracycline 80 10.6 63 11.7 17 7.9 4 0.8 76 27.5
Taxane 54 7.2 36 6.7 18 8.4 5 1.0 49 17.8
Endocrine therapy 356 47.2 348 64.6 8 3.7 195 40.8 161 58.3
Radiotherapy 140 18.6 111 20.6 29 13.5 62 13.0 78 28.3
ECOG PS Eastern Cooperative Oncology Group Performance Status, ER estrogen receptor, PgR progesterone receptor
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cNumber (%) of distant metastasis
dNumber (%) of patients with breast cancer recurrence
The proportions of cohort B patients with distant metastasis and metastasis to ≥ 3 organs were generally higher in those receiving first-line therapy than in those receiving second-line therapy; however, there were no differences for the other prognostic factors (Supplementary Table 1a).
Treatment exposure
Most patients received treatment in accordance with the treatment regimen used in the JO19901 study [7]. Details of treatment exposure in eligible patients are shown in Table 2 and Supplementary Table 2a. Median duration of bevacizumab and paclitaxel exposure was 5.1 and 4.9 months, respectively. Contrary to our expectation, duration of bevacizumab monotherapy after discontinuation of bevacizumab in combination with paclitaxel was extremely short and about 90% of cases discontinued bevacizumab at almost the same time as paclitaxel was discontinued (Table2, Supplementary Table 2a–c).Table 2 Treatment exposure (eligible patients)
All eligible patients Cohort Aa Cohort Bb First-line therapy Second-line therapy
N (%) n (%) n (%) n (%) n (%)
No. of patients 754 100 539 100 215 100 478 100 276 100
Median duration of study treatment (25th, 75th percentiles), months 5.1 (3.1, 8.7) 5.5 (3.3, 9.5) 4.0 (2.3, 6.5) 5.3 (3.0, 8.7) 4.8 (2.4, 8.8)
Median duration of bevacizumab (25th, 75th percentiles), months 5.1 (2.8, 8.5) 5.4 (3.3, 9.5) 3.7 (2.3, 6.2) 5.1 (2.8, 8.5) 4.6 (2.4, 8.7)
Median RDI of bevacizumab (25th, 75th percentiles), 97.5 (86.2, 100) 95.9 (86.5, 100) 100 (85.7, 100) 95.6 (87.2–100) 100 (84.8–100)
Discontinuations of bevacizumab, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of bevacizumab, n (%)
Disease progression 379 50.7 261 48.7 118 55.7 221 46.5 158 57.9
Adverse events 214 28.6 169 31.5 45 21.2 143 30.1 71 26.0
Other 152 20.3 105 19.6 47 22.2 109 22.9 43 15.8
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Bevacizumab dose reductions, n (T) 15 2.0 12 2.2 3 1.4 13 2.7 2 0.7
Reason for bevacizumab dose reduction, n (%)c
Hypertension 3 20.0 2 16.7 1 33.3 3 23.1 0 0.0
Proteinuria 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Bleeding 1 6.7 1 8.3 0 0.0 1 7.7 0 0.0
Neutropenia 1 6.7 1 8.3 0 0.0 0 0.0 1 50.0
Other adverse events 3 20.0 3 25.0 0 0.0 3 23.1 0 0.0
Other 4 26.7 2 16.7 2 66.7 3 23.1 0 0.0
Bevacizumab dose interruptions or delays, n (%) 263 34.9 188 34.9 75 34.9 155 32.4 108 39.1
Reason for bevacizumab dose interruption or delay, n (%)c
Hypertension 18 6.8 15 8.0 3 4.0 16 10.3 2 1.9
Proteinuria 53 20.2 36 19.1 17 22.7 35 22.6 18 16.7
Bleeding 3 1.1 2 1.1 1 1.3 2 1.3 1 0.9
Neutropenia 77 29.3 61 32.4 16 21.3 38 24.5 39 36.1
Other adverse events 106 40.3 77 41.0 29 38.7 61 39.4 45 41.7
Other 114 43.3 79 42.0 35 46.7 63 40.6 51 47.2
Median duration of paclitaxel (25th, 75th percentiles), months 4.9 (2.8, 8.1) 5.3 (3.2, 9.0) 3.9 (2.3, 6.0) 5.1 (3.0, 8.1) 4.6 (2.4, 8.2)
Median RDI of paclitaxel (25th, 75th percentiles), 90.9 (70.6, 100) 88.9 (69.5, 100) 96.0 (75.6, 105) 91.7 (72.7, 100) 89.8 (68.6, 100)
Discontinuations of paclitaxel, n (%) 748 99.2 536 99.4 212 98.6 475 99.4 273 98.9
Reason for discontinuation of paclitaxel, n (%)
Disease progression 363 48.5 245 45.7 118 55.7 216 45.5 147 53.8
Adverse events 246 32.9 198 36.9 48 22.6 158 33.3 88 32.2
Other 136 18.2 92 17.2 44 20.8 99 20.8 37 13.6
Unknown 3 0.4 1 0.2 2 0.9 2 0.4 1 0.4
Paclitaxel dose reductions, n (%) 276 36.6 208 38.6 68 31.6 185 38.7 91 33.0
Reason for paclitaxel dose reduction, n (%)c
Peripheral neutropenia 114 41.3 89 42.8 25 36.8 81 43.8 33 36.3
Neutropenia 117 42.4 88 42.3 29 42.6 67 36.2 50 54.9
Other adverse events 81 29.3 61 29.3 20 29.4 57 30.8 24 26.4
Other 28 10.1 20 9.6 8 11.8 19 10.3 9 9.9
Paclitaxel dose interruptions or delays, n () 351 46.6 259 48.1 92 42.8 207 43.3 144 52.2
Reason for paclitaxel dose interruption or delay, n (%)c
Peripheral neutropenia 65 18.5 52 20.1 13 14.1 39 18.8 26 18.1
Neutropenia 159 45.3 123 47.5 36 39.1 82 39.6 77 53.5
Other adverse events 168 47.9 118 45.6 50 54.3 94 45.4 74 51.4
Other 127 36.2 90 34.7 37 40.2 72 34.8 55 38.2
Median duration of bevacizumab monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 1.4 (N = 79) 0.5, 3.9 1.4 (N = 65) 0.5, 3.9 0.6 (N = 14) 0.2, 3.0 1.4 (N = 52) 0.5, 3.9 0.8 (N = 27) 0.3, 3.7
Median duration of paclitaxel monotherapy after discontinuation of bevacizumab + paclitaxel (25 percentile, 75 percentile), months 0.2 (N = 133) 0.2, 0.7 0.2 (N = 86) 0.2, 0.7 0.2 (N = 47) 0.2, 0.9 0.2 (N = 87) 0.2, 1.2 0.2 (N = 46) 0.2, 0.3
RDI relative dose intensity
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
cMultiple items could be selected
Of the 754 eligible patients, 748 (99.2%) discontinued the study treatment; of these, 28.6% and 32.9% discontinued bevacizumab and paclitaxel, respectively, due to AEs. Regarding discontinuations due to other reasons, those recorded for ≥ 1% of patients included patient request (4.9%), maximum response (2.8%), breast surgery (2.7%), completion of scheduled treatment (2.3%), and treatment for other disease (1.5%).
The dose of bevacizumab or paclitaxel was reduced due to AEs in 1.5% and 33.1%, respectively, and it was suspended due to AEs in 19.7% and 29.7%, respectively.
When the treatment schedule of bevacizumab plus paclitaxel was the same as that in the JO19901 study [7], relative dose intensity of bevacizumab and paclitaxel was 99.2% and 90.9%, respectively.
Details of treatment exposure for patents in the treated patient population are shown in Supplementary Table 2b, c. Treatment exposure in this population was similar to that in the eligible patient population.
Effectiveness
Overall survival
Median observation period was 19.7 months. Events occurred in 496 of the 754 eligible patients (65.8%) during observation. Median OS was 21.7 months (95% CI 19.8–23.6 months), 25.2 months (95% CI 22.4–27.4 months), 13.2 months (95% CI 11.3–16.6 months), 24.4 months (95% CI 21.9–27.2 months), and 17.6 months (95% CI 15.2–20.0 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Fig. 1a–c). Additionally, 1-year OS was 71.0%, 77.6%, 54.3%, 74.1%, 65.7%, in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively. Details of OS for eligible populations by cohort and treatment-line are shown in Supplementary Table 3 and Fig. 1d, e. Interestingly, OS was significantly longer in patients receiving the study treatment as first-line therapy than in those receiving it as second-line therapy in cohort A (log-rank test p < 0.0001, Fig. 2d), but not in cohort B (p = 0.3583, Fig. 1e).Fig. 1 Overall survival in the eligible patient population: a all eligible patients; b cohort A (patients with hormone receptor-positive breast cancer) versus cohort B (patients with triple-negative breast cancer); c, all eligible patients receiving first-line versus second-line therapy; d first-line versus second-line therapy in cohort A; e first-line versus second-line therapy in cohort B
The results of multivariate analysis for OS in the eligible patient population are summarized in Table 3a. In decreasing order of hazard ratio (HR), the baseline characteristics independently associated with OS were TNBC, second-line therapy, ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, cancer-related symptoms, and visceral metastasis.Table 3 Results of univariate and multivariate analyses for overall survival
(a) All eligible patients
Univariate analysis (N = 754) Multivariate analysis (N = 736)a
Variable N HR 95% CI p HR 95% CI p
Cohort A vs cohort B 754 1.63 1.35–1.97 < 0.0001 1.75 1.44–2.14 < 0.0001
First- vs second-line therapy 754 1.46 1.22–1.74 < 0.0001 1.35 1.13–1.63 0.0011
Age: < 50 years vs ≥ 50 years 754 0.92 0.77–1.10 0.3361
ECOG PS: 0 vs 1, 2, or 3 754 1.59 1.32–1.91 < 0.0001 1.28 1.04–1.57 0.0175
Visceral metastasis: yes vs no 754 0.55 0.44–0.70 < 0.0001 0.52 0.40–0.66 < 0.0001
Cancer-related symptoms: yes vs no 749 0.57 0.48–0.69 < 0.0001 0.56 0.46–0.68 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.63 0.53–0.75 < 0.0001 0.87 0.66–1.14 0.3139
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.60 0.50–0.72 < 0.0001 0.65 0.49–0.86 0.0026
History of taxane-based chemotherapy: yes vs no 754 0.90 0.64–1.26 0.5380
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.78–1.38 0.8108
History of hormone therapy: yes vs no 754 1.02 0.86–1.22 0.8031
Nuclear grade: ≤ 2 vs 3 442 1.31 1.05–1.64 0.0186
Ki-67 index: < 30 vs ≥ 30 332 1.64 1.25–2.16 0.0004
Disease-free interval: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.02 0.92–1.13 0.7575
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 521 1.52 1.22–1.90 0.0002 1.27 0.94–1.71 0.1251
First- vs second-line therapy 521 1.33 1.08–1.64 0.0069 1.20 0.95–1.52 0.1210
Age: < 50 years vs ≥ 50 years 521 0.92 0.75–1.13 0.4072
ECOG PS: 0 vs 1, 2, or 3 521 1.65 1.32–2.06 < 0.0001 1.32 1.02–1.71 0.0333
Visceral metastasis: yes vs no 521 0.58 0.44–0.77 0.0001 0.53 0.39–0.72 0.0001
Cancer-related symptoms: yes vs no 518 0.50 0.41–0.62 < 0.0001 0.52 0.41–0.66 < 0.0001
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.68 0.53–0.86 0.0016 1.08 0.76–1.54 0.6634
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.66 0.53–0.81 0.0001 0.70 0.51–0.95 0.0209
History of taxane-based chemotherapy: yes vs no 521 0.86 0.56–1.32 0.4944
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.57–1.36 0.5617
History of hormone therapy: yes vs no 521 1.28 1.04–1.57 0.0190 1.14 0.87–1.50 0.3367
Nuclear grade: ≤ 2 vs 3 299 1.17 0.90–1.52 0.2389
Ki-67 index: < 30 vs ≥ 30 178 1.81 1.27–2.57 0.0011
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.45 0.36–0.56 < 0.0001 0.50 0.39–0.63 < 0.0001
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
The results of multivariate analysis in the 521 patients with recurrent breast cancer are summarized in Table 3b. The following baseline characteristics were identified as independent predictors of OS: ECOG PS ≥ 1, neoadjuvant or adjuvant taxane-based chemotherapy, visceral metastasis, cancer-related symptoms, and disease-free interval (DFI) ≤ 24 months.
The results of univariate and multivariate analyses of baseline characteristics associated with OS by cohort are shown in Supplementary Tables 4 and 5.
Progression-free survival and objective response rates
Median PFS was 8.5 months (95% CI 7.8–9.2 months), 9.4 months (95% CI 8.7–10.7 months), 6.0 months (95% CI 5.5–7.4 months), 9.3 months (95% CI 8.5–10.7 months), and 7.2 months (95% CI 6.0–8.4 months) in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Supplementary Fig. 2a, 2b, 2c). Details of PFS for eligible populations by cohort and treatment line are shown in Supplementary Table 6 and Supplementary Fig. 2d, 2e.
Multivariate analysis identified the following baseline characteristics independently associated with PFS (Table 4a): TNBC, ECOG PS ≥ 1, history of endocrine therapy, cancer-related symptoms, history of neoadjuvant or adjuvant chemotherapy, history of neoadjuvant or adjuvant taxane-based chemotherapy, and visceral metastasis.Table 4 Results of univariate and multivariate analyses for progression-free survival
(a) All eligible patients
Univariate analysis (n = 754) Multivariate analysis (n = 687)a
Variable n HR 95% CI P HR 95% CI P
Cohort A vs cohort B 754 1.33 1.13–1.58 0.0008 1.56 1.26–1.93 0.0001
First- vs second-line therapy 754 1.40 1.20–1.64 < 0.0001 1.19 0.99–1.42 0.0622
Age: < 50 years vs ≥ 50 years 754 1.00 0.86–1.16 0.9589
ECOG PS: 0 vs 1, 2, or 3 754 1.60 1.36–1.88 < 0.0001 1.36 1.13–1.64 0.0013
Visceral metastasis: yes vs no 754 0.63 0.52–0.76 < 0.0001 0.68 0.55–0.85 0.0005
Cancer-related symptoms: yes vs no 749 0.68 0.58–0.79 < 0.0001 0.72 0.60–0.86 0.0003
Neoadjuvant or adjuvant chemotherapy: yes vs no 741 0.62 0.53–0.72 < 0.0001 0.71 0.53–0.95 0.0227
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 741 0.61 0.52–0.72 < 0.0001 0.69 0.54–0.89 0.0044
History of taxane-based chemotherapy: yes vs no 754 0.69 0.52–0.92 0.0113 0.82 0.58–1.14 0.2358
History of anthracycline-based chemotherapy: yes vs no 754 1.04 0.80–1.31 0.8458
History of endocrine therapy: yes vs no 754 0.85 0.73–0.99 0.0411 0.76 0.62–0.93 0.0075
Nuclear grade: ≤ 2 vs 3 442 1.18 0.97–1.44 0.0961
Ki-67 index: < 30 vs ≥ 30 332 1.54 1.22–1.96 0.0003
Disease-free interval 1: 0 (advanced breast cancer) vs ≤ 24 months vs > 24 months 703 1.07 0.99–1.17 0.1040 0.89 0.78–1.01 0.0663
(b) Patients with recurrent breast cancer
Univariate analysis (n = 521) Multivariate analysis (n = 456)a
Variable n HR 95% CI p HR 95% CI p
Cohort A vs cohort B 521 1.31 1.08–1.60 0.0073 1.12 0.89–1.40 0.3505
First- vs second-line therapy 521 1.33 1.11–1.60 0.0021 1.16 0.94–1.43 0.1643
Age: < 50 years vs ≥ 50 years 521 1.01 0.84–1.20 0.9470
PS: 0 vs 1, 2, or 3 521 1.74 1.43–2.11 < 0.0001 1.49 1.19–1.88 0.0006
Visceral metastasis: yes vs no 521 0.74 0.59–0.93 0.0086 0.78 0.60–1.00 0.0518
Cancer-related symptoms: yes vs no 518 0.62 0.52–0.74 < 0.0001 0.67 0.55–0.83 0.0002
Neoadjuvant or adjuvant chemotherapy: yes vs no 508 0.66 0.54–0.81 0.0001 0.85 0.63–1.14 0.2795
Neoadjuvant or adjuvant taxane-based chemotherapy: yes vs no 508 0.67 0.56–0.81 < 0.0001 0.78 0.60–1.01 0.0573
History of taxane-based chemotherapy: yes vs no 521 0.66 0.45–0.97 0.0361 0.75 0.47–1.21 0.2333
History of anthracycline-based chemotherapy: yes vs no 521 0.88 0.60–1.28 0.5067
History of hormone therapy: yes vs no 521 1.07 0.89–1.28 0.4891
Nuclear grade: ≤ 2 vs 3 299 1.05 0.83–1.33 0.6669
Ki-67 index: < 30 vs ≥ 30 178 1.46 1.07–2.00 0.0174
Disease-free interval 1: ≤ 24 months vs > 24 months 470 0.51 0.42–0.61 < 0.0001 0.54 0.44–0.67 < 0.0001
Variables with a significance level < 0.15 in the univariate analysis and without ≥ 0.67 missing values were included in the multivariate analysis
CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio
Multivariate analysis also identified several baseline characteristics as independent predictors of prognosis in the 521 patients with recurrent breast cancer (Table 4b): ECOG PS ≥ 1, cancer-related symptoms, and DFI ≤ 24 months.
In the sensitivity analysis, the results for OS and PFS in treated patients were similar to those for the eligible patient population (Supplementary Tables 3 and 6).
ORR in patients with measurable lesions was 56.1%, 59.3%, 48.8%, 62.2%, and 45.1% in the full eligible patient population, in cohort A, in cohort B, in patients receiving the study treatment as first-line chemotherapy, and in those receiving it as second-line chemotherapy, respectively (Table 5a). ORRs by cohort and treatment line are summarized in Table 5b.Table 5 Overall response rate in patients with measurable lesions
(a) All eligible patients
All eligible patients Cohort Aa Cohort Bb P First-line therapy Second-line therapy p
No. of patients with target lesions 545 383 162 352 193
Best response, n (%)
CR 14 (2.6%) 8 (2.1%) 6 (3.7%) 0.0180 (W) 10 (2.8%) 4 (2.1%) 0.0001 (W)
PR 292 (53.6%) 219 (57.2%) 73 (45.1%) 209 (59.4%) 83 (43.0%)
SD 139 (25.5%) 104 (27.2%) 35 (21.6%) 77 (21.9%) 62 (32.1%)
PD 71 (13.0%) 36 (9.4%) 35 (21.6%) 35 (9.9%) 36 (18.7%)
NE 29 (5.3%) 16 (4.2%) 13 (8.0%) 21 (6.0%) 8 (4.1%)
Response rate, n (%)
CR plus PR 306 (56.1%) 227 (59.3%) 79 (48.8%) 0.0297 (F) 219 (62.2%) 87 (45.1%) 0.0001 (F)
95% CI 51.9–60.4 54.2–64.2 40.8–56.7 56.9–67.3 37.9–52.4
(b) Cohorts A and B
Cohort Aa First-line therapy Second-line therapy P Cohort Bb First-line therapy Second-line therapy p
No. of patients with target lesions 383 252 131 162 100 62
Best response
CR 8 (2.1%) 6 (2.4%) 2 (1.5%) 0.0048 (W) 6 (3.7%) 4 (4.0%) 2 (3.2%) 0.0011 (W)
PR 219 (57.2%) 155 (61.5%) 64 (48.9%) 73 (45.1%) 54 (54.0%) 19 (30.6%)
SD 104 (27.2%) 57 (22.6%) 47 (35.9%) 35 (21.6%) 20 (20.0%) 15 (24.2%)
PD 36 (9.4%) 21 (8.3%) 15 (11.5%) 35 (21.6%) 14 (14.0%) 21 (33.9%)
NE 16 (4.2%) 13 (5.2%) 3 (2.3%) 13 (8.0%) 8 (8.0%) 5 (8.1%)
Response rate
CR plus PR 227 (59.3%) 161 (63.9%) 66 (50.4%) 0.0119 (F) 79 (48.8%) 58 (58.0%) 21 (33.9%) 0.0036 (F)
95% CI 54.2–64.2 57.6–69.8 41.5–59.2 40.8–56.7 47.7–67.8 22.3–47.0
CR complete response, F Fisher’s exact test, NE not evaluable, PD progressive disease, PR partial response, SD stable disease, W Wilcoxon rank sum test
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Safety
The great majority of eligible patients (96.3%) experienced at least one AE, and 63.1% experienced one or more grade ≥ 3 AEs. Table 6 lists the AEs in treated patients. Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively.Table 6 Incidence of adverse events (AEs)
Treated patient population Cohort Aa Cohort Bb First-line therapy Second-line therapy
n (%) n (%) n (%) n (%) n (%)
(a) Selected AEs
No. of patients 750 100 538 100 212 100 475 100 275 100
Hypertension
All grades 602 80.3 429 79.7 173 81.6 383 80.6 219 79.6
Grade ≥ 3 268 35.7 190 35.3 78 36.8 167 35.2 101 36.7
Peripheral neuropathy
All grades 535 71.3 400 74.3 135 63.7 341 71.8 194 70.5
Grade ≥ 3 54 7.2 41 7.6 13 6.1 36 7.6 18 6.5
Neutropenia
All grades 347 46.3 256 47.6 91 42.9 203 42.7 144 52.4
Grade ≥ 3 204 27.2 151 28.1 53 25.0 115 24.2 89 32.4
Proteinuria
All grades 223 29.7 160 29.7 63 29.7 156 32.8 67 24.4
Grade ≥ 3 28 3.7 18 3.3 10 4.7 20 4.2 8 2.9
Bleeding
All grades 131 17.5 96 17.8 35 16.5 87 18.3 44 16.0
Grade ≥ 3 2 0.3 2 0.4 0 0.0 1 0.2 1 0.4
(b) Bevacizumab-specific AEs other than the selected adverse events (grade ≥ 3)
No. of patients 750 100 538 100 212 100 475 100 275 100
Congestive heart failure 5 0.7 4 0.7 1 0.5 3 0.6 2 0.7
Gastrointestinal perforation 2 0.3 2 0.4 0 0.0 2 0.4 0 0.0
Thromboembolism 3 0.4 3 0.6 0 0.0 2 0.4 1 0.4
Wound dehiscence 2 0.3 1 0.2 1 0.5 0 0.0 2 0.7
(c) Other adverse events grade ≥ 3
No. of patients 750 100 538 100 212 100 475 100 275 100
Fatigue 12 1.6 6 1.1 6 2.8 4 0.8 8 2.9
Stomatitis 6 0.8 6 1.1 0 0.0 3 0.6 3 1.1
Febrile neutropenia 4 0.5 2 0.4 2 0.9 1 0.2 3 1.1
Other infections 23 3.1 18 3.3 5 2.4 15 3.2 8 2.9
Skin disorders 11 1.5 10 1.9 1 0.5 9 1.9 2 0.7
Anemia 10 1.3 8 1.5 2 0.9 5 1.1 5 1.8
AST/ALT elevation 10 1.3 6 1.1 4 1.9 8 1.7 2 0.7
Appetite loss 7 0.9 5 0.9 2 0.9 3 0.6 4 1.5
Diarrhea 5 0.7 3 0.6 2 0.9 5 1.1 0 0.0
Drug-induced pneumonitis 5 0.7 4 0.7 1 0.5 2 0.4 3 1.1
Pain 4 0.5 3 0.6 1 0.5 2 0.4 2 0.7
Others 31 4.1 24 4.5 7 3.3 13 2.7 18 6.5
ALT alanine aminotransferase, AST aspartate aminotransferase
aPatients with hormone receptor-positive breast cancer
bPatients with triple-negative breast cancer
Serious AEs were recorded in 66 patients (8.8%) including 15 patients with infection, five patients with congestive heart failure and 4 patients with drug-induced pneumonitis, fracture, gastrointestinal perforation, or liver dysfunction (Supplementary Table 7). Treatment-related deaths occurred in 6 patients (0.8%); the causes were liver failure (3 patients), acute gastroenteritis and heart failure (1 patient), gastrointestinal bleeding (1 patient), and gastrointestinal perforation (1 patient). Of the 3 deaths due to liver failure, one had liver failure associated with disease progression, and the other two had so-called pseudocirrhosis, which is associated with liver atrophy due to acute tumor response by chemotherapy on massive liver metastases and disorder of subsequent liver regeneration process.
Discussion
The B-SHARE study was a prospective observational study to investigate the effectiveness and safety of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for HER2-negative LA/mBC under real-world clinical conditions in Japan. During the median observation period of 19.7 months, median OS for eligible patients was 21.7 months, and median OS for eligible patients receiving first-line therapy was 24.4 months. These results are within the range (21.6–30.2 months) achieved in previous phase III studies [14–16] and observational studies [8–11, 17]. Although there have been no previous observational studies on bevacizumab plus paclitaxel as second-line therapy, median OS for eligible patients receiving second-line therapy in the present study (17.6 months) was similar to the 18.0 months achieved in the RIBBON-2 study conducted as second-line chemotherapy [18], in which the efficacy and safety of bevacizumab combined with standard chemotherapy was compared with standard chemotherapy alone.
The 74.1% 1-year median OS for first-line therapy was a good result and similar to that determined by a meta-analysis of data from randomized controlled studies of bevacizumab combined with chemotherapy as first-line therapy (i.e. 71%) [6], showing that bevacizumab combined with chemotherapy may improve 1-year OS when compared with chemotherapy alone in high-risk patients.
The multivariate analysis results for OS in eligible patients identified TNBC, second-line therapy, poor PS, perioperative history of taxane therapy, cancer-related symptoms, DFI ≤ 2 years (i.e. recurrent breast cancer), and visceral metastasis as independent factors for poor prognosis. This is similar to the findings of previous studies on chemotherapy with [19] or without bevacizumab [20–23].
OS was significantly longer in patients receiving first-line therapy than in those receiving second-line therapy in cohort A but not in cohort B. Regarding baseline characteristics in cohort B, the proportions of patients with distant metastasis and metastasis to ≥ 3 organs were higher in those receiving first-line therapy than in those receiving second-line therapy, but no differences were found for the other factors. After completion of the study treatment, a greater proportion of patients receiving first-line therapy in cohort B were transferred to best supportive care compared with those in cohort A (33.1% and 21.2%, respectively). These findings suggest that patients with TNBC are less likely than those with hormone receptor-positive cancer to continue therapy because of many poor prognostic factors, but when patients were able to undergo second-line and subsequent therapy, they are likely to have a better prognosis.
As for first-line therapy, median PFS in eligible patients was 9.3 months and ORR in those with measurable lesions was 62.2%. As with OS, the results were consistent with those of previous randomized controlled studies [14, 15, 24, 25] and observational studies [8–11, 17]. For second-line therapy, median PFS was 7.2 months and ORR was 45.1%, similar to the results of the RIBBON-2 study [18].
The multivariate analysis results for PFS in eligible patients, including those with advanced disease, identified TNBC, poor PS, history of endocrine therapy, cancer-related symptoms, history of perioperative chemotherapy, history of perioperative taxane, and visceral metastasis as factors indicating poor prognosis. However, in patients with recurrent breast cancer, poor PS, cancer-related symptoms, and DFI ≤ 2 years were independent factors for poor prognosis. Therefore, poor prognostic factors for PFS differed with patient background. Although poor PS and cancer-related symptoms may be considered mutually associated, they were independent poor prognostic factors for both OS and PFS, regardless of whether the cancer was advanced or recurrent. The possibility that cancer-related symptoms are a poor prognostic factor in LA/mBC is supported by several other studies [23, 26, 27].
Despite the similarity in effectiveness (i.e. OS, PFS, and ORR) shown in the present study to that obtained in randomized controlled studies [14–16, 24] and observational studies [8–11, 17], the dosing period for bevacizumab in first-line therapy (5.3 months) was shorter than in randomized controlled studies [24, 25]. In fact, the bevacizumab dosing period tends to be shorter in observational studies [8–11, 17] than in randomized controlled studies [24, 25]. However, the bevacizumab dosing period in a retrospective cohort study [11] using information from the French Epidemiological Strategy and Medical Economics database was similar to that of the present study. The shorter dosing period in the present study compared with in randomized controlled studies may have been due to differences in patient selection (with poorer PS) and adherence to treatment. In the present study, 15.3% of patients were aged ≥ 70 years, and 8.0% had PS of ≥ 2. About 30% of patients discontinued treatment because of AEs, which is similar to that in the randomized controlled studies, whereas about 20% discontinued treatment without having disease progress (e.g. undergoing surgery after tumor shrinkage or switching to endocrine therapy).
No new AEs related to bevacizumab plus paclitaxel were detected in the present study. Incidence of all grades of AEs (96.3%) and those of grade ≥ 3 (63.1%) were higher than in previous randomized controlled studies [14, 18, 24, 25] and observational studies [8–10, 17]. However, there was no increase in the incidence of serious AEs or treatment-related deaths. We experienced 2 cases of treatment-related death due to so-called pseudocirrhosis during treatment of bevacizumab plus paclitaxel. Pseudocirrhosis is characterized by morphological changes in the liver that resembling cirrhosis on the radiological findings without typical histopathology of cirrhosis [28]. Pseudocirrhosis as adverse events by chemotherapy is not rare and an important complication of chemotherapy in patients with liver metastases. Recently, Oliai et al. [29] reported that pseudocirrhosis developed in 37 (55%) of 67 metastatic breast cancer patients with liver metastasis and was associated with poor prognosis in patients with live metastasis. They also described that chemotherapy agents associated with the development of pseudocirrhosis were albumin-bound paclitaxel, capecitabine, cisplatin, everolimus and vinorelbine. This adverse event is not bevacizumab-specific. However, the possibility that bevacizumab may inhibit the process of liver regeneration after treatment-induced hepatic injury cannot be ruled out.
The present study had several limitations. First, it was a single-arm observational study of bevacizumab plus paclitaxel combination therapy, so there was no direct comparison in terms of the effectiveness and safety between bevacizumab plus paclitaxel and paclitaxel alone. Second, treatment effectiveness (PFS and ORR) was assessed by attending physicians, and HR and HER2 status were also assessed at each facility. Central assessment or review was not done for the evaluation of effectiveness and those receptors status. Third, most patients received treatment in accordance with the treatment regimen used in the JO19901 study. Therefore, we could not examine the relationship between the dosage or the schedule of bevacizumab plus paclitaxel and its effectiveness to find the optimal use of this combination. Fourth, because the present study was done under daily clinical conditions, discontinuation due to the wishes of the patient or the decision of the attending physician was possible, regardless of whether the effects of treatment were sustained. During the course of treatment, various strategies were adopted after tumor reduction due to study treatment, such as discontinuation of treatment, switching to hormonal therapy for maintenance, or surgical intervention, which are uncommon in randomized controlled studies. The limitations of the present study make it difficult to obtain a true result for PFS and ORR. However, OS is a robust endpoint and we consider the OS reported here to be close to its true value, because it was achieved in patients treated with bevacizumab plus paclitaxel under real clinical conditions.
In conclusion, bevacizumab plus paclitaxel as first- or second-line chemotherapy in Japanese patients with HER2-negative LA/mBC was as effective as in previous randomized controlled studies and prospective observational studies. Furthermore, the good tolerability of this regimen was confirmed.
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Acknowledgements
The authors thank patients who participated in this study and their families, as well as the ranchers and medical staff involved in the study.
Funding
The study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Compliance with ethical standards
Conflict of interest
Yamamoto Y reports grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eisai, grants and personal fees from Eli Lilly, grants and personal fees from Takeda, personal fees from Sysmex, personal fees from GE Health Care Japan, personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Nihon Kayaku, grants and personal fees from Kyowa-Kirin, grants and personal fees from Taiho, grants and personal fees from Chugai, outside the submitted work; and A board member of the Japanese Breast Cancer Society, A board member of the Japan Breast Cancer Research Group. Yamashiro H reports personal fees from Chugai, personal fees from Daiich Sankyo, personal fees from Pfizer, personal fees from Kyowa Kirin, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Taiho outside the submitted work; Toh U reports remuneration from Chugai, Kyowa Kirin, Daiichi Sankyo, Taiho, Nihon Kayaku and Eisai, outside the submitted work; Kondo N reports personal fees from Chugai, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; Nakamura R reports personal fees from Chugai, outside the submitted work; Kashiwaba M reports Speaker's bureaus from Chugai, Novartis, Kyowa Kirin, Pfizer, AstraZeneca, Taiho, Eisai, Daiichi Sankyo and Shionogi, outside the submitted work; Takahashi M reports personal fees from Chugai, grants and personal fees from Nippon Kayaku, outside the submitted work; Tsugawa K reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, grants and personal fees from Takeda, grants and personal fees from Nippon Kayaku, grants from MSD, personal fees from Eli Lilly, personal fees from Daiichi Sankyo, personal fees from Pfizer, during the conduct of the study; Ishikawa T reports grants and other from Eisai, grants and other from Nihon Kayaku, grants and other from Chugai, grants and other from Taiho, grants from Sanofi, grants and other from Eli Lilly, other from Pfizer, outside the submitted work; Nakayama T reports personal fees from Chugai, personal fees from Novartis, personal fees from Eli Lilly, personal fees from AstraZeneca, personal fees from Taiho, personal fees from Eisai, personal fees from Takeda, outside the submitted work; Ohtani S reports other from Chugai, other from Eisai, other from AstraZeneca, other from Pfizer, other from Eli Lilly, outside the submitted work; Takano T reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Kyowa Kirin, grants and personal fees from Eisai, personal fees from Pfizer, personal fees from Eli Lilly, grants from Ono, grants from MSD, grants from Merck Serono, grants from Taiho, grants from Novartis, grants from Chugai, outside the submitted work; Fujisawa T reports personal fees from Chugai, personal fees from Eli Lilly, during the conduct of the study; Toyama T reports grants and personal fees from Chugai, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Takeda, during the conduct of the study; Kawaguchi H reports personal fees from Pfizer, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Eisai, personal fees from Kyowa Kirin, personal fees from Novartis, personal fees from Taiho, personal fees from Takeda, personal fees from Nippon Chemiphar, personal fees from Daiichi Sankyo, during the conduct of the study; Mashino K reports personal fees from Chugai, outside the submitted work; Tanino Y reports grants from Sysmex Corporation, other from Ono, other from Chugai, other from Novartis, other from Pfizer, other from Daiichi-Sankyo, other from Eli Lilly, other from Taiho, other from Eisai, outside the submitted work; Dr. Morita reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb Company, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Taiho, outside the submitted work; Toi M reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi Sankyo, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. Ohno S reports personal fees from Chugai, grants and personal fees from Eisai, grants and personal fees from Taiho, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kyowa Kirin, personal fees from Nippon Kayaku, outside the submitted work;
Ethical statement
The study was carried out in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol, procedures, and consent forms were approved by the institutional review board of each participating institution.
Informed consent
Written informed consent was obtained from all patients. | Fatal | ReactionOutcome | CC BY | 32715420 | 18,780,432 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adverse event'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'General physical health deterioration'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Leukopenia'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphopenia'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to liver'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myocardial ischaemia'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pharyngeal abscess'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pharyngitis bacterial'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'. | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | MELPHALAN, PEGFILGRASTIM | DrugsGivenReaction | CC BY | 32761328 | 18,919,159 | 2021-02 |
What was the administration route of drug 'PEGFILGRASTIM'? | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
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T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | Subcutaneous | DrugAdministrationRoute | CC BY | 32761328 | 18,919,159 | 2021-02 |
What was the dosage of drug 'MELPHALAN'? | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | 3 MILLIGRAM/KILOGRAM | DrugDosageText | CC BY | 32761328 | 18,919,159 | 2021-02 |
What was the dosage of drug 'PEGFILGRASTIM'? | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | 6 MILLIGRAM | DrugDosageText | CC BY | 32761328 | 18,919,159 | 2021-02 |
What was the outcome of reaction 'Death'? | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | Fatal | ReactionOutcome | CC BY | 32761328 | 18,919,159 | 2021-02 |
What was the outcome of reaction 'General physical health deterioration'? | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | Recovered | ReactionOutcome | CC BY | 32761328 | 18,919,159 | 2021-02 |
What was the outcome of reaction 'Myocardial ischaemia'? | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | Recovered | ReactionOutcome | CC BY | 32761328 | 18,919,159 | 2021-02 |
What was the outcome of reaction 'Pharyngeal abscess'? | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | Recovered | ReactionOutcome | CC BY | 32761328 | 18,919,159 | 2021-02 |
What was the outcome of reaction 'Pharyngitis bacterial'? | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | Recovered | ReactionOutcome | CC BY | 32761328 | 18,919,159 | 2021-02 |
What was the outcome of reaction 'Sepsis'? | Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.
BACKGROUND
Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.
METHODS
Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.
CONCLUSIONS
M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.
Ocular melanoma is the most common primary intraocular malignancy in adults.1 It most frequently arises from melanocytes in the uveal tract, which is subdivided in an anterior part containing the iris (~ 5%) and a posterior part containing the choroid and ciliary corpus (~ 80%).1,2 The rest of ocular melanomas develop in the conjunctiva (~ 5%) or elsewhere in the orbit (~ 10%). The incidence of uveal melanoma in Europe varies with latitude, being higher in Northern (≥ 8 per million) than Southern Europe (< 2 per million), due to a positive association with Caucasian ethnicity, fair skin, and light eye colour.4 Most patients are diagnosed after age 50 years, with a peak range of 65–75 years.1–5 Despite successful treatment of the primary tumor, up to 50% of patients will eventually develop metastatic disease with predominant liver involvement.1–3
Metastatic ocular melanoma carries a poor prognosis, because there are no effective systemic treatments. Reported median overall survival (OS) following systemic treatment, including immunotherapy and kinase inhibitors, ranges from 4.4 to 12.7 months with a 1-year OS rate ranging from 29 to 53%.6,7 Meta-analyses have demonstrated that patients treated with liver-directed therapies had a significantly longer progression-free survival (PFS) and OS compared with patients receiving systemic therapy.6,7 Liver-directed therapies used to treat ocular melanoma liver metastases include chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion with melphalan (M-PHP) (Table 1).8–30Table 1 Summary of progression-free survival and overall survival following chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion, and percutaneous hepatic perfusion
First author (year) Study design No. of pts Transarterial catheter-directed therapy and drug Median PFS (mo) Median OS (mo)
Agarwala (2004)8 Phase I/II, dose-esc. 19 Chemoembolization (cisplatin) N/A 8.5
Patel (2005)9 Phase II 30 Chemoembolization (BCNU) N/A 5.2
Vogl (2007)10 PS, pilot 12 Chemoembolization (mitomycin C) N/A 21
Schuster (2010)11 RS 25 Chemoembolization (fotemustine/cisplatin) 3 6
Gupta (2010)12 RS 125 Chemoembolization (mostly cisplatina) 3.8 6.7
Huppert (2010)13 PS, pilot 14 Chemoembolization (cisplatin/carboplatin) 8.5 11.5
Edelhauser (2012)14 RS 21 Chemoembolization (fotemustine) 7.3 28.7
Valpione (2015)15 RS 58 Chemoembolization (irinotecan) N/A 16.5
Shibayama (2017)16 RS 29 Chemoembolization (cisplatin) 6 23
Yamamoto (2009)17 RS 53 Immunoembolization vs. chemoembolization (BCNU) 12.4 vs. 4.8 20.4 vs. 9.8
Valsecchi (2015)18 Phase II 52 Immunoembolization vs. bland embolization 3.9 vs. 5.9 21.5 vs. 17.2
Gonsalves (2011)19 RS 32 Radioembolization (Y-90) 4.7 10
Klingenstein (2013)20 RS 13 Radioembolization (Y-90) N/A 7
Eldredge-Hindy (2016)21 RS 71 Radioembolization (Y-90) 5.9 12.3
Tulokas (2018)22 RS 16 Radioembolization (Y-90) 5.6 13.5
Gonsalves (2019)23 PS 24 Radioembolization (Y-90) 8.1 18.5
Alexander (2000)24 Phase I/II 22 Isolated hepatic perfusion (melphalan) ± TNFb 9c 11d
Alexander (2003)25 Phase II 29 Isolated hepatic perfusion (melphalan) 8 12.1
Noter (2004)26 Phase II 8 Isolated hepatic perfusion (melphalan) 6.7 9.9
van Etten (2009)27 Phase I/II 8 Isolated hypoxic hepatic perfusion (melphalan) 6 11
Vogl (2017)28 RS 18 Percutaneous hepatic perfusion (melphalan) 12.4 9.6
Karydis (2018)29 RS 51 Percutaneous hepatic perfusion (melphalan) 8.1 15.3
Artzner (2019)30 RS 16 Percutaneous hepatic perfusion (melphalan) 11.1 27.4
BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea, mo months, N/A not available, OS overall survival, PFS progression-free survival, PS prospective, pts patients, RS retrospective, TNF tumor necrosis factor, Y-90 yttrium-90
aCisplatin (n = 122), cisplatin + paclitaxel (n = 2), cisplatin + doxorubicin + MMC (n = 1)
bIsolated hepatic perfusion (n = 11), isolated hepatic perfusion with TNF (n = 11)
c14 months for patients without TNF vs 6 months for patients with TNF (p = 0.04)
dNo difference between both groups (p = 0.17)
M-PHP is a minimally invasive, repeatable technique in which the liver is isolated from the systemic circulation and subsequently perfused with high-dose chemotherapy. M-PHP is the only liver-directed therapy that has been investigated in a multicenter, randomized, controlled trial (RCT).31 A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP compared with best alternative care, but the median OS after M-PHP was only 10.6 months. Approximately 40% of patients in this study had extrahepatic metastases, and M-PHP may have had a limited effect on their OS. Additionally, 11% of patients in the study had metastases from cutaneous melanoma.
Concerns regarding the safety of M-PHP have been raised as high rates of hematologic toxicity were reported in prior studies.31–34 To address the issue of hematologic toxicity, a new hemofiltration system with a second-generation detoxification cartridge (GEN 2 filter) was developed. This filter has a higher melphalan extraction rate than the first-generation filters and was shown to reduce hematologic toxicity.35,36 So far, only retrospective studies have reported on M-PHP using the GEN 2 filter in ocular melanoma patients.28–30
The purpose of this study was to prospectively investigate the efficacy and safety of M-PHP using the GEN 2 filter in well-selected patients with unresectable metastases from ocular melanoma confined to the liver.
Methods
This prospective, single-arm, single-center, phase II study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee and registered on www.trialregister.nl (NTR4112). All participants provided written informed consent.
Patients
Eligible patients were those with histologically proven, unresectable ocular melanoma metastases confined to the liver. All patients were discussed at a multidisciplinary meeting before inclusion. Exclusion criteria are listed in Table 2.Table 2 Exclusion criteria
Laboratory test results Other
APTT > 1.5 × ULN Age < 18 or > 75 yr
PT > 1.5 × ULN Extrahepatic disease (on CECT or FDG-PET/CT)
Leukocytes < 3.0 × 109/L WHO performance status ≥ 2
Thrombocytes < 100 × 109/L Severe comorbidity precluding general anesthesia
Creatinine clearance < 40 ml/min Diabetes with nephropathy
AST > 2.5 × ULN Active infections
ALT > 2.5 × ULN < 40% healthy liver tissue
Serum bilirubin > 1.5 × ULN Other liver disease
ALP > 2.5 × ULN Vascular anatomy impeding M-PHP
LDH > 2 × ULNa Intracranial lesions with propensity to bleed (on CT/MRI)
Pregnancy
ALP alkaline phosphatase, ALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, CECT contrast-enhanced CT of chest and abdomen, FDG-PET/CT positron emission tomography with integrated noncontrast enhanced CT and 18F-2-fluoro-2-deoxy-d-glucose as radiotracer, LDH lactate dehydrogenase, M-PHP percutaneous hepatic perfusion with melphalan, PT prothrombin time, ULN upper limit of normal
aIncluded in the protocol during the course of the study
Study Protocol
Pretreatment angiography was routinely performed approximately 1 week before the first M-PHP to evaluate hepatic arterial vasculature. If deemed necessary, hepatico-enteric shunts (e.g., right gastric and gastroduodenal artery) were embolized to prevent inadvertent leakage of melphalan.
Treatment consisted of two M-PHP procedures with hepatic artery infusion of melphalan 3 mg/kg (maximum dose 220 mg) at 6–8 weeks interval. Patients demonstrating progressive disease (PD) or unacceptable adverse events after the first M-PHP received only one procedure. If grade 3/4 hematologic toxicity occurred after the first procedure, melphalan dose was reduced by 20–25%. Patients routinely received a subcutaneous injection of granulocyte-colony stimulating factor (pegfilgrastim 6 mg) within 72 h after each M-PHP.
Contrast-enhanced CT of chest and abdomen was performed at baseline, 4–8 weeks after each M-PHP, every 3 months in the first year and every 6 months thereafter until PD occurred. MRI of the liver was performed if lesions were not or poorly visible on CT.
Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30 v3.0). Questionnaires were filled out at baseline, 6 weeks after the first and second M-PHP, and 6 months after the first M-PHP.
All adverse events were monitored continuously throughout the entire study and reported according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
Procedure
All M-PHP procedures were performed using the CHEMOSAT (GEN 2) system (Delcath Systems Inc, New York). General anesthesia was performed with continuous monitoring of the central venous and arterial pressure. Access to the right internal jugular vein (IJV, 10-F sheath), right common femoral vein (CFV, 18-F sheath), and left common femoral artery (5-F sheath) was created. Heparin was administered at an initial dose of 300 U/kg and an activated clotting time of ≥ 450 s was maintained throughout the procedure. A 2.4-F or 2.7-F microcatheter was placed into the hepatic artery at the intended location of infusion. A 16-F double-balloon catheter (Isofuse Isolation Aspiration Catheter, Delcath Systems Inc, New York, NY) was placed in the inferior vena cava (IVC) via the right CFV. The cranial and caudal balloons were inflated at the atriocaval junction and infrahepatic IVC, respectively, to prohibit leakage of melphalan into the systemic circulation. The entire dose of melphalan was infused into the proper hepatic artery or split and infused in the right and left hepatic artery. Melphalan-rich blood was aspirated through catheter fenestrations in a segment between the two balloons, pumped through an extracorporeal hemofiltration system and returned to the patient via the sheath in the right IJV. Once all melphalan was administered, filtration was continued for 30 min to allow complete clearance of melphalan from the liver. The anticoagulant effects of heparin were reversed by protamine sulphate 3 mg/kg, the arterial sheath was removed and hemostasis was achieved using a closure device.37
Endpoints
All imaging was reviewed by independent radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.38 Primary endpoints were overall response rate (ORR) and best overall response (BOR) according to RECIST 1.1. Secondary endpoints were best hepatic response according to RECIST 1.1, OS, PFS, hepatic progression-free survival (hPFS), safety, and QoL.
OS was defined as time of first M-PHP until death or censoring. PFS and hPFS were defined as time of first M-PHP until PD, death, or censoring.
Statistical Analysis
Kaplan–Meier estimations were used to assess OS, PFS, and hPFS. OS data were censored at the date of last follow-up if patients were still alive. The log-rank test was used to compare curves.
Cox regression analyses were performed to determine possible independent predictors for OS. The Wilcoxon signed-rank test was used to compare scores from questionnaires filled in at baseline and after treatment. P < 0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 35 patients (16 men; median age 59 years, range 41–71) were prospectively enrolled between February 2014 and June 2017. Baseline demographic and clinical characteristics of all patients are listed in Table 3.Table 3 Baseline characteristics for all 35 patients with liver metastases from ocular melanoma
Parameter N Percentage
Gender
Men 16 46
Women 19 54
Age, yr [median (range)] 59 (41–71) …
BMI, kg/m2 [median (range)] 25 (20–32) …
Tumor location
Choroid 19 54
Choroid with ciliary corpus involvement 12 34
Ciliary corpus 4 11
Type of metastases
Synchronous 4 11
Metachronous 31 89
Mutations in liver metastases
GNAQ 21 60
GNA11 12 34
No GNAQ/GNA11 2 6
Time between diagnosis primary tumor and liver metastases, months [median (range)] 28 (0–71) …
Prior therapy for liver metastases
Systemic therapya 8 23
Regional therapyb 4 11
Regional and systemic therapy 2 6
None 21 60
Radiological aspect metastases
Hypovascular 3 9
Hypervascular 26 74
Mixed 6 17
Total number of metastases ≥ 10 20 57
Diameter of largest metastasis ≥ 3 cm 14 40
LDH level, IU/L [median (range)] 196 (78–657) …
Elevated LDH levelc 8 23
Elevated AFP leveld 7 20
AFP alkaline phosphatase, BMI body mass index, GNAQ guanine nucleotide-binding protein G(q) subunit alpha, GNA11 guanine nucleotide-binding protein G(Y) subunit alpha-11, LDH lactate dehydrogenase, SD standard deviation, ULN upper limit of normal
aTreatment in randomized phase II SUMIT-trial (selumetinib with dacarbazine vs. placebo) or phase I AEB071-study (protein kinase C inhibitor), ipilimumab, or dendritic cell therapy
bRadiofrequency ablation and/or metastasectomy
cNormal limits 0–247 for men and women
dNormal limits 0–115 U/L for men and 0–98 U/L for women
A total of 64 M-PHP procedures were performed. Twenty-nine of 35 (83%) patients underwent two M-PHP procedures as per protocol. Six of 35 (17%) patients received only one M-PHP due to PD (n = 1) or an adverse event (n = 5) after the first M-PHP procedure. An example treatment of a study participant is shown in Fig. 1.Fig. 1 Percutaneous hepatic perfusion with melphalan (M-PHP) in a 66-year-old man with bilobar liver metastases from ocular melanoma. (a) Pretreatment angiographic image from the common hepatic artery (CHA) shows a right gastric artery (RGA, white arrowheads) and gastroduodenal artery (GDA, white arrow). Also a 5F macrocatheter in the CHA (dotted white arrow) and the duodenal bulb (black arrow) are shown. The RGA and GDA were successfully coiled. (b) Postero-anterior image during venography. The cranial balloon (black arrow) is inflated at the atriocaval junction to prevent flow to the right atrium, and the caudal balloon (dotted black arrow) is inflated in the infrahepatic inferior vena cava (IVC) to prevent retrograde flow to the infrarenal IVC. A 2.7F microcatheter was inserted through the macrocatheter (dotted white arrow) and placed into the proper hepatic artery for the infusion of melphalan. The right hepatic vein (asterisk) and accessory right inferior hepatic vein (black arrowhead) are opacified. Note the coils in the RGA (white arrowhead) and GDA (white arrow). (c) Axial CT image in portovenous phase before treatment shows a metastasis in liver segment II and VII/VIII (white arrowheads). A third lesion in segment VI is not shown. (d) Axial CT image in portovenous phase after two M-PHP procedures shows reduction in size of the metastasis in liver segment II (white arrowhead). The other two lesions showed a complete radiological response
Response Analysis
Thirty-two of 35 patients were included in the response analysis (Fig. 2a). In two patients, a therapeutic melphalan dose could not be administered due to peri-procedural complications and therefore no treatment effect could be evaluated. In one patient, target lesions were absent (all lesions with maximal diameter < 1 cm).Fig. 2 Treatment outcome. (a) Best overall response and best hepatic response in all evaluable patients (n = 32) and evaluable patients that received two M-PHP procedures (n = 27). (b-c) Change from baseline in the sum of target lesions at best overall response and best hepatic response in all evaluable patients. CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; PD progressive disease; PR partial response; pts patients; SD stable disease
The ORR was 72% with complete response (CR) in 3% (n = 1) and partial response (PR) in 69% (n = 22). A confirmed hepatic response occurred in 26 (81%) patients (3% CR and 78% PR). Five patients had PD as BOR due to extrahepatic metastases; the sum of target lesions in the liver remained stable (n = 3) or decreased with > 30% (n = 2). The magnitude of BOR and best hepatic response is shown in Fig. 2b, c.
Survival Analysis
There was no loss to follow-up. After a median follow-up of 19.1 months, 6 of 35 (17%) patients were still alive. The 1- and 2-year OS was 77% and 43%, respectively. Median OS was 19.1 months for all included patients (n = 35; Fig. 3a). Median OS was significantly longer in patients with CR/PR as BOR than in patients with SD/PD as BOR (p < 0.001; Fig. 3b). Median OS for patients with CR/PR, SD, and PD as BOR was 27.5 months (95% confidence interval [CI]: 23.7–31.3), 14.2 months (95% CI: 11.4–17.0), and 9.1 months (95% CI: 5.5–12.8), respectively. Median OS also was significantly longer (p = 0.001) in patients with CR/PR as best hepatic response than in patients with SD as best hepatic response: 26.3 months (95% CI: 15.8–36.8) versus 11.9 months (95% CI: 7.3–16.5) (Fig. 3c).Fig. 3 Survival outcomes. (a) Kaplan–Meier estimate of OS for all included patients (n = 35). (b-c) Kaplan–Meier estimates of OS in all evaluable patients stratified by best overall response and best hepatic response. CI confidence interval; CR complete response; M-PHP percutaneous hepatic perfusion with melphalan; OS overall survival; PD progressive disease; PR partial response; SD stable disease
Univariate analysis revealed that the presence of a liver metastasis with diameter ≥ 3 cm (p = 0.01) and an elevated baseline lactate dehydrogenase (LDH) (> 248 U/L, p = 0.03) were significantly associated with a poorer OS. Age (< 65 versus ≥ 65 years, p = 0.51), gender (p = 0.42), previous local/systemic therapy of liver metastases (p = 0.36), mutation status (GNAQ versus GNA11, p = 0.57), high tumor burden (> 10 metastases, p = 0.65), radiological aspect of metastases (mixed/hypovascular versus hypervascular, p = 0.77), and elevated baseline alkaline phosphatase (ALP) (> 115 U/L for men and > 98 U/L for women, p = 0.12) were not found to be predictors for OS.
Median PFS was 7.6 months (95% CI: 4.9–10.3) with a 1-year PFS of 26.5%. PFS for patients with a hepatic response was significantly (p = 0.001) longer than for nonresponders: 9.3 months (95% CI: 8.6–10.0) versus 5.6 months (95% CI: 2.7–8.5). Median hPFS was 11.2 months (95% CI: 9.0–13.4) with a 1-year hPFS of 35.3%. Median OS in patients with a relatively long hPFS (i.e., ≥ median hPFS of 11.2 months) was significantly (p < 0.001) longer than in patients with a relatively short hPFS (< 11.2 months): 29.9 months (95% CI: 11.1–48.7) versus 14.2 months (95% CI: 10.1–183).
Twenty of 34 (59%) patients who eventually showed PD during the course of this study received one or more subsequent treatments (Table 4). Twenty-six of 35 (74%) patients developed extrahepatic metastases during follow-up.Table 4 All patients that received subsequent treatment(s) after showing progressive disease (n = 20)
Pt study no. Progression sites* Subsequent treatments
1 Liver 2x M-PHP, RFA liver
3 Liver, bone RFA liver + ipilimumaba
4 Liver, bone, lung 2x M-PHP, RTx bone, pembrolizumab, PKC-inhibitorb, dacarbazine
5 Bone, liver Ipilimumab
6 Lung Ipilimumab
8 (Sub)cutis, parotid gland, rectosigmoid Resection cutaneous nodes
9 Liver, subcutis, lung RFA liver, resection subcutaneous node
10 Liver, muscles, subcutis, retroperitoneum, lymph nodes RFA liver, RT lymph nodes
11 Bone, liver, subcutis RFA bone and liver
14 Liver Pembrolizumab, PKC inhibitorb
16 Liver, lung, kidney PKC-inhibitorb
18 Bone, liver PKC-inhibitorb
20 Liver, peritoneum, retroperitoneum, lung 1x M-PHP, PKC-inhibitorb
22 Liver, subcutis, peritoneum Radioembolization, PKC-inhibitorb, panitimumabc
26 Liver, brain Resection liver metastases
27 Liver 2x M-PHP
29 Liver, bone 2x M-PHP, RFA liver
30 Liver 3x M-PHP
34 Liver PKC-inhibitorb
35 Liver RFA liver
M-PHP percutaneous hepatic perfusion with melphalan, no. number, PKC-inhibitor protein kinase C-inhibitor, Pt patient, RFA radiofrequency ablation, RTx radiation therapy
*Progression sites given in bold represent the initial progression sites
aSECIRA-UM study (EudraCT Number: 2011-004200-38)
bPhase I study with a protein kinase C-inhibitor
cPhase II study with various targeted anti-cancer drugs
Safety
No deaths occurred. A total of 14 severe adverse events were recorded, including 5 cases of prolonged hospital stay (4–5 days instead of 3 days) and 8 readmissions with a median hospital stay of 6 days (range 1–15). The majority of patients developed grade 3/4 hematologic events with leukopenia (75.6%) and lymphocytopenia (84.8%) being most common. Fourteen grade 3 nonhematologic events occurred, including one case of peri-procedural transient cardiac ischemia, which was managed conservatively and resolved without sequelae. The only patient with a grade 4 nonhematologic event developed a sepsis with bacterial pharyngitis and retropharyngeal abscess formation. This was successfully treated with the intravenous administration of antibiotics and immunoglobulins, followed by percutaneous abscess aspiration. A more detailed description of safety and toxicity has been reported previously as medical authorities and patient organisations requested for the safety profile of M-PHP using the GEN 2 filter to become publicly available at the earliest possible stage.36 At that time, the follow-up period was too short to publish data on efficacy.
Quality of Life
At baseline, 18 of 35 (51%) patients completed the EORTC QLQ-C30 v3.0 form. Return rates of the questionnaire at 6 weeks after the first M-PHP procedure, 6 weeks after the second M-PHP procedure, and 6 months after the first M-PHP procedure were 74% (26/35), 59% (17/29), and 49% (17/35), respectively. Questionnaire scores after treatment did not significantly differ from scores prior to treatment, except for physical functioning which was significantly impaired 6 weeks after the second M-PHP (p = 0.011). The level of physical functioning was restored to normal 3 months later (Table 5).Table 5 Quality of life. Scores for each scale evaluated in the EORTC QLQ-C30 v3.0 questionnaire
Prior to treatment 6 wk after 1st M-PHP 6 wk after 2nd M-PHP 6 mo after 1st M-PHP
Median (range) Median (range) Median (range) Median (range)
Functional scales (0–100)
Physical functioning 97 (20–100) 93 (33–100) 87 (33–100)a 93 (0–100)
Role functioning 92 (33–100) 67 (17–100) 83 (33–100) 100 (0–100)
Emotional functioning 88 (33–100) 92 (42–100) 83 (58–100) 83 (50–100)
Cognitive functioning 100 (67–100) 100 (50–100) 100 (67–100) 100 (0–100)
Social functioning 100 (50–100) 83 (33–100) 100 (33–100) 100 (50–100)
Symptom scales (0–100)
Fatigue 6 (0–78) 22 (0–100) 22 (0–78) 11 (0–100)
Nausea and vomiting 0 (0–83) 0 (0–83) 0 (0–33) 0 (0–33)
Pain 0 (0–67) 0 (0–67) 0 (0–50) 0 (0–100)
Dyspnoea 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–33)
Insomnia 0 (0–67) 0 (0–67) 0 (0–100) 0 (0–100)
Appetite loss 0 (0–67) 0 (0–67) 0 (0–67) 0 (0–67)
Constipation 0 (0–33) 0 (0–33) 0 (0–0) 0 (0–67)
Diarrhoea 0 (0–33) 0 (0–67) 0 (0–33) 0 (0–0)
Financial difficulties 0 (0–33) 0 (0–67) 0 (0–67) 0 (0–100)
Global health status/QoL (0–100)
Global health status/QoL 83 (33–100) 83 (33–100) 83 (42–100) 83 (25–100)
EORTC QLQ-C30 v3.0 European organization for research and treatment of cancer quality of life questionnaire version 3.0, mo months, M-PHP percutaneous hepatic perfusion with melphalan, QoL quality of life, wk week
aStatistically different compared to baseline score, p = 0.011. All other scores were not statistically different compared to scores prior to treatment
Discussion
This study was designed to prospectively investigate the efficacy of M-PHP with the GEN 2 filter in patients with unresectable ocular melanoma metastases confined to the liver. The ORR of 72% and survival rate (median OS 19.1 months; 1- and 2-year OS of 77% and 43%, respectively) appeared to be much longer compared to published data on other treatment modalities and provide convincing evidence for the efficacy of M-PHP.
The prognosis of patients with metastatic ocular melanoma is very poor, and there is a lack of effective systemic therapies. A meta-analysis that included 29 prospective trials that reported patients with metastatic ocular melanoma who were treated with immunotherapy, kinase inhibitors, chemotherapy, or liver-directed therapy, reported a median OS of 10.2 months, 1-year OS of 43%, and median PFS of 3.3 months.6 Another recent meta-analysis, which included 78 peer-reviewed articles, reported similar outcomes in patients with metastatic ocular melanoma receiving either surgical, interventional radiology, or systemic treatment.7 Median OS across all treatment modalities was 1.07 years and 1-year OS was 52%. In both meta-analyses, patients treated with liver-directed therapies had a significantly longer OS but given the paucity of RCTs the evidence is not compelling. Many studies included in the meta-analyses were retrospective cohort studies with a small sample size and differences in OS between various therapies therefore may be attributable to lead-time, selection, and publication bias.
M-PHP is the only liver-directed therapy for which efficacy was shown in an RCT by Hughes et al. 31 This trial included 93 patients with unresectable liver metastases from either ocular (n = 83) or cutaneous (n = 10) melanoma. Patients were randomized to M-PHP (n = 44) or best alternative care (BAC) (n = 49). Approximately 82% of patients in the BAC group received active treatment such as systemic chemotherapy, chemoembolization, radioembolization, and surgery. A significant improvement in hepatic and overall PFS was demonstrated in patients treated with M-PHP: 7.0 versus 1.7 months (p < 0.0001) and 5.4 versus 1.6 months (p < 0.0001), respectively. The gain in PFS did not result in OS benefit though. The failure to demonstrate OS benefit was most likely caused by the substantial number of patients (40%) with extrahepatic metastases, thereby limiting the optimal effect of a liver-directed therapy. Additionally, almost 60% of patients crossed over to the M-PHP group, receiving M-PHP once disease progression occurred.
The median OS of 19.1 months in the current study compares favorably to the median OS reported in the aforementioned systematic reviews and RCT. It is also longer than the median OS of 15.3 months reported in the largest retrospective study on M-PHP in patients (n = 51) with metastatic ocular melanoma.29 This study included patients with extrahepatic metastases if these were nonprogressive following previous treatments or amenable to ablative treatment modalities.
Clearly, our favorable survival outcomes can (partly) be attributed to the exclusion of patients with extrahepatic disease. Additionally, we excluded patients with elevated LDH levels (> 2 × ULN) at baseline, and it has been demonstrated that an elevated LDH is associated with a poor OS in patients with metastatic ocular melanoma.6,39,40 Median baseline LDH level was 196 IU/L in our study versus a mean baseline LDH of 524 IU/L in the RCT by Hughes et al.31
The hepatic response rate in our study (81%) is much higher than in the study by Hughes et al. (36%) and Karydis et al. (49%).29,31 The median number of M-PHP procedures that patients received under study protocol was comparable between all these three studies.
The majority of patients received some form of subsequent treatment (i.e., liver-directed therapy and/or systemic therapy) after showing PD. Although this might have influenced survival, all of these therapies were also available and used at the time of the retrospective studies by Karydis et al. (median OS 15.3 months).29 This does not apply for the RCT by Hughes et al., which was conducted before checkpoint- and kinase inhibitors were used for metastatic ocular melanoma.31 It is unlikely though that subsequent systemic therapies had a large impact on OS as the efficacy of systemic treatments has been limited so far.3,41–44
We found that the median OS in patients with a relatively long hPFS (≥ median hPFS) was significantly longer than in patients with a shorter hPFS (< median hPFS). This, together with the finding that the median OS was significantly longer in responders than nonresponders, suggests that controlling liver disease with M-PHP in patients with liver-only disease improves OS. Ideally, this should be confirmed in a phase III RCT with OS as primary endpoint and no permission for crossover. This, however, has already been proven to be difficult as the FOCUS trial (M-PHP versus best available care, NCT02678572) was recently modified into a single-arm study due to a slow inclusion rate.
We found the presence of a liver metastasis with diameter ≥ 3 cm and elevated LDH level to be poor prognostic factors for OS, as was already reported by Khoja et al. 6 We were unable to confirm their findings that an age ≥ 65 years, male sex, and elevated ALP are also poor prognostic factors for OS.
Concerns have been raised about the safety of M-PHP as prior studies reported high rates of hematologic toxicity. In previous publications, it was demonstrated that the GEN 2 filter has an improved filter extraction rate and improved safety profile.34,35 We now also provide evidence that M-PHP is well-tolerated with maintenance of QoL. The QoL was only mildly affected with a temporary impaired physical functioning at 6 weeks after the second M-PHP.
The majority of patients (74%) developed extrahepatic metastatic disease during follow-up. These may have been new metastases that developed after M-PHP or metastases that were radiologically occult at baseline. This indicates that many patients with ocular melanoma will suffer from systemic spread for which liver-directed therapy is only a temporarily treatment solution. We recently started a phase I/II study investigating combination therapy of M-PHP with ipilimumab/nivolumab in order to better control both hepatic and extrahepatic disease (CHOPIN trial, NCT04283890). Results of trials investigating the efficacy of check-point inhibitors alone have been disappointing in patients with ocular melanoma metastases. Ocular melanoma cancer cells carry a low tumor mutational burden, which is thought to decrease the likelihood of neoantigen presentation necessary to evoke antitumoral response by T-cells.45 Tumor lysis and necrosis induced by M-PHP could potentially provoke antigen release that may stimulate cancer-specific immune response and increase the efficacy of check-point inhibitors.
Our study had several limitations. First, this was a single-arm study with a relatively small sample size. Second, we studied a selected group of patients by applying multiple specific exclusion criteria such as the presence of extrahepatic disease, elevated LDH level, and patient age. The relatively high median OS could therefore partly be attributed to selection.
Conclusions
Although this prospective study was not designed for direct comparison, the results indicate that M-PHP using the GEN 2 filter is more effective in treating liver metastases from ocular melanoma than systemic therapies. We found a high ORR and median OS of 19.1 months in patients with liver-only ocular melanoma metastases. As responders demonstrated an improved survival compared with nonresponders, controlling liver disease with M-PHP seems to prolong the life expectancy of these patients. Future research should aim to reproduce these results in a multicenter trial with larger study populations and to develop standardized criteria for patient selection.
Ellen Kapiteijn and Alexander L. Vahrmeijer share senior authorship.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T. Susanna Meijer and Mark C. Burgmans have contributed equally to this work.
Acknowledgment
The authors thank Gerrit Kracht for his help in producing the figures.
Funding
The Leiden University Medical Center received financial support (no grant number applies) and in kind contributions from Delcath Systems Inc, New York, NY, for conducting this study. The authors declare that Delcath Systems Inc. had no involvement in any part of the study. | Recovered | ReactionOutcome | CC BY | 32761328 | 18,919,159 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bacterial sepsis'. | Hyper- and hypocoagulability in COVID-19 as assessed by thromboelastometry -two case reports.
Coronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6, and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent.
Here, we describe two critically ill patients with COVID-19 admitted to our intensive care unit demonstrating different thromboelastometry and biomarker patterns. One patient presented with hypercoagulability and the other patient with hypocoagulability and fibrinolysis shutdown in thromboelastometry. The pathophysiology and the potential impact on treatment options are discussed.
A combination of biomarkers and thromboelastometry results can be helpful in the future to decide which therapeutic strategy might be most appropriate for critically ill patients with COVID-19. This would be an important step to establish precision medicine in this high-risk patient population.
Coronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6 (IL-6), and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays [1]. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent [2]. In contrast, sepsis-associated coagulopathy due to bacterial infection is characterized by hypocoagulability in thromboelastometry which has been shown to be a good predictor of increased mortality [3]. Here, we describe two critically ill patients with COVID-19 admitted to our intensive care unit (ICU) at Brighton and Sussex University Hospitals NHS Trust presenting with different thromboelastometry phenotypes, clinical courses, and outcomes.
Case Reports
The NHS Institutional Review Board waived the requirement of informed consent from each patient.
Case 1
A 48-year-old South Asian woman (Patient A) from Bangladesh (height 168 cm, weight 80 kg) was admitted to the medical ward for three days after which she was transferred to the ICU; she had cough and increasing dyspnea for three days before hospital admission. Comorbidities included hypertension, hypercholesterinemia, coronary artery disease, previous stroke (fully recovered), and type 2 diabetes. On admission, her laboratory results were as follows: hemoglobin (Hb): 143 g/L, white blood cells (WBC): 9.0 × 109/L, lymphocytes: 1.4 × 109/L, platelets: 261 × 109/L, international normalized ratio (INR): 1.1, D-dimer: 510 μg/L, fibrinogen plasma concentration: 8.4 g/L, and C-reactive protein (CRP): 52 mg/L. Her chest radiograph showed cardiomegaly and extensive bilateral peripherally predominant ground-glass opacities. Polymerase chain reaction (PCR) result was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and negative for influence/respiratory syncytial virus (RSV). Blood cultures were negative. The patient was treated with nasal oxygen therapy and antibiotics (ceftriaxone and doxycycline, according the hospital’s COVID-19 protocol). Antiviral therapy and dexamethasone were not administered. Later, CRP increased to 137 mg/L on the second day of hospitalization. The patient was transferred to the ICU on the third day because of increased respiratory rate and oxygen requirement. ROTEM performed 2 hours after ICU admission (Fig. 1A) revealed that Patient A was hypercoagulable with the EXTEM assay showing an increased clot firmness with an amplitude of clot firmness 5 minutes after coagulation time (CT) (A5) of 65 mm and a maximum clot firmness (MCF) of 78 mm, indicating hypercoagulability with a high risk of thrombosis [4]. FIBTEM also showed increased clot firmness (A5 41 mm and MCF 50 mm), indicating increased fibrinogen concentration and fibrin polymerization. Furthermore, the EXTEM lysis index 60 minutes after CT (LI60) was 97%, i.e., in the physiologic range (82–97.9%), whereas FIBTEM LI60 was 100% [5]. Treatment consisted of continuation of antibiotics, enoxaparin 40 mg twice a day in view of ROTEM results, and high flow nasal oxygen and intermittent face mask continuous positive airway pressure (CPAP) therapies. The patient did not need intermittent positive pressure ventilation (IPPV) or any vasoactive support. Laboratory results on the second day in the ICU were as follows: Hb: 131 g/L, WBC: 10.8 × 109/L, platelet count: 307 × 109/L, INR: 1.1, activated partial thromboplastin time (APTT) ratio: 1.3, D-dimer: 510 μg/L, and CRP: 196 mg/L. The patient recovered well and was transferred from the ICU to the medical ward after two days in the ICU with a CRP of 73 mg/L and was discharged three days later with a prescription of her usual medication plus enoxaparin 40 mg once daily for 2 weeks. The patient did not show any clinical signs of thrombosis during her hospital stay.
Case 2
A 68-year-old Caucasian man (Patient B) from the United Kingdom (height 177 cm, weight 85 kg) was admitted with cough and a week-long increasing dyspnea, before which he was healthy. His wife and daughter probably had COVID-19 with resolving symptoms, and they were all living in the same house. The patient markedly experienced shortness of breath on the day of admission to the emergency department (ED) and, therefore, called an ambulance. His laboratory results on admission were as follows: Hb: 140 g/L, creatinine: 117 μmol/L, WBC: 8.6 × 109/L, lymphocytes: 0.2 × 109/L, platelet count: 126 × 109/L, INR: 1.4, APTT ratio: 1.3, D-dimer > 20,000 μg/L (i.e., higher than the upper limit of the measurement range), fibrinogen plasma concentration: 6.8 g/L, and CRP: 336 mg/L. His chest radiograph showed dense bilateral mid-zone and right lower zone consolidation. PCR result was positive for SARS-CoV-2 and negative for influenza/RSV. Blood cultures showed coagulase-negative staphylococci. The patient was treated with antibiotics (ceftriaxone and doxycycline, according the hospital’s COVID-19 protocol). Antiviral therapy and dexamethasone were not administered. As the patient was severely hypoxemic in the ED, he was transferred directly to the ICU. Orotracheal intubation and IPPV (positive end-expiratory pressure 15 mmHg) were performed about 3 hours after ICU admission as respiratory effort was not improved by face mask CPAP therapy. Chest radiography repeated after intubation showed bilateral interstitial lung changes similar to the imaging conducted earlier on the same day. Prone position did not improve oxygenation. Laboratory results on the next day were as follows: Hb: 133 g/L, creatinine: 265 μmol/L, WBC: 16.3 × 109/L, platelet count: 56 × 109/L, INR: 1.6, APTT ratio: 1.5, D-dimer: 4,340 μg/L, fibrinogen plasma concentration: 2.9 g/L, and CRP: 478 mg/L. By ROTEM, Patient B presented with hypocoagulability in the EXTEM assay with a prolonged CT of 99 s, clot formation time (CFT) of 253 s, and decreased clot firmness amplitudes (A5, 22 mm and MCF, 48 mm) (Fig. 1B). Furthermore, EXTEM and FIBTEM analyses demonstrated a complete fibrinolysis shutdown [5]. Both hypocoagulability and fibrinolysis shutdown have been shown to be associated with increased mortality in bacterial sepsis [3,6]. The FIBTEM trace was within normal limits which may be owing to impaired fibrin polymerization, given that fibrinogen concentration was elevated. The patient deteriorated within a few hours of ICU admission and died the following day despite invasive ventilation, norepinephrine for hypotension, and renal replacement therapy for acute kidney failure. Patient B did not show any clinical signs of thrombosis during his hospital stay.
Discussion
We have presented two cases that illustrate the additional value of using thromboelastometry to monitor patients with COVID-19. Increased clot firmness in EXTEM and INTEM (amplitude of clot firmness 10 minutes after CT (A10) > 61.5 mm or MCF > 68 mm) assays has been shown to be associated with an increased incidence of thrombosis in adults and neonates undergoing cardiac and non-cardiac surgery [4]. Furthermore, increased clot firmness in the FIBTEM assay (MCF > 25 mm) has been shown to be associated with an increased incidence of thrombosis in patients with cirrhosis and hepatocellular carcinoma as well as in patients with thrombophilic predisposition after liver transplantation [7,8]. Thromboelastometry in Patient A showed hypercoagulability despite upper normal ranged D-dimer levels and a normal INR. Patients with D-dimer > 3,000 µg/L and/or sepsis-induced coagulopathy score ≥ 4 seem to benefit from increased anticoagulation [9]. However, in critically ill patients with COVID-19, the incidence of thrombosis and pulmonary embolism is high despite pharmacological thromboprophylaxis [2].
The case of Patient B demonstrated that not all critically ill patients with COVID-19 present the same thromboelastometric pattern. This might be attributed to ethnic and genetic difference, such as gene polymorphisms, bacterial superinfection, or the phase of the disease. Both hypocoagulability and fibrinolysis shutdown, as presented by Patient B, have been shown to be associated with increased mortality in cases involving bacterial sepsis [3,6]. Furthermore, lymphocytopenia has been shown to be associated with poor outcomes in COVID-19 [10]. Although thrombocytopenia, which is an important determinant of clot firmness, is rare in COVID-19, it is associated with poor outcomes in the patient population [7,11]. Furthermore, the mismatch between FIBTEM MCF (14 mm) and Clauss fibrinogen plasma concentration (6.8 g/L) in Patient B might reflect an acquired factor XIII deficiency, which often occurs in sepsis, cirrhosis, acute renal failure, and malignancies [12]. Unfortunately, factor XIII activity is not available for Patient B, which leaves this interpretation speculative. The rapid deterioration of Patient B with acute renal failure and a fatal outcome is in-line with the data published by Wright et al. [13] showing that patients with the combination of high D-dimer (> 2,600 µg/L, here > 20,000 µg/L) and fibrinolysis shutdown (lysis 30 minutes after maximum amplitude in thrombelastography (TEG LY30) of 0% or ROTEM LI60 of 100%) are associated with the highest incidence of thrombosis (50%) and acute renal failure (80%). Here, increased D-dimers and fibrinolysis shutdown may reflect an imbalance in hemostasis with increased clot formation but impaired fibrinolysis – similar to disseminated intravascular coagulation. It remains to be determined whether fibrinolytic therapy with recombinant tissue plasminogen activator (rtPA) has a therapeutic role in critically ill patients with COVID-19 who cannot be oxygenated adequately despite mechanical ventilation and prone positioning. Notably, extracorporeal membrane oxygenation is associated with very high mortality in patients with COVID-19, particularly in patients with hyperinflammation characterized by high IL-6 levels. Although this might support the use of fibrinolytic therapy with rtPA in these patients, Campello et al. [14] demonstrated that a FIBTEM MCF < 14.5 mm is highly predictive of bleeding complications (such as hemorrhagic stroke) after rtPA. Therefore, hypocoagulability in thromboelastometry, particularly a FIBTEM MCF < 14.5 mm should be considered a contraindication for fibrinolytic therapy in critically ill patients with COVID-19.
Nevertheless, this case report has several limitations. First, no follow-up ROTEM analyses are available for these patients. Accordingly, the presented ROTEM analyses only represent a snapshot of the COVID-19-associated coagulopathy that can be considered as a dynamic process. Here, different thromboelastometric phenotypes may represent different conditions of the patients or different phases of the coagulopathy. Second, the cut-off values for fibrinolysis shutdown established in trauma and bacterial sepsis cases have been used as clear cut-off values for fibrinolysis shutdown in COVID-19-associated coagulopathy have not been established yet. Further studies are needed to characterize COVID-19-associated coagulopathy and its differences from trauma- and sepsis-induced coagulopathy.
These two cases demonstrate that the thromboelastometric phenotype can be different and thromboelastometry can easily distinguish between hyper- and hypocoagulability in critically ill patients with COVID-19. Furthermore, thromboelastometry can identify patients with fibrinolysis shutdown [5,6]. The combination of thromboelastometry parameters (EXTEM and FIBTEM CT, CFT, A5, A10, MCF and LI60) and conventional biomarkers (D-dimer, Clauss fibrinogen, and IL-6) might be superior in predicting clinical outcomes such as thrombosis, renal failure and death in patients with COVID-19 than each diagnostic test alone. Therefore, these test combinations can be helpful in the future to decide which therapeutic strategy might be the most appropriate one in critically ill patients with COVID-19. This would be an important step to establish precision medicine not only in thromboelastometry-guided bleeding management but also in this high-risk patient population [15].
Fig. 1. ROTEM graphs and results of Patient A and Patient B. (A) Critically ill Patient A with COVID-19, with a hypercoagulable phenotype. (B) Critically ill Patient B with COVID-19 with a hypocoagulable phenotype. EXTEM: extrinsically activated (tissue factor) thromboelastometric assay, FIBTEM: extrinsically activated thromboelastometric assay with the addition of cytochalasin to eliminate platelet contribution to clot firmness, CT: coagulation time, CFT: clot formation time, alpha: alpha angle, A5: amplitude of clot firmness 5 minutes after CT, A10: amplitude of clot firmness 10 minutes after CT, MCF: maximum clot firmness, LI60: lysis index in percentage of maximum clot firmness 60 minutes after CT, ML: maximum lysis during run time, *Reference range for physiological fibrinolysis in EXTEM as published by Stettler et al. [5].
Conflicts of Interest
Klaus Görlinger is working as the Medical Director of Tem Innovations since July 2012. Robert Kong and Nevil Hutchinson reported no potential conflict of interest relevant to this article.
Author Contributions
Robert Kong (Conceptualization; Investigation; Writing – review & editing)
Nevil Hutchiinson (Conceptualization; Investigation; Writing – review & editing)
Klaus Görlinger (Conceptualization; Writing – original draft) | CEFTRIAXONE, DOXYCYCLINE, NOREPINEPHRINE | DrugsGivenReaction | CC BY-NC | 32773727 | 20,408,037 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Hyper- and hypocoagulability in COVID-19 as assessed by thromboelastometry -two case reports.
Coronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6, and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent.
Here, we describe two critically ill patients with COVID-19 admitted to our intensive care unit demonstrating different thromboelastometry and biomarker patterns. One patient presented with hypercoagulability and the other patient with hypocoagulability and fibrinolysis shutdown in thromboelastometry. The pathophysiology and the potential impact on treatment options are discussed.
A combination of biomarkers and thromboelastometry results can be helpful in the future to decide which therapeutic strategy might be most appropriate for critically ill patients with COVID-19. This would be an important step to establish precision medicine in this high-risk patient population.
Coronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6 (IL-6), and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays [1]. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent [2]. In contrast, sepsis-associated coagulopathy due to bacterial infection is characterized by hypocoagulability in thromboelastometry which has been shown to be a good predictor of increased mortality [3]. Here, we describe two critically ill patients with COVID-19 admitted to our intensive care unit (ICU) at Brighton and Sussex University Hospitals NHS Trust presenting with different thromboelastometry phenotypes, clinical courses, and outcomes.
Case Reports
The NHS Institutional Review Board waived the requirement of informed consent from each patient.
Case 1
A 48-year-old South Asian woman (Patient A) from Bangladesh (height 168 cm, weight 80 kg) was admitted to the medical ward for three days after which she was transferred to the ICU; she had cough and increasing dyspnea for three days before hospital admission. Comorbidities included hypertension, hypercholesterinemia, coronary artery disease, previous stroke (fully recovered), and type 2 diabetes. On admission, her laboratory results were as follows: hemoglobin (Hb): 143 g/L, white blood cells (WBC): 9.0 × 109/L, lymphocytes: 1.4 × 109/L, platelets: 261 × 109/L, international normalized ratio (INR): 1.1, D-dimer: 510 μg/L, fibrinogen plasma concentration: 8.4 g/L, and C-reactive protein (CRP): 52 mg/L. Her chest radiograph showed cardiomegaly and extensive bilateral peripherally predominant ground-glass opacities. Polymerase chain reaction (PCR) result was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and negative for influence/respiratory syncytial virus (RSV). Blood cultures were negative. The patient was treated with nasal oxygen therapy and antibiotics (ceftriaxone and doxycycline, according the hospital’s COVID-19 protocol). Antiviral therapy and dexamethasone were not administered. Later, CRP increased to 137 mg/L on the second day of hospitalization. The patient was transferred to the ICU on the third day because of increased respiratory rate and oxygen requirement. ROTEM performed 2 hours after ICU admission (Fig. 1A) revealed that Patient A was hypercoagulable with the EXTEM assay showing an increased clot firmness with an amplitude of clot firmness 5 minutes after coagulation time (CT) (A5) of 65 mm and a maximum clot firmness (MCF) of 78 mm, indicating hypercoagulability with a high risk of thrombosis [4]. FIBTEM also showed increased clot firmness (A5 41 mm and MCF 50 mm), indicating increased fibrinogen concentration and fibrin polymerization. Furthermore, the EXTEM lysis index 60 minutes after CT (LI60) was 97%, i.e., in the physiologic range (82–97.9%), whereas FIBTEM LI60 was 100% [5]. Treatment consisted of continuation of antibiotics, enoxaparin 40 mg twice a day in view of ROTEM results, and high flow nasal oxygen and intermittent face mask continuous positive airway pressure (CPAP) therapies. The patient did not need intermittent positive pressure ventilation (IPPV) or any vasoactive support. Laboratory results on the second day in the ICU were as follows: Hb: 131 g/L, WBC: 10.8 × 109/L, platelet count: 307 × 109/L, INR: 1.1, activated partial thromboplastin time (APTT) ratio: 1.3, D-dimer: 510 μg/L, and CRP: 196 mg/L. The patient recovered well and was transferred from the ICU to the medical ward after two days in the ICU with a CRP of 73 mg/L and was discharged three days later with a prescription of her usual medication plus enoxaparin 40 mg once daily for 2 weeks. The patient did not show any clinical signs of thrombosis during her hospital stay.
Case 2
A 68-year-old Caucasian man (Patient B) from the United Kingdom (height 177 cm, weight 85 kg) was admitted with cough and a week-long increasing dyspnea, before which he was healthy. His wife and daughter probably had COVID-19 with resolving symptoms, and they were all living in the same house. The patient markedly experienced shortness of breath on the day of admission to the emergency department (ED) and, therefore, called an ambulance. His laboratory results on admission were as follows: Hb: 140 g/L, creatinine: 117 μmol/L, WBC: 8.6 × 109/L, lymphocytes: 0.2 × 109/L, platelet count: 126 × 109/L, INR: 1.4, APTT ratio: 1.3, D-dimer > 20,000 μg/L (i.e., higher than the upper limit of the measurement range), fibrinogen plasma concentration: 6.8 g/L, and CRP: 336 mg/L. His chest radiograph showed dense bilateral mid-zone and right lower zone consolidation. PCR result was positive for SARS-CoV-2 and negative for influenza/RSV. Blood cultures showed coagulase-negative staphylococci. The patient was treated with antibiotics (ceftriaxone and doxycycline, according the hospital’s COVID-19 protocol). Antiviral therapy and dexamethasone were not administered. As the patient was severely hypoxemic in the ED, he was transferred directly to the ICU. Orotracheal intubation and IPPV (positive end-expiratory pressure 15 mmHg) were performed about 3 hours after ICU admission as respiratory effort was not improved by face mask CPAP therapy. Chest radiography repeated after intubation showed bilateral interstitial lung changes similar to the imaging conducted earlier on the same day. Prone position did not improve oxygenation. Laboratory results on the next day were as follows: Hb: 133 g/L, creatinine: 265 μmol/L, WBC: 16.3 × 109/L, platelet count: 56 × 109/L, INR: 1.6, APTT ratio: 1.5, D-dimer: 4,340 μg/L, fibrinogen plasma concentration: 2.9 g/L, and CRP: 478 mg/L. By ROTEM, Patient B presented with hypocoagulability in the EXTEM assay with a prolonged CT of 99 s, clot formation time (CFT) of 253 s, and decreased clot firmness amplitudes (A5, 22 mm and MCF, 48 mm) (Fig. 1B). Furthermore, EXTEM and FIBTEM analyses demonstrated a complete fibrinolysis shutdown [5]. Both hypocoagulability and fibrinolysis shutdown have been shown to be associated with increased mortality in bacterial sepsis [3,6]. The FIBTEM trace was within normal limits which may be owing to impaired fibrin polymerization, given that fibrinogen concentration was elevated. The patient deteriorated within a few hours of ICU admission and died the following day despite invasive ventilation, norepinephrine for hypotension, and renal replacement therapy for acute kidney failure. Patient B did not show any clinical signs of thrombosis during his hospital stay.
Discussion
We have presented two cases that illustrate the additional value of using thromboelastometry to monitor patients with COVID-19. Increased clot firmness in EXTEM and INTEM (amplitude of clot firmness 10 minutes after CT (A10) > 61.5 mm or MCF > 68 mm) assays has been shown to be associated with an increased incidence of thrombosis in adults and neonates undergoing cardiac and non-cardiac surgery [4]. Furthermore, increased clot firmness in the FIBTEM assay (MCF > 25 mm) has been shown to be associated with an increased incidence of thrombosis in patients with cirrhosis and hepatocellular carcinoma as well as in patients with thrombophilic predisposition after liver transplantation [7,8]. Thromboelastometry in Patient A showed hypercoagulability despite upper normal ranged D-dimer levels and a normal INR. Patients with D-dimer > 3,000 µg/L and/or sepsis-induced coagulopathy score ≥ 4 seem to benefit from increased anticoagulation [9]. However, in critically ill patients with COVID-19, the incidence of thrombosis and pulmonary embolism is high despite pharmacological thromboprophylaxis [2].
The case of Patient B demonstrated that not all critically ill patients with COVID-19 present the same thromboelastometric pattern. This might be attributed to ethnic and genetic difference, such as gene polymorphisms, bacterial superinfection, or the phase of the disease. Both hypocoagulability and fibrinolysis shutdown, as presented by Patient B, have been shown to be associated with increased mortality in cases involving bacterial sepsis [3,6]. Furthermore, lymphocytopenia has been shown to be associated with poor outcomes in COVID-19 [10]. Although thrombocytopenia, which is an important determinant of clot firmness, is rare in COVID-19, it is associated with poor outcomes in the patient population [7,11]. Furthermore, the mismatch between FIBTEM MCF (14 mm) and Clauss fibrinogen plasma concentration (6.8 g/L) in Patient B might reflect an acquired factor XIII deficiency, which often occurs in sepsis, cirrhosis, acute renal failure, and malignancies [12]. Unfortunately, factor XIII activity is not available for Patient B, which leaves this interpretation speculative. The rapid deterioration of Patient B with acute renal failure and a fatal outcome is in-line with the data published by Wright et al. [13] showing that patients with the combination of high D-dimer (> 2,600 µg/L, here > 20,000 µg/L) and fibrinolysis shutdown (lysis 30 minutes after maximum amplitude in thrombelastography (TEG LY30) of 0% or ROTEM LI60 of 100%) are associated with the highest incidence of thrombosis (50%) and acute renal failure (80%). Here, increased D-dimers and fibrinolysis shutdown may reflect an imbalance in hemostasis with increased clot formation but impaired fibrinolysis – similar to disseminated intravascular coagulation. It remains to be determined whether fibrinolytic therapy with recombinant tissue plasminogen activator (rtPA) has a therapeutic role in critically ill patients with COVID-19 who cannot be oxygenated adequately despite mechanical ventilation and prone positioning. Notably, extracorporeal membrane oxygenation is associated with very high mortality in patients with COVID-19, particularly in patients with hyperinflammation characterized by high IL-6 levels. Although this might support the use of fibrinolytic therapy with rtPA in these patients, Campello et al. [14] demonstrated that a FIBTEM MCF < 14.5 mm is highly predictive of bleeding complications (such as hemorrhagic stroke) after rtPA. Therefore, hypocoagulability in thromboelastometry, particularly a FIBTEM MCF < 14.5 mm should be considered a contraindication for fibrinolytic therapy in critically ill patients with COVID-19.
Nevertheless, this case report has several limitations. First, no follow-up ROTEM analyses are available for these patients. Accordingly, the presented ROTEM analyses only represent a snapshot of the COVID-19-associated coagulopathy that can be considered as a dynamic process. Here, different thromboelastometric phenotypes may represent different conditions of the patients or different phases of the coagulopathy. Second, the cut-off values for fibrinolysis shutdown established in trauma and bacterial sepsis cases have been used as clear cut-off values for fibrinolysis shutdown in COVID-19-associated coagulopathy have not been established yet. Further studies are needed to characterize COVID-19-associated coagulopathy and its differences from trauma- and sepsis-induced coagulopathy.
These two cases demonstrate that the thromboelastometric phenotype can be different and thromboelastometry can easily distinguish between hyper- and hypocoagulability in critically ill patients with COVID-19. Furthermore, thromboelastometry can identify patients with fibrinolysis shutdown [5,6]. The combination of thromboelastometry parameters (EXTEM and FIBTEM CT, CFT, A5, A10, MCF and LI60) and conventional biomarkers (D-dimer, Clauss fibrinogen, and IL-6) might be superior in predicting clinical outcomes such as thrombosis, renal failure and death in patients with COVID-19 than each diagnostic test alone. Therefore, these test combinations can be helpful in the future to decide which therapeutic strategy might be the most appropriate one in critically ill patients with COVID-19. This would be an important step to establish precision medicine not only in thromboelastometry-guided bleeding management but also in this high-risk patient population [15].
Fig. 1. ROTEM graphs and results of Patient A and Patient B. (A) Critically ill Patient A with COVID-19, with a hypercoagulable phenotype. (B) Critically ill Patient B with COVID-19 with a hypocoagulable phenotype. EXTEM: extrinsically activated (tissue factor) thromboelastometric assay, FIBTEM: extrinsically activated thromboelastometric assay with the addition of cytochalasin to eliminate platelet contribution to clot firmness, CT: coagulation time, CFT: clot formation time, alpha: alpha angle, A5: amplitude of clot firmness 5 minutes after CT, A10: amplitude of clot firmness 10 minutes after CT, MCF: maximum clot firmness, LI60: lysis index in percentage of maximum clot firmness 60 minutes after CT, ML: maximum lysis during run time, *Reference range for physiological fibrinolysis in EXTEM as published by Stettler et al. [5].
Conflicts of Interest
Klaus Görlinger is working as the Medical Director of Tem Innovations since July 2012. Robert Kong and Nevil Hutchinson reported no potential conflict of interest relevant to this article.
Author Contributions
Robert Kong (Conceptualization; Investigation; Writing – review & editing)
Nevil Hutchiinson (Conceptualization; Investigation; Writing – review & editing)
Klaus Görlinger (Conceptualization; Writing – original draft) | CEFTRIAXONE, DOXYCYCLINE, NOREPINEPHRINE | DrugsGivenReaction | CC BY-NC | 32773727 | 20,408,037 | 2021-08 |
What was the outcome of reaction 'Condition aggravated'? | Hyper- and hypocoagulability in COVID-19 as assessed by thromboelastometry -two case reports.
Coronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6, and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent.
Here, we describe two critically ill patients with COVID-19 admitted to our intensive care unit demonstrating different thromboelastometry and biomarker patterns. One patient presented with hypercoagulability and the other patient with hypocoagulability and fibrinolysis shutdown in thromboelastometry. The pathophysiology and the potential impact on treatment options are discussed.
A combination of biomarkers and thromboelastometry results can be helpful in the future to decide which therapeutic strategy might be most appropriate for critically ill patients with COVID-19. This would be an important step to establish precision medicine in this high-risk patient population.
Coronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6 (IL-6), and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays [1]. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent [2]. In contrast, sepsis-associated coagulopathy due to bacterial infection is characterized by hypocoagulability in thromboelastometry which has been shown to be a good predictor of increased mortality [3]. Here, we describe two critically ill patients with COVID-19 admitted to our intensive care unit (ICU) at Brighton and Sussex University Hospitals NHS Trust presenting with different thromboelastometry phenotypes, clinical courses, and outcomes.
Case Reports
The NHS Institutional Review Board waived the requirement of informed consent from each patient.
Case 1
A 48-year-old South Asian woman (Patient A) from Bangladesh (height 168 cm, weight 80 kg) was admitted to the medical ward for three days after which she was transferred to the ICU; she had cough and increasing dyspnea for three days before hospital admission. Comorbidities included hypertension, hypercholesterinemia, coronary artery disease, previous stroke (fully recovered), and type 2 diabetes. On admission, her laboratory results were as follows: hemoglobin (Hb): 143 g/L, white blood cells (WBC): 9.0 × 109/L, lymphocytes: 1.4 × 109/L, platelets: 261 × 109/L, international normalized ratio (INR): 1.1, D-dimer: 510 μg/L, fibrinogen plasma concentration: 8.4 g/L, and C-reactive protein (CRP): 52 mg/L. Her chest radiograph showed cardiomegaly and extensive bilateral peripherally predominant ground-glass opacities. Polymerase chain reaction (PCR) result was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and negative for influence/respiratory syncytial virus (RSV). Blood cultures were negative. The patient was treated with nasal oxygen therapy and antibiotics (ceftriaxone and doxycycline, according the hospital’s COVID-19 protocol). Antiviral therapy and dexamethasone were not administered. Later, CRP increased to 137 mg/L on the second day of hospitalization. The patient was transferred to the ICU on the third day because of increased respiratory rate and oxygen requirement. ROTEM performed 2 hours after ICU admission (Fig. 1A) revealed that Patient A was hypercoagulable with the EXTEM assay showing an increased clot firmness with an amplitude of clot firmness 5 minutes after coagulation time (CT) (A5) of 65 mm and a maximum clot firmness (MCF) of 78 mm, indicating hypercoagulability with a high risk of thrombosis [4]. FIBTEM also showed increased clot firmness (A5 41 mm and MCF 50 mm), indicating increased fibrinogen concentration and fibrin polymerization. Furthermore, the EXTEM lysis index 60 minutes after CT (LI60) was 97%, i.e., in the physiologic range (82–97.9%), whereas FIBTEM LI60 was 100% [5]. Treatment consisted of continuation of antibiotics, enoxaparin 40 mg twice a day in view of ROTEM results, and high flow nasal oxygen and intermittent face mask continuous positive airway pressure (CPAP) therapies. The patient did not need intermittent positive pressure ventilation (IPPV) or any vasoactive support. Laboratory results on the second day in the ICU were as follows: Hb: 131 g/L, WBC: 10.8 × 109/L, platelet count: 307 × 109/L, INR: 1.1, activated partial thromboplastin time (APTT) ratio: 1.3, D-dimer: 510 μg/L, and CRP: 196 mg/L. The patient recovered well and was transferred from the ICU to the medical ward after two days in the ICU with a CRP of 73 mg/L and was discharged three days later with a prescription of her usual medication plus enoxaparin 40 mg once daily for 2 weeks. The patient did not show any clinical signs of thrombosis during her hospital stay.
Case 2
A 68-year-old Caucasian man (Patient B) from the United Kingdom (height 177 cm, weight 85 kg) was admitted with cough and a week-long increasing dyspnea, before which he was healthy. His wife and daughter probably had COVID-19 with resolving symptoms, and they were all living in the same house. The patient markedly experienced shortness of breath on the day of admission to the emergency department (ED) and, therefore, called an ambulance. His laboratory results on admission were as follows: Hb: 140 g/L, creatinine: 117 μmol/L, WBC: 8.6 × 109/L, lymphocytes: 0.2 × 109/L, platelet count: 126 × 109/L, INR: 1.4, APTT ratio: 1.3, D-dimer > 20,000 μg/L (i.e., higher than the upper limit of the measurement range), fibrinogen plasma concentration: 6.8 g/L, and CRP: 336 mg/L. His chest radiograph showed dense bilateral mid-zone and right lower zone consolidation. PCR result was positive for SARS-CoV-2 and negative for influenza/RSV. Blood cultures showed coagulase-negative staphylococci. The patient was treated with antibiotics (ceftriaxone and doxycycline, according the hospital’s COVID-19 protocol). Antiviral therapy and dexamethasone were not administered. As the patient was severely hypoxemic in the ED, he was transferred directly to the ICU. Orotracheal intubation and IPPV (positive end-expiratory pressure 15 mmHg) were performed about 3 hours after ICU admission as respiratory effort was not improved by face mask CPAP therapy. Chest radiography repeated after intubation showed bilateral interstitial lung changes similar to the imaging conducted earlier on the same day. Prone position did not improve oxygenation. Laboratory results on the next day were as follows: Hb: 133 g/L, creatinine: 265 μmol/L, WBC: 16.3 × 109/L, platelet count: 56 × 109/L, INR: 1.6, APTT ratio: 1.5, D-dimer: 4,340 μg/L, fibrinogen plasma concentration: 2.9 g/L, and CRP: 478 mg/L. By ROTEM, Patient B presented with hypocoagulability in the EXTEM assay with a prolonged CT of 99 s, clot formation time (CFT) of 253 s, and decreased clot firmness amplitudes (A5, 22 mm and MCF, 48 mm) (Fig. 1B). Furthermore, EXTEM and FIBTEM analyses demonstrated a complete fibrinolysis shutdown [5]. Both hypocoagulability and fibrinolysis shutdown have been shown to be associated with increased mortality in bacterial sepsis [3,6]. The FIBTEM trace was within normal limits which may be owing to impaired fibrin polymerization, given that fibrinogen concentration was elevated. The patient deteriorated within a few hours of ICU admission and died the following day despite invasive ventilation, norepinephrine for hypotension, and renal replacement therapy for acute kidney failure. Patient B did not show any clinical signs of thrombosis during his hospital stay.
Discussion
We have presented two cases that illustrate the additional value of using thromboelastometry to monitor patients with COVID-19. Increased clot firmness in EXTEM and INTEM (amplitude of clot firmness 10 minutes after CT (A10) > 61.5 mm or MCF > 68 mm) assays has been shown to be associated with an increased incidence of thrombosis in adults and neonates undergoing cardiac and non-cardiac surgery [4]. Furthermore, increased clot firmness in the FIBTEM assay (MCF > 25 mm) has been shown to be associated with an increased incidence of thrombosis in patients with cirrhosis and hepatocellular carcinoma as well as in patients with thrombophilic predisposition after liver transplantation [7,8]. Thromboelastometry in Patient A showed hypercoagulability despite upper normal ranged D-dimer levels and a normal INR. Patients with D-dimer > 3,000 µg/L and/or sepsis-induced coagulopathy score ≥ 4 seem to benefit from increased anticoagulation [9]. However, in critically ill patients with COVID-19, the incidence of thrombosis and pulmonary embolism is high despite pharmacological thromboprophylaxis [2].
The case of Patient B demonstrated that not all critically ill patients with COVID-19 present the same thromboelastometric pattern. This might be attributed to ethnic and genetic difference, such as gene polymorphisms, bacterial superinfection, or the phase of the disease. Both hypocoagulability and fibrinolysis shutdown, as presented by Patient B, have been shown to be associated with increased mortality in cases involving bacterial sepsis [3,6]. Furthermore, lymphocytopenia has been shown to be associated with poor outcomes in COVID-19 [10]. Although thrombocytopenia, which is an important determinant of clot firmness, is rare in COVID-19, it is associated with poor outcomes in the patient population [7,11]. Furthermore, the mismatch between FIBTEM MCF (14 mm) and Clauss fibrinogen plasma concentration (6.8 g/L) in Patient B might reflect an acquired factor XIII deficiency, which often occurs in sepsis, cirrhosis, acute renal failure, and malignancies [12]. Unfortunately, factor XIII activity is not available for Patient B, which leaves this interpretation speculative. The rapid deterioration of Patient B with acute renal failure and a fatal outcome is in-line with the data published by Wright et al. [13] showing that patients with the combination of high D-dimer (> 2,600 µg/L, here > 20,000 µg/L) and fibrinolysis shutdown (lysis 30 minutes after maximum amplitude in thrombelastography (TEG LY30) of 0% or ROTEM LI60 of 100%) are associated with the highest incidence of thrombosis (50%) and acute renal failure (80%). Here, increased D-dimers and fibrinolysis shutdown may reflect an imbalance in hemostasis with increased clot formation but impaired fibrinolysis – similar to disseminated intravascular coagulation. It remains to be determined whether fibrinolytic therapy with recombinant tissue plasminogen activator (rtPA) has a therapeutic role in critically ill patients with COVID-19 who cannot be oxygenated adequately despite mechanical ventilation and prone positioning. Notably, extracorporeal membrane oxygenation is associated with very high mortality in patients with COVID-19, particularly in patients with hyperinflammation characterized by high IL-6 levels. Although this might support the use of fibrinolytic therapy with rtPA in these patients, Campello et al. [14] demonstrated that a FIBTEM MCF < 14.5 mm is highly predictive of bleeding complications (such as hemorrhagic stroke) after rtPA. Therefore, hypocoagulability in thromboelastometry, particularly a FIBTEM MCF < 14.5 mm should be considered a contraindication for fibrinolytic therapy in critically ill patients with COVID-19.
Nevertheless, this case report has several limitations. First, no follow-up ROTEM analyses are available for these patients. Accordingly, the presented ROTEM analyses only represent a snapshot of the COVID-19-associated coagulopathy that can be considered as a dynamic process. Here, different thromboelastometric phenotypes may represent different conditions of the patients or different phases of the coagulopathy. Second, the cut-off values for fibrinolysis shutdown established in trauma and bacterial sepsis cases have been used as clear cut-off values for fibrinolysis shutdown in COVID-19-associated coagulopathy have not been established yet. Further studies are needed to characterize COVID-19-associated coagulopathy and its differences from trauma- and sepsis-induced coagulopathy.
These two cases demonstrate that the thromboelastometric phenotype can be different and thromboelastometry can easily distinguish between hyper- and hypocoagulability in critically ill patients with COVID-19. Furthermore, thromboelastometry can identify patients with fibrinolysis shutdown [5,6]. The combination of thromboelastometry parameters (EXTEM and FIBTEM CT, CFT, A5, A10, MCF and LI60) and conventional biomarkers (D-dimer, Clauss fibrinogen, and IL-6) might be superior in predicting clinical outcomes such as thrombosis, renal failure and death in patients with COVID-19 than each diagnostic test alone. Therefore, these test combinations can be helpful in the future to decide which therapeutic strategy might be the most appropriate one in critically ill patients with COVID-19. This would be an important step to establish precision medicine not only in thromboelastometry-guided bleeding management but also in this high-risk patient population [15].
Fig. 1. ROTEM graphs and results of Patient A and Patient B. (A) Critically ill Patient A with COVID-19, with a hypercoagulable phenotype. (B) Critically ill Patient B with COVID-19 with a hypocoagulable phenotype. EXTEM: extrinsically activated (tissue factor) thromboelastometric assay, FIBTEM: extrinsically activated thromboelastometric assay with the addition of cytochalasin to eliminate platelet contribution to clot firmness, CT: coagulation time, CFT: clot formation time, alpha: alpha angle, A5: amplitude of clot firmness 5 minutes after CT, A10: amplitude of clot firmness 10 minutes after CT, MCF: maximum clot firmness, LI60: lysis index in percentage of maximum clot firmness 60 minutes after CT, ML: maximum lysis during run time, *Reference range for physiological fibrinolysis in EXTEM as published by Stettler et al. [5].
Conflicts of Interest
Klaus Görlinger is working as the Medical Director of Tem Innovations since July 2012. Robert Kong and Nevil Hutchinson reported no potential conflict of interest relevant to this article.
Author Contributions
Robert Kong (Conceptualization; Investigation; Writing – review & editing)
Nevil Hutchiinson (Conceptualization; Investigation; Writing – review & editing)
Klaus Görlinger (Conceptualization; Writing – original draft) | Fatal | ReactionOutcome | CC BY-NC | 32773727 | 20,408,037 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal impairment'. | Case reports of hypercalcemia and chronic renal disease due to cosmetic injections of polymethylmethacrylate (PMMA).
Cosmetic injections of fillers are common plastic surgery procedures worldwide. Polymethylmethacrylate (PMMA) is a filler approved only for minimally invasive procedures in facial tissue and is among the most frequently used injectable substances for cosmetic purposes. Injection of a large volume of PMMA may lead to the development of severe hypercalcemia and chronic kidney damage in a probably underestimated frequency. In such cases, hypercalcemia develops due to a granulomatous foreign body reaction with extrarenal production of calcitriol. In the present report, we describe the cases of two patients who received injections of large volumes of PMMA and developed severe hypercalcemia and advanced chronic kidney disease. These reports highlight the importance of adhering to regulations regarding the use of PMMA and properly informing patients of the possibility of complications before undertaking such procedures.
Introduction
Approximately 8.5 million cosmetic procedures using injectable fillers occurred worldwide in 20171. According to the Food and Drug Administration (FDA) regulations, polymethylmethacrylate (PMMA), a semi-permanent dermal filler, is approved only for minimally invasive procedures in facial tissue around the mouth (i.e., nasolabial folds)2. However, an unknown frequency of the off-label cosmetic injection of this filler has been done for decades in much larger amounts in other body parts, including gluteal region and upper and lower limbs. Foreign body granulomas associated with cosmetic injections may occur in up to 1% of the cases and uncommonly may trigger calcitriol-mediated hypercalcemia, even when adequately used3 , 4. Notwithstanding, off-label injection of large volumes of PMMA can lead to the formation of significant foreign body granulomas that uncommonly lead to severe, life-threatening hypercalcemia, chronic kidney disease (CKD), and death5 - 7.
Here we report the cases of two patients that underwent aesthetic procedures with large volumes of PMMA injections who developed severe hypercalcemia and advanced CKD because of such procedures.
Case Reports
Case 1
A 65-year-old female sought medical attention complaining of polyuria, asthenia, and weakness in recent months. She reported recurrent urolithiasis and injections of PMMA in the face, lips, and gluteal grooves five years before. She presented in good general condition, hydrated, afebrile, with normal blood pressure and cardiac frequency. General physical examination was unremarkable and the only finding was the presence of irregular indurations on buttocks and posterior thighs.
Laboratory evaluation showed hypercalcemia (total calcium 13.9 mg/dL, normal range [NR] 8.8 - 10.3 mg/dL), ionized calcium 1.98 mg/dL, NR 1.1 - 1.35 mmol/L) increased serum creatinine (1.7 mg/dL, MDRD estimated glomerular filtration rate [eGFR] 31 mL/min/1.73m2), and increased blood urea nitrogen (45 mg/dL), with normal blood range levels of sodium, potassium, bicarbonate, uric acid, albumin, and phosphorus. Twenty-four-hour urine analysis revealed mild proteinuria (650 mg/24h) and hypercalciuria (350 mg/24h), with normal uricosuria, citraturia, phosphaturia, and oxaluria. Urinalysis presented ++/4 proteinuria, and urine was sterile in culture. Abdominal ultrasound and computerized tomography showed multiple bilateral urolithiasis. Intact PTH (46 pg/mL, NR 15-65 pg/mL) and 25(OH) vitamin D3 (22 ng/mL, NR 20 - 60 ng/mL) levels were within normal ranges while 1-25 (OH)2D3 (84 pg/mL, NR 16.0 - 65.0 pg/mL) was increased. Intravenous saline hydration and prednisone (60 mg QD) were started for the management of hypercalcemia attributed to a granulomatous reaction due to the PMMA implants. A fluorodeoxyglucose positron-emission tomography (FDG-PET) demonstrated diffuse fluorodeoxyglucose uptake in subcutaneous and muscle tissues of the gluteal region and thighs (Figure 1). The surgical consultation ruled out the possibility of removing the PMMA implants. The patient refused therapy with bisphosphonates given the risk of mandibular osteonecrosis.
Figure 1 Fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrating diffuse uptake in subcutaneous and muscle tissues of the gluteal region and thighs.
Hypercalcemia persisted and the renal function deteriorated (serum creatinine of 6.1 mg/dL, MDRD eGFR 6 mL/min/1.73m2). The patient became uremic and underwent intermittent hemodialysis with low dialysate calcium (2.5 mEq/L) for a brief period. At this time she received denosumab with partial response of the serum calcium (10.7 mg/dL) and renal function, both not sustained, leading to denosumab discontinuation. Over the following two years, hypercalcemia persisted and the renal function kept deteriorating, eventually requiring chronic renal replacement therapy with hemodialysis.
Case 2
A 69-year-old female patient was admitted to the hospital complaining of asthenia, malaise, and weight-loss. The patient had no relevant previous medical history and no family history for kidney disorders. She reported having performed injections of PMMA gel on both arms eight months before admission. She presented pale, in good general condition, normal blood pressure, cardiac rate, and temperature. There was no abnormality in physical examination, except for the presence of dense nodules in forearms.
Laboratory findings were anemia, increased serum creatinine (2.6 mg/dL, MDRD eGFR 18 mL/min/1.73m2), normal urinalysis, and absence of proteinuria. Renal ultrasound showed normal-sized kidneys. The attending team suspected of vasculitis and a renal biopsy was performed and a methylprednisolone pulse was initiated. The renal function further declined (creatinine 3.43 mg/dL, MDRD eGFR 13 mL/min/1.73m2) and hypercalcemia (ionized calcium 1.54 mmol/L) was detected. Laboratory work up revealed normal serum protein electrophoresis, ANCA, anti-cardiolipin, lupus anticoagulant, ANA, serum complement levels, anti-DNA, anti-HIV, anti-HCV, and HBsAg. Serum levels of intact PTH were 25.3 pg/mL, 25(OH) vitamin D3 42ng/mL, and 1-25 (OH)2D3 52.3 pg/dL. Biopsy revealed normal glomeruli, tubular degeneration with atrophy, moderate interstitial fibrosis, and discrete arterial intimal hyperplasia, but no vasculitis. Prednisone was tapered to 20 mg QD and kept for management of hypercalcemia secondary to granulomatous reaction due to PMMA implants. Therapy succeeded in lowering calcium (serum ionized calcium 1.2 mmol/L) and improving renal function (serum creatinine 1.3 mg/dL, MDRD eGFR 41 mL/min/1.73m2).
Due to the cosmetic effects, the patient discontinued the steroid treatment returning after four years with a loss of renal function (serum creatinine 2.86 mg/dL, MDRD eGFR 16 mL/min/1.73m2), and hypercalcemia (serum total calcium 11.0 mg/dL). Reintroduction of prednisone led to an improvement in renal function and hypercalcemia. However, the patient persisted with the pattern of poor adherence, with recrudescence of hypercalcemia and worsening chronic kidney disease. The surgical consultation team performed the removal of the larger granulomas of the right forearm but several implants could not be removed and no response in hypercalcemia occurred. Histological examination showed deposits of inorganic globular material in fibro adipose tissue surrounding muscle fasciculi leading to granulomatous foreign body reaction. Currently, the patient is on prednisone (10 mg QD), with controlled serum total calcium (9.7 mg/dL) and receiving conservative treatment for stage IV chronic kidney disease (MDRD eGFR 22 mL/min/1.73m2).
Table 1 summarizes the main clinical and laboratory characteristics of the two cases.
Table 1 Main clinical and laboratory characteristics of patients with hypercalcemia and renal damage that received esthetic injections of polymethylmethacrylate.
Patient Age Gender Symptoms Injection site Serum calcium* Serum creatinine* Treatments Outcome
1 65 Female Polyuria, asthenia, weakness Buttocks 13.9 mg/dL (total) 1.7 mg/dL Steroids, Denozumab CKD stage 5 Hemodialysis
2 69 Female Asthenia, malaise, weight loss Arms 1.54 mmol/L (ionized) 2.6 mg/dL Steroids, surgical removal CKD stage 4
* At presentation
Discussion
In this report, we described two cases of severe hypercalcemia and CKD due to granulomatous reactions to PMMA injections used in aesthetic filling procedures. Although uncommon, granulomatous reactions may occur as a response to the presence of permanent filling materials such as silicones, PMMA, and paraffin. Kozeny and collaborators originally described the occurrence of hypercalcemia with the use of silicone injections8. Later, a case series of four patients called attention to the occurrence of hypercalcemia and CKD in patients that received PMMA in the gluteus and lower limbs5. In one of their cases, a muscle biopsy showed PMMA globules surrounded by a granulomatous inflammatory reaction, describing the pathological process related to hypercalcemia in such cases. More recently, Hindi and collaborators demonstrated the overexpression of CYP27B1 in skeletal muscle lesions of an HIV infected patient that developed a granulomatous reaction five years after injecting PMMA. The enzyme CYP27B1 seems to be highly specific for catalyzing 1α-hydroxylation on a range of endogenously produced vitamin D metabolites and its overexpression supports extra-renal calcitriol production, by activated macrophages, in a foreign body reaction to PMMA, as a mechanism for hypercalcemia9 , 10.
Both patients presented with severe hypercalcemia and loss of renal function detected over the years (case 1) or months (case 2) after an injection of a large volume of PMMA. The described cases, despite similarities in clinical and laboratory presentation, had distinct diagnostic approaches due to initial clinical hypothesis of the attending teams. In the first case, the presence of urolithiasis incited an anticipated evaluation of calcium levels; in the second case, however, this investigation was made in a second moment, after the worsening of kidney function despite treatment for suspected vasculitis. Interestingly, both patients presented with normal, non-suppressed PTH, in spite of very elevated serum calcium, normal levels of 25-hydroxyvitamin D, and increased level of 1,25(OH)2D3 in one case. In our first patient, the hypercalcemia response to corticosteroids and denosumab was not sustained, and the renal function deteriorated. However, partial and transitory recovery of renal function occurred after near normalization of the serum calcium with hemodialysis with low dialysate calcium, suggesting that the renal failure was partially mediated by hypercalcemia-induced arteriolar vasoconstriction(11, 12). The second patient presented a much better response to corticosteroid therapy, however, the steroid-related cosmetic effects led her to a non-adherence behavior and recrudescence of hypercalcemia, which led to a deterioration of the renal function. The reasons why one patient responded to corticosteroid therapy and the other did not are not clear. We can only hypothesize that the amount of PMMA inoculum and perhaps the possibility of partial removal in one of the cases might be involved in the outcome.
Recently, Tachamo and collaborators published a systematic review of 23 cases of patients with hypercalcemia associated with cosmetic injections. Silicone was the most used filler, followed by PMMA. The vast majority of patients were females (cisgender and transgender), the most common body parts for injection were buttocks, breasts, and thighs. In this report, hypercalcemia was discovered on average eight years after the cosmetic procedures. The majority of the patients presented renal failure as a complication of hypercalcemia and two patients died. Elevated calcitriol level was present in two-thirds of the patients and suppression of the PTH occurred in more than 80% of the cases. Recurrence of hypercalcemia occurred in almost half of the patients despite a variety of treatments7.
Our cases share similarities and differences with the main behavior of the cases described by Tachano et al7. Gender, hypercalcemia-related symptoms at onset, and, most importantly, occurrence of significant and permanent loss of renal function were seen as the main similarities. However, our patients were older, presented non-suppressed PTH, and one of them did not have elevated calcitriol levels. Perhaps, the non-suppressed PTH can be at least partially explained by the occurrence of secondary hyperparathyroidism. Normal range calcitriol levels were also found in one-third of the patients in a previous systematic review, therefore, not excluding hypercalcemia related to granulomatous reaction. Reasons why calcitriol levels can be normal in such patients are yet to be understood, but they might be related to baseline 25-hydroxyvitamin D levels7. However, the ultimate reasons for the differences are not possible to uncover at present. Moreover, one must consider that the Tachamo systematic review included patients that received different implants other than PMMA. It is conceivable that these fillers may produce different biological reactions leading to distinct laboratory phenotypes.
Briefly, the mechanism of renal damage is related to severe long-standing hypercalcemia and hypercalciuria, which may lead to the development of interstitial fibrosis and nephrocalcinosis causing CKD. In such patients, the usual clinical presentations are polyuria, nephrolithiasis, type 1 renal tubular acidosis, and renal failure. The intensity and chronicity of the kidney damage are dependent on hypercalcemia severity and duration11 , 13.
In conclusion, we recommend following the regulations regarding the use of PMMA and believe that there is enough evidence to recommend warning patients of the uncommon but noxious complications associated with such procedures. A multidisciplinary collaboration may help uncover the actual frequency and relevant aspects of hypercalcemia and renal damage associated with the use of PMMA fillers. | PREDNISONE | DrugsGivenReaction | CC BY | 32779690 | 19,967,040 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'. | Case reports of hypercalcemia and chronic renal disease due to cosmetic injections of polymethylmethacrylate (PMMA).
Cosmetic injections of fillers are common plastic surgery procedures worldwide. Polymethylmethacrylate (PMMA) is a filler approved only for minimally invasive procedures in facial tissue and is among the most frequently used injectable substances for cosmetic purposes. Injection of a large volume of PMMA may lead to the development of severe hypercalcemia and chronic kidney damage in a probably underestimated frequency. In such cases, hypercalcemia develops due to a granulomatous foreign body reaction with extrarenal production of calcitriol. In the present report, we describe the cases of two patients who received injections of large volumes of PMMA and developed severe hypercalcemia and advanced chronic kidney disease. These reports highlight the importance of adhering to regulations regarding the use of PMMA and properly informing patients of the possibility of complications before undertaking such procedures.
Introduction
Approximately 8.5 million cosmetic procedures using injectable fillers occurred worldwide in 20171. According to the Food and Drug Administration (FDA) regulations, polymethylmethacrylate (PMMA), a semi-permanent dermal filler, is approved only for minimally invasive procedures in facial tissue around the mouth (i.e., nasolabial folds)2. However, an unknown frequency of the off-label cosmetic injection of this filler has been done for decades in much larger amounts in other body parts, including gluteal region and upper and lower limbs. Foreign body granulomas associated with cosmetic injections may occur in up to 1% of the cases and uncommonly may trigger calcitriol-mediated hypercalcemia, even when adequately used3 , 4. Notwithstanding, off-label injection of large volumes of PMMA can lead to the formation of significant foreign body granulomas that uncommonly lead to severe, life-threatening hypercalcemia, chronic kidney disease (CKD), and death5 - 7.
Here we report the cases of two patients that underwent aesthetic procedures with large volumes of PMMA injections who developed severe hypercalcemia and advanced CKD because of such procedures.
Case Reports
Case 1
A 65-year-old female sought medical attention complaining of polyuria, asthenia, and weakness in recent months. She reported recurrent urolithiasis and injections of PMMA in the face, lips, and gluteal grooves five years before. She presented in good general condition, hydrated, afebrile, with normal blood pressure and cardiac frequency. General physical examination was unremarkable and the only finding was the presence of irregular indurations on buttocks and posterior thighs.
Laboratory evaluation showed hypercalcemia (total calcium 13.9 mg/dL, normal range [NR] 8.8 - 10.3 mg/dL), ionized calcium 1.98 mg/dL, NR 1.1 - 1.35 mmol/L) increased serum creatinine (1.7 mg/dL, MDRD estimated glomerular filtration rate [eGFR] 31 mL/min/1.73m2), and increased blood urea nitrogen (45 mg/dL), with normal blood range levels of sodium, potassium, bicarbonate, uric acid, albumin, and phosphorus. Twenty-four-hour urine analysis revealed mild proteinuria (650 mg/24h) and hypercalciuria (350 mg/24h), with normal uricosuria, citraturia, phosphaturia, and oxaluria. Urinalysis presented ++/4 proteinuria, and urine was sterile in culture. Abdominal ultrasound and computerized tomography showed multiple bilateral urolithiasis. Intact PTH (46 pg/mL, NR 15-65 pg/mL) and 25(OH) vitamin D3 (22 ng/mL, NR 20 - 60 ng/mL) levels were within normal ranges while 1-25 (OH)2D3 (84 pg/mL, NR 16.0 - 65.0 pg/mL) was increased. Intravenous saline hydration and prednisone (60 mg QD) were started for the management of hypercalcemia attributed to a granulomatous reaction due to the PMMA implants. A fluorodeoxyglucose positron-emission tomography (FDG-PET) demonstrated diffuse fluorodeoxyglucose uptake in subcutaneous and muscle tissues of the gluteal region and thighs (Figure 1). The surgical consultation ruled out the possibility of removing the PMMA implants. The patient refused therapy with bisphosphonates given the risk of mandibular osteonecrosis.
Figure 1 Fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrating diffuse uptake in subcutaneous and muscle tissues of the gluteal region and thighs.
Hypercalcemia persisted and the renal function deteriorated (serum creatinine of 6.1 mg/dL, MDRD eGFR 6 mL/min/1.73m2). The patient became uremic and underwent intermittent hemodialysis with low dialysate calcium (2.5 mEq/L) for a brief period. At this time she received denosumab with partial response of the serum calcium (10.7 mg/dL) and renal function, both not sustained, leading to denosumab discontinuation. Over the following two years, hypercalcemia persisted and the renal function kept deteriorating, eventually requiring chronic renal replacement therapy with hemodialysis.
Case 2
A 69-year-old female patient was admitted to the hospital complaining of asthenia, malaise, and weight-loss. The patient had no relevant previous medical history and no family history for kidney disorders. She reported having performed injections of PMMA gel on both arms eight months before admission. She presented pale, in good general condition, normal blood pressure, cardiac rate, and temperature. There was no abnormality in physical examination, except for the presence of dense nodules in forearms.
Laboratory findings were anemia, increased serum creatinine (2.6 mg/dL, MDRD eGFR 18 mL/min/1.73m2), normal urinalysis, and absence of proteinuria. Renal ultrasound showed normal-sized kidneys. The attending team suspected of vasculitis and a renal biopsy was performed and a methylprednisolone pulse was initiated. The renal function further declined (creatinine 3.43 mg/dL, MDRD eGFR 13 mL/min/1.73m2) and hypercalcemia (ionized calcium 1.54 mmol/L) was detected. Laboratory work up revealed normal serum protein electrophoresis, ANCA, anti-cardiolipin, lupus anticoagulant, ANA, serum complement levels, anti-DNA, anti-HIV, anti-HCV, and HBsAg. Serum levels of intact PTH were 25.3 pg/mL, 25(OH) vitamin D3 42ng/mL, and 1-25 (OH)2D3 52.3 pg/dL. Biopsy revealed normal glomeruli, tubular degeneration with atrophy, moderate interstitial fibrosis, and discrete arterial intimal hyperplasia, but no vasculitis. Prednisone was tapered to 20 mg QD and kept for management of hypercalcemia secondary to granulomatous reaction due to PMMA implants. Therapy succeeded in lowering calcium (serum ionized calcium 1.2 mmol/L) and improving renal function (serum creatinine 1.3 mg/dL, MDRD eGFR 41 mL/min/1.73m2).
Due to the cosmetic effects, the patient discontinued the steroid treatment returning after four years with a loss of renal function (serum creatinine 2.86 mg/dL, MDRD eGFR 16 mL/min/1.73m2), and hypercalcemia (serum total calcium 11.0 mg/dL). Reintroduction of prednisone led to an improvement in renal function and hypercalcemia. However, the patient persisted with the pattern of poor adherence, with recrudescence of hypercalcemia and worsening chronic kidney disease. The surgical consultation team performed the removal of the larger granulomas of the right forearm but several implants could not be removed and no response in hypercalcemia occurred. Histological examination showed deposits of inorganic globular material in fibro adipose tissue surrounding muscle fasciculi leading to granulomatous foreign body reaction. Currently, the patient is on prednisone (10 mg QD), with controlled serum total calcium (9.7 mg/dL) and receiving conservative treatment for stage IV chronic kidney disease (MDRD eGFR 22 mL/min/1.73m2).
Table 1 summarizes the main clinical and laboratory characteristics of the two cases.
Table 1 Main clinical and laboratory characteristics of patients with hypercalcemia and renal damage that received esthetic injections of polymethylmethacrylate.
Patient Age Gender Symptoms Injection site Serum calcium* Serum creatinine* Treatments Outcome
1 65 Female Polyuria, asthenia, weakness Buttocks 13.9 mg/dL (total) 1.7 mg/dL Steroids, Denozumab CKD stage 5 Hemodialysis
2 69 Female Asthenia, malaise, weight loss Arms 1.54 mmol/L (ionized) 2.6 mg/dL Steroids, surgical removal CKD stage 4
* At presentation
Discussion
In this report, we described two cases of severe hypercalcemia and CKD due to granulomatous reactions to PMMA injections used in aesthetic filling procedures. Although uncommon, granulomatous reactions may occur as a response to the presence of permanent filling materials such as silicones, PMMA, and paraffin. Kozeny and collaborators originally described the occurrence of hypercalcemia with the use of silicone injections8. Later, a case series of four patients called attention to the occurrence of hypercalcemia and CKD in patients that received PMMA in the gluteus and lower limbs5. In one of their cases, a muscle biopsy showed PMMA globules surrounded by a granulomatous inflammatory reaction, describing the pathological process related to hypercalcemia in such cases. More recently, Hindi and collaborators demonstrated the overexpression of CYP27B1 in skeletal muscle lesions of an HIV infected patient that developed a granulomatous reaction five years after injecting PMMA. The enzyme CYP27B1 seems to be highly specific for catalyzing 1α-hydroxylation on a range of endogenously produced vitamin D metabolites and its overexpression supports extra-renal calcitriol production, by activated macrophages, in a foreign body reaction to PMMA, as a mechanism for hypercalcemia9 , 10.
Both patients presented with severe hypercalcemia and loss of renal function detected over the years (case 1) or months (case 2) after an injection of a large volume of PMMA. The described cases, despite similarities in clinical and laboratory presentation, had distinct diagnostic approaches due to initial clinical hypothesis of the attending teams. In the first case, the presence of urolithiasis incited an anticipated evaluation of calcium levels; in the second case, however, this investigation was made in a second moment, after the worsening of kidney function despite treatment for suspected vasculitis. Interestingly, both patients presented with normal, non-suppressed PTH, in spite of very elevated serum calcium, normal levels of 25-hydroxyvitamin D, and increased level of 1,25(OH)2D3 in one case. In our first patient, the hypercalcemia response to corticosteroids and denosumab was not sustained, and the renal function deteriorated. However, partial and transitory recovery of renal function occurred after near normalization of the serum calcium with hemodialysis with low dialysate calcium, suggesting that the renal failure was partially mediated by hypercalcemia-induced arteriolar vasoconstriction(11, 12). The second patient presented a much better response to corticosteroid therapy, however, the steroid-related cosmetic effects led her to a non-adherence behavior and recrudescence of hypercalcemia, which led to a deterioration of the renal function. The reasons why one patient responded to corticosteroid therapy and the other did not are not clear. We can only hypothesize that the amount of PMMA inoculum and perhaps the possibility of partial removal in one of the cases might be involved in the outcome.
Recently, Tachamo and collaborators published a systematic review of 23 cases of patients with hypercalcemia associated with cosmetic injections. Silicone was the most used filler, followed by PMMA. The vast majority of patients were females (cisgender and transgender), the most common body parts for injection were buttocks, breasts, and thighs. In this report, hypercalcemia was discovered on average eight years after the cosmetic procedures. The majority of the patients presented renal failure as a complication of hypercalcemia and two patients died. Elevated calcitriol level was present in two-thirds of the patients and suppression of the PTH occurred in more than 80% of the cases. Recurrence of hypercalcemia occurred in almost half of the patients despite a variety of treatments7.
Our cases share similarities and differences with the main behavior of the cases described by Tachano et al7. Gender, hypercalcemia-related symptoms at onset, and, most importantly, occurrence of significant and permanent loss of renal function were seen as the main similarities. However, our patients were older, presented non-suppressed PTH, and one of them did not have elevated calcitriol levels. Perhaps, the non-suppressed PTH can be at least partially explained by the occurrence of secondary hyperparathyroidism. Normal range calcitriol levels were also found in one-third of the patients in a previous systematic review, therefore, not excluding hypercalcemia related to granulomatous reaction. Reasons why calcitriol levels can be normal in such patients are yet to be understood, but they might be related to baseline 25-hydroxyvitamin D levels7. However, the ultimate reasons for the differences are not possible to uncover at present. Moreover, one must consider that the Tachamo systematic review included patients that received different implants other than PMMA. It is conceivable that these fillers may produce different biological reactions leading to distinct laboratory phenotypes.
Briefly, the mechanism of renal damage is related to severe long-standing hypercalcemia and hypercalciuria, which may lead to the development of interstitial fibrosis and nephrocalcinosis causing CKD. In such patients, the usual clinical presentations are polyuria, nephrolithiasis, type 1 renal tubular acidosis, and renal failure. The intensity and chronicity of the kidney damage are dependent on hypercalcemia severity and duration11 , 13.
In conclusion, we recommend following the regulations regarding the use of PMMA and believe that there is enough evidence to recommend warning patients of the uncommon but noxious complications associated with such procedures. A multidisciplinary collaboration may help uncover the actual frequency and relevant aspects of hypercalcemia and renal damage associated with the use of PMMA fillers. | PREDNISONE | DrugsGivenReaction | CC BY | 32779690 | 19,967,040 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug intolerance'. | Autologous haematopoietic stem cell transplantation for refractory stiff-person syndrome: the UK experience.
Stiff Person Syndrome (SPS) is a rare immune-mediated disabling neurological disorder characterised by muscle spasms and high GAD antibodies. There are only a few case reports of autologous haematopoietic stem cell transplantation (auto-HSCT) as a treatment for SPS.
OBJECTIVE
To describe the UK experience of treating refractory SPS with auto-HSCT.
METHODS
Between 2015 and 2019, 10 patients with SPS were referred to our institution for consideration of auto-HSCT. Eight patients were deemed suitable for autograft and four were treated. Of the treated patients, three had classical SPS and one had the progressive encephalomyelitis with rigidity and myoclonus variant. All patients were significantly disabled and had failed conventional immunosuppressive therapy. Patients were mobilised with Cyclophosphamide (Cy) 2 g/m2 + G-CSF and conditioned with Cy 200 mg/kg + ATG followed by auto-HSCT.
RESULTS
Despite their significantly reduced performance status, all patients tolerated the procedure with no unexpected toxicities. Following autograft, all patients improved symptomatically and stopped all forms of immunosuppressive therapies. Two patients were able to ambulate independently from being wheelchair dependent. One patient's walking distance improved from 300 meters to 5 miles and one patient's ambulation improved from being confined to a wheelchair to be able to walk with a frame. Two patients became seronegative for anti-GAD antibodies and normalised their neurophysiological abnormalities.
CONCLUSIONS
Auto-HSCT is an intensive but well tolerated and effective treatment option for patients with SPS refractory to conventional immunotherapy. Further work is warranted to optimise patient selection and establish the efficacy, long-term safety, and cost-effectiveness of this treatment.
Introduction
Stiff person syndrome (SPS) is a rare autoimmune neurological disorder characterised by progressive axial muscle stiffness, central nervous system hyper-excitability, and stimulus sensitive painful muscle spasms. Needle electromyography (EMG) often shows continuous motor unit activity at rest [1, 2]. The combination of these features represents the classical form of SPS which is associated with antibodies against glutamic acid decarboxylase (anti-GAD) in around 70% of cases [3].
Other variants include focal or segmental SPS (stiff limb or stiff trunk), para-neoplastic SPS and progressive encephalomyelitis with rigidity and myoclonus (PERM), which in addition to the classic symptoms of SPS, manifests with brainstem signs, hyperekplexia, myoclonus, ataxia and dysautonomia. PERM is associated with anti-glycine receptor antibodies and is reported to be more responsive to immunotherapy [4–6]. Stiff Person Spectrum Disorder has recently been suggested as an overarching term to encompass the various clinical presentations of this condition.
The direct pathological role of the anti-GAD and anti-glycine receptors antibodies is uncertain. The immune-mediated pathogenesis of SPS is evidenced by co-existing autoimmune diseases and partial response to treatments such as intravenous immunoglobulin (IVIG), plasmapheresis and other immunosuppressive therapies including rituximab, mycophenolate and azathioprine [4]. Symptomatic improvement can be achieved using agents such as diazepam, dantrolene, gabapentin or baclofen. Nonetheless, SPS remains a significantly disabling condition with over half of patients requiring long term mobility aids [7].
Autologous Haematopoietic Stem Cell Transplantation (auto-HSCT) has been reported as a treatment option in a limited number of SPS patients with promising results [8]. Here we describe the UK’s experience in using auto-HSCT to treat patients with refractory SPS.
Methods
Between 2015 and 2019 ten patients with SPS were referred to our institution, one of three national referral centres in the UK, for consideration of auto-HSCT from different UK and European centres. Patients’ clinical characteristics and outcomes are summarised in Table 1. All patients were assessed in a joint neurology and haematology transplant clinic. Before considering auto-HSCT the following criteria needed to be met: (1) established diagnosis of SPS; (2) significant disability secondary to SPS; (3) failure of at least one form of immunotherapy; and (4) absence of significant co-morbidities that would increase mortality risk associated with auto-HSCT. Funding requests from the NHS were made for UK patients.Table 1 Summary of patients’ demographics, clinical phenotypes, neurophysiological and serological profiles, treatments tried and outcomes of patients with Stiff Person Syndrome (SPS) referred for consideration of auto-HSCT
Patient Age/gender SPS phenotype Co-morbidities EMG/blink reflex Antibodies Immunotherapy tried Disease duration before HSCT Neurological outcome after HSCT
A 36/F Classical SPS None Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
8 years Two years from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG remain positive
B 48/F Classical SPS Pulmonary sarcoidosis
Type 1 diabetes
Peripheral neuropathy
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
4 years One year from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG became negative
C 37/F Classical SPS Type 1 diabetes Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
9 years Nine months from HSCT:
Marked clinical improvement (from walking 300 meters to 5 miles)
No further immunotherapy needed
Anti-GAD and EMG remain positive
D 52/M PERM & Gluten ataxia Pulmonary embolism Blink reflex hyperexcitability GAD 372 U/ml
Glycine positive
Anti-gliadin positive
IVIG
Plasmapheresis
5 years Three years from HSCT:
Partial clinical improvement (wheelchair to frame)
No further immunotherapy needed
Anti-GAD, anti-glycine and anti-gliadin became negative
Blink reflex normalised
E 44/M Classical SPS Type 1 diabetes
Gluten sensitivity
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
Mycophenolate
7 years Not transplanted as condition stable on mycophenolate
F 70/F Classical SPS Type 1 diabetes
Hypothyroidism
Coeliac disease
Bronchiectasis with haemophilus colonisation and lobectomy.
Continuous motor unit activity GAD > 2000 U/ml IVIG (not tolerated)
Azathioprine
Methotrexate
20 years Not transplanted due to co-existing lung disease
G 47/M PERM Recurrent thrombosis of AV fistula. Continuous motor unit activity in paraspinal muscles GAD negative
Glycine negative
IVIG
Plasmapheresis
Azathioprine
Mycophenolate
9 years Not transplanted
Funding declined
H 53/F Classical SPS Type 1 diabetes
Hypothyroidism
Gluten sensitivity
Psoriatic arthropathy
Sacral abscess
Recurrent sebaceous cysts
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml
Anti-TPO 397 U/ml
IVIG 15 years Not transplanted
Funding declined
Later died from pneumonia (autopsy was not done)
I 35/F Classical SPS Deep venous thrombosis
Heparin-induced thrombocytopenia
Continuous motor unit activity GAD > 2000 U/ml IVIG
Plasmapheresis
2 years Not transplanted
Ongoing assessment
J 48/F Classical SPS None Continuous motor unit activity GAD > 2000 U/ml IVIG
Mycophenolate
3 years Not transplanted
Ongoing assessment
PERM Progressive Encephalomyelitis, Rigidity and Myoclonus, Auto-HSCT autologous haematopoietic stem cell transplantation, GAD glutamic acid decarboxylase, EMG electromyography, IVIG intravenous Immunoglobulin
Patients deemed suitable for auto-HSCT underwent detailed assessments including MRI of the brain and spine, nerve conduction studies, needle EMG to assess spontaneous motor unit activity and blink reflex study to assess brainstem hyperexcitability. Autoimmune screening included antinuclear, para-neoplastic, anti-GAD and anti-glycine antibodies as well as immunoglobulins and protein electrophoresis. Gluten sensitivity screening was undertaken including anti-gliadin antibodies, anti-TTG antibodies and anti-endomysial antibodies. This is because there is an overlap between anti-GAD associated disease and gluten sensitivity [9]. Infection screening included HIV, Hepatitis B & C, VZV, CMV, EBV, Toxoplasmosis and VDRL. Other baseline pre-transplant assessments included echocardiogram and pulmonary function tests.
Of the 10 patients referred, one was found to be stable on mycophenolate and was declined transplant (patient E), and another was declined due to significant co-morbidities conferring an unacceptable risk (patient F). Eight patients were deemed suitable for auto-HSCT. Two patients did not proceed to transplant because funding requests were declined by their health authority (patient G and H). Patient H subsequently died from a chest infection. Two patients are currently being assessed (patient I and J).
Four patients proceeded to auto-HSCT (patient A, B, C and D). Patient A, B and C had classical SPS. Patient D had the PERM variant of SPS.
In accordance with current auto-HSCT guidelines [10] patients received a standard regimen, with stem cell mobilisation consisting of cyclophosphamide 2 g/m2 and G-CSF followed by apheresis to achieve a minimum CD34+ stem cell dose of 2 × 106/kg. Auto-HSCT conditioning regimen was cyclophosphamide 200 mg/kg (total dose, given as 50 mg/kg over days − 5 to − 2) with rabbit anti-thymocyte globulin (ATG, Thymoglobulin) total dose 6.0 mg/kg (given over days − 5 to − 2 as 0.5, 1.0, 1.5 and 1.5 mg/kg respectively with methylprednisolone cover) after which autologous peripheral blood stem cells were infused (on day 0). This is a non-myeloablative regimen which is similar to the one used by Dr Burt in Chicago for the treatment of this condition except that rituximab was not included in our regimen [11].
Data related to the duration of hospital stay, engraftment periods and complications of those who proceeded to auto-HSCT are summarised in Table 2. All patients were followed every 6-9 months in a joint neurology and haematology clinic.Table 2 Summary of data relating length of hospital stay, engraftment time and complications of autologous haematopoietic stem cell transplantation (auto-HSCT) in the four patients treated for refractory stiff person syndrome
Patient Age/Gender Complications during priming and harvesting Engraftment time after auto-HSCT (neutrophils > 0.5 × 109/L and platelets > 20 × 109/L) Length of hospital stay for auto-HSCT Required blood products/ transfusions Complications during auto-HSCT Long term sequelae
A 36/F Headache
E.coli UTI
Pain
Neutrophils:
13 days
Platelets:
12 days
26 days Yes Enterococcus UTI
Pulmonary embolism
Mucositis and rectal bleeding
Post-menopausal symptoms
Alive with no complications
B 48/F None Neutrophils:
11 days
Platelets:
never dropped below 50
18 days No ESBL UTI
Transient exacerbation of diabetes due to steroids
Alive with no complications
C 37/F Gram-negative pantoea agglomerans from Hickman line-treated successfully with antibiotics Neutrophils:
14 days
Platelets:
13 days
21 days Yes Febrile neutropenia covered with antibiotics
Transiently deranged LFTs
Transient CMV and EBV viraemia
Alive with no complications
D 52/M None Neutrophils:
11 days
Platelets:
10 days
16 days Yes Coagulase-negative staphylococcus line infection
Transient EBV viraemia
URTI (RSV)
Alive with no complications
Transplanted patients
Patient A
36-year-old female with no past medical history developed lower limbs and para-spinal muscle spasms that progressed over 3 months. Severe muscle spasms leading to arching of her back were triggered by sudden noise or cutaneous touch. Her symptoms continued to progress and she became wheelchair-bound 6 months later.
MRI of the neuroaxis and CSF examination were normal. Anti-GAD antibodies were positive (> 2000 U/ml). She was diagnosed with the classical form of SPS. She responded partially to plasmapheresis at the referring centre but continued to require very frequent treatments and was therefore started on IVIG.
When she was reviewed at our institution, she was severely disabled by her symptoms requiring regular IVIG treatments at a dose of 90 g every 12 days. She was taking regular diazepam at a dose of 30 mg per day and morphine up to 60 mg a day to control pain. On examination, she had brisk reflexes and severe clonus. She was exquisitely touch-sensitive which induced severe prolonged painful muscle spasms. The muscle spasms were severe enough to compromise her breathing and she required intermittent oxygen. EMG showed continuous muscle fibre activity. Blink reflex study was abnormal with marked amplification of the R2 component recorded following test stimulus in keeping with brainstem hyperexcitability (Fig. 2A). Given her extreme stimulus sensitivity, she underwent EEG/EMG polygraphy recording which captured exaggerated startle response to auditory stimuli in keeping with brainstem hyperexcitability (Fig. 1). The rest of her work-up and immunology screen were negative.Fig. 1 EEG/EMG polygraphy recording of patient A with classical stiff-person syndrome capturing exaggerated startle response to an unanticipated auditory stimulus. Low intensity unanticipated auditory stimulus around 50 dB elicited prominent muscle jerks (within 92 ms from stimulus presentation) followed by protracted spasms in multiple muscle groups. Obc orbicularis Oculi, Obr orbicularis oris, Mass massetter, Stern sternocleidomastoid, Trap trapezius, Delt deltoid, UPA upper abdominals, TA tibialis anterior, STAR sensor marking the onset of the unanticipated auditory stimulus
She received auto-HSCT 8 years from the onset of her symptoms. Transplantation proceeded with no unexpected complications apart from routine toxicities (Table 2).
When reviewed 5 months after auto-HSCT, the majority of her neurological symptoms had improved significantly. She was ambulating independently and required no further IVIG but continued to take diazepam. She had mild startle responses. Anti-GAD antibodies remained positive at > 2000 U/ml.
Repeat EMG undertaken a year post-auto-HSCT remained abnormal with continuous motor unit activity. Blink reflex study with short interstimulus intervals was not possible as immediately following the first electrical stimulus protracted contraction of facial muscle tended to emerge. Therefore, no meaningful comparison could be made with the previous study. Overall, the neurophysiological assessment continued to show features in keeping with SPS despite the clinical improvement.
She was reviewed again 2 years following auto-HSCT and was noted to have remained off all immunotherapy and was able to walk independently. She reported occasional muscle spasms affecting her arms and legs and poor exercise tolerance. Neurological examination was normal. She declined repeat neurophysiological assessment. Her anti-GAD antibodies remained positive.
Patient B
Forty-eight-year-old female with a past medical history of type 1 diabetes, diabetic neuropathy and pulmonary sarcoidosis presented with intermittent muscle spasms affecting all four limbs. The spasms progressed gradually causing increasing difficulties with her mobility over a period of 4 years. At that point, she was mostly wheelchair-bound and only able to ambulate indoors with the help of a frame (supplementary electronic material). Painful muscle spasms were triggered by cutaneous touching. Prior to her referral to our institution she had been diagnosed with stiff person syndrome and was started on IVIG which helped her symptoms. However, she was requiring an infusion every 2 weeks. Subsequently, two doses of rituximab were given which improved her symptoms but did not reduce the need for regular IVIG. She was reliant on diazepam and baclofen for symptomatic relief.
When reviewed at our institution she was noted to have intermittent sustained muscle spasms on examination. She also had clinical signs of length-dependent peripheral neuropathy which was confirmed on nerve conduction studies. EMG displayed continuous motor potential activity and blink reflex demonstrated brainstem hyper-excitability with lack of suppression of R2 component following the test stimulus (Fig. 2Bi). Anti-GAD antibodies were positive (> 2000 U/ml) and the rest of her immunology screen was negative. Infection screening prior to auto-HSCT identified hepatitis B core antigen positivity. In the absence of any risk factors, this was thought to be caused by repeated IVIG infusions. Hepatitis B DNA PCR was negative.Fig. 2 Blink reflex excitability studies at the short inter-stimulus interval between a conditioning and a test stimulus after 160 ms. Single square pulse electrical stimulation of the supraorbital nerve on one side is given at 20–25 mA and 0.2 s pulse width. The polysynaptic R2 response which is recorded following a test electrical stimulus from the contralateral side is typically supressed at such small interstimulus interval in healthy subjects. The least affected by artefact, rectified R2 waveform contralateral to the site of stimulation was used for analysis. In both patient A and patient B (classical stiff person syndrome) the contralateral R2 component that follows the test stimulus is enhanced (area estimates for R2 between cursors S1b/S1e and S2b/S2e are shown in the relevant embedded tables). The pre-HSCT study of patient A shows clear enhancement of the R2 response that follows the test stimulus in comparison to the earlier R2 waveform that followed the conditioning stimulus. For patient B, comparison between the pre-HSCT (Bi) and post-HSCT (Bii) examination shows relative normalisation of blink reflex excitability in the latter; the R2 area following the test stimulus is relatively suppressed in comparison to the R2 area of the conditioning stimulus (Bii). This electrophysiological assessment is used as a semiquantitative assessment of brainstem excitability
Auto-HSCT was undertaken at our institution 4 years into her illness and progressed uneventfully (Table 2). Hepatitis B DNA PCR was pre-emptively monitored throughout her immunosuppression and remained negative.
When reviewed in clinic 6 months after auto-HSCT, her muscle spasms were noted to have improved significantly. She required no further doses of IVIG but continued to use a small dose of Baclofen. She was no longer requiring a wheelchair and started walking with the support of a stick. She continued to suffer from fatigue.
Repeat EMG showed significant improvement with the patient being able to completely suppress all motor unit potential activity in muscles that were previously affected by severe stiffness. The blink reflex excitability studies also improved with a more suppressed R2 component following the test stimulus compared to the R2 component from the conditioning stimulus (Fig. 2Bii). She was able to walk 10 meters in 15.2 s with a stick.
Serologically, anti-GAD antibodies reduced from > 2000 to < 0.5 U/ml.
A year after auto-HSCT her marked improvement continued. She was no longer reporting any spasms and was able to walk independently for long distances (Electronic supplementary material). Her diabetes control also improved and she came off all her anti-diabetic treatments. She walked 10 meters in 9 s without assistance or stopping. A repeat EMG at that point showed no evidence of stiff person syndrome. Anti-GAD antibodies remained negative.
Patient C
Thirty-seven-year-old female with a history of type 1 diabetes. She developed progressive painful muscle spasms affecting her core musculature and limbs, which were not controlled despite high doses of diazepam (30 mg/day) and gabapentin (2700 mg/day). Nine years into her symptoms she was able to walk unaided for a maximum of 300 meters. She struggled with social anxiety due to muscle spasms, which progressed to affect her face and jaw.
Prior to her referral for auto-HSCT the patient had received five courses of IVIG, which provided transient benefit. She had three infusions of rituximab, which did not relieve her symptoms. Azathioprine was not tolerated.
Neurological examination showed marked stiffness of her abdominal and para-spinal muscles. EMG showed continued motor activity in the para-spinal muscles. Blink reflex study showed evidence of brainstem hyperexcitability. Anti-GAD antibodies were positive (> 2000 U/ml). The rest of the immunology, paraneoplastic and infective screens were negative. Auto-HSCT was offered 9 years after symptom onset. There were no major complications from auto-HSCT apart from routine toxicities (Table 2).
Nine months after transplantation the patient reported marked improvement of the severity of her muscle spasms and stiffness. She reported mild fatigue but she was able to walk for up to 5 miles a day. She continued to use diazepam and gabapentin albeit at much lower doses (10 mg of Diazepam/day and 500 mg of Gabapentin/day). Blink reflex study did not show evidence of brainstem hyperexcitability however, limited lumbar paraspinals EMG (patient was needle phobic) showed continued motor potentials. Anti-GAD antibodies remained positive after transplantation.
Patient D
52-year-old male with no significant past medical history presented with progressive asymmetrical muscle stiffness affecting initially the right leg but subsequently other parts of his body. The stiffness progressed over 5 years to involve all four limbs, which significantly impaired his ability to carry out the activities of daily living. Facial muscles involvement interfered with speech and swallowing and he occasionally bit his tongue.
Examination revealed marked muscle rigidity, brisk reflexes and clonus. MRI of the spine showed moderate spondylosis which did not account for the patient’s symptoms. Serological testing for gluten sensitivity revealed positive anti-gliadin antibodies and a gluten-free diet was adopted. MRI of the brain showed mild atrophy of the cerebellar hemispheres. MRI spectroscopy demonstrated low NAA/Creatine ratio of 0.85 from the superior vermis (normal over 1.00) (Fig. 3). CSF examination was normal.Fig. 3 MRI spectroscopy of 52-year-old male with stiff person synonym (PERM - patient D) who underwent autologous haematopoietic stem cell transplantation (auto-HSCT). The MRI demonstrate cerebellar involvement showing NAA/creatine ratio of 0.85 from the superior vermis (normal above 1.00) before auto-HSCT which improved to 0.93 after auto-HSCT
Nerve conduction studies were normal. EMG did not show continuous motor unit activity however, blink reflex studies showed evidence of hyper-excitability. Anti-GAD antibodies were positive at 372 U/ml. Anti-glycine antibodies were positive. Paraneoplastic, anti-NMDA and anti-VGKC antibodies were negative.
He was diagnosed with the PERM variant of SPS on the basis of the clinical features and the serology results. He was started on IVIG which resulted in partial clinical improvement. However, he continued to require infusions at a dose of 150 g every 3 months. He could not tolerate Diazepam, Baclofen, Tizanidine or Dantrolene. He did not tolerate mycophenolate which he tried for 2 months. Over the subsequent years, he became wheelchair-bound and dependent on IVIG which he continued for a year.
Auto-HSCT was offered 5 years after symptom onset. While he was being considered for auto-HSCT he developed deep vein thrombosis and a large saddle pulmonary embolism thought to be related to poor mobility and regular IVIGs. He was started on rivaroxaban. Auto-HSCT proceeded uneventfully apart from routine toxicities (Table 2).
Four months after auto-HSCT, his mobility improved from wheelchair to a frame. His legs remained stiff but arms improved significantly so he was able to feed and wash himself. Anti-GAD and anti-glycine antibodies became negative. Repeat blink reflex study post-transplantation showed no evidence of hyperexcitability. He was no longer requiring regular IVIG. His speech remained dysarthric but his swallowing normalised. He was no longer biting his tongue. He stopped all regular medications.
Two years after auto-HSCT he remained off IVIG and had good use of his upper limbs but continued to use a walking frame. EMG and blink reflex studies remained normal and anti-GAD was negative. MRI spectroscopy of the cerebellum showed improvement of his NAA/creatine ratio (Fig. 3).
Discussion
We report our experience in using auto-HSCT to treat four patients with refractory SPS.
All four patients experienced marked improvement in their symptoms and mobility following treatment. In spite of clinical improvement, patient A and C (classical SPS) continued to have high circulating anti-GAD antibody titre. EMG and blink reflex excitability assessment remained abnormal in patient A but normalised in patient C. On the other hand, patient B (classical SPS) and patient D (PERM) became seronegative for circulating antibodies and their EMG and blink reflex studies normalised. Furthermore, MRI spectroscopy values in patient D improved following treatment.
Significantly, with respect to both clinical impact and health resource utilisation all our patients stopped regular IVIG and other forms of immunotherapy with sustained symptomatic and clinical improvement.
The response to auto-HSCT confirms the autoimmune basis of SPS. Continued seropositivity for anti-GAD in half of our patients is comparable to the previous two case reports of using auto-HSCT to treat SPS [8].
The role of anti-GAD in the pathogenesis of SPS remains uncertain. GAD is the rate-limiting step in the decarboxylation of L-glutamate to γ-aminobutyric acid (GABA). Thus, anti-GAD antibodies are postulated to lead to decreased levels of GABA in the brainstem and spinal cord resulting in dis-inhibition and hyper-excitability [12]. However, several observations question anti-GAD pathogenicity in SPS. These include lack of correlation of antibody titres and disease severity [13], absence of anti-GAD antibodies in some SPS patients [14] and reports of clinical improvement with ongoing high circulating antibodies [8].
Interestingly patient B who became anti-GAD negative after auto-HSCT also reported improvement of her diabetic control. Thus, anti-GAD may support the diagnosis of SPS and other autoimmune dysfunction but does not fully explain the pathophysiology.
Glycine receptors are inhibitory receptors found on the neuronal cell surface predominantly in the brainstem and spinal cord. They exert their effects through chloride current resulting in membrane hyperpolarisation and reduction in excitation [15]. Antibodies against the alpha-1 subunit of glycine receptors are, therefore, associated with hyperexcitability. Null mutations in glycine receptors result in hereditary hyperekplexia characterised by an excessive startle and often muscle rigidity [16].
When anti-glycine receptor antibodies are present, they are typically associated with the PERM variant of SPS [5]. However, anti-glycine receptors antibodies are also found in around 15% of patient with classical SPS patients with uncertain significance [17]. Furthermore, glycine receptor antibodies have been reported to occur in other autoimmune conditions with heterogeneous phenotypes including ataxia, limbic encephalitis and myoclonic epilepsy [16].
The pathogenic roles of B cell and T cell immunity in SPS are similarly not well defined. Intrathecal production of oligoclonal anti-GAD IgG antibodies is continued by active B cells with the help of T cells that are activated by neural antigens [18]. Thus, immuno-ablative therapy to eliminate the dysfunctional immune response is expected to offer benefit. Immuno-ablative chemotherapy is followed by the re-introduction of autologous stem cell graft aiming to restart a new self-tolerant immune system. The CSF was not assayed for the presence of anti-GAD antibodies in our patients, but this should be considered in future studies to assess whether this parameter would correlate with treatment response.
At the time of writing of this case series all our transplanted patients manifested sustained clinical improvement without the need for any form of immunotherapy. Follow-up post-transplant has ranged from 12 months to 3 years. No patient encountered major or unexpected complications. Longer-term benefit of auto-HSCT in SPS remains to be ascertained.
Autologous HSCT has shown promise as a treatment option for a range of treatment-refractory autoimmune neurological conditions such as multiple sclerosis, neuromyelitis optica, myasthenia gravis and chronic inflammatory demyelinating polyneuropathy [10, 19]. Our experience further supports its use for refractory stiff-person syndrome. Auto-HSCT may prove to be a more cost-effective treatment in patients requiring regular treatment with expensive modalities, such as IVIG. Further work is warranted to establish long-term safety, efficacy and cost-effectiveness of auto-HSCT in SPS, along with optimising patient selection and transplant technique. This calls for collaboration between centres that provide this service.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary material 1 (MP4 82628 kb)
Supplementary material 2 (MP4 5421 kb)
Acknowledgements
We acknowledge the support of the NIHR Sheffield biomedical research centre and clinical trial unit.
Author contributions
LKI assessed patients, collected data, drafted and revised the first manuscript. AT assessed patients, collected data and revised the manuscript. JS, MH, BS assessed patients, supervised and delivered treatment, conceived the report and revised the manuscript. HJ delivered treatment, coordinated assessments, revised the manuscript. PS conducted neurophysiological assessment, provided neurophysiology figures and revised the manuscript. AC assessed patients, supervised and delivered treatment and revised the manuscript.
Funding
Individual funding requests were made from the NHS for UK patients.
Availability of data and material
Available.
Compliance with ethical standards
Conflicts of interest
Lewis Kass-Iliyya declares no conflict of interest. John A Snowden declares speaker fees from Jazz, Gilead, Mallinckrodt and Janssen. Alice Thorpe declares no conflict of interest. Helen Jessop declares no conflict of interest. Andrew D Chantry declares no conflict of interest. Ptolemaios Sarrigiannis declares no conflict of interest. Marios Hadjivassiliou declares no conflict of interest. Basil Sharrack declares no conflict of interest.
Ethical statement
The manuscript does not contain clinical studies. The patient whose videos are included in the electronic supplementary material gave their consent for the videos to be used in this publication. | IMMUNE GLOBULIN NOS, MYCOPHENOLATE MOFETIL | DrugsGivenReaction | CC BY | 32785838 | 19,728,152 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatitis B core antigen positive'. | Autologous haematopoietic stem cell transplantation for refractory stiff-person syndrome: the UK experience.
Stiff Person Syndrome (SPS) is a rare immune-mediated disabling neurological disorder characterised by muscle spasms and high GAD antibodies. There are only a few case reports of autologous haematopoietic stem cell transplantation (auto-HSCT) as a treatment for SPS.
OBJECTIVE
To describe the UK experience of treating refractory SPS with auto-HSCT.
METHODS
Between 2015 and 2019, 10 patients with SPS were referred to our institution for consideration of auto-HSCT. Eight patients were deemed suitable for autograft and four were treated. Of the treated patients, three had classical SPS and one had the progressive encephalomyelitis with rigidity and myoclonus variant. All patients were significantly disabled and had failed conventional immunosuppressive therapy. Patients were mobilised with Cyclophosphamide (Cy) 2 g/m2 + G-CSF and conditioned with Cy 200 mg/kg + ATG followed by auto-HSCT.
RESULTS
Despite their significantly reduced performance status, all patients tolerated the procedure with no unexpected toxicities. Following autograft, all patients improved symptomatically and stopped all forms of immunosuppressive therapies. Two patients were able to ambulate independently from being wheelchair dependent. One patient's walking distance improved from 300 meters to 5 miles and one patient's ambulation improved from being confined to a wheelchair to be able to walk with a frame. Two patients became seronegative for anti-GAD antibodies and normalised their neurophysiological abnormalities.
CONCLUSIONS
Auto-HSCT is an intensive but well tolerated and effective treatment option for patients with SPS refractory to conventional immunotherapy. Further work is warranted to optimise patient selection and establish the efficacy, long-term safety, and cost-effectiveness of this treatment.
Introduction
Stiff person syndrome (SPS) is a rare autoimmune neurological disorder characterised by progressive axial muscle stiffness, central nervous system hyper-excitability, and stimulus sensitive painful muscle spasms. Needle electromyography (EMG) often shows continuous motor unit activity at rest [1, 2]. The combination of these features represents the classical form of SPS which is associated with antibodies against glutamic acid decarboxylase (anti-GAD) in around 70% of cases [3].
Other variants include focal or segmental SPS (stiff limb or stiff trunk), para-neoplastic SPS and progressive encephalomyelitis with rigidity and myoclonus (PERM), which in addition to the classic symptoms of SPS, manifests with brainstem signs, hyperekplexia, myoclonus, ataxia and dysautonomia. PERM is associated with anti-glycine receptor antibodies and is reported to be more responsive to immunotherapy [4–6]. Stiff Person Spectrum Disorder has recently been suggested as an overarching term to encompass the various clinical presentations of this condition.
The direct pathological role of the anti-GAD and anti-glycine receptors antibodies is uncertain. The immune-mediated pathogenesis of SPS is evidenced by co-existing autoimmune diseases and partial response to treatments such as intravenous immunoglobulin (IVIG), plasmapheresis and other immunosuppressive therapies including rituximab, mycophenolate and azathioprine [4]. Symptomatic improvement can be achieved using agents such as diazepam, dantrolene, gabapentin or baclofen. Nonetheless, SPS remains a significantly disabling condition with over half of patients requiring long term mobility aids [7].
Autologous Haematopoietic Stem Cell Transplantation (auto-HSCT) has been reported as a treatment option in a limited number of SPS patients with promising results [8]. Here we describe the UK’s experience in using auto-HSCT to treat patients with refractory SPS.
Methods
Between 2015 and 2019 ten patients with SPS were referred to our institution, one of three national referral centres in the UK, for consideration of auto-HSCT from different UK and European centres. Patients’ clinical characteristics and outcomes are summarised in Table 1. All patients were assessed in a joint neurology and haematology transplant clinic. Before considering auto-HSCT the following criteria needed to be met: (1) established diagnosis of SPS; (2) significant disability secondary to SPS; (3) failure of at least one form of immunotherapy; and (4) absence of significant co-morbidities that would increase mortality risk associated with auto-HSCT. Funding requests from the NHS were made for UK patients.Table 1 Summary of patients’ demographics, clinical phenotypes, neurophysiological and serological profiles, treatments tried and outcomes of patients with Stiff Person Syndrome (SPS) referred for consideration of auto-HSCT
Patient Age/gender SPS phenotype Co-morbidities EMG/blink reflex Antibodies Immunotherapy tried Disease duration before HSCT Neurological outcome after HSCT
A 36/F Classical SPS None Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
8 years Two years from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG remain positive
B 48/F Classical SPS Pulmonary sarcoidosis
Type 1 diabetes
Peripheral neuropathy
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
4 years One year from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG became negative
C 37/F Classical SPS Type 1 diabetes Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
9 years Nine months from HSCT:
Marked clinical improvement (from walking 300 meters to 5 miles)
No further immunotherapy needed
Anti-GAD and EMG remain positive
D 52/M PERM & Gluten ataxia Pulmonary embolism Blink reflex hyperexcitability GAD 372 U/ml
Glycine positive
Anti-gliadin positive
IVIG
Plasmapheresis
5 years Three years from HSCT:
Partial clinical improvement (wheelchair to frame)
No further immunotherapy needed
Anti-GAD, anti-glycine and anti-gliadin became negative
Blink reflex normalised
E 44/M Classical SPS Type 1 diabetes
Gluten sensitivity
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
Mycophenolate
7 years Not transplanted as condition stable on mycophenolate
F 70/F Classical SPS Type 1 diabetes
Hypothyroidism
Coeliac disease
Bronchiectasis with haemophilus colonisation and lobectomy.
Continuous motor unit activity GAD > 2000 U/ml IVIG (not tolerated)
Azathioprine
Methotrexate
20 years Not transplanted due to co-existing lung disease
G 47/M PERM Recurrent thrombosis of AV fistula. Continuous motor unit activity in paraspinal muscles GAD negative
Glycine negative
IVIG
Plasmapheresis
Azathioprine
Mycophenolate
9 years Not transplanted
Funding declined
H 53/F Classical SPS Type 1 diabetes
Hypothyroidism
Gluten sensitivity
Psoriatic arthropathy
Sacral abscess
Recurrent sebaceous cysts
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml
Anti-TPO 397 U/ml
IVIG 15 years Not transplanted
Funding declined
Later died from pneumonia (autopsy was not done)
I 35/F Classical SPS Deep venous thrombosis
Heparin-induced thrombocytopenia
Continuous motor unit activity GAD > 2000 U/ml IVIG
Plasmapheresis
2 years Not transplanted
Ongoing assessment
J 48/F Classical SPS None Continuous motor unit activity GAD > 2000 U/ml IVIG
Mycophenolate
3 years Not transplanted
Ongoing assessment
PERM Progressive Encephalomyelitis, Rigidity and Myoclonus, Auto-HSCT autologous haematopoietic stem cell transplantation, GAD glutamic acid decarboxylase, EMG electromyography, IVIG intravenous Immunoglobulin
Patients deemed suitable for auto-HSCT underwent detailed assessments including MRI of the brain and spine, nerve conduction studies, needle EMG to assess spontaneous motor unit activity and blink reflex study to assess brainstem hyperexcitability. Autoimmune screening included antinuclear, para-neoplastic, anti-GAD and anti-glycine antibodies as well as immunoglobulins and protein electrophoresis. Gluten sensitivity screening was undertaken including anti-gliadin antibodies, anti-TTG antibodies and anti-endomysial antibodies. This is because there is an overlap between anti-GAD associated disease and gluten sensitivity [9]. Infection screening included HIV, Hepatitis B & C, VZV, CMV, EBV, Toxoplasmosis and VDRL. Other baseline pre-transplant assessments included echocardiogram and pulmonary function tests.
Of the 10 patients referred, one was found to be stable on mycophenolate and was declined transplant (patient E), and another was declined due to significant co-morbidities conferring an unacceptable risk (patient F). Eight patients were deemed suitable for auto-HSCT. Two patients did not proceed to transplant because funding requests were declined by their health authority (patient G and H). Patient H subsequently died from a chest infection. Two patients are currently being assessed (patient I and J).
Four patients proceeded to auto-HSCT (patient A, B, C and D). Patient A, B and C had classical SPS. Patient D had the PERM variant of SPS.
In accordance with current auto-HSCT guidelines [10] patients received a standard regimen, with stem cell mobilisation consisting of cyclophosphamide 2 g/m2 and G-CSF followed by apheresis to achieve a minimum CD34+ stem cell dose of 2 × 106/kg. Auto-HSCT conditioning regimen was cyclophosphamide 200 mg/kg (total dose, given as 50 mg/kg over days − 5 to − 2) with rabbit anti-thymocyte globulin (ATG, Thymoglobulin) total dose 6.0 mg/kg (given over days − 5 to − 2 as 0.5, 1.0, 1.5 and 1.5 mg/kg respectively with methylprednisolone cover) after which autologous peripheral blood stem cells were infused (on day 0). This is a non-myeloablative regimen which is similar to the one used by Dr Burt in Chicago for the treatment of this condition except that rituximab was not included in our regimen [11].
Data related to the duration of hospital stay, engraftment periods and complications of those who proceeded to auto-HSCT are summarised in Table 2. All patients were followed every 6-9 months in a joint neurology and haematology clinic.Table 2 Summary of data relating length of hospital stay, engraftment time and complications of autologous haematopoietic stem cell transplantation (auto-HSCT) in the four patients treated for refractory stiff person syndrome
Patient Age/Gender Complications during priming and harvesting Engraftment time after auto-HSCT (neutrophils > 0.5 × 109/L and platelets > 20 × 109/L) Length of hospital stay for auto-HSCT Required blood products/ transfusions Complications during auto-HSCT Long term sequelae
A 36/F Headache
E.coli UTI
Pain
Neutrophils:
13 days
Platelets:
12 days
26 days Yes Enterococcus UTI
Pulmonary embolism
Mucositis and rectal bleeding
Post-menopausal symptoms
Alive with no complications
B 48/F None Neutrophils:
11 days
Platelets:
never dropped below 50
18 days No ESBL UTI
Transient exacerbation of diabetes due to steroids
Alive with no complications
C 37/F Gram-negative pantoea agglomerans from Hickman line-treated successfully with antibiotics Neutrophils:
14 days
Platelets:
13 days
21 days Yes Febrile neutropenia covered with antibiotics
Transiently deranged LFTs
Transient CMV and EBV viraemia
Alive with no complications
D 52/M None Neutrophils:
11 days
Platelets:
10 days
16 days Yes Coagulase-negative staphylococcus line infection
Transient EBV viraemia
URTI (RSV)
Alive with no complications
Transplanted patients
Patient A
36-year-old female with no past medical history developed lower limbs and para-spinal muscle spasms that progressed over 3 months. Severe muscle spasms leading to arching of her back were triggered by sudden noise or cutaneous touch. Her symptoms continued to progress and she became wheelchair-bound 6 months later.
MRI of the neuroaxis and CSF examination were normal. Anti-GAD antibodies were positive (> 2000 U/ml). She was diagnosed with the classical form of SPS. She responded partially to plasmapheresis at the referring centre but continued to require very frequent treatments and was therefore started on IVIG.
When she was reviewed at our institution, she was severely disabled by her symptoms requiring regular IVIG treatments at a dose of 90 g every 12 days. She was taking regular diazepam at a dose of 30 mg per day and morphine up to 60 mg a day to control pain. On examination, she had brisk reflexes and severe clonus. She was exquisitely touch-sensitive which induced severe prolonged painful muscle spasms. The muscle spasms were severe enough to compromise her breathing and she required intermittent oxygen. EMG showed continuous muscle fibre activity. Blink reflex study was abnormal with marked amplification of the R2 component recorded following test stimulus in keeping with brainstem hyperexcitability (Fig. 2A). Given her extreme stimulus sensitivity, she underwent EEG/EMG polygraphy recording which captured exaggerated startle response to auditory stimuli in keeping with brainstem hyperexcitability (Fig. 1). The rest of her work-up and immunology screen were negative.Fig. 1 EEG/EMG polygraphy recording of patient A with classical stiff-person syndrome capturing exaggerated startle response to an unanticipated auditory stimulus. Low intensity unanticipated auditory stimulus around 50 dB elicited prominent muscle jerks (within 92 ms from stimulus presentation) followed by protracted spasms in multiple muscle groups. Obc orbicularis Oculi, Obr orbicularis oris, Mass massetter, Stern sternocleidomastoid, Trap trapezius, Delt deltoid, UPA upper abdominals, TA tibialis anterior, STAR sensor marking the onset of the unanticipated auditory stimulus
She received auto-HSCT 8 years from the onset of her symptoms. Transplantation proceeded with no unexpected complications apart from routine toxicities (Table 2).
When reviewed 5 months after auto-HSCT, the majority of her neurological symptoms had improved significantly. She was ambulating independently and required no further IVIG but continued to take diazepam. She had mild startle responses. Anti-GAD antibodies remained positive at > 2000 U/ml.
Repeat EMG undertaken a year post-auto-HSCT remained abnormal with continuous motor unit activity. Blink reflex study with short interstimulus intervals was not possible as immediately following the first electrical stimulus protracted contraction of facial muscle tended to emerge. Therefore, no meaningful comparison could be made with the previous study. Overall, the neurophysiological assessment continued to show features in keeping with SPS despite the clinical improvement.
She was reviewed again 2 years following auto-HSCT and was noted to have remained off all immunotherapy and was able to walk independently. She reported occasional muscle spasms affecting her arms and legs and poor exercise tolerance. Neurological examination was normal. She declined repeat neurophysiological assessment. Her anti-GAD antibodies remained positive.
Patient B
Forty-eight-year-old female with a past medical history of type 1 diabetes, diabetic neuropathy and pulmonary sarcoidosis presented with intermittent muscle spasms affecting all four limbs. The spasms progressed gradually causing increasing difficulties with her mobility over a period of 4 years. At that point, she was mostly wheelchair-bound and only able to ambulate indoors with the help of a frame (supplementary electronic material). Painful muscle spasms were triggered by cutaneous touching. Prior to her referral to our institution she had been diagnosed with stiff person syndrome and was started on IVIG which helped her symptoms. However, she was requiring an infusion every 2 weeks. Subsequently, two doses of rituximab were given which improved her symptoms but did not reduce the need for regular IVIG. She was reliant on diazepam and baclofen for symptomatic relief.
When reviewed at our institution she was noted to have intermittent sustained muscle spasms on examination. She also had clinical signs of length-dependent peripheral neuropathy which was confirmed on nerve conduction studies. EMG displayed continuous motor potential activity and blink reflex demonstrated brainstem hyper-excitability with lack of suppression of R2 component following the test stimulus (Fig. 2Bi). Anti-GAD antibodies were positive (> 2000 U/ml) and the rest of her immunology screen was negative. Infection screening prior to auto-HSCT identified hepatitis B core antigen positivity. In the absence of any risk factors, this was thought to be caused by repeated IVIG infusions. Hepatitis B DNA PCR was negative.Fig. 2 Blink reflex excitability studies at the short inter-stimulus interval between a conditioning and a test stimulus after 160 ms. Single square pulse electrical stimulation of the supraorbital nerve on one side is given at 20–25 mA and 0.2 s pulse width. The polysynaptic R2 response which is recorded following a test electrical stimulus from the contralateral side is typically supressed at such small interstimulus interval in healthy subjects. The least affected by artefact, rectified R2 waveform contralateral to the site of stimulation was used for analysis. In both patient A and patient B (classical stiff person syndrome) the contralateral R2 component that follows the test stimulus is enhanced (area estimates for R2 between cursors S1b/S1e and S2b/S2e are shown in the relevant embedded tables). The pre-HSCT study of patient A shows clear enhancement of the R2 response that follows the test stimulus in comparison to the earlier R2 waveform that followed the conditioning stimulus. For patient B, comparison between the pre-HSCT (Bi) and post-HSCT (Bii) examination shows relative normalisation of blink reflex excitability in the latter; the R2 area following the test stimulus is relatively suppressed in comparison to the R2 area of the conditioning stimulus (Bii). This electrophysiological assessment is used as a semiquantitative assessment of brainstem excitability
Auto-HSCT was undertaken at our institution 4 years into her illness and progressed uneventfully (Table 2). Hepatitis B DNA PCR was pre-emptively monitored throughout her immunosuppression and remained negative.
When reviewed in clinic 6 months after auto-HSCT, her muscle spasms were noted to have improved significantly. She required no further doses of IVIG but continued to use a small dose of Baclofen. She was no longer requiring a wheelchair and started walking with the support of a stick. She continued to suffer from fatigue.
Repeat EMG showed significant improvement with the patient being able to completely suppress all motor unit potential activity in muscles that were previously affected by severe stiffness. The blink reflex excitability studies also improved with a more suppressed R2 component following the test stimulus compared to the R2 component from the conditioning stimulus (Fig. 2Bii). She was able to walk 10 meters in 15.2 s with a stick.
Serologically, anti-GAD antibodies reduced from > 2000 to < 0.5 U/ml.
A year after auto-HSCT her marked improvement continued. She was no longer reporting any spasms and was able to walk independently for long distances (Electronic supplementary material). Her diabetes control also improved and she came off all her anti-diabetic treatments. She walked 10 meters in 9 s without assistance or stopping. A repeat EMG at that point showed no evidence of stiff person syndrome. Anti-GAD antibodies remained negative.
Patient C
Thirty-seven-year-old female with a history of type 1 diabetes. She developed progressive painful muscle spasms affecting her core musculature and limbs, which were not controlled despite high doses of diazepam (30 mg/day) and gabapentin (2700 mg/day). Nine years into her symptoms she was able to walk unaided for a maximum of 300 meters. She struggled with social anxiety due to muscle spasms, which progressed to affect her face and jaw.
Prior to her referral for auto-HSCT the patient had received five courses of IVIG, which provided transient benefit. She had three infusions of rituximab, which did not relieve her symptoms. Azathioprine was not tolerated.
Neurological examination showed marked stiffness of her abdominal and para-spinal muscles. EMG showed continued motor activity in the para-spinal muscles. Blink reflex study showed evidence of brainstem hyperexcitability. Anti-GAD antibodies were positive (> 2000 U/ml). The rest of the immunology, paraneoplastic and infective screens were negative. Auto-HSCT was offered 9 years after symptom onset. There were no major complications from auto-HSCT apart from routine toxicities (Table 2).
Nine months after transplantation the patient reported marked improvement of the severity of her muscle spasms and stiffness. She reported mild fatigue but she was able to walk for up to 5 miles a day. She continued to use diazepam and gabapentin albeit at much lower doses (10 mg of Diazepam/day and 500 mg of Gabapentin/day). Blink reflex study did not show evidence of brainstem hyperexcitability however, limited lumbar paraspinals EMG (patient was needle phobic) showed continued motor potentials. Anti-GAD antibodies remained positive after transplantation.
Patient D
52-year-old male with no significant past medical history presented with progressive asymmetrical muscle stiffness affecting initially the right leg but subsequently other parts of his body. The stiffness progressed over 5 years to involve all four limbs, which significantly impaired his ability to carry out the activities of daily living. Facial muscles involvement interfered with speech and swallowing and he occasionally bit his tongue.
Examination revealed marked muscle rigidity, brisk reflexes and clonus. MRI of the spine showed moderate spondylosis which did not account for the patient’s symptoms. Serological testing for gluten sensitivity revealed positive anti-gliadin antibodies and a gluten-free diet was adopted. MRI of the brain showed mild atrophy of the cerebellar hemispheres. MRI spectroscopy demonstrated low NAA/Creatine ratio of 0.85 from the superior vermis (normal over 1.00) (Fig. 3). CSF examination was normal.Fig. 3 MRI spectroscopy of 52-year-old male with stiff person synonym (PERM - patient D) who underwent autologous haematopoietic stem cell transplantation (auto-HSCT). The MRI demonstrate cerebellar involvement showing NAA/creatine ratio of 0.85 from the superior vermis (normal above 1.00) before auto-HSCT which improved to 0.93 after auto-HSCT
Nerve conduction studies were normal. EMG did not show continuous motor unit activity however, blink reflex studies showed evidence of hyper-excitability. Anti-GAD antibodies were positive at 372 U/ml. Anti-glycine antibodies were positive. Paraneoplastic, anti-NMDA and anti-VGKC antibodies were negative.
He was diagnosed with the PERM variant of SPS on the basis of the clinical features and the serology results. He was started on IVIG which resulted in partial clinical improvement. However, he continued to require infusions at a dose of 150 g every 3 months. He could not tolerate Diazepam, Baclofen, Tizanidine or Dantrolene. He did not tolerate mycophenolate which he tried for 2 months. Over the subsequent years, he became wheelchair-bound and dependent on IVIG which he continued for a year.
Auto-HSCT was offered 5 years after symptom onset. While he was being considered for auto-HSCT he developed deep vein thrombosis and a large saddle pulmonary embolism thought to be related to poor mobility and regular IVIGs. He was started on rivaroxaban. Auto-HSCT proceeded uneventfully apart from routine toxicities (Table 2).
Four months after auto-HSCT, his mobility improved from wheelchair to a frame. His legs remained stiff but arms improved significantly so he was able to feed and wash himself. Anti-GAD and anti-glycine antibodies became negative. Repeat blink reflex study post-transplantation showed no evidence of hyperexcitability. He was no longer requiring regular IVIG. His speech remained dysarthric but his swallowing normalised. He was no longer biting his tongue. He stopped all regular medications.
Two years after auto-HSCT he remained off IVIG and had good use of his upper limbs but continued to use a walking frame. EMG and blink reflex studies remained normal and anti-GAD was negative. MRI spectroscopy of the cerebellum showed improvement of his NAA/creatine ratio (Fig. 3).
Discussion
We report our experience in using auto-HSCT to treat four patients with refractory SPS.
All four patients experienced marked improvement in their symptoms and mobility following treatment. In spite of clinical improvement, patient A and C (classical SPS) continued to have high circulating anti-GAD antibody titre. EMG and blink reflex excitability assessment remained abnormal in patient A but normalised in patient C. On the other hand, patient B (classical SPS) and patient D (PERM) became seronegative for circulating antibodies and their EMG and blink reflex studies normalised. Furthermore, MRI spectroscopy values in patient D improved following treatment.
Significantly, with respect to both clinical impact and health resource utilisation all our patients stopped regular IVIG and other forms of immunotherapy with sustained symptomatic and clinical improvement.
The response to auto-HSCT confirms the autoimmune basis of SPS. Continued seropositivity for anti-GAD in half of our patients is comparable to the previous two case reports of using auto-HSCT to treat SPS [8].
The role of anti-GAD in the pathogenesis of SPS remains uncertain. GAD is the rate-limiting step in the decarboxylation of L-glutamate to γ-aminobutyric acid (GABA). Thus, anti-GAD antibodies are postulated to lead to decreased levels of GABA in the brainstem and spinal cord resulting in dis-inhibition and hyper-excitability [12]. However, several observations question anti-GAD pathogenicity in SPS. These include lack of correlation of antibody titres and disease severity [13], absence of anti-GAD antibodies in some SPS patients [14] and reports of clinical improvement with ongoing high circulating antibodies [8].
Interestingly patient B who became anti-GAD negative after auto-HSCT also reported improvement of her diabetic control. Thus, anti-GAD may support the diagnosis of SPS and other autoimmune dysfunction but does not fully explain the pathophysiology.
Glycine receptors are inhibitory receptors found on the neuronal cell surface predominantly in the brainstem and spinal cord. They exert their effects through chloride current resulting in membrane hyperpolarisation and reduction in excitation [15]. Antibodies against the alpha-1 subunit of glycine receptors are, therefore, associated with hyperexcitability. Null mutations in glycine receptors result in hereditary hyperekplexia characterised by an excessive startle and often muscle rigidity [16].
When anti-glycine receptor antibodies are present, they are typically associated with the PERM variant of SPS [5]. However, anti-glycine receptors antibodies are also found in around 15% of patient with classical SPS patients with uncertain significance [17]. Furthermore, glycine receptor antibodies have been reported to occur in other autoimmune conditions with heterogeneous phenotypes including ataxia, limbic encephalitis and myoclonic epilepsy [16].
The pathogenic roles of B cell and T cell immunity in SPS are similarly not well defined. Intrathecal production of oligoclonal anti-GAD IgG antibodies is continued by active B cells with the help of T cells that are activated by neural antigens [18]. Thus, immuno-ablative therapy to eliminate the dysfunctional immune response is expected to offer benefit. Immuno-ablative chemotherapy is followed by the re-introduction of autologous stem cell graft aiming to restart a new self-tolerant immune system. The CSF was not assayed for the presence of anti-GAD antibodies in our patients, but this should be considered in future studies to assess whether this parameter would correlate with treatment response.
At the time of writing of this case series all our transplanted patients manifested sustained clinical improvement without the need for any form of immunotherapy. Follow-up post-transplant has ranged from 12 months to 3 years. No patient encountered major or unexpected complications. Longer-term benefit of auto-HSCT in SPS remains to be ascertained.
Autologous HSCT has shown promise as a treatment option for a range of treatment-refractory autoimmune neurological conditions such as multiple sclerosis, neuromyelitis optica, myasthenia gravis and chronic inflammatory demyelinating polyneuropathy [10, 19]. Our experience further supports its use for refractory stiff-person syndrome. Auto-HSCT may prove to be a more cost-effective treatment in patients requiring regular treatment with expensive modalities, such as IVIG. Further work is warranted to establish long-term safety, efficacy and cost-effectiveness of auto-HSCT in SPS, along with optimising patient selection and transplant technique. This calls for collaboration between centres that provide this service.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary material 1 (MP4 82628 kb)
Supplementary material 2 (MP4 5421 kb)
Acknowledgements
We acknowledge the support of the NIHR Sheffield biomedical research centre and clinical trial unit.
Author contributions
LKI assessed patients, collected data, drafted and revised the first manuscript. AT assessed patients, collected data and revised the manuscript. JS, MH, BS assessed patients, supervised and delivered treatment, conceived the report and revised the manuscript. HJ delivered treatment, coordinated assessments, revised the manuscript. PS conducted neurophysiological assessment, provided neurophysiology figures and revised the manuscript. AC assessed patients, supervised and delivered treatment and revised the manuscript.
Funding
Individual funding requests were made from the NHS for UK patients.
Availability of data and material
Available.
Compliance with ethical standards
Conflicts of interest
Lewis Kass-Iliyya declares no conflict of interest. John A Snowden declares speaker fees from Jazz, Gilead, Mallinckrodt and Janssen. Alice Thorpe declares no conflict of interest. Helen Jessop declares no conflict of interest. Andrew D Chantry declares no conflict of interest. Ptolemaios Sarrigiannis declares no conflict of interest. Marios Hadjivassiliou declares no conflict of interest. Basil Sharrack declares no conflict of interest.
Ethical statement
The manuscript does not contain clinical studies. The patient whose videos are included in the electronic supplementary material gave their consent for the videos to be used in this publication. | HUMAN IMMUNOGLOBULIN G, RITUXIMAB | DrugsGivenReaction | CC BY | 32785838 | 19,779,285 | 2021-01 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Autologous haematopoietic stem cell transplantation for refractory stiff-person syndrome: the UK experience.
Stiff Person Syndrome (SPS) is a rare immune-mediated disabling neurological disorder characterised by muscle spasms and high GAD antibodies. There are only a few case reports of autologous haematopoietic stem cell transplantation (auto-HSCT) as a treatment for SPS.
OBJECTIVE
To describe the UK experience of treating refractory SPS with auto-HSCT.
METHODS
Between 2015 and 2019, 10 patients with SPS were referred to our institution for consideration of auto-HSCT. Eight patients were deemed suitable for autograft and four were treated. Of the treated patients, three had classical SPS and one had the progressive encephalomyelitis with rigidity and myoclonus variant. All patients were significantly disabled and had failed conventional immunosuppressive therapy. Patients were mobilised with Cyclophosphamide (Cy) 2 g/m2 + G-CSF and conditioned with Cy 200 mg/kg + ATG followed by auto-HSCT.
RESULTS
Despite their significantly reduced performance status, all patients tolerated the procedure with no unexpected toxicities. Following autograft, all patients improved symptomatically and stopped all forms of immunosuppressive therapies. Two patients were able to ambulate independently from being wheelchair dependent. One patient's walking distance improved from 300 meters to 5 miles and one patient's ambulation improved from being confined to a wheelchair to be able to walk with a frame. Two patients became seronegative for anti-GAD antibodies and normalised their neurophysiological abnormalities.
CONCLUSIONS
Auto-HSCT is an intensive but well tolerated and effective treatment option for patients with SPS refractory to conventional immunotherapy. Further work is warranted to optimise patient selection and establish the efficacy, long-term safety, and cost-effectiveness of this treatment.
Introduction
Stiff person syndrome (SPS) is a rare autoimmune neurological disorder characterised by progressive axial muscle stiffness, central nervous system hyper-excitability, and stimulus sensitive painful muscle spasms. Needle electromyography (EMG) often shows continuous motor unit activity at rest [1, 2]. The combination of these features represents the classical form of SPS which is associated with antibodies against glutamic acid decarboxylase (anti-GAD) in around 70% of cases [3].
Other variants include focal or segmental SPS (stiff limb or stiff trunk), para-neoplastic SPS and progressive encephalomyelitis with rigidity and myoclonus (PERM), which in addition to the classic symptoms of SPS, manifests with brainstem signs, hyperekplexia, myoclonus, ataxia and dysautonomia. PERM is associated with anti-glycine receptor antibodies and is reported to be more responsive to immunotherapy [4–6]. Stiff Person Spectrum Disorder has recently been suggested as an overarching term to encompass the various clinical presentations of this condition.
The direct pathological role of the anti-GAD and anti-glycine receptors antibodies is uncertain. The immune-mediated pathogenesis of SPS is evidenced by co-existing autoimmune diseases and partial response to treatments such as intravenous immunoglobulin (IVIG), plasmapheresis and other immunosuppressive therapies including rituximab, mycophenolate and azathioprine [4]. Symptomatic improvement can be achieved using agents such as diazepam, dantrolene, gabapentin or baclofen. Nonetheless, SPS remains a significantly disabling condition with over half of patients requiring long term mobility aids [7].
Autologous Haematopoietic Stem Cell Transplantation (auto-HSCT) has been reported as a treatment option in a limited number of SPS patients with promising results [8]. Here we describe the UK’s experience in using auto-HSCT to treat patients with refractory SPS.
Methods
Between 2015 and 2019 ten patients with SPS were referred to our institution, one of three national referral centres in the UK, for consideration of auto-HSCT from different UK and European centres. Patients’ clinical characteristics and outcomes are summarised in Table 1. All patients were assessed in a joint neurology and haematology transplant clinic. Before considering auto-HSCT the following criteria needed to be met: (1) established diagnosis of SPS; (2) significant disability secondary to SPS; (3) failure of at least one form of immunotherapy; and (4) absence of significant co-morbidities that would increase mortality risk associated with auto-HSCT. Funding requests from the NHS were made for UK patients.Table 1 Summary of patients’ demographics, clinical phenotypes, neurophysiological and serological profiles, treatments tried and outcomes of patients with Stiff Person Syndrome (SPS) referred for consideration of auto-HSCT
Patient Age/gender SPS phenotype Co-morbidities EMG/blink reflex Antibodies Immunotherapy tried Disease duration before HSCT Neurological outcome after HSCT
A 36/F Classical SPS None Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
8 years Two years from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG remain positive
B 48/F Classical SPS Pulmonary sarcoidosis
Type 1 diabetes
Peripheral neuropathy
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
4 years One year from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG became negative
C 37/F Classical SPS Type 1 diabetes Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
9 years Nine months from HSCT:
Marked clinical improvement (from walking 300 meters to 5 miles)
No further immunotherapy needed
Anti-GAD and EMG remain positive
D 52/M PERM & Gluten ataxia Pulmonary embolism Blink reflex hyperexcitability GAD 372 U/ml
Glycine positive
Anti-gliadin positive
IVIG
Plasmapheresis
5 years Three years from HSCT:
Partial clinical improvement (wheelchair to frame)
No further immunotherapy needed
Anti-GAD, anti-glycine and anti-gliadin became negative
Blink reflex normalised
E 44/M Classical SPS Type 1 diabetes
Gluten sensitivity
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
Mycophenolate
7 years Not transplanted as condition stable on mycophenolate
F 70/F Classical SPS Type 1 diabetes
Hypothyroidism
Coeliac disease
Bronchiectasis with haemophilus colonisation and lobectomy.
Continuous motor unit activity GAD > 2000 U/ml IVIG (not tolerated)
Azathioprine
Methotrexate
20 years Not transplanted due to co-existing lung disease
G 47/M PERM Recurrent thrombosis of AV fistula. Continuous motor unit activity in paraspinal muscles GAD negative
Glycine negative
IVIG
Plasmapheresis
Azathioprine
Mycophenolate
9 years Not transplanted
Funding declined
H 53/F Classical SPS Type 1 diabetes
Hypothyroidism
Gluten sensitivity
Psoriatic arthropathy
Sacral abscess
Recurrent sebaceous cysts
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml
Anti-TPO 397 U/ml
IVIG 15 years Not transplanted
Funding declined
Later died from pneumonia (autopsy was not done)
I 35/F Classical SPS Deep venous thrombosis
Heparin-induced thrombocytopenia
Continuous motor unit activity GAD > 2000 U/ml IVIG
Plasmapheresis
2 years Not transplanted
Ongoing assessment
J 48/F Classical SPS None Continuous motor unit activity GAD > 2000 U/ml IVIG
Mycophenolate
3 years Not transplanted
Ongoing assessment
PERM Progressive Encephalomyelitis, Rigidity and Myoclonus, Auto-HSCT autologous haematopoietic stem cell transplantation, GAD glutamic acid decarboxylase, EMG electromyography, IVIG intravenous Immunoglobulin
Patients deemed suitable for auto-HSCT underwent detailed assessments including MRI of the brain and spine, nerve conduction studies, needle EMG to assess spontaneous motor unit activity and blink reflex study to assess brainstem hyperexcitability. Autoimmune screening included antinuclear, para-neoplastic, anti-GAD and anti-glycine antibodies as well as immunoglobulins and protein electrophoresis. Gluten sensitivity screening was undertaken including anti-gliadin antibodies, anti-TTG antibodies and anti-endomysial antibodies. This is because there is an overlap between anti-GAD associated disease and gluten sensitivity [9]. Infection screening included HIV, Hepatitis B & C, VZV, CMV, EBV, Toxoplasmosis and VDRL. Other baseline pre-transplant assessments included echocardiogram and pulmonary function tests.
Of the 10 patients referred, one was found to be stable on mycophenolate and was declined transplant (patient E), and another was declined due to significant co-morbidities conferring an unacceptable risk (patient F). Eight patients were deemed suitable for auto-HSCT. Two patients did not proceed to transplant because funding requests were declined by their health authority (patient G and H). Patient H subsequently died from a chest infection. Two patients are currently being assessed (patient I and J).
Four patients proceeded to auto-HSCT (patient A, B, C and D). Patient A, B and C had classical SPS. Patient D had the PERM variant of SPS.
In accordance with current auto-HSCT guidelines [10] patients received a standard regimen, with stem cell mobilisation consisting of cyclophosphamide 2 g/m2 and G-CSF followed by apheresis to achieve a minimum CD34+ stem cell dose of 2 × 106/kg. Auto-HSCT conditioning regimen was cyclophosphamide 200 mg/kg (total dose, given as 50 mg/kg over days − 5 to − 2) with rabbit anti-thymocyte globulin (ATG, Thymoglobulin) total dose 6.0 mg/kg (given over days − 5 to − 2 as 0.5, 1.0, 1.5 and 1.5 mg/kg respectively with methylprednisolone cover) after which autologous peripheral blood stem cells were infused (on day 0). This is a non-myeloablative regimen which is similar to the one used by Dr Burt in Chicago for the treatment of this condition except that rituximab was not included in our regimen [11].
Data related to the duration of hospital stay, engraftment periods and complications of those who proceeded to auto-HSCT are summarised in Table 2. All patients were followed every 6-9 months in a joint neurology and haematology clinic.Table 2 Summary of data relating length of hospital stay, engraftment time and complications of autologous haematopoietic stem cell transplantation (auto-HSCT) in the four patients treated for refractory stiff person syndrome
Patient Age/Gender Complications during priming and harvesting Engraftment time after auto-HSCT (neutrophils > 0.5 × 109/L and platelets > 20 × 109/L) Length of hospital stay for auto-HSCT Required blood products/ transfusions Complications during auto-HSCT Long term sequelae
A 36/F Headache
E.coli UTI
Pain
Neutrophils:
13 days
Platelets:
12 days
26 days Yes Enterococcus UTI
Pulmonary embolism
Mucositis and rectal bleeding
Post-menopausal symptoms
Alive with no complications
B 48/F None Neutrophils:
11 days
Platelets:
never dropped below 50
18 days No ESBL UTI
Transient exacerbation of diabetes due to steroids
Alive with no complications
C 37/F Gram-negative pantoea agglomerans from Hickman line-treated successfully with antibiotics Neutrophils:
14 days
Platelets:
13 days
21 days Yes Febrile neutropenia covered with antibiotics
Transiently deranged LFTs
Transient CMV and EBV viraemia
Alive with no complications
D 52/M None Neutrophils:
11 days
Platelets:
10 days
16 days Yes Coagulase-negative staphylococcus line infection
Transient EBV viraemia
URTI (RSV)
Alive with no complications
Transplanted patients
Patient A
36-year-old female with no past medical history developed lower limbs and para-spinal muscle spasms that progressed over 3 months. Severe muscle spasms leading to arching of her back were triggered by sudden noise or cutaneous touch. Her symptoms continued to progress and she became wheelchair-bound 6 months later.
MRI of the neuroaxis and CSF examination were normal. Anti-GAD antibodies were positive (> 2000 U/ml). She was diagnosed with the classical form of SPS. She responded partially to plasmapheresis at the referring centre but continued to require very frequent treatments and was therefore started on IVIG.
When she was reviewed at our institution, she was severely disabled by her symptoms requiring regular IVIG treatments at a dose of 90 g every 12 days. She was taking regular diazepam at a dose of 30 mg per day and morphine up to 60 mg a day to control pain. On examination, she had brisk reflexes and severe clonus. She was exquisitely touch-sensitive which induced severe prolonged painful muscle spasms. The muscle spasms were severe enough to compromise her breathing and she required intermittent oxygen. EMG showed continuous muscle fibre activity. Blink reflex study was abnormal with marked amplification of the R2 component recorded following test stimulus in keeping with brainstem hyperexcitability (Fig. 2A). Given her extreme stimulus sensitivity, she underwent EEG/EMG polygraphy recording which captured exaggerated startle response to auditory stimuli in keeping with brainstem hyperexcitability (Fig. 1). The rest of her work-up and immunology screen were negative.Fig. 1 EEG/EMG polygraphy recording of patient A with classical stiff-person syndrome capturing exaggerated startle response to an unanticipated auditory stimulus. Low intensity unanticipated auditory stimulus around 50 dB elicited prominent muscle jerks (within 92 ms from stimulus presentation) followed by protracted spasms in multiple muscle groups. Obc orbicularis Oculi, Obr orbicularis oris, Mass massetter, Stern sternocleidomastoid, Trap trapezius, Delt deltoid, UPA upper abdominals, TA tibialis anterior, STAR sensor marking the onset of the unanticipated auditory stimulus
She received auto-HSCT 8 years from the onset of her symptoms. Transplantation proceeded with no unexpected complications apart from routine toxicities (Table 2).
When reviewed 5 months after auto-HSCT, the majority of her neurological symptoms had improved significantly. She was ambulating independently and required no further IVIG but continued to take diazepam. She had mild startle responses. Anti-GAD antibodies remained positive at > 2000 U/ml.
Repeat EMG undertaken a year post-auto-HSCT remained abnormal with continuous motor unit activity. Blink reflex study with short interstimulus intervals was not possible as immediately following the first electrical stimulus protracted contraction of facial muscle tended to emerge. Therefore, no meaningful comparison could be made with the previous study. Overall, the neurophysiological assessment continued to show features in keeping with SPS despite the clinical improvement.
She was reviewed again 2 years following auto-HSCT and was noted to have remained off all immunotherapy and was able to walk independently. She reported occasional muscle spasms affecting her arms and legs and poor exercise tolerance. Neurological examination was normal. She declined repeat neurophysiological assessment. Her anti-GAD antibodies remained positive.
Patient B
Forty-eight-year-old female with a past medical history of type 1 diabetes, diabetic neuropathy and pulmonary sarcoidosis presented with intermittent muscle spasms affecting all four limbs. The spasms progressed gradually causing increasing difficulties with her mobility over a period of 4 years. At that point, she was mostly wheelchair-bound and only able to ambulate indoors with the help of a frame (supplementary electronic material). Painful muscle spasms were triggered by cutaneous touching. Prior to her referral to our institution she had been diagnosed with stiff person syndrome and was started on IVIG which helped her symptoms. However, she was requiring an infusion every 2 weeks. Subsequently, two doses of rituximab were given which improved her symptoms but did not reduce the need for regular IVIG. She was reliant on diazepam and baclofen for symptomatic relief.
When reviewed at our institution she was noted to have intermittent sustained muscle spasms on examination. She also had clinical signs of length-dependent peripheral neuropathy which was confirmed on nerve conduction studies. EMG displayed continuous motor potential activity and blink reflex demonstrated brainstem hyper-excitability with lack of suppression of R2 component following the test stimulus (Fig. 2Bi). Anti-GAD antibodies were positive (> 2000 U/ml) and the rest of her immunology screen was negative. Infection screening prior to auto-HSCT identified hepatitis B core antigen positivity. In the absence of any risk factors, this was thought to be caused by repeated IVIG infusions. Hepatitis B DNA PCR was negative.Fig. 2 Blink reflex excitability studies at the short inter-stimulus interval between a conditioning and a test stimulus after 160 ms. Single square pulse electrical stimulation of the supraorbital nerve on one side is given at 20–25 mA and 0.2 s pulse width. The polysynaptic R2 response which is recorded following a test electrical stimulus from the contralateral side is typically supressed at such small interstimulus interval in healthy subjects. The least affected by artefact, rectified R2 waveform contralateral to the site of stimulation was used for analysis. In both patient A and patient B (classical stiff person syndrome) the contralateral R2 component that follows the test stimulus is enhanced (area estimates for R2 between cursors S1b/S1e and S2b/S2e are shown in the relevant embedded tables). The pre-HSCT study of patient A shows clear enhancement of the R2 response that follows the test stimulus in comparison to the earlier R2 waveform that followed the conditioning stimulus. For patient B, comparison between the pre-HSCT (Bi) and post-HSCT (Bii) examination shows relative normalisation of blink reflex excitability in the latter; the R2 area following the test stimulus is relatively suppressed in comparison to the R2 area of the conditioning stimulus (Bii). This electrophysiological assessment is used as a semiquantitative assessment of brainstem excitability
Auto-HSCT was undertaken at our institution 4 years into her illness and progressed uneventfully (Table 2). Hepatitis B DNA PCR was pre-emptively monitored throughout her immunosuppression and remained negative.
When reviewed in clinic 6 months after auto-HSCT, her muscle spasms were noted to have improved significantly. She required no further doses of IVIG but continued to use a small dose of Baclofen. She was no longer requiring a wheelchair and started walking with the support of a stick. She continued to suffer from fatigue.
Repeat EMG showed significant improvement with the patient being able to completely suppress all motor unit potential activity in muscles that were previously affected by severe stiffness. The blink reflex excitability studies also improved with a more suppressed R2 component following the test stimulus compared to the R2 component from the conditioning stimulus (Fig. 2Bii). She was able to walk 10 meters in 15.2 s with a stick.
Serologically, anti-GAD antibodies reduced from > 2000 to < 0.5 U/ml.
A year after auto-HSCT her marked improvement continued. She was no longer reporting any spasms and was able to walk independently for long distances (Electronic supplementary material). Her diabetes control also improved and she came off all her anti-diabetic treatments. She walked 10 meters in 9 s without assistance or stopping. A repeat EMG at that point showed no evidence of stiff person syndrome. Anti-GAD antibodies remained negative.
Patient C
Thirty-seven-year-old female with a history of type 1 diabetes. She developed progressive painful muscle spasms affecting her core musculature and limbs, which were not controlled despite high doses of diazepam (30 mg/day) and gabapentin (2700 mg/day). Nine years into her symptoms she was able to walk unaided for a maximum of 300 meters. She struggled with social anxiety due to muscle spasms, which progressed to affect her face and jaw.
Prior to her referral for auto-HSCT the patient had received five courses of IVIG, which provided transient benefit. She had three infusions of rituximab, which did not relieve her symptoms. Azathioprine was not tolerated.
Neurological examination showed marked stiffness of her abdominal and para-spinal muscles. EMG showed continued motor activity in the para-spinal muscles. Blink reflex study showed evidence of brainstem hyperexcitability. Anti-GAD antibodies were positive (> 2000 U/ml). The rest of the immunology, paraneoplastic and infective screens were negative. Auto-HSCT was offered 9 years after symptom onset. There were no major complications from auto-HSCT apart from routine toxicities (Table 2).
Nine months after transplantation the patient reported marked improvement of the severity of her muscle spasms and stiffness. She reported mild fatigue but she was able to walk for up to 5 miles a day. She continued to use diazepam and gabapentin albeit at much lower doses (10 mg of Diazepam/day and 500 mg of Gabapentin/day). Blink reflex study did not show evidence of brainstem hyperexcitability however, limited lumbar paraspinals EMG (patient was needle phobic) showed continued motor potentials. Anti-GAD antibodies remained positive after transplantation.
Patient D
52-year-old male with no significant past medical history presented with progressive asymmetrical muscle stiffness affecting initially the right leg but subsequently other parts of his body. The stiffness progressed over 5 years to involve all four limbs, which significantly impaired his ability to carry out the activities of daily living. Facial muscles involvement interfered with speech and swallowing and he occasionally bit his tongue.
Examination revealed marked muscle rigidity, brisk reflexes and clonus. MRI of the spine showed moderate spondylosis which did not account for the patient’s symptoms. Serological testing for gluten sensitivity revealed positive anti-gliadin antibodies and a gluten-free diet was adopted. MRI of the brain showed mild atrophy of the cerebellar hemispheres. MRI spectroscopy demonstrated low NAA/Creatine ratio of 0.85 from the superior vermis (normal over 1.00) (Fig. 3). CSF examination was normal.Fig. 3 MRI spectroscopy of 52-year-old male with stiff person synonym (PERM - patient D) who underwent autologous haematopoietic stem cell transplantation (auto-HSCT). The MRI demonstrate cerebellar involvement showing NAA/creatine ratio of 0.85 from the superior vermis (normal above 1.00) before auto-HSCT which improved to 0.93 after auto-HSCT
Nerve conduction studies were normal. EMG did not show continuous motor unit activity however, blink reflex studies showed evidence of hyper-excitability. Anti-GAD antibodies were positive at 372 U/ml. Anti-glycine antibodies were positive. Paraneoplastic, anti-NMDA and anti-VGKC antibodies were negative.
He was diagnosed with the PERM variant of SPS on the basis of the clinical features and the serology results. He was started on IVIG which resulted in partial clinical improvement. However, he continued to require infusions at a dose of 150 g every 3 months. He could not tolerate Diazepam, Baclofen, Tizanidine or Dantrolene. He did not tolerate mycophenolate which he tried for 2 months. Over the subsequent years, he became wheelchair-bound and dependent on IVIG which he continued for a year.
Auto-HSCT was offered 5 years after symptom onset. While he was being considered for auto-HSCT he developed deep vein thrombosis and a large saddle pulmonary embolism thought to be related to poor mobility and regular IVIGs. He was started on rivaroxaban. Auto-HSCT proceeded uneventfully apart from routine toxicities (Table 2).
Four months after auto-HSCT, his mobility improved from wheelchair to a frame. His legs remained stiff but arms improved significantly so he was able to feed and wash himself. Anti-GAD and anti-glycine antibodies became negative. Repeat blink reflex study post-transplantation showed no evidence of hyperexcitability. He was no longer requiring regular IVIG. His speech remained dysarthric but his swallowing normalised. He was no longer biting his tongue. He stopped all regular medications.
Two years after auto-HSCT he remained off IVIG and had good use of his upper limbs but continued to use a walking frame. EMG and blink reflex studies remained normal and anti-GAD was negative. MRI spectroscopy of the cerebellum showed improvement of his NAA/creatine ratio (Fig. 3).
Discussion
We report our experience in using auto-HSCT to treat four patients with refractory SPS.
All four patients experienced marked improvement in their symptoms and mobility following treatment. In spite of clinical improvement, patient A and C (classical SPS) continued to have high circulating anti-GAD antibody titre. EMG and blink reflex excitability assessment remained abnormal in patient A but normalised in patient C. On the other hand, patient B (classical SPS) and patient D (PERM) became seronegative for circulating antibodies and their EMG and blink reflex studies normalised. Furthermore, MRI spectroscopy values in patient D improved following treatment.
Significantly, with respect to both clinical impact and health resource utilisation all our patients stopped regular IVIG and other forms of immunotherapy with sustained symptomatic and clinical improvement.
The response to auto-HSCT confirms the autoimmune basis of SPS. Continued seropositivity for anti-GAD in half of our patients is comparable to the previous two case reports of using auto-HSCT to treat SPS [8].
The role of anti-GAD in the pathogenesis of SPS remains uncertain. GAD is the rate-limiting step in the decarboxylation of L-glutamate to γ-aminobutyric acid (GABA). Thus, anti-GAD antibodies are postulated to lead to decreased levels of GABA in the brainstem and spinal cord resulting in dis-inhibition and hyper-excitability [12]. However, several observations question anti-GAD pathogenicity in SPS. These include lack of correlation of antibody titres and disease severity [13], absence of anti-GAD antibodies in some SPS patients [14] and reports of clinical improvement with ongoing high circulating antibodies [8].
Interestingly patient B who became anti-GAD negative after auto-HSCT also reported improvement of her diabetic control. Thus, anti-GAD may support the diagnosis of SPS and other autoimmune dysfunction but does not fully explain the pathophysiology.
Glycine receptors are inhibitory receptors found on the neuronal cell surface predominantly in the brainstem and spinal cord. They exert their effects through chloride current resulting in membrane hyperpolarisation and reduction in excitation [15]. Antibodies against the alpha-1 subunit of glycine receptors are, therefore, associated with hyperexcitability. Null mutations in glycine receptors result in hereditary hyperekplexia characterised by an excessive startle and often muscle rigidity [16].
When anti-glycine receptor antibodies are present, they are typically associated with the PERM variant of SPS [5]. However, anti-glycine receptors antibodies are also found in around 15% of patient with classical SPS patients with uncertain significance [17]. Furthermore, glycine receptor antibodies have been reported to occur in other autoimmune conditions with heterogeneous phenotypes including ataxia, limbic encephalitis and myoclonic epilepsy [16].
The pathogenic roles of B cell and T cell immunity in SPS are similarly not well defined. Intrathecal production of oligoclonal anti-GAD IgG antibodies is continued by active B cells with the help of T cells that are activated by neural antigens [18]. Thus, immuno-ablative therapy to eliminate the dysfunctional immune response is expected to offer benefit. Immuno-ablative chemotherapy is followed by the re-introduction of autologous stem cell graft aiming to restart a new self-tolerant immune system. The CSF was not assayed for the presence of anti-GAD antibodies in our patients, but this should be considered in future studies to assess whether this parameter would correlate with treatment response.
At the time of writing of this case series all our transplanted patients manifested sustained clinical improvement without the need for any form of immunotherapy. Follow-up post-transplant has ranged from 12 months to 3 years. No patient encountered major or unexpected complications. Longer-term benefit of auto-HSCT in SPS remains to be ascertained.
Autologous HSCT has shown promise as a treatment option for a range of treatment-refractory autoimmune neurological conditions such as multiple sclerosis, neuromyelitis optica, myasthenia gravis and chronic inflammatory demyelinating polyneuropathy [10, 19]. Our experience further supports its use for refractory stiff-person syndrome. Auto-HSCT may prove to be a more cost-effective treatment in patients requiring regular treatment with expensive modalities, such as IVIG. Further work is warranted to establish long-term safety, efficacy and cost-effectiveness of auto-HSCT in SPS, along with optimising patient selection and transplant technique. This calls for collaboration between centres that provide this service.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary material 1 (MP4 82628 kb)
Supplementary material 2 (MP4 5421 kb)
Acknowledgements
We acknowledge the support of the NIHR Sheffield biomedical research centre and clinical trial unit.
Author contributions
LKI assessed patients, collected data, drafted and revised the first manuscript. AT assessed patients, collected data and revised the manuscript. JS, MH, BS assessed patients, supervised and delivered treatment, conceived the report and revised the manuscript. HJ delivered treatment, coordinated assessments, revised the manuscript. PS conducted neurophysiological assessment, provided neurophysiology figures and revised the manuscript. AC assessed patients, supervised and delivered treatment and revised the manuscript.
Funding
Individual funding requests were made from the NHS for UK patients.
Availability of data and material
Available.
Compliance with ethical standards
Conflicts of interest
Lewis Kass-Iliyya declares no conflict of interest. John A Snowden declares speaker fees from Jazz, Gilead, Mallinckrodt and Janssen. Alice Thorpe declares no conflict of interest. Helen Jessop declares no conflict of interest. Andrew D Chantry declares no conflict of interest. Ptolemaios Sarrigiannis declares no conflict of interest. Marios Hadjivassiliou declares no conflict of interest. Basil Sharrack declares no conflict of interest.
Ethical statement
The manuscript does not contain clinical studies. The patient whose videos are included in the electronic supplementary material gave their consent for the videos to be used in this publication. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 32785838 | 19,779,285 | 2021-01 |
What was the administration route of drug 'IMMUNE GLOBULIN NOS'? | Autologous haematopoietic stem cell transplantation for refractory stiff-person syndrome: the UK experience.
Stiff Person Syndrome (SPS) is a rare immune-mediated disabling neurological disorder characterised by muscle spasms and high GAD antibodies. There are only a few case reports of autologous haematopoietic stem cell transplantation (auto-HSCT) as a treatment for SPS.
OBJECTIVE
To describe the UK experience of treating refractory SPS with auto-HSCT.
METHODS
Between 2015 and 2019, 10 patients with SPS were referred to our institution for consideration of auto-HSCT. Eight patients were deemed suitable for autograft and four were treated. Of the treated patients, three had classical SPS and one had the progressive encephalomyelitis with rigidity and myoclonus variant. All patients were significantly disabled and had failed conventional immunosuppressive therapy. Patients were mobilised with Cyclophosphamide (Cy) 2 g/m2 + G-CSF and conditioned with Cy 200 mg/kg + ATG followed by auto-HSCT.
RESULTS
Despite their significantly reduced performance status, all patients tolerated the procedure with no unexpected toxicities. Following autograft, all patients improved symptomatically and stopped all forms of immunosuppressive therapies. Two patients were able to ambulate independently from being wheelchair dependent. One patient's walking distance improved from 300 meters to 5 miles and one patient's ambulation improved from being confined to a wheelchair to be able to walk with a frame. Two patients became seronegative for anti-GAD antibodies and normalised their neurophysiological abnormalities.
CONCLUSIONS
Auto-HSCT is an intensive but well tolerated and effective treatment option for patients with SPS refractory to conventional immunotherapy. Further work is warranted to optimise patient selection and establish the efficacy, long-term safety, and cost-effectiveness of this treatment.
Introduction
Stiff person syndrome (SPS) is a rare autoimmune neurological disorder characterised by progressive axial muscle stiffness, central nervous system hyper-excitability, and stimulus sensitive painful muscle spasms. Needle electromyography (EMG) often shows continuous motor unit activity at rest [1, 2]. The combination of these features represents the classical form of SPS which is associated with antibodies against glutamic acid decarboxylase (anti-GAD) in around 70% of cases [3].
Other variants include focal or segmental SPS (stiff limb or stiff trunk), para-neoplastic SPS and progressive encephalomyelitis with rigidity and myoclonus (PERM), which in addition to the classic symptoms of SPS, manifests with brainstem signs, hyperekplexia, myoclonus, ataxia and dysautonomia. PERM is associated with anti-glycine receptor antibodies and is reported to be more responsive to immunotherapy [4–6]. Stiff Person Spectrum Disorder has recently been suggested as an overarching term to encompass the various clinical presentations of this condition.
The direct pathological role of the anti-GAD and anti-glycine receptors antibodies is uncertain. The immune-mediated pathogenesis of SPS is evidenced by co-existing autoimmune diseases and partial response to treatments such as intravenous immunoglobulin (IVIG), plasmapheresis and other immunosuppressive therapies including rituximab, mycophenolate and azathioprine [4]. Symptomatic improvement can be achieved using agents such as diazepam, dantrolene, gabapentin or baclofen. Nonetheless, SPS remains a significantly disabling condition with over half of patients requiring long term mobility aids [7].
Autologous Haematopoietic Stem Cell Transplantation (auto-HSCT) has been reported as a treatment option in a limited number of SPS patients with promising results [8]. Here we describe the UK’s experience in using auto-HSCT to treat patients with refractory SPS.
Methods
Between 2015 and 2019 ten patients with SPS were referred to our institution, one of three national referral centres in the UK, for consideration of auto-HSCT from different UK and European centres. Patients’ clinical characteristics and outcomes are summarised in Table 1. All patients were assessed in a joint neurology and haematology transplant clinic. Before considering auto-HSCT the following criteria needed to be met: (1) established diagnosis of SPS; (2) significant disability secondary to SPS; (3) failure of at least one form of immunotherapy; and (4) absence of significant co-morbidities that would increase mortality risk associated with auto-HSCT. Funding requests from the NHS were made for UK patients.Table 1 Summary of patients’ demographics, clinical phenotypes, neurophysiological and serological profiles, treatments tried and outcomes of patients with Stiff Person Syndrome (SPS) referred for consideration of auto-HSCT
Patient Age/gender SPS phenotype Co-morbidities EMG/blink reflex Antibodies Immunotherapy tried Disease duration before HSCT Neurological outcome after HSCT
A 36/F Classical SPS None Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
8 years Two years from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG remain positive
B 48/F Classical SPS Pulmonary sarcoidosis
Type 1 diabetes
Peripheral neuropathy
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
4 years One year from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG became negative
C 37/F Classical SPS Type 1 diabetes Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
9 years Nine months from HSCT:
Marked clinical improvement (from walking 300 meters to 5 miles)
No further immunotherapy needed
Anti-GAD and EMG remain positive
D 52/M PERM & Gluten ataxia Pulmonary embolism Blink reflex hyperexcitability GAD 372 U/ml
Glycine positive
Anti-gliadin positive
IVIG
Plasmapheresis
5 years Three years from HSCT:
Partial clinical improvement (wheelchair to frame)
No further immunotherapy needed
Anti-GAD, anti-glycine and anti-gliadin became negative
Blink reflex normalised
E 44/M Classical SPS Type 1 diabetes
Gluten sensitivity
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
Mycophenolate
7 years Not transplanted as condition stable on mycophenolate
F 70/F Classical SPS Type 1 diabetes
Hypothyroidism
Coeliac disease
Bronchiectasis with haemophilus colonisation and lobectomy.
Continuous motor unit activity GAD > 2000 U/ml IVIG (not tolerated)
Azathioprine
Methotrexate
20 years Not transplanted due to co-existing lung disease
G 47/M PERM Recurrent thrombosis of AV fistula. Continuous motor unit activity in paraspinal muscles GAD negative
Glycine negative
IVIG
Plasmapheresis
Azathioprine
Mycophenolate
9 years Not transplanted
Funding declined
H 53/F Classical SPS Type 1 diabetes
Hypothyroidism
Gluten sensitivity
Psoriatic arthropathy
Sacral abscess
Recurrent sebaceous cysts
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml
Anti-TPO 397 U/ml
IVIG 15 years Not transplanted
Funding declined
Later died from pneumonia (autopsy was not done)
I 35/F Classical SPS Deep venous thrombosis
Heparin-induced thrombocytopenia
Continuous motor unit activity GAD > 2000 U/ml IVIG
Plasmapheresis
2 years Not transplanted
Ongoing assessment
J 48/F Classical SPS None Continuous motor unit activity GAD > 2000 U/ml IVIG
Mycophenolate
3 years Not transplanted
Ongoing assessment
PERM Progressive Encephalomyelitis, Rigidity and Myoclonus, Auto-HSCT autologous haematopoietic stem cell transplantation, GAD glutamic acid decarboxylase, EMG electromyography, IVIG intravenous Immunoglobulin
Patients deemed suitable for auto-HSCT underwent detailed assessments including MRI of the brain and spine, nerve conduction studies, needle EMG to assess spontaneous motor unit activity and blink reflex study to assess brainstem hyperexcitability. Autoimmune screening included antinuclear, para-neoplastic, anti-GAD and anti-glycine antibodies as well as immunoglobulins and protein electrophoresis. Gluten sensitivity screening was undertaken including anti-gliadin antibodies, anti-TTG antibodies and anti-endomysial antibodies. This is because there is an overlap between anti-GAD associated disease and gluten sensitivity [9]. Infection screening included HIV, Hepatitis B & C, VZV, CMV, EBV, Toxoplasmosis and VDRL. Other baseline pre-transplant assessments included echocardiogram and pulmonary function tests.
Of the 10 patients referred, one was found to be stable on mycophenolate and was declined transplant (patient E), and another was declined due to significant co-morbidities conferring an unacceptable risk (patient F). Eight patients were deemed suitable for auto-HSCT. Two patients did not proceed to transplant because funding requests were declined by their health authority (patient G and H). Patient H subsequently died from a chest infection. Two patients are currently being assessed (patient I and J).
Four patients proceeded to auto-HSCT (patient A, B, C and D). Patient A, B and C had classical SPS. Patient D had the PERM variant of SPS.
In accordance with current auto-HSCT guidelines [10] patients received a standard regimen, with stem cell mobilisation consisting of cyclophosphamide 2 g/m2 and G-CSF followed by apheresis to achieve a minimum CD34+ stem cell dose of 2 × 106/kg. Auto-HSCT conditioning regimen was cyclophosphamide 200 mg/kg (total dose, given as 50 mg/kg over days − 5 to − 2) with rabbit anti-thymocyte globulin (ATG, Thymoglobulin) total dose 6.0 mg/kg (given over days − 5 to − 2 as 0.5, 1.0, 1.5 and 1.5 mg/kg respectively with methylprednisolone cover) after which autologous peripheral blood stem cells were infused (on day 0). This is a non-myeloablative regimen which is similar to the one used by Dr Burt in Chicago for the treatment of this condition except that rituximab was not included in our regimen [11].
Data related to the duration of hospital stay, engraftment periods and complications of those who proceeded to auto-HSCT are summarised in Table 2. All patients were followed every 6-9 months in a joint neurology and haematology clinic.Table 2 Summary of data relating length of hospital stay, engraftment time and complications of autologous haematopoietic stem cell transplantation (auto-HSCT) in the four patients treated for refractory stiff person syndrome
Patient Age/Gender Complications during priming and harvesting Engraftment time after auto-HSCT (neutrophils > 0.5 × 109/L and platelets > 20 × 109/L) Length of hospital stay for auto-HSCT Required blood products/ transfusions Complications during auto-HSCT Long term sequelae
A 36/F Headache
E.coli UTI
Pain
Neutrophils:
13 days
Platelets:
12 days
26 days Yes Enterococcus UTI
Pulmonary embolism
Mucositis and rectal bleeding
Post-menopausal symptoms
Alive with no complications
B 48/F None Neutrophils:
11 days
Platelets:
never dropped below 50
18 days No ESBL UTI
Transient exacerbation of diabetes due to steroids
Alive with no complications
C 37/F Gram-negative pantoea agglomerans from Hickman line-treated successfully with antibiotics Neutrophils:
14 days
Platelets:
13 days
21 days Yes Febrile neutropenia covered with antibiotics
Transiently deranged LFTs
Transient CMV and EBV viraemia
Alive with no complications
D 52/M None Neutrophils:
11 days
Platelets:
10 days
16 days Yes Coagulase-negative staphylococcus line infection
Transient EBV viraemia
URTI (RSV)
Alive with no complications
Transplanted patients
Patient A
36-year-old female with no past medical history developed lower limbs and para-spinal muscle spasms that progressed over 3 months. Severe muscle spasms leading to arching of her back were triggered by sudden noise or cutaneous touch. Her symptoms continued to progress and she became wheelchair-bound 6 months later.
MRI of the neuroaxis and CSF examination were normal. Anti-GAD antibodies were positive (> 2000 U/ml). She was diagnosed with the classical form of SPS. She responded partially to plasmapheresis at the referring centre but continued to require very frequent treatments and was therefore started on IVIG.
When she was reviewed at our institution, she was severely disabled by her symptoms requiring regular IVIG treatments at a dose of 90 g every 12 days. She was taking regular diazepam at a dose of 30 mg per day and morphine up to 60 mg a day to control pain. On examination, she had brisk reflexes and severe clonus. She was exquisitely touch-sensitive which induced severe prolonged painful muscle spasms. The muscle spasms were severe enough to compromise her breathing and she required intermittent oxygen. EMG showed continuous muscle fibre activity. Blink reflex study was abnormal with marked amplification of the R2 component recorded following test stimulus in keeping with brainstem hyperexcitability (Fig. 2A). Given her extreme stimulus sensitivity, she underwent EEG/EMG polygraphy recording which captured exaggerated startle response to auditory stimuli in keeping with brainstem hyperexcitability (Fig. 1). The rest of her work-up and immunology screen were negative.Fig. 1 EEG/EMG polygraphy recording of patient A with classical stiff-person syndrome capturing exaggerated startle response to an unanticipated auditory stimulus. Low intensity unanticipated auditory stimulus around 50 dB elicited prominent muscle jerks (within 92 ms from stimulus presentation) followed by protracted spasms in multiple muscle groups. Obc orbicularis Oculi, Obr orbicularis oris, Mass massetter, Stern sternocleidomastoid, Trap trapezius, Delt deltoid, UPA upper abdominals, TA tibialis anterior, STAR sensor marking the onset of the unanticipated auditory stimulus
She received auto-HSCT 8 years from the onset of her symptoms. Transplantation proceeded with no unexpected complications apart from routine toxicities (Table 2).
When reviewed 5 months after auto-HSCT, the majority of her neurological symptoms had improved significantly. She was ambulating independently and required no further IVIG but continued to take diazepam. She had mild startle responses. Anti-GAD antibodies remained positive at > 2000 U/ml.
Repeat EMG undertaken a year post-auto-HSCT remained abnormal with continuous motor unit activity. Blink reflex study with short interstimulus intervals was not possible as immediately following the first electrical stimulus protracted contraction of facial muscle tended to emerge. Therefore, no meaningful comparison could be made with the previous study. Overall, the neurophysiological assessment continued to show features in keeping with SPS despite the clinical improvement.
She was reviewed again 2 years following auto-HSCT and was noted to have remained off all immunotherapy and was able to walk independently. She reported occasional muscle spasms affecting her arms and legs and poor exercise tolerance. Neurological examination was normal. She declined repeat neurophysiological assessment. Her anti-GAD antibodies remained positive.
Patient B
Forty-eight-year-old female with a past medical history of type 1 diabetes, diabetic neuropathy and pulmonary sarcoidosis presented with intermittent muscle spasms affecting all four limbs. The spasms progressed gradually causing increasing difficulties with her mobility over a period of 4 years. At that point, she was mostly wheelchair-bound and only able to ambulate indoors with the help of a frame (supplementary electronic material). Painful muscle spasms were triggered by cutaneous touching. Prior to her referral to our institution she had been diagnosed with stiff person syndrome and was started on IVIG which helped her symptoms. However, she was requiring an infusion every 2 weeks. Subsequently, two doses of rituximab were given which improved her symptoms but did not reduce the need for regular IVIG. She was reliant on diazepam and baclofen for symptomatic relief.
When reviewed at our institution she was noted to have intermittent sustained muscle spasms on examination. She also had clinical signs of length-dependent peripheral neuropathy which was confirmed on nerve conduction studies. EMG displayed continuous motor potential activity and blink reflex demonstrated brainstem hyper-excitability with lack of suppression of R2 component following the test stimulus (Fig. 2Bi). Anti-GAD antibodies were positive (> 2000 U/ml) and the rest of her immunology screen was negative. Infection screening prior to auto-HSCT identified hepatitis B core antigen positivity. In the absence of any risk factors, this was thought to be caused by repeated IVIG infusions. Hepatitis B DNA PCR was negative.Fig. 2 Blink reflex excitability studies at the short inter-stimulus interval between a conditioning and a test stimulus after 160 ms. Single square pulse electrical stimulation of the supraorbital nerve on one side is given at 20–25 mA and 0.2 s pulse width. The polysynaptic R2 response which is recorded following a test electrical stimulus from the contralateral side is typically supressed at such small interstimulus interval in healthy subjects. The least affected by artefact, rectified R2 waveform contralateral to the site of stimulation was used for analysis. In both patient A and patient B (classical stiff person syndrome) the contralateral R2 component that follows the test stimulus is enhanced (area estimates for R2 between cursors S1b/S1e and S2b/S2e are shown in the relevant embedded tables). The pre-HSCT study of patient A shows clear enhancement of the R2 response that follows the test stimulus in comparison to the earlier R2 waveform that followed the conditioning stimulus. For patient B, comparison between the pre-HSCT (Bi) and post-HSCT (Bii) examination shows relative normalisation of blink reflex excitability in the latter; the R2 area following the test stimulus is relatively suppressed in comparison to the R2 area of the conditioning stimulus (Bii). This electrophysiological assessment is used as a semiquantitative assessment of brainstem excitability
Auto-HSCT was undertaken at our institution 4 years into her illness and progressed uneventfully (Table 2). Hepatitis B DNA PCR was pre-emptively monitored throughout her immunosuppression and remained negative.
When reviewed in clinic 6 months after auto-HSCT, her muscle spasms were noted to have improved significantly. She required no further doses of IVIG but continued to use a small dose of Baclofen. She was no longer requiring a wheelchair and started walking with the support of a stick. She continued to suffer from fatigue.
Repeat EMG showed significant improvement with the patient being able to completely suppress all motor unit potential activity in muscles that were previously affected by severe stiffness. The blink reflex excitability studies also improved with a more suppressed R2 component following the test stimulus compared to the R2 component from the conditioning stimulus (Fig. 2Bii). She was able to walk 10 meters in 15.2 s with a stick.
Serologically, anti-GAD antibodies reduced from > 2000 to < 0.5 U/ml.
A year after auto-HSCT her marked improvement continued. She was no longer reporting any spasms and was able to walk independently for long distances (Electronic supplementary material). Her diabetes control also improved and she came off all her anti-diabetic treatments. She walked 10 meters in 9 s without assistance or stopping. A repeat EMG at that point showed no evidence of stiff person syndrome. Anti-GAD antibodies remained negative.
Patient C
Thirty-seven-year-old female with a history of type 1 diabetes. She developed progressive painful muscle spasms affecting her core musculature and limbs, which were not controlled despite high doses of diazepam (30 mg/day) and gabapentin (2700 mg/day). Nine years into her symptoms she was able to walk unaided for a maximum of 300 meters. She struggled with social anxiety due to muscle spasms, which progressed to affect her face and jaw.
Prior to her referral for auto-HSCT the patient had received five courses of IVIG, which provided transient benefit. She had three infusions of rituximab, which did not relieve her symptoms. Azathioprine was not tolerated.
Neurological examination showed marked stiffness of her abdominal and para-spinal muscles. EMG showed continued motor activity in the para-spinal muscles. Blink reflex study showed evidence of brainstem hyperexcitability. Anti-GAD antibodies were positive (> 2000 U/ml). The rest of the immunology, paraneoplastic and infective screens were negative. Auto-HSCT was offered 9 years after symptom onset. There were no major complications from auto-HSCT apart from routine toxicities (Table 2).
Nine months after transplantation the patient reported marked improvement of the severity of her muscle spasms and stiffness. She reported mild fatigue but she was able to walk for up to 5 miles a day. She continued to use diazepam and gabapentin albeit at much lower doses (10 mg of Diazepam/day and 500 mg of Gabapentin/day). Blink reflex study did not show evidence of brainstem hyperexcitability however, limited lumbar paraspinals EMG (patient was needle phobic) showed continued motor potentials. Anti-GAD antibodies remained positive after transplantation.
Patient D
52-year-old male with no significant past medical history presented with progressive asymmetrical muscle stiffness affecting initially the right leg but subsequently other parts of his body. The stiffness progressed over 5 years to involve all four limbs, which significantly impaired his ability to carry out the activities of daily living. Facial muscles involvement interfered with speech and swallowing and he occasionally bit his tongue.
Examination revealed marked muscle rigidity, brisk reflexes and clonus. MRI of the spine showed moderate spondylosis which did not account for the patient’s symptoms. Serological testing for gluten sensitivity revealed positive anti-gliadin antibodies and a gluten-free diet was adopted. MRI of the brain showed mild atrophy of the cerebellar hemispheres. MRI spectroscopy demonstrated low NAA/Creatine ratio of 0.85 from the superior vermis (normal over 1.00) (Fig. 3). CSF examination was normal.Fig. 3 MRI spectroscopy of 52-year-old male with stiff person synonym (PERM - patient D) who underwent autologous haematopoietic stem cell transplantation (auto-HSCT). The MRI demonstrate cerebellar involvement showing NAA/creatine ratio of 0.85 from the superior vermis (normal above 1.00) before auto-HSCT which improved to 0.93 after auto-HSCT
Nerve conduction studies were normal. EMG did not show continuous motor unit activity however, blink reflex studies showed evidence of hyper-excitability. Anti-GAD antibodies were positive at 372 U/ml. Anti-glycine antibodies were positive. Paraneoplastic, anti-NMDA and anti-VGKC antibodies were negative.
He was diagnosed with the PERM variant of SPS on the basis of the clinical features and the serology results. He was started on IVIG which resulted in partial clinical improvement. However, he continued to require infusions at a dose of 150 g every 3 months. He could not tolerate Diazepam, Baclofen, Tizanidine or Dantrolene. He did not tolerate mycophenolate which he tried for 2 months. Over the subsequent years, he became wheelchair-bound and dependent on IVIG which he continued for a year.
Auto-HSCT was offered 5 years after symptom onset. While he was being considered for auto-HSCT he developed deep vein thrombosis and a large saddle pulmonary embolism thought to be related to poor mobility and regular IVIGs. He was started on rivaroxaban. Auto-HSCT proceeded uneventfully apart from routine toxicities (Table 2).
Four months after auto-HSCT, his mobility improved from wheelchair to a frame. His legs remained stiff but arms improved significantly so he was able to feed and wash himself. Anti-GAD and anti-glycine antibodies became negative. Repeat blink reflex study post-transplantation showed no evidence of hyperexcitability. He was no longer requiring regular IVIG. His speech remained dysarthric but his swallowing normalised. He was no longer biting his tongue. He stopped all regular medications.
Two years after auto-HSCT he remained off IVIG and had good use of his upper limbs but continued to use a walking frame. EMG and blink reflex studies remained normal and anti-GAD was negative. MRI spectroscopy of the cerebellum showed improvement of his NAA/creatine ratio (Fig. 3).
Discussion
We report our experience in using auto-HSCT to treat four patients with refractory SPS.
All four patients experienced marked improvement in their symptoms and mobility following treatment. In spite of clinical improvement, patient A and C (classical SPS) continued to have high circulating anti-GAD antibody titre. EMG and blink reflex excitability assessment remained abnormal in patient A but normalised in patient C. On the other hand, patient B (classical SPS) and patient D (PERM) became seronegative for circulating antibodies and their EMG and blink reflex studies normalised. Furthermore, MRI spectroscopy values in patient D improved following treatment.
Significantly, with respect to both clinical impact and health resource utilisation all our patients stopped regular IVIG and other forms of immunotherapy with sustained symptomatic and clinical improvement.
The response to auto-HSCT confirms the autoimmune basis of SPS. Continued seropositivity for anti-GAD in half of our patients is comparable to the previous two case reports of using auto-HSCT to treat SPS [8].
The role of anti-GAD in the pathogenesis of SPS remains uncertain. GAD is the rate-limiting step in the decarboxylation of L-glutamate to γ-aminobutyric acid (GABA). Thus, anti-GAD antibodies are postulated to lead to decreased levels of GABA in the brainstem and spinal cord resulting in dis-inhibition and hyper-excitability [12]. However, several observations question anti-GAD pathogenicity in SPS. These include lack of correlation of antibody titres and disease severity [13], absence of anti-GAD antibodies in some SPS patients [14] and reports of clinical improvement with ongoing high circulating antibodies [8].
Interestingly patient B who became anti-GAD negative after auto-HSCT also reported improvement of her diabetic control. Thus, anti-GAD may support the diagnosis of SPS and other autoimmune dysfunction but does not fully explain the pathophysiology.
Glycine receptors are inhibitory receptors found on the neuronal cell surface predominantly in the brainstem and spinal cord. They exert their effects through chloride current resulting in membrane hyperpolarisation and reduction in excitation [15]. Antibodies against the alpha-1 subunit of glycine receptors are, therefore, associated with hyperexcitability. Null mutations in glycine receptors result in hereditary hyperekplexia characterised by an excessive startle and often muscle rigidity [16].
When anti-glycine receptor antibodies are present, they are typically associated with the PERM variant of SPS [5]. However, anti-glycine receptors antibodies are also found in around 15% of patient with classical SPS patients with uncertain significance [17]. Furthermore, glycine receptor antibodies have been reported to occur in other autoimmune conditions with heterogeneous phenotypes including ataxia, limbic encephalitis and myoclonic epilepsy [16].
The pathogenic roles of B cell and T cell immunity in SPS are similarly not well defined. Intrathecal production of oligoclonal anti-GAD IgG antibodies is continued by active B cells with the help of T cells that are activated by neural antigens [18]. Thus, immuno-ablative therapy to eliminate the dysfunctional immune response is expected to offer benefit. Immuno-ablative chemotherapy is followed by the re-introduction of autologous stem cell graft aiming to restart a new self-tolerant immune system. The CSF was not assayed for the presence of anti-GAD antibodies in our patients, but this should be considered in future studies to assess whether this parameter would correlate with treatment response.
At the time of writing of this case series all our transplanted patients manifested sustained clinical improvement without the need for any form of immunotherapy. Follow-up post-transplant has ranged from 12 months to 3 years. No patient encountered major or unexpected complications. Longer-term benefit of auto-HSCT in SPS remains to be ascertained.
Autologous HSCT has shown promise as a treatment option for a range of treatment-refractory autoimmune neurological conditions such as multiple sclerosis, neuromyelitis optica, myasthenia gravis and chronic inflammatory demyelinating polyneuropathy [10, 19]. Our experience further supports its use for refractory stiff-person syndrome. Auto-HSCT may prove to be a more cost-effective treatment in patients requiring regular treatment with expensive modalities, such as IVIG. Further work is warranted to establish long-term safety, efficacy and cost-effectiveness of auto-HSCT in SPS, along with optimising patient selection and transplant technique. This calls for collaboration between centres that provide this service.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary material 1 (MP4 82628 kb)
Supplementary material 2 (MP4 5421 kb)
Acknowledgements
We acknowledge the support of the NIHR Sheffield biomedical research centre and clinical trial unit.
Author contributions
LKI assessed patients, collected data, drafted and revised the first manuscript. AT assessed patients, collected data and revised the manuscript. JS, MH, BS assessed patients, supervised and delivered treatment, conceived the report and revised the manuscript. HJ delivered treatment, coordinated assessments, revised the manuscript. PS conducted neurophysiological assessment, provided neurophysiology figures and revised the manuscript. AC assessed patients, supervised and delivered treatment and revised the manuscript.
Funding
Individual funding requests were made from the NHS for UK patients.
Availability of data and material
Available.
Compliance with ethical standards
Conflicts of interest
Lewis Kass-Iliyya declares no conflict of interest. John A Snowden declares speaker fees from Jazz, Gilead, Mallinckrodt and Janssen. Alice Thorpe declares no conflict of interest. Helen Jessop declares no conflict of interest. Andrew D Chantry declares no conflict of interest. Ptolemaios Sarrigiannis declares no conflict of interest. Marios Hadjivassiliou declares no conflict of interest. Basil Sharrack declares no conflict of interest.
Ethical statement
The manuscript does not contain clinical studies. The patient whose videos are included in the electronic supplementary material gave their consent for the videos to be used in this publication. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 32785838 | 19,729,244 | 2021-01 |
What was the dosage of drug 'HUMAN IMMUNOGLOBULIN G'? | Autologous haematopoietic stem cell transplantation for refractory stiff-person syndrome: the UK experience.
Stiff Person Syndrome (SPS) is a rare immune-mediated disabling neurological disorder characterised by muscle spasms and high GAD antibodies. There are only a few case reports of autologous haematopoietic stem cell transplantation (auto-HSCT) as a treatment for SPS.
OBJECTIVE
To describe the UK experience of treating refractory SPS with auto-HSCT.
METHODS
Between 2015 and 2019, 10 patients with SPS were referred to our institution for consideration of auto-HSCT. Eight patients were deemed suitable for autograft and four were treated. Of the treated patients, three had classical SPS and one had the progressive encephalomyelitis with rigidity and myoclonus variant. All patients were significantly disabled and had failed conventional immunosuppressive therapy. Patients were mobilised with Cyclophosphamide (Cy) 2 g/m2 + G-CSF and conditioned with Cy 200 mg/kg + ATG followed by auto-HSCT.
RESULTS
Despite their significantly reduced performance status, all patients tolerated the procedure with no unexpected toxicities. Following autograft, all patients improved symptomatically and stopped all forms of immunosuppressive therapies. Two patients were able to ambulate independently from being wheelchair dependent. One patient's walking distance improved from 300 meters to 5 miles and one patient's ambulation improved from being confined to a wheelchair to be able to walk with a frame. Two patients became seronegative for anti-GAD antibodies and normalised their neurophysiological abnormalities.
CONCLUSIONS
Auto-HSCT is an intensive but well tolerated and effective treatment option for patients with SPS refractory to conventional immunotherapy. Further work is warranted to optimise patient selection and establish the efficacy, long-term safety, and cost-effectiveness of this treatment.
Introduction
Stiff person syndrome (SPS) is a rare autoimmune neurological disorder characterised by progressive axial muscle stiffness, central nervous system hyper-excitability, and stimulus sensitive painful muscle spasms. Needle electromyography (EMG) often shows continuous motor unit activity at rest [1, 2]. The combination of these features represents the classical form of SPS which is associated with antibodies against glutamic acid decarboxylase (anti-GAD) in around 70% of cases [3].
Other variants include focal or segmental SPS (stiff limb or stiff trunk), para-neoplastic SPS and progressive encephalomyelitis with rigidity and myoclonus (PERM), which in addition to the classic symptoms of SPS, manifests with brainstem signs, hyperekplexia, myoclonus, ataxia and dysautonomia. PERM is associated with anti-glycine receptor antibodies and is reported to be more responsive to immunotherapy [4–6]. Stiff Person Spectrum Disorder has recently been suggested as an overarching term to encompass the various clinical presentations of this condition.
The direct pathological role of the anti-GAD and anti-glycine receptors antibodies is uncertain. The immune-mediated pathogenesis of SPS is evidenced by co-existing autoimmune diseases and partial response to treatments such as intravenous immunoglobulin (IVIG), plasmapheresis and other immunosuppressive therapies including rituximab, mycophenolate and azathioprine [4]. Symptomatic improvement can be achieved using agents such as diazepam, dantrolene, gabapentin or baclofen. Nonetheless, SPS remains a significantly disabling condition with over half of patients requiring long term mobility aids [7].
Autologous Haematopoietic Stem Cell Transplantation (auto-HSCT) has been reported as a treatment option in a limited number of SPS patients with promising results [8]. Here we describe the UK’s experience in using auto-HSCT to treat patients with refractory SPS.
Methods
Between 2015 and 2019 ten patients with SPS were referred to our institution, one of three national referral centres in the UK, for consideration of auto-HSCT from different UK and European centres. Patients’ clinical characteristics and outcomes are summarised in Table 1. All patients were assessed in a joint neurology and haematology transplant clinic. Before considering auto-HSCT the following criteria needed to be met: (1) established diagnosis of SPS; (2) significant disability secondary to SPS; (3) failure of at least one form of immunotherapy; and (4) absence of significant co-morbidities that would increase mortality risk associated with auto-HSCT. Funding requests from the NHS were made for UK patients.Table 1 Summary of patients’ demographics, clinical phenotypes, neurophysiological and serological profiles, treatments tried and outcomes of patients with Stiff Person Syndrome (SPS) referred for consideration of auto-HSCT
Patient Age/gender SPS phenotype Co-morbidities EMG/blink reflex Antibodies Immunotherapy tried Disease duration before HSCT Neurological outcome after HSCT
A 36/F Classical SPS None Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
8 years Two years from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG remain positive
B 48/F Classical SPS Pulmonary sarcoidosis
Type 1 diabetes
Peripheral neuropathy
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
4 years One year from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG became negative
C 37/F Classical SPS Type 1 diabetes Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
9 years Nine months from HSCT:
Marked clinical improvement (from walking 300 meters to 5 miles)
No further immunotherapy needed
Anti-GAD and EMG remain positive
D 52/M PERM & Gluten ataxia Pulmonary embolism Blink reflex hyperexcitability GAD 372 U/ml
Glycine positive
Anti-gliadin positive
IVIG
Plasmapheresis
5 years Three years from HSCT:
Partial clinical improvement (wheelchair to frame)
No further immunotherapy needed
Anti-GAD, anti-glycine and anti-gliadin became negative
Blink reflex normalised
E 44/M Classical SPS Type 1 diabetes
Gluten sensitivity
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
Mycophenolate
7 years Not transplanted as condition stable on mycophenolate
F 70/F Classical SPS Type 1 diabetes
Hypothyroidism
Coeliac disease
Bronchiectasis with haemophilus colonisation and lobectomy.
Continuous motor unit activity GAD > 2000 U/ml IVIG (not tolerated)
Azathioprine
Methotrexate
20 years Not transplanted due to co-existing lung disease
G 47/M PERM Recurrent thrombosis of AV fistula. Continuous motor unit activity in paraspinal muscles GAD negative
Glycine negative
IVIG
Plasmapheresis
Azathioprine
Mycophenolate
9 years Not transplanted
Funding declined
H 53/F Classical SPS Type 1 diabetes
Hypothyroidism
Gluten sensitivity
Psoriatic arthropathy
Sacral abscess
Recurrent sebaceous cysts
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml
Anti-TPO 397 U/ml
IVIG 15 years Not transplanted
Funding declined
Later died from pneumonia (autopsy was not done)
I 35/F Classical SPS Deep venous thrombosis
Heparin-induced thrombocytopenia
Continuous motor unit activity GAD > 2000 U/ml IVIG
Plasmapheresis
2 years Not transplanted
Ongoing assessment
J 48/F Classical SPS None Continuous motor unit activity GAD > 2000 U/ml IVIG
Mycophenolate
3 years Not transplanted
Ongoing assessment
PERM Progressive Encephalomyelitis, Rigidity and Myoclonus, Auto-HSCT autologous haematopoietic stem cell transplantation, GAD glutamic acid decarboxylase, EMG electromyography, IVIG intravenous Immunoglobulin
Patients deemed suitable for auto-HSCT underwent detailed assessments including MRI of the brain and spine, nerve conduction studies, needle EMG to assess spontaneous motor unit activity and blink reflex study to assess brainstem hyperexcitability. Autoimmune screening included antinuclear, para-neoplastic, anti-GAD and anti-glycine antibodies as well as immunoglobulins and protein electrophoresis. Gluten sensitivity screening was undertaken including anti-gliadin antibodies, anti-TTG antibodies and anti-endomysial antibodies. This is because there is an overlap between anti-GAD associated disease and gluten sensitivity [9]. Infection screening included HIV, Hepatitis B & C, VZV, CMV, EBV, Toxoplasmosis and VDRL. Other baseline pre-transplant assessments included echocardiogram and pulmonary function tests.
Of the 10 patients referred, one was found to be stable on mycophenolate and was declined transplant (patient E), and another was declined due to significant co-morbidities conferring an unacceptable risk (patient F). Eight patients were deemed suitable for auto-HSCT. Two patients did not proceed to transplant because funding requests were declined by their health authority (patient G and H). Patient H subsequently died from a chest infection. Two patients are currently being assessed (patient I and J).
Four patients proceeded to auto-HSCT (patient A, B, C and D). Patient A, B and C had classical SPS. Patient D had the PERM variant of SPS.
In accordance with current auto-HSCT guidelines [10] patients received a standard regimen, with stem cell mobilisation consisting of cyclophosphamide 2 g/m2 and G-CSF followed by apheresis to achieve a minimum CD34+ stem cell dose of 2 × 106/kg. Auto-HSCT conditioning regimen was cyclophosphamide 200 mg/kg (total dose, given as 50 mg/kg over days − 5 to − 2) with rabbit anti-thymocyte globulin (ATG, Thymoglobulin) total dose 6.0 mg/kg (given over days − 5 to − 2 as 0.5, 1.0, 1.5 and 1.5 mg/kg respectively with methylprednisolone cover) after which autologous peripheral blood stem cells were infused (on day 0). This is a non-myeloablative regimen which is similar to the one used by Dr Burt in Chicago for the treatment of this condition except that rituximab was not included in our regimen [11].
Data related to the duration of hospital stay, engraftment periods and complications of those who proceeded to auto-HSCT are summarised in Table 2. All patients were followed every 6-9 months in a joint neurology and haematology clinic.Table 2 Summary of data relating length of hospital stay, engraftment time and complications of autologous haematopoietic stem cell transplantation (auto-HSCT) in the four patients treated for refractory stiff person syndrome
Patient Age/Gender Complications during priming and harvesting Engraftment time after auto-HSCT (neutrophils > 0.5 × 109/L and platelets > 20 × 109/L) Length of hospital stay for auto-HSCT Required blood products/ transfusions Complications during auto-HSCT Long term sequelae
A 36/F Headache
E.coli UTI
Pain
Neutrophils:
13 days
Platelets:
12 days
26 days Yes Enterococcus UTI
Pulmonary embolism
Mucositis and rectal bleeding
Post-menopausal symptoms
Alive with no complications
B 48/F None Neutrophils:
11 days
Platelets:
never dropped below 50
18 days No ESBL UTI
Transient exacerbation of diabetes due to steroids
Alive with no complications
C 37/F Gram-negative pantoea agglomerans from Hickman line-treated successfully with antibiotics Neutrophils:
14 days
Platelets:
13 days
21 days Yes Febrile neutropenia covered with antibiotics
Transiently deranged LFTs
Transient CMV and EBV viraemia
Alive with no complications
D 52/M None Neutrophils:
11 days
Platelets:
10 days
16 days Yes Coagulase-negative staphylococcus line infection
Transient EBV viraemia
URTI (RSV)
Alive with no complications
Transplanted patients
Patient A
36-year-old female with no past medical history developed lower limbs and para-spinal muscle spasms that progressed over 3 months. Severe muscle spasms leading to arching of her back were triggered by sudden noise or cutaneous touch. Her symptoms continued to progress and she became wheelchair-bound 6 months later.
MRI of the neuroaxis and CSF examination were normal. Anti-GAD antibodies were positive (> 2000 U/ml). She was diagnosed with the classical form of SPS. She responded partially to plasmapheresis at the referring centre but continued to require very frequent treatments and was therefore started on IVIG.
When she was reviewed at our institution, she was severely disabled by her symptoms requiring regular IVIG treatments at a dose of 90 g every 12 days. She was taking regular diazepam at a dose of 30 mg per day and morphine up to 60 mg a day to control pain. On examination, she had brisk reflexes and severe clonus. She was exquisitely touch-sensitive which induced severe prolonged painful muscle spasms. The muscle spasms were severe enough to compromise her breathing and she required intermittent oxygen. EMG showed continuous muscle fibre activity. Blink reflex study was abnormal with marked amplification of the R2 component recorded following test stimulus in keeping with brainstem hyperexcitability (Fig. 2A). Given her extreme stimulus sensitivity, she underwent EEG/EMG polygraphy recording which captured exaggerated startle response to auditory stimuli in keeping with brainstem hyperexcitability (Fig. 1). The rest of her work-up and immunology screen were negative.Fig. 1 EEG/EMG polygraphy recording of patient A with classical stiff-person syndrome capturing exaggerated startle response to an unanticipated auditory stimulus. Low intensity unanticipated auditory stimulus around 50 dB elicited prominent muscle jerks (within 92 ms from stimulus presentation) followed by protracted spasms in multiple muscle groups. Obc orbicularis Oculi, Obr orbicularis oris, Mass massetter, Stern sternocleidomastoid, Trap trapezius, Delt deltoid, UPA upper abdominals, TA tibialis anterior, STAR sensor marking the onset of the unanticipated auditory stimulus
She received auto-HSCT 8 years from the onset of her symptoms. Transplantation proceeded with no unexpected complications apart from routine toxicities (Table 2).
When reviewed 5 months after auto-HSCT, the majority of her neurological symptoms had improved significantly. She was ambulating independently and required no further IVIG but continued to take diazepam. She had mild startle responses. Anti-GAD antibodies remained positive at > 2000 U/ml.
Repeat EMG undertaken a year post-auto-HSCT remained abnormal with continuous motor unit activity. Blink reflex study with short interstimulus intervals was not possible as immediately following the first electrical stimulus protracted contraction of facial muscle tended to emerge. Therefore, no meaningful comparison could be made with the previous study. Overall, the neurophysiological assessment continued to show features in keeping with SPS despite the clinical improvement.
She was reviewed again 2 years following auto-HSCT and was noted to have remained off all immunotherapy and was able to walk independently. She reported occasional muscle spasms affecting her arms and legs and poor exercise tolerance. Neurological examination was normal. She declined repeat neurophysiological assessment. Her anti-GAD antibodies remained positive.
Patient B
Forty-eight-year-old female with a past medical history of type 1 diabetes, diabetic neuropathy and pulmonary sarcoidosis presented with intermittent muscle spasms affecting all four limbs. The spasms progressed gradually causing increasing difficulties with her mobility over a period of 4 years. At that point, she was mostly wheelchair-bound and only able to ambulate indoors with the help of a frame (supplementary electronic material). Painful muscle spasms were triggered by cutaneous touching. Prior to her referral to our institution she had been diagnosed with stiff person syndrome and was started on IVIG which helped her symptoms. However, she was requiring an infusion every 2 weeks. Subsequently, two doses of rituximab were given which improved her symptoms but did not reduce the need for regular IVIG. She was reliant on diazepam and baclofen for symptomatic relief.
When reviewed at our institution she was noted to have intermittent sustained muscle spasms on examination. She also had clinical signs of length-dependent peripheral neuropathy which was confirmed on nerve conduction studies. EMG displayed continuous motor potential activity and blink reflex demonstrated brainstem hyper-excitability with lack of suppression of R2 component following the test stimulus (Fig. 2Bi). Anti-GAD antibodies were positive (> 2000 U/ml) and the rest of her immunology screen was negative. Infection screening prior to auto-HSCT identified hepatitis B core antigen positivity. In the absence of any risk factors, this was thought to be caused by repeated IVIG infusions. Hepatitis B DNA PCR was negative.Fig. 2 Blink reflex excitability studies at the short inter-stimulus interval between a conditioning and a test stimulus after 160 ms. Single square pulse electrical stimulation of the supraorbital nerve on one side is given at 20–25 mA and 0.2 s pulse width. The polysynaptic R2 response which is recorded following a test electrical stimulus from the contralateral side is typically supressed at such small interstimulus interval in healthy subjects. The least affected by artefact, rectified R2 waveform contralateral to the site of stimulation was used for analysis. In both patient A and patient B (classical stiff person syndrome) the contralateral R2 component that follows the test stimulus is enhanced (area estimates for R2 between cursors S1b/S1e and S2b/S2e are shown in the relevant embedded tables). The pre-HSCT study of patient A shows clear enhancement of the R2 response that follows the test stimulus in comparison to the earlier R2 waveform that followed the conditioning stimulus. For patient B, comparison between the pre-HSCT (Bi) and post-HSCT (Bii) examination shows relative normalisation of blink reflex excitability in the latter; the R2 area following the test stimulus is relatively suppressed in comparison to the R2 area of the conditioning stimulus (Bii). This electrophysiological assessment is used as a semiquantitative assessment of brainstem excitability
Auto-HSCT was undertaken at our institution 4 years into her illness and progressed uneventfully (Table 2). Hepatitis B DNA PCR was pre-emptively monitored throughout her immunosuppression and remained negative.
When reviewed in clinic 6 months after auto-HSCT, her muscle spasms were noted to have improved significantly. She required no further doses of IVIG but continued to use a small dose of Baclofen. She was no longer requiring a wheelchair and started walking with the support of a stick. She continued to suffer from fatigue.
Repeat EMG showed significant improvement with the patient being able to completely suppress all motor unit potential activity in muscles that were previously affected by severe stiffness. The blink reflex excitability studies also improved with a more suppressed R2 component following the test stimulus compared to the R2 component from the conditioning stimulus (Fig. 2Bii). She was able to walk 10 meters in 15.2 s with a stick.
Serologically, anti-GAD antibodies reduced from > 2000 to < 0.5 U/ml.
A year after auto-HSCT her marked improvement continued. She was no longer reporting any spasms and was able to walk independently for long distances (Electronic supplementary material). Her diabetes control also improved and she came off all her anti-diabetic treatments. She walked 10 meters in 9 s without assistance or stopping. A repeat EMG at that point showed no evidence of stiff person syndrome. Anti-GAD antibodies remained negative.
Patient C
Thirty-seven-year-old female with a history of type 1 diabetes. She developed progressive painful muscle spasms affecting her core musculature and limbs, which were not controlled despite high doses of diazepam (30 mg/day) and gabapentin (2700 mg/day). Nine years into her symptoms she was able to walk unaided for a maximum of 300 meters. She struggled with social anxiety due to muscle spasms, which progressed to affect her face and jaw.
Prior to her referral for auto-HSCT the patient had received five courses of IVIG, which provided transient benefit. She had three infusions of rituximab, which did not relieve her symptoms. Azathioprine was not tolerated.
Neurological examination showed marked stiffness of her abdominal and para-spinal muscles. EMG showed continued motor activity in the para-spinal muscles. Blink reflex study showed evidence of brainstem hyperexcitability. Anti-GAD antibodies were positive (> 2000 U/ml). The rest of the immunology, paraneoplastic and infective screens were negative. Auto-HSCT was offered 9 years after symptom onset. There were no major complications from auto-HSCT apart from routine toxicities (Table 2).
Nine months after transplantation the patient reported marked improvement of the severity of her muscle spasms and stiffness. She reported mild fatigue but she was able to walk for up to 5 miles a day. She continued to use diazepam and gabapentin albeit at much lower doses (10 mg of Diazepam/day and 500 mg of Gabapentin/day). Blink reflex study did not show evidence of brainstem hyperexcitability however, limited lumbar paraspinals EMG (patient was needle phobic) showed continued motor potentials. Anti-GAD antibodies remained positive after transplantation.
Patient D
52-year-old male with no significant past medical history presented with progressive asymmetrical muscle stiffness affecting initially the right leg but subsequently other parts of his body. The stiffness progressed over 5 years to involve all four limbs, which significantly impaired his ability to carry out the activities of daily living. Facial muscles involvement interfered with speech and swallowing and he occasionally bit his tongue.
Examination revealed marked muscle rigidity, brisk reflexes and clonus. MRI of the spine showed moderate spondylosis which did not account for the patient’s symptoms. Serological testing for gluten sensitivity revealed positive anti-gliadin antibodies and a gluten-free diet was adopted. MRI of the brain showed mild atrophy of the cerebellar hemispheres. MRI spectroscopy demonstrated low NAA/Creatine ratio of 0.85 from the superior vermis (normal over 1.00) (Fig. 3). CSF examination was normal.Fig. 3 MRI spectroscopy of 52-year-old male with stiff person synonym (PERM - patient D) who underwent autologous haematopoietic stem cell transplantation (auto-HSCT). The MRI demonstrate cerebellar involvement showing NAA/creatine ratio of 0.85 from the superior vermis (normal above 1.00) before auto-HSCT which improved to 0.93 after auto-HSCT
Nerve conduction studies were normal. EMG did not show continuous motor unit activity however, blink reflex studies showed evidence of hyper-excitability. Anti-GAD antibodies were positive at 372 U/ml. Anti-glycine antibodies were positive. Paraneoplastic, anti-NMDA and anti-VGKC antibodies were negative.
He was diagnosed with the PERM variant of SPS on the basis of the clinical features and the serology results. He was started on IVIG which resulted in partial clinical improvement. However, he continued to require infusions at a dose of 150 g every 3 months. He could not tolerate Diazepam, Baclofen, Tizanidine or Dantrolene. He did not tolerate mycophenolate which he tried for 2 months. Over the subsequent years, he became wheelchair-bound and dependent on IVIG which he continued for a year.
Auto-HSCT was offered 5 years after symptom onset. While he was being considered for auto-HSCT he developed deep vein thrombosis and a large saddle pulmonary embolism thought to be related to poor mobility and regular IVIGs. He was started on rivaroxaban. Auto-HSCT proceeded uneventfully apart from routine toxicities (Table 2).
Four months after auto-HSCT, his mobility improved from wheelchair to a frame. His legs remained stiff but arms improved significantly so he was able to feed and wash himself. Anti-GAD and anti-glycine antibodies became negative. Repeat blink reflex study post-transplantation showed no evidence of hyperexcitability. He was no longer requiring regular IVIG. His speech remained dysarthric but his swallowing normalised. He was no longer biting his tongue. He stopped all regular medications.
Two years after auto-HSCT he remained off IVIG and had good use of his upper limbs but continued to use a walking frame. EMG and blink reflex studies remained normal and anti-GAD was negative. MRI spectroscopy of the cerebellum showed improvement of his NAA/creatine ratio (Fig. 3).
Discussion
We report our experience in using auto-HSCT to treat four patients with refractory SPS.
All four patients experienced marked improvement in their symptoms and mobility following treatment. In spite of clinical improvement, patient A and C (classical SPS) continued to have high circulating anti-GAD antibody titre. EMG and blink reflex excitability assessment remained abnormal in patient A but normalised in patient C. On the other hand, patient B (classical SPS) and patient D (PERM) became seronegative for circulating antibodies and their EMG and blink reflex studies normalised. Furthermore, MRI spectroscopy values in patient D improved following treatment.
Significantly, with respect to both clinical impact and health resource utilisation all our patients stopped regular IVIG and other forms of immunotherapy with sustained symptomatic and clinical improvement.
The response to auto-HSCT confirms the autoimmune basis of SPS. Continued seropositivity for anti-GAD in half of our patients is comparable to the previous two case reports of using auto-HSCT to treat SPS [8].
The role of anti-GAD in the pathogenesis of SPS remains uncertain. GAD is the rate-limiting step in the decarboxylation of L-glutamate to γ-aminobutyric acid (GABA). Thus, anti-GAD antibodies are postulated to lead to decreased levels of GABA in the brainstem and spinal cord resulting in dis-inhibition and hyper-excitability [12]. However, several observations question anti-GAD pathogenicity in SPS. These include lack of correlation of antibody titres and disease severity [13], absence of anti-GAD antibodies in some SPS patients [14] and reports of clinical improvement with ongoing high circulating antibodies [8].
Interestingly patient B who became anti-GAD negative after auto-HSCT also reported improvement of her diabetic control. Thus, anti-GAD may support the diagnosis of SPS and other autoimmune dysfunction but does not fully explain the pathophysiology.
Glycine receptors are inhibitory receptors found on the neuronal cell surface predominantly in the brainstem and spinal cord. They exert their effects through chloride current resulting in membrane hyperpolarisation and reduction in excitation [15]. Antibodies against the alpha-1 subunit of glycine receptors are, therefore, associated with hyperexcitability. Null mutations in glycine receptors result in hereditary hyperekplexia characterised by an excessive startle and often muscle rigidity [16].
When anti-glycine receptor antibodies are present, they are typically associated with the PERM variant of SPS [5]. However, anti-glycine receptors antibodies are also found in around 15% of patient with classical SPS patients with uncertain significance [17]. Furthermore, glycine receptor antibodies have been reported to occur in other autoimmune conditions with heterogeneous phenotypes including ataxia, limbic encephalitis and myoclonic epilepsy [16].
The pathogenic roles of B cell and T cell immunity in SPS are similarly not well defined. Intrathecal production of oligoclonal anti-GAD IgG antibodies is continued by active B cells with the help of T cells that are activated by neural antigens [18]. Thus, immuno-ablative therapy to eliminate the dysfunctional immune response is expected to offer benefit. Immuno-ablative chemotherapy is followed by the re-introduction of autologous stem cell graft aiming to restart a new self-tolerant immune system. The CSF was not assayed for the presence of anti-GAD antibodies in our patients, but this should be considered in future studies to assess whether this parameter would correlate with treatment response.
At the time of writing of this case series all our transplanted patients manifested sustained clinical improvement without the need for any form of immunotherapy. Follow-up post-transplant has ranged from 12 months to 3 years. No patient encountered major or unexpected complications. Longer-term benefit of auto-HSCT in SPS remains to be ascertained.
Autologous HSCT has shown promise as a treatment option for a range of treatment-refractory autoimmune neurological conditions such as multiple sclerosis, neuromyelitis optica, myasthenia gravis and chronic inflammatory demyelinating polyneuropathy [10, 19]. Our experience further supports its use for refractory stiff-person syndrome. Auto-HSCT may prove to be a more cost-effective treatment in patients requiring regular treatment with expensive modalities, such as IVIG. Further work is warranted to establish long-term safety, efficacy and cost-effectiveness of auto-HSCT in SPS, along with optimising patient selection and transplant technique. This calls for collaboration between centres that provide this service.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary material 1 (MP4 82628 kb)
Supplementary material 2 (MP4 5421 kb)
Acknowledgements
We acknowledge the support of the NIHR Sheffield biomedical research centre and clinical trial unit.
Author contributions
LKI assessed patients, collected data, drafted and revised the first manuscript. AT assessed patients, collected data and revised the manuscript. JS, MH, BS assessed patients, supervised and delivered treatment, conceived the report and revised the manuscript. HJ delivered treatment, coordinated assessments, revised the manuscript. PS conducted neurophysiological assessment, provided neurophysiology figures and revised the manuscript. AC assessed patients, supervised and delivered treatment and revised the manuscript.
Funding
Individual funding requests were made from the NHS for UK patients.
Availability of data and material
Available.
Compliance with ethical standards
Conflicts of interest
Lewis Kass-Iliyya declares no conflict of interest. John A Snowden declares speaker fees from Jazz, Gilead, Mallinckrodt and Janssen. Alice Thorpe declares no conflict of interest. Helen Jessop declares no conflict of interest. Andrew D Chantry declares no conflict of interest. Ptolemaios Sarrigiannis declares no conflict of interest. Marios Hadjivassiliou declares no conflict of interest. Basil Sharrack declares no conflict of interest.
Ethical statement
The manuscript does not contain clinical studies. The patient whose videos are included in the electronic supplementary material gave their consent for the videos to be used in this publication. | UNK UNK, QOW | DrugDosageText | CC BY | 32785838 | 19,779,285 | 2021-01 |
What was the dosage of drug 'RITUXIMAB'? | Autologous haematopoietic stem cell transplantation for refractory stiff-person syndrome: the UK experience.
Stiff Person Syndrome (SPS) is a rare immune-mediated disabling neurological disorder characterised by muscle spasms and high GAD antibodies. There are only a few case reports of autologous haematopoietic stem cell transplantation (auto-HSCT) as a treatment for SPS.
OBJECTIVE
To describe the UK experience of treating refractory SPS with auto-HSCT.
METHODS
Between 2015 and 2019, 10 patients with SPS were referred to our institution for consideration of auto-HSCT. Eight patients were deemed suitable for autograft and four were treated. Of the treated patients, three had classical SPS and one had the progressive encephalomyelitis with rigidity and myoclonus variant. All patients were significantly disabled and had failed conventional immunosuppressive therapy. Patients were mobilised with Cyclophosphamide (Cy) 2 g/m2 + G-CSF and conditioned with Cy 200 mg/kg + ATG followed by auto-HSCT.
RESULTS
Despite their significantly reduced performance status, all patients tolerated the procedure with no unexpected toxicities. Following autograft, all patients improved symptomatically and stopped all forms of immunosuppressive therapies. Two patients were able to ambulate independently from being wheelchair dependent. One patient's walking distance improved from 300 meters to 5 miles and one patient's ambulation improved from being confined to a wheelchair to be able to walk with a frame. Two patients became seronegative for anti-GAD antibodies and normalised their neurophysiological abnormalities.
CONCLUSIONS
Auto-HSCT is an intensive but well tolerated and effective treatment option for patients with SPS refractory to conventional immunotherapy. Further work is warranted to optimise patient selection and establish the efficacy, long-term safety, and cost-effectiveness of this treatment.
Introduction
Stiff person syndrome (SPS) is a rare autoimmune neurological disorder characterised by progressive axial muscle stiffness, central nervous system hyper-excitability, and stimulus sensitive painful muscle spasms. Needle electromyography (EMG) often shows continuous motor unit activity at rest [1, 2]. The combination of these features represents the classical form of SPS which is associated with antibodies against glutamic acid decarboxylase (anti-GAD) in around 70% of cases [3].
Other variants include focal or segmental SPS (stiff limb or stiff trunk), para-neoplastic SPS and progressive encephalomyelitis with rigidity and myoclonus (PERM), which in addition to the classic symptoms of SPS, manifests with brainstem signs, hyperekplexia, myoclonus, ataxia and dysautonomia. PERM is associated with anti-glycine receptor antibodies and is reported to be more responsive to immunotherapy [4–6]. Stiff Person Spectrum Disorder has recently been suggested as an overarching term to encompass the various clinical presentations of this condition.
The direct pathological role of the anti-GAD and anti-glycine receptors antibodies is uncertain. The immune-mediated pathogenesis of SPS is evidenced by co-existing autoimmune diseases and partial response to treatments such as intravenous immunoglobulin (IVIG), plasmapheresis and other immunosuppressive therapies including rituximab, mycophenolate and azathioprine [4]. Symptomatic improvement can be achieved using agents such as diazepam, dantrolene, gabapentin or baclofen. Nonetheless, SPS remains a significantly disabling condition with over half of patients requiring long term mobility aids [7].
Autologous Haematopoietic Stem Cell Transplantation (auto-HSCT) has been reported as a treatment option in a limited number of SPS patients with promising results [8]. Here we describe the UK’s experience in using auto-HSCT to treat patients with refractory SPS.
Methods
Between 2015 and 2019 ten patients with SPS were referred to our institution, one of three national referral centres in the UK, for consideration of auto-HSCT from different UK and European centres. Patients’ clinical characteristics and outcomes are summarised in Table 1. All patients were assessed in a joint neurology and haematology transplant clinic. Before considering auto-HSCT the following criteria needed to be met: (1) established diagnosis of SPS; (2) significant disability secondary to SPS; (3) failure of at least one form of immunotherapy; and (4) absence of significant co-morbidities that would increase mortality risk associated with auto-HSCT. Funding requests from the NHS were made for UK patients.Table 1 Summary of patients’ demographics, clinical phenotypes, neurophysiological and serological profiles, treatments tried and outcomes of patients with Stiff Person Syndrome (SPS) referred for consideration of auto-HSCT
Patient Age/gender SPS phenotype Co-morbidities EMG/blink reflex Antibodies Immunotherapy tried Disease duration before HSCT Neurological outcome after HSCT
A 36/F Classical SPS None Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
8 years Two years from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG remain positive
B 48/F Classical SPS Pulmonary sarcoidosis
Type 1 diabetes
Peripheral neuropathy
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
4 years One year from HSCT:
Marked clinical improvement (wheelchair to independent walking)
No further immunotherapy needed
Anti-GAD and EMG became negative
C 37/F Classical SPS Type 1 diabetes Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Rituximab
9 years Nine months from HSCT:
Marked clinical improvement (from walking 300 meters to 5 miles)
No further immunotherapy needed
Anti-GAD and EMG remain positive
D 52/M PERM & Gluten ataxia Pulmonary embolism Blink reflex hyperexcitability GAD 372 U/ml
Glycine positive
Anti-gliadin positive
IVIG
Plasmapheresis
5 years Three years from HSCT:
Partial clinical improvement (wheelchair to frame)
No further immunotherapy needed
Anti-GAD, anti-glycine and anti-gliadin became negative
Blink reflex normalised
E 44/M Classical SPS Type 1 diabetes
Gluten sensitivity
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml IVIG
Plasmapheresis
Mycophenolate
7 years Not transplanted as condition stable on mycophenolate
F 70/F Classical SPS Type 1 diabetes
Hypothyroidism
Coeliac disease
Bronchiectasis with haemophilus colonisation and lobectomy.
Continuous motor unit activity GAD > 2000 U/ml IVIG (not tolerated)
Azathioprine
Methotrexate
20 years Not transplanted due to co-existing lung disease
G 47/M PERM Recurrent thrombosis of AV fistula. Continuous motor unit activity in paraspinal muscles GAD negative
Glycine negative
IVIG
Plasmapheresis
Azathioprine
Mycophenolate
9 years Not transplanted
Funding declined
H 53/F Classical SPS Type 1 diabetes
Hypothyroidism
Gluten sensitivity
Psoriatic arthropathy
Sacral abscess
Recurrent sebaceous cysts
Continuous motor unit activity/blink reflex hyperexcitability GAD > 2000 U/ml
Anti-TPO 397 U/ml
IVIG 15 years Not transplanted
Funding declined
Later died from pneumonia (autopsy was not done)
I 35/F Classical SPS Deep venous thrombosis
Heparin-induced thrombocytopenia
Continuous motor unit activity GAD > 2000 U/ml IVIG
Plasmapheresis
2 years Not transplanted
Ongoing assessment
J 48/F Classical SPS None Continuous motor unit activity GAD > 2000 U/ml IVIG
Mycophenolate
3 years Not transplanted
Ongoing assessment
PERM Progressive Encephalomyelitis, Rigidity and Myoclonus, Auto-HSCT autologous haematopoietic stem cell transplantation, GAD glutamic acid decarboxylase, EMG electromyography, IVIG intravenous Immunoglobulin
Patients deemed suitable for auto-HSCT underwent detailed assessments including MRI of the brain and spine, nerve conduction studies, needle EMG to assess spontaneous motor unit activity and blink reflex study to assess brainstem hyperexcitability. Autoimmune screening included antinuclear, para-neoplastic, anti-GAD and anti-glycine antibodies as well as immunoglobulins and protein electrophoresis. Gluten sensitivity screening was undertaken including anti-gliadin antibodies, anti-TTG antibodies and anti-endomysial antibodies. This is because there is an overlap between anti-GAD associated disease and gluten sensitivity [9]. Infection screening included HIV, Hepatitis B & C, VZV, CMV, EBV, Toxoplasmosis and VDRL. Other baseline pre-transplant assessments included echocardiogram and pulmonary function tests.
Of the 10 patients referred, one was found to be stable on mycophenolate and was declined transplant (patient E), and another was declined due to significant co-morbidities conferring an unacceptable risk (patient F). Eight patients were deemed suitable for auto-HSCT. Two patients did not proceed to transplant because funding requests were declined by their health authority (patient G and H). Patient H subsequently died from a chest infection. Two patients are currently being assessed (patient I and J).
Four patients proceeded to auto-HSCT (patient A, B, C and D). Patient A, B and C had classical SPS. Patient D had the PERM variant of SPS.
In accordance with current auto-HSCT guidelines [10] patients received a standard regimen, with stem cell mobilisation consisting of cyclophosphamide 2 g/m2 and G-CSF followed by apheresis to achieve a minimum CD34+ stem cell dose of 2 × 106/kg. Auto-HSCT conditioning regimen was cyclophosphamide 200 mg/kg (total dose, given as 50 mg/kg over days − 5 to − 2) with rabbit anti-thymocyte globulin (ATG, Thymoglobulin) total dose 6.0 mg/kg (given over days − 5 to − 2 as 0.5, 1.0, 1.5 and 1.5 mg/kg respectively with methylprednisolone cover) after which autologous peripheral blood stem cells were infused (on day 0). This is a non-myeloablative regimen which is similar to the one used by Dr Burt in Chicago for the treatment of this condition except that rituximab was not included in our regimen [11].
Data related to the duration of hospital stay, engraftment periods and complications of those who proceeded to auto-HSCT are summarised in Table 2. All patients were followed every 6-9 months in a joint neurology and haematology clinic.Table 2 Summary of data relating length of hospital stay, engraftment time and complications of autologous haematopoietic stem cell transplantation (auto-HSCT) in the four patients treated for refractory stiff person syndrome
Patient Age/Gender Complications during priming and harvesting Engraftment time after auto-HSCT (neutrophils > 0.5 × 109/L and platelets > 20 × 109/L) Length of hospital stay for auto-HSCT Required blood products/ transfusions Complications during auto-HSCT Long term sequelae
A 36/F Headache
E.coli UTI
Pain
Neutrophils:
13 days
Platelets:
12 days
26 days Yes Enterococcus UTI
Pulmonary embolism
Mucositis and rectal bleeding
Post-menopausal symptoms
Alive with no complications
B 48/F None Neutrophils:
11 days
Platelets:
never dropped below 50
18 days No ESBL UTI
Transient exacerbation of diabetes due to steroids
Alive with no complications
C 37/F Gram-negative pantoea agglomerans from Hickman line-treated successfully with antibiotics Neutrophils:
14 days
Platelets:
13 days
21 days Yes Febrile neutropenia covered with antibiotics
Transiently deranged LFTs
Transient CMV and EBV viraemia
Alive with no complications
D 52/M None Neutrophils:
11 days
Platelets:
10 days
16 days Yes Coagulase-negative staphylococcus line infection
Transient EBV viraemia
URTI (RSV)
Alive with no complications
Transplanted patients
Patient A
36-year-old female with no past medical history developed lower limbs and para-spinal muscle spasms that progressed over 3 months. Severe muscle spasms leading to arching of her back were triggered by sudden noise or cutaneous touch. Her symptoms continued to progress and she became wheelchair-bound 6 months later.
MRI of the neuroaxis and CSF examination were normal. Anti-GAD antibodies were positive (> 2000 U/ml). She was diagnosed with the classical form of SPS. She responded partially to plasmapheresis at the referring centre but continued to require very frequent treatments and was therefore started on IVIG.
When she was reviewed at our institution, she was severely disabled by her symptoms requiring regular IVIG treatments at a dose of 90 g every 12 days. She was taking regular diazepam at a dose of 30 mg per day and morphine up to 60 mg a day to control pain. On examination, she had brisk reflexes and severe clonus. She was exquisitely touch-sensitive which induced severe prolonged painful muscle spasms. The muscle spasms were severe enough to compromise her breathing and she required intermittent oxygen. EMG showed continuous muscle fibre activity. Blink reflex study was abnormal with marked amplification of the R2 component recorded following test stimulus in keeping with brainstem hyperexcitability (Fig. 2A). Given her extreme stimulus sensitivity, she underwent EEG/EMG polygraphy recording which captured exaggerated startle response to auditory stimuli in keeping with brainstem hyperexcitability (Fig. 1). The rest of her work-up and immunology screen were negative.Fig. 1 EEG/EMG polygraphy recording of patient A with classical stiff-person syndrome capturing exaggerated startle response to an unanticipated auditory stimulus. Low intensity unanticipated auditory stimulus around 50 dB elicited prominent muscle jerks (within 92 ms from stimulus presentation) followed by protracted spasms in multiple muscle groups. Obc orbicularis Oculi, Obr orbicularis oris, Mass massetter, Stern sternocleidomastoid, Trap trapezius, Delt deltoid, UPA upper abdominals, TA tibialis anterior, STAR sensor marking the onset of the unanticipated auditory stimulus
She received auto-HSCT 8 years from the onset of her symptoms. Transplantation proceeded with no unexpected complications apart from routine toxicities (Table 2).
When reviewed 5 months after auto-HSCT, the majority of her neurological symptoms had improved significantly. She was ambulating independently and required no further IVIG but continued to take diazepam. She had mild startle responses. Anti-GAD antibodies remained positive at > 2000 U/ml.
Repeat EMG undertaken a year post-auto-HSCT remained abnormal with continuous motor unit activity. Blink reflex study with short interstimulus intervals was not possible as immediately following the first electrical stimulus protracted contraction of facial muscle tended to emerge. Therefore, no meaningful comparison could be made with the previous study. Overall, the neurophysiological assessment continued to show features in keeping with SPS despite the clinical improvement.
She was reviewed again 2 years following auto-HSCT and was noted to have remained off all immunotherapy and was able to walk independently. She reported occasional muscle spasms affecting her arms and legs and poor exercise tolerance. Neurological examination was normal. She declined repeat neurophysiological assessment. Her anti-GAD antibodies remained positive.
Patient B
Forty-eight-year-old female with a past medical history of type 1 diabetes, diabetic neuropathy and pulmonary sarcoidosis presented with intermittent muscle spasms affecting all four limbs. The spasms progressed gradually causing increasing difficulties with her mobility over a period of 4 years. At that point, she was mostly wheelchair-bound and only able to ambulate indoors with the help of a frame (supplementary electronic material). Painful muscle spasms were triggered by cutaneous touching. Prior to her referral to our institution she had been diagnosed with stiff person syndrome and was started on IVIG which helped her symptoms. However, she was requiring an infusion every 2 weeks. Subsequently, two doses of rituximab were given which improved her symptoms but did not reduce the need for regular IVIG. She was reliant on diazepam and baclofen for symptomatic relief.
When reviewed at our institution she was noted to have intermittent sustained muscle spasms on examination. She also had clinical signs of length-dependent peripheral neuropathy which was confirmed on nerve conduction studies. EMG displayed continuous motor potential activity and blink reflex demonstrated brainstem hyper-excitability with lack of suppression of R2 component following the test stimulus (Fig. 2Bi). Anti-GAD antibodies were positive (> 2000 U/ml) and the rest of her immunology screen was negative. Infection screening prior to auto-HSCT identified hepatitis B core antigen positivity. In the absence of any risk factors, this was thought to be caused by repeated IVIG infusions. Hepatitis B DNA PCR was negative.Fig. 2 Blink reflex excitability studies at the short inter-stimulus interval between a conditioning and a test stimulus after 160 ms. Single square pulse electrical stimulation of the supraorbital nerve on one side is given at 20–25 mA and 0.2 s pulse width. The polysynaptic R2 response which is recorded following a test electrical stimulus from the contralateral side is typically supressed at such small interstimulus interval in healthy subjects. The least affected by artefact, rectified R2 waveform contralateral to the site of stimulation was used for analysis. In both patient A and patient B (classical stiff person syndrome) the contralateral R2 component that follows the test stimulus is enhanced (area estimates for R2 between cursors S1b/S1e and S2b/S2e are shown in the relevant embedded tables). The pre-HSCT study of patient A shows clear enhancement of the R2 response that follows the test stimulus in comparison to the earlier R2 waveform that followed the conditioning stimulus. For patient B, comparison between the pre-HSCT (Bi) and post-HSCT (Bii) examination shows relative normalisation of blink reflex excitability in the latter; the R2 area following the test stimulus is relatively suppressed in comparison to the R2 area of the conditioning stimulus (Bii). This electrophysiological assessment is used as a semiquantitative assessment of brainstem excitability
Auto-HSCT was undertaken at our institution 4 years into her illness and progressed uneventfully (Table 2). Hepatitis B DNA PCR was pre-emptively monitored throughout her immunosuppression and remained negative.
When reviewed in clinic 6 months after auto-HSCT, her muscle spasms were noted to have improved significantly. She required no further doses of IVIG but continued to use a small dose of Baclofen. She was no longer requiring a wheelchair and started walking with the support of a stick. She continued to suffer from fatigue.
Repeat EMG showed significant improvement with the patient being able to completely suppress all motor unit potential activity in muscles that were previously affected by severe stiffness. The blink reflex excitability studies also improved with a more suppressed R2 component following the test stimulus compared to the R2 component from the conditioning stimulus (Fig. 2Bii). She was able to walk 10 meters in 15.2 s with a stick.
Serologically, anti-GAD antibodies reduced from > 2000 to < 0.5 U/ml.
A year after auto-HSCT her marked improvement continued. She was no longer reporting any spasms and was able to walk independently for long distances (Electronic supplementary material). Her diabetes control also improved and she came off all her anti-diabetic treatments. She walked 10 meters in 9 s without assistance or stopping. A repeat EMG at that point showed no evidence of stiff person syndrome. Anti-GAD antibodies remained negative.
Patient C
Thirty-seven-year-old female with a history of type 1 diabetes. She developed progressive painful muscle spasms affecting her core musculature and limbs, which were not controlled despite high doses of diazepam (30 mg/day) and gabapentin (2700 mg/day). Nine years into her symptoms she was able to walk unaided for a maximum of 300 meters. She struggled with social anxiety due to muscle spasms, which progressed to affect her face and jaw.
Prior to her referral for auto-HSCT the patient had received five courses of IVIG, which provided transient benefit. She had three infusions of rituximab, which did not relieve her symptoms. Azathioprine was not tolerated.
Neurological examination showed marked stiffness of her abdominal and para-spinal muscles. EMG showed continued motor activity in the para-spinal muscles. Blink reflex study showed evidence of brainstem hyperexcitability. Anti-GAD antibodies were positive (> 2000 U/ml). The rest of the immunology, paraneoplastic and infective screens were negative. Auto-HSCT was offered 9 years after symptom onset. There were no major complications from auto-HSCT apart from routine toxicities (Table 2).
Nine months after transplantation the patient reported marked improvement of the severity of her muscle spasms and stiffness. She reported mild fatigue but she was able to walk for up to 5 miles a day. She continued to use diazepam and gabapentin albeit at much lower doses (10 mg of Diazepam/day and 500 mg of Gabapentin/day). Blink reflex study did not show evidence of brainstem hyperexcitability however, limited lumbar paraspinals EMG (patient was needle phobic) showed continued motor potentials. Anti-GAD antibodies remained positive after transplantation.
Patient D
52-year-old male with no significant past medical history presented with progressive asymmetrical muscle stiffness affecting initially the right leg but subsequently other parts of his body. The stiffness progressed over 5 years to involve all four limbs, which significantly impaired his ability to carry out the activities of daily living. Facial muscles involvement interfered with speech and swallowing and he occasionally bit his tongue.
Examination revealed marked muscle rigidity, brisk reflexes and clonus. MRI of the spine showed moderate spondylosis which did not account for the patient’s symptoms. Serological testing for gluten sensitivity revealed positive anti-gliadin antibodies and a gluten-free diet was adopted. MRI of the brain showed mild atrophy of the cerebellar hemispheres. MRI spectroscopy demonstrated low NAA/Creatine ratio of 0.85 from the superior vermis (normal over 1.00) (Fig. 3). CSF examination was normal.Fig. 3 MRI spectroscopy of 52-year-old male with stiff person synonym (PERM - patient D) who underwent autologous haematopoietic stem cell transplantation (auto-HSCT). The MRI demonstrate cerebellar involvement showing NAA/creatine ratio of 0.85 from the superior vermis (normal above 1.00) before auto-HSCT which improved to 0.93 after auto-HSCT
Nerve conduction studies were normal. EMG did not show continuous motor unit activity however, blink reflex studies showed evidence of hyper-excitability. Anti-GAD antibodies were positive at 372 U/ml. Anti-glycine antibodies were positive. Paraneoplastic, anti-NMDA and anti-VGKC antibodies were negative.
He was diagnosed with the PERM variant of SPS on the basis of the clinical features and the serology results. He was started on IVIG which resulted in partial clinical improvement. However, he continued to require infusions at a dose of 150 g every 3 months. He could not tolerate Diazepam, Baclofen, Tizanidine or Dantrolene. He did not tolerate mycophenolate which he tried for 2 months. Over the subsequent years, he became wheelchair-bound and dependent on IVIG which he continued for a year.
Auto-HSCT was offered 5 years after symptom onset. While he was being considered for auto-HSCT he developed deep vein thrombosis and a large saddle pulmonary embolism thought to be related to poor mobility and regular IVIGs. He was started on rivaroxaban. Auto-HSCT proceeded uneventfully apart from routine toxicities (Table 2).
Four months after auto-HSCT, his mobility improved from wheelchair to a frame. His legs remained stiff but arms improved significantly so he was able to feed and wash himself. Anti-GAD and anti-glycine antibodies became negative. Repeat blink reflex study post-transplantation showed no evidence of hyperexcitability. He was no longer requiring regular IVIG. His speech remained dysarthric but his swallowing normalised. He was no longer biting his tongue. He stopped all regular medications.
Two years after auto-HSCT he remained off IVIG and had good use of his upper limbs but continued to use a walking frame. EMG and blink reflex studies remained normal and anti-GAD was negative. MRI spectroscopy of the cerebellum showed improvement of his NAA/creatine ratio (Fig. 3).
Discussion
We report our experience in using auto-HSCT to treat four patients with refractory SPS.
All four patients experienced marked improvement in their symptoms and mobility following treatment. In spite of clinical improvement, patient A and C (classical SPS) continued to have high circulating anti-GAD antibody titre. EMG and blink reflex excitability assessment remained abnormal in patient A but normalised in patient C. On the other hand, patient B (classical SPS) and patient D (PERM) became seronegative for circulating antibodies and their EMG and blink reflex studies normalised. Furthermore, MRI spectroscopy values in patient D improved following treatment.
Significantly, with respect to both clinical impact and health resource utilisation all our patients stopped regular IVIG and other forms of immunotherapy with sustained symptomatic and clinical improvement.
The response to auto-HSCT confirms the autoimmune basis of SPS. Continued seropositivity for anti-GAD in half of our patients is comparable to the previous two case reports of using auto-HSCT to treat SPS [8].
The role of anti-GAD in the pathogenesis of SPS remains uncertain. GAD is the rate-limiting step in the decarboxylation of L-glutamate to γ-aminobutyric acid (GABA). Thus, anti-GAD antibodies are postulated to lead to decreased levels of GABA in the brainstem and spinal cord resulting in dis-inhibition and hyper-excitability [12]. However, several observations question anti-GAD pathogenicity in SPS. These include lack of correlation of antibody titres and disease severity [13], absence of anti-GAD antibodies in some SPS patients [14] and reports of clinical improvement with ongoing high circulating antibodies [8].
Interestingly patient B who became anti-GAD negative after auto-HSCT also reported improvement of her diabetic control. Thus, anti-GAD may support the diagnosis of SPS and other autoimmune dysfunction but does not fully explain the pathophysiology.
Glycine receptors are inhibitory receptors found on the neuronal cell surface predominantly in the brainstem and spinal cord. They exert their effects through chloride current resulting in membrane hyperpolarisation and reduction in excitation [15]. Antibodies against the alpha-1 subunit of glycine receptors are, therefore, associated with hyperexcitability. Null mutations in glycine receptors result in hereditary hyperekplexia characterised by an excessive startle and often muscle rigidity [16].
When anti-glycine receptor antibodies are present, they are typically associated with the PERM variant of SPS [5]. However, anti-glycine receptors antibodies are also found in around 15% of patient with classical SPS patients with uncertain significance [17]. Furthermore, glycine receptor antibodies have been reported to occur in other autoimmune conditions with heterogeneous phenotypes including ataxia, limbic encephalitis and myoclonic epilepsy [16].
The pathogenic roles of B cell and T cell immunity in SPS are similarly not well defined. Intrathecal production of oligoclonal anti-GAD IgG antibodies is continued by active B cells with the help of T cells that are activated by neural antigens [18]. Thus, immuno-ablative therapy to eliminate the dysfunctional immune response is expected to offer benefit. Immuno-ablative chemotherapy is followed by the re-introduction of autologous stem cell graft aiming to restart a new self-tolerant immune system. The CSF was not assayed for the presence of anti-GAD antibodies in our patients, but this should be considered in future studies to assess whether this parameter would correlate with treatment response.
At the time of writing of this case series all our transplanted patients manifested sustained clinical improvement without the need for any form of immunotherapy. Follow-up post-transplant has ranged from 12 months to 3 years. No patient encountered major or unexpected complications. Longer-term benefit of auto-HSCT in SPS remains to be ascertained.
Autologous HSCT has shown promise as a treatment option for a range of treatment-refractory autoimmune neurological conditions such as multiple sclerosis, neuromyelitis optica, myasthenia gravis and chronic inflammatory demyelinating polyneuropathy [10, 19]. Our experience further supports its use for refractory stiff-person syndrome. Auto-HSCT may prove to be a more cost-effective treatment in patients requiring regular treatment with expensive modalities, such as IVIG. Further work is warranted to establish long-term safety, efficacy and cost-effectiveness of auto-HSCT in SPS, along with optimising patient selection and transplant technique. This calls for collaboration between centres that provide this service.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary material 1 (MP4 82628 kb)
Supplementary material 2 (MP4 5421 kb)
Acknowledgements
We acknowledge the support of the NIHR Sheffield biomedical research centre and clinical trial unit.
Author contributions
LKI assessed patients, collected data, drafted and revised the first manuscript. AT assessed patients, collected data and revised the manuscript. JS, MH, BS assessed patients, supervised and delivered treatment, conceived the report and revised the manuscript. HJ delivered treatment, coordinated assessments, revised the manuscript. PS conducted neurophysiological assessment, provided neurophysiology figures and revised the manuscript. AC assessed patients, supervised and delivered treatment and revised the manuscript.
Funding
Individual funding requests were made from the NHS for UK patients.
Availability of data and material
Available.
Compliance with ethical standards
Conflicts of interest
Lewis Kass-Iliyya declares no conflict of interest. John A Snowden declares speaker fees from Jazz, Gilead, Mallinckrodt and Janssen. Alice Thorpe declares no conflict of interest. Helen Jessop declares no conflict of interest. Andrew D Chantry declares no conflict of interest. Ptolemaios Sarrigiannis declares no conflict of interest. Marios Hadjivassiliou declares no conflict of interest. Basil Sharrack declares no conflict of interest.
Ethical statement
The manuscript does not contain clinical studies. The patient whose videos are included in the electronic supplementary material gave their consent for the videos to be used in this publication. | SHE HAD RECEIVED THREE INFUSIONS OF RITUXIMAB | DrugDosageText | CC BY | 32785838 | 19,729,213 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Portal vein thrombosis'. | Portal Vein Thrombosis in Metastatic Colorectal Cancer During FOLFIRI-bevacizumab Chemotherapy Successfully Treated with Apixaban.
Portal vein thrombosis (PVT) while using an angiogenesis inhibitor is relatively rare. A 70-year-old Asian man was diagnosed with PVT two months after initiating 5-fluorouracil/leucovorin, irinotecan, and bevacizumab therapy for rectal cancer with liver metastases. Because the metastases were small and shrinking, we suspected that the thrombosis might have been caused by bevacizumab-containing chemotherapy. We stopped bevacizumab and started apixaban, a direct oral anticoagulant (DOAC). Eight months later, the complete dissolution of the thrombus and recanalization of the portal vein were attained. Our case suggests that PVT can occur during bevacizumab-containing chemotherapy, and DOAC therapy might be beneficial for treating PVT in patients with cancer.
Introduction
Angiogenesis plays an important role in tumor growth and metastasis, and angiogenesis inhibitors, such as bevacizumab, ramucirumab, and aflibercept, are now frequently used for a variety of cancer types (1). The mechanism by which these agents act involves blocking vascular endothelial growth factor (VEGF) or VEGF receptor, interrupting the angiogenesis process, and blocking tumor cell growth. In addition, these agents are also reported to inhibit the immunosuppressive effect in the tumor microenvironment, suggesting the possibility of having synergetic effects when used with immune checkpoint inhibitors (2,3). Thus, the application of these agents is expected to steadily increase.
However, venous thromboembolism (VTE) has been frequently documented during the use of angiogenesis inhibitors in advanced-stage cancer patients. In particular, deep vein thrombosis (DVT) and pulmonary embolism (PE) are the main thrombotic events caused by these agents (4). Although treatment guidelines for cancer-VTE have been gradually established, no strategy for treating portal vein thrombosis (PVT) in patients with cancer has yet been developed well due to a lack of sufficient evidence.
We herein report a case of metastatic rectal cancer complicated with PVT formed soon after the initiation of 5-fluorouracil/leucovorin, irinotecan (FOLFIRI) plus bevacizumab therapy. Bevacizumab was suspended, and apixaban, a direct oral anticoagulant (DOAC), was initiated. The thrombus dissolved successfully with this intervention, and the patient has been receiving FOLFIRI therapy, maintaining a partial response to metastatic rectal cancer.
Case Report
A 70-year-old man with chronic kidney disease, type 2 diabetes mellitus, fatty liver, and hypertension came to our hospital with a diagnosis of stage IV, RAS-wild, BRAF-wild, microsatellite instability (MSI)-negative rectal adenocarcinoma with small liver metastases and was referred to our department after resection of the primary tumor. Computed tomography (CT) showed two small liver metastases and no thrombus (Fig. 1A, B). FOLFIRI and bevacizumab treatment was started because the patient declined surgery for liver metastasis, the use of anti-epidermal growth factor receptor (EGFR) monoclonal antibody due to its possible skin toxicities, and the administration of oxaliplatin due to possible peripheral neuropathy. The laboratory data when the chemotherapy was started are shown in Table 1.
Figure 1. CT images of liver metastasis and portal vein thrombosis before and after chemotherapy. (A) Liver metastasis (arrow) is seen before starting chemotherapy. (B) There is no thrombus in the portal vein before the initiation of chemotherapy. (C) Two months after initiating FOLFIRI+Bevacizumab therapy. Portal vein thrombosis is formed (arrow) with liver metastasis shrinking (arrowhead). (D) Two months after initiating FOLFIRI+Bevacizumab therapy. Thrombus has also developed in the superior mesenteric vein (arrow).
Table 1. Initial Laboratory Data When Chemotherapy was Started.
Complete blood cell Biochemistry
WBC 6,700 /μL TP 7.4 g/dL
Stab+Seg 28 % Alb 4.6 g/dL
Lymphocyte 59 % LDH 128 IU/L
Monocyte 9 % T-Bil 0.4 mg/dL
Eosinophil 3 % AST 17 U/L
Basophil 1 ALT 13 U/L
RBC 458 104/μL ALP 161 U/L
Hgb 14.3 g/dL γGTP 29 U/L
MCV 91.9 fL CK 59 U/L
PLT 272,000 /μL BUN 28.9 mg/dL
Cr 1.48 mg/dL
Tumor markers eGFR 37.3 mL/min/L
CEA 6.4 ng/mL Na 140 mEq/L
CA19-9 13.9 ng/mL K 4.8 mEq/L
Cl 106 mEq/L
Coagulation test Ca 9.9 mg/dL
PT 12.6 second CRP 0.1 mg/dL
PT-INR 0.96
APTT 29.6 second
Fibrinogen 339 mg/dL
D-Dimer 0.6 mg/dL
WBC: white blood cell, RBC: red blood cell, Hgb: hemoglobin, MCV: mean corpuscular volume, PLT: platelet: CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9, PT: prothrombin time, PT-INR: prothrombin time international normalized ratio, APTT: activated partial thromboplastin time, TP: total protein, Alb: albumin, LDH: lactate dehydrogenase, T-Bil: Total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γGTP: gamma glutamyl transpeptidase, CK: creatine kinase, BUN: blood urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration rate, CRP: C-reactive protein
After two months, CT showed not only shrunken liver metastases with a partial response (PR) as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) but also thrombosis in the PV and superior mesenteric vein (SMV) (Fig. 1C, D). PE was not detected by this CT scan, and ultrasound of the lower extremities did not reveal any evidence of DVT. At this time, the patient did not have any symptoms related to cancer or thrombosis, such as abdominal pain or diarrhea. His vital signs were within normal limits, and a physical examination showed no abnormal findings. Laboratory data showed an elevated level of D-dimer (1.1 mg/dL). Prothrombin and partial thromboplastin times were within the normal range. The activities of proteins C and S were both normal. Lupus anticoagulant and anti-cardiolipin-β2-glycoprotein I complex antibodies were also negative. The liver function was normal. The patient had chronic kidney disease (Grade 3) with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2, but it was stable without any changes during chemotherapy. Abdominal ultrasound did not detect evidence of portal hypertension. In addition, there were no collateral vessels on CT or ultrasound, suggesting that this PVT was in the acute phase.
Because the patient had not had thrombosis before starting chemotherapy and the liver metastases were small and far from the PV, we attributed the thrombus formation to the use of bevacizumab. We therefore stopped the use of bevacizumab and started apixaban (10 mg twice a day for seven days followed by 5 mg twice a day) to treat the thrombosis instead of using subcutaneous injection agents, considering the patient’s quality of life. Soon after this intervention, the thrombus dissolved gradually (Fig. 2A-C). CT eight months after this treatment showed no thrombus in the PV or SMV (Fig. 2D).
Figure 2. CT images of portal vein thrombosis after anticoagulant therapy. (A) Thrombus is seen in the PV at the diagnosis (arrow). (B) Two months after anticoagulant therapy, the thrombus is still found in the PV (arrow). (C) Four months after anticoagulant therapy, the thrombus is dissolving gradually (arrow). (D) Eight months after apixaban therapy, the PVT has resolved completely (arrow).
Chronological changes in tumor marker and D-dimer levels during treatment for PVT are shown in Table 2. Upon confirming the complete dissolution of the thrombus, apixaban was finished because the thrombus was thought to have been caused not by the increased tumor burden but mainly by the initiation of bevacizumab-included chemotherapy. After the discontinuation of apixaban, there has been no recurrence of PVT for about a half year. The patient is now receiving FOLFIRI therapy and has been doing well, maintaining a PR according to the RECIST for more than one year.
Table 2. Time Course of D-Dimer and Tumor Markers during PVT Treatment.
-2 M* 0 M** 1 M 2 M 4 M 6 M 8 M*** 10 M 12 M
CEA [ng/mL] 6.4 1.3 1.1 1.2 1.5 1.4 1.7 2.5 2.0
CA19-9 [ng/mL] 13.9 3.6 2.2 2.2 2.7 2.9 3.9 3.2 3.1
D-Dimer [mg/dL] 0.6 1.1 ≤0.5 ≤0.5 ≤0.5 ≤0.5 ≤0.5 NA 0.6
* Two months before PVT was formed. Chemotherapy was started at this time.
** The time course is based on PVT diagnosis and treatment. Apixaban treatment was started at this time.
*** Apixaban was finished when CT confirmed the dissolution of thrombosis. Data here was taken after discontinuation of apixaban.
PVT: portal vein thrombosis, M: month(s), CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9
Discussion
In this report, we described a case of PV and SMV thrombosis in rectal cancer with small liver metastases under FOLFIRI plus bevacizumab therapy. Generally, thrombotic events are frequently seen in patients using angiogenesis inhibitors such as bevacizumab. Bevacizumab is a monoclonal antibody that binds VEGF-A and inhibits its binding to VEGF receptors. The mechanism underlying thrombosis formation induced by angiogenesis inhibitors is complex, but one of the main causes is endothelial dysfunction. VEGF inhibitors may facilitate an imbalance in vasodilation and vasoconstriction induced by changes in the endothelial environment. This dysfunction induces hemostasis and vascular thrombosis (5). In addition, with the use of bevacizumab, VEGF binds heparin and forms an immune complex, exacerbating aggregation and increasing procoagulant activities in the microvasculature (6). However, thrombosis in the portal system during the treatment of angiogenesis inhibitors is rare. We identified just six cases of PV or portal system thrombosis that occurred in cases receiving bevacizumab-included chemotherapy. The details of the five cases are not available because they are written in other languages (7-10). One report written in English was published by Donadon et al. and described a colon cancer patient with liver metastasis in whom PVT occurred during preoperative FOLFIRI plus bevacizumab chemotherapy. In that case, PVT and partial steatohepatitis occurred simultaneously, and the authors suspected that FOLFIRI plus bevacizumab combination therapy might contribute to chemotherapy-induced liver injury (11).
Generally, the risk factors for PVT include cirrhosis, malignancy, myeloproliferative disorders, medications, thrombophilia, local infection/inflammation, and surgery (12). Our patient had risk factors such as malignancy and steatosis that may facilitate thrombosis. However, no thrombus was seen before the initiation of chemotherapy, and there were no changes in liver function during chemotherapy. Furthermore, the liver metastases were small, and the tumor burden was thought to be low in this case. These facts suggest that the use of bevacizumab-included chemotherapy might have contributed to the formation of PVT.
Although thrombotic events are occasionally seen when using angiogenesis inhibitors, PVT is rarely observed, and the evidence supporting how PVT should be treated among patients with cancer is insufficient. General treatment options for PVT are low-molecular-weight heparin or oral anticoagulants, such as a DOAC or warfarin (13). However, this strategy has been developed to treat PVT mainly in patients with cirrhosis, and whether or not this strategy can be applied to treat PVT in patients with cancer is unclear. Although some case reports have found that the use of an antiplatelet agent or urokinase was partially effective in treating PVT in patients with cancer, cases of PVT treated by a DOAC in patients with cancer have not been well reported (7,10). Recently, treatment guidelines for venous thromboembolism (VTE) in patients with cancer have been developed, and DOAC administration has become a standard treatment option for VTE, although most cases involve DVT and PE (14). Apixaban, a DOAC, was selected to treat PVT in this case for several reasons. For one, apixaban and rivaroxaban (another DOAC) are known to be useful for treating VTE orally in the acute phase. Therefore, choosing these agents to treat VTE both in the acute and late phases of thrombosis can avoid hospitalization and maintain the quality of life. Furthermore, apixaban is known to carry less risk of bleeding than rivaroxaban (15). The successful treatment course of this patient indicates that DOACs such as apixaban are effective for PVT in patients with cancer undergoing chemotherapy, and the further accumulation of cases is necessary to establish a solid strategy to treat PVT in patients with cancer.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank the patient and his family members. | BEVACIZUMAB, FLUOROURACIL, IRINOTECAN, LEUCOVORIN | DrugsGivenReaction | CC BY-NC-ND | 32788527 | 18,923,636 | 2021-01-01 |
What was the outcome of reaction 'Portal vein thrombosis'? | Portal Vein Thrombosis in Metastatic Colorectal Cancer During FOLFIRI-bevacizumab Chemotherapy Successfully Treated with Apixaban.
Portal vein thrombosis (PVT) while using an angiogenesis inhibitor is relatively rare. A 70-year-old Asian man was diagnosed with PVT two months after initiating 5-fluorouracil/leucovorin, irinotecan, and bevacizumab therapy for rectal cancer with liver metastases. Because the metastases were small and shrinking, we suspected that the thrombosis might have been caused by bevacizumab-containing chemotherapy. We stopped bevacizumab and started apixaban, a direct oral anticoagulant (DOAC). Eight months later, the complete dissolution of the thrombus and recanalization of the portal vein were attained. Our case suggests that PVT can occur during bevacizumab-containing chemotherapy, and DOAC therapy might be beneficial for treating PVT in patients with cancer.
Introduction
Angiogenesis plays an important role in tumor growth and metastasis, and angiogenesis inhibitors, such as bevacizumab, ramucirumab, and aflibercept, are now frequently used for a variety of cancer types (1). The mechanism by which these agents act involves blocking vascular endothelial growth factor (VEGF) or VEGF receptor, interrupting the angiogenesis process, and blocking tumor cell growth. In addition, these agents are also reported to inhibit the immunosuppressive effect in the tumor microenvironment, suggesting the possibility of having synergetic effects when used with immune checkpoint inhibitors (2,3). Thus, the application of these agents is expected to steadily increase.
However, venous thromboembolism (VTE) has been frequently documented during the use of angiogenesis inhibitors in advanced-stage cancer patients. In particular, deep vein thrombosis (DVT) and pulmonary embolism (PE) are the main thrombotic events caused by these agents (4). Although treatment guidelines for cancer-VTE have been gradually established, no strategy for treating portal vein thrombosis (PVT) in patients with cancer has yet been developed well due to a lack of sufficient evidence.
We herein report a case of metastatic rectal cancer complicated with PVT formed soon after the initiation of 5-fluorouracil/leucovorin, irinotecan (FOLFIRI) plus bevacizumab therapy. Bevacizumab was suspended, and apixaban, a direct oral anticoagulant (DOAC), was initiated. The thrombus dissolved successfully with this intervention, and the patient has been receiving FOLFIRI therapy, maintaining a partial response to metastatic rectal cancer.
Case Report
A 70-year-old man with chronic kidney disease, type 2 diabetes mellitus, fatty liver, and hypertension came to our hospital with a diagnosis of stage IV, RAS-wild, BRAF-wild, microsatellite instability (MSI)-negative rectal adenocarcinoma with small liver metastases and was referred to our department after resection of the primary tumor. Computed tomography (CT) showed two small liver metastases and no thrombus (Fig. 1A, B). FOLFIRI and bevacizumab treatment was started because the patient declined surgery for liver metastasis, the use of anti-epidermal growth factor receptor (EGFR) monoclonal antibody due to its possible skin toxicities, and the administration of oxaliplatin due to possible peripheral neuropathy. The laboratory data when the chemotherapy was started are shown in Table 1.
Figure 1. CT images of liver metastasis and portal vein thrombosis before and after chemotherapy. (A) Liver metastasis (arrow) is seen before starting chemotherapy. (B) There is no thrombus in the portal vein before the initiation of chemotherapy. (C) Two months after initiating FOLFIRI+Bevacizumab therapy. Portal vein thrombosis is formed (arrow) with liver metastasis shrinking (arrowhead). (D) Two months after initiating FOLFIRI+Bevacizumab therapy. Thrombus has also developed in the superior mesenteric vein (arrow).
Table 1. Initial Laboratory Data When Chemotherapy was Started.
Complete blood cell Biochemistry
WBC 6,700 /μL TP 7.4 g/dL
Stab+Seg 28 % Alb 4.6 g/dL
Lymphocyte 59 % LDH 128 IU/L
Monocyte 9 % T-Bil 0.4 mg/dL
Eosinophil 3 % AST 17 U/L
Basophil 1 ALT 13 U/L
RBC 458 104/μL ALP 161 U/L
Hgb 14.3 g/dL γGTP 29 U/L
MCV 91.9 fL CK 59 U/L
PLT 272,000 /μL BUN 28.9 mg/dL
Cr 1.48 mg/dL
Tumor markers eGFR 37.3 mL/min/L
CEA 6.4 ng/mL Na 140 mEq/L
CA19-9 13.9 ng/mL K 4.8 mEq/L
Cl 106 mEq/L
Coagulation test Ca 9.9 mg/dL
PT 12.6 second CRP 0.1 mg/dL
PT-INR 0.96
APTT 29.6 second
Fibrinogen 339 mg/dL
D-Dimer 0.6 mg/dL
WBC: white blood cell, RBC: red blood cell, Hgb: hemoglobin, MCV: mean corpuscular volume, PLT: platelet: CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9, PT: prothrombin time, PT-INR: prothrombin time international normalized ratio, APTT: activated partial thromboplastin time, TP: total protein, Alb: albumin, LDH: lactate dehydrogenase, T-Bil: Total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γGTP: gamma glutamyl transpeptidase, CK: creatine kinase, BUN: blood urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration rate, CRP: C-reactive protein
After two months, CT showed not only shrunken liver metastases with a partial response (PR) as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) but also thrombosis in the PV and superior mesenteric vein (SMV) (Fig. 1C, D). PE was not detected by this CT scan, and ultrasound of the lower extremities did not reveal any evidence of DVT. At this time, the patient did not have any symptoms related to cancer or thrombosis, such as abdominal pain or diarrhea. His vital signs were within normal limits, and a physical examination showed no abnormal findings. Laboratory data showed an elevated level of D-dimer (1.1 mg/dL). Prothrombin and partial thromboplastin times were within the normal range. The activities of proteins C and S were both normal. Lupus anticoagulant and anti-cardiolipin-β2-glycoprotein I complex antibodies were also negative. The liver function was normal. The patient had chronic kidney disease (Grade 3) with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2, but it was stable without any changes during chemotherapy. Abdominal ultrasound did not detect evidence of portal hypertension. In addition, there were no collateral vessels on CT or ultrasound, suggesting that this PVT was in the acute phase.
Because the patient had not had thrombosis before starting chemotherapy and the liver metastases were small and far from the PV, we attributed the thrombus formation to the use of bevacizumab. We therefore stopped the use of bevacizumab and started apixaban (10 mg twice a day for seven days followed by 5 mg twice a day) to treat the thrombosis instead of using subcutaneous injection agents, considering the patient’s quality of life. Soon after this intervention, the thrombus dissolved gradually (Fig. 2A-C). CT eight months after this treatment showed no thrombus in the PV or SMV (Fig. 2D).
Figure 2. CT images of portal vein thrombosis after anticoagulant therapy. (A) Thrombus is seen in the PV at the diagnosis (arrow). (B) Two months after anticoagulant therapy, the thrombus is still found in the PV (arrow). (C) Four months after anticoagulant therapy, the thrombus is dissolving gradually (arrow). (D) Eight months after apixaban therapy, the PVT has resolved completely (arrow).
Chronological changes in tumor marker and D-dimer levels during treatment for PVT are shown in Table 2. Upon confirming the complete dissolution of the thrombus, apixaban was finished because the thrombus was thought to have been caused not by the increased tumor burden but mainly by the initiation of bevacizumab-included chemotherapy. After the discontinuation of apixaban, there has been no recurrence of PVT for about a half year. The patient is now receiving FOLFIRI therapy and has been doing well, maintaining a PR according to the RECIST for more than one year.
Table 2. Time Course of D-Dimer and Tumor Markers during PVT Treatment.
-2 M* 0 M** 1 M 2 M 4 M 6 M 8 M*** 10 M 12 M
CEA [ng/mL] 6.4 1.3 1.1 1.2 1.5 1.4 1.7 2.5 2.0
CA19-9 [ng/mL] 13.9 3.6 2.2 2.2 2.7 2.9 3.9 3.2 3.1
D-Dimer [mg/dL] 0.6 1.1 ≤0.5 ≤0.5 ≤0.5 ≤0.5 ≤0.5 NA 0.6
* Two months before PVT was formed. Chemotherapy was started at this time.
** The time course is based on PVT diagnosis and treatment. Apixaban treatment was started at this time.
*** Apixaban was finished when CT confirmed the dissolution of thrombosis. Data here was taken after discontinuation of apixaban.
PVT: portal vein thrombosis, M: month(s), CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9
Discussion
In this report, we described a case of PV and SMV thrombosis in rectal cancer with small liver metastases under FOLFIRI plus bevacizumab therapy. Generally, thrombotic events are frequently seen in patients using angiogenesis inhibitors such as bevacizumab. Bevacizumab is a monoclonal antibody that binds VEGF-A and inhibits its binding to VEGF receptors. The mechanism underlying thrombosis formation induced by angiogenesis inhibitors is complex, but one of the main causes is endothelial dysfunction. VEGF inhibitors may facilitate an imbalance in vasodilation and vasoconstriction induced by changes in the endothelial environment. This dysfunction induces hemostasis and vascular thrombosis (5). In addition, with the use of bevacizumab, VEGF binds heparin and forms an immune complex, exacerbating aggregation and increasing procoagulant activities in the microvasculature (6). However, thrombosis in the portal system during the treatment of angiogenesis inhibitors is rare. We identified just six cases of PV or portal system thrombosis that occurred in cases receiving bevacizumab-included chemotherapy. The details of the five cases are not available because they are written in other languages (7-10). One report written in English was published by Donadon et al. and described a colon cancer patient with liver metastasis in whom PVT occurred during preoperative FOLFIRI plus bevacizumab chemotherapy. In that case, PVT and partial steatohepatitis occurred simultaneously, and the authors suspected that FOLFIRI plus bevacizumab combination therapy might contribute to chemotherapy-induced liver injury (11).
Generally, the risk factors for PVT include cirrhosis, malignancy, myeloproliferative disorders, medications, thrombophilia, local infection/inflammation, and surgery (12). Our patient had risk factors such as malignancy and steatosis that may facilitate thrombosis. However, no thrombus was seen before the initiation of chemotherapy, and there were no changes in liver function during chemotherapy. Furthermore, the liver metastases were small, and the tumor burden was thought to be low in this case. These facts suggest that the use of bevacizumab-included chemotherapy might have contributed to the formation of PVT.
Although thrombotic events are occasionally seen when using angiogenesis inhibitors, PVT is rarely observed, and the evidence supporting how PVT should be treated among patients with cancer is insufficient. General treatment options for PVT are low-molecular-weight heparin or oral anticoagulants, such as a DOAC or warfarin (13). However, this strategy has been developed to treat PVT mainly in patients with cirrhosis, and whether or not this strategy can be applied to treat PVT in patients with cancer is unclear. Although some case reports have found that the use of an antiplatelet agent or urokinase was partially effective in treating PVT in patients with cancer, cases of PVT treated by a DOAC in patients with cancer have not been well reported (7,10). Recently, treatment guidelines for venous thromboembolism (VTE) in patients with cancer have been developed, and DOAC administration has become a standard treatment option for VTE, although most cases involve DVT and PE (14). Apixaban, a DOAC, was selected to treat PVT in this case for several reasons. For one, apixaban and rivaroxaban (another DOAC) are known to be useful for treating VTE orally in the acute phase. Therefore, choosing these agents to treat VTE both in the acute and late phases of thrombosis can avoid hospitalization and maintain the quality of life. Furthermore, apixaban is known to carry less risk of bleeding than rivaroxaban (15). The successful treatment course of this patient indicates that DOACs such as apixaban are effective for PVT in patients with cancer undergoing chemotherapy, and the further accumulation of cases is necessary to establish a solid strategy to treat PVT in patients with cancer.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank the patient and his family members. | Recovered | ReactionOutcome | CC BY-NC-ND | 32788527 | 18,923,636 | 2021-01-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Angle closure glaucoma'. | Acute angle-closure glaucoma and effusion syndrome after phacoemulsification.
A 72-year-old female patient developed bilateral secondary iridocorneal angle-closure glaucoma with uveal effusion syndrome after uncomplicated cataract surgery. The postoperative intake of acetazolamide was identified as causative for the development of the effusion syndrome. Taking a sulfonamide-free systemic and local intraocular pressure lowering and anti-inflammatory treatment into account, a rapid improvement of the ocular manifestation was achieved. The case illustrates a rare but clinically severe adverse effect of acetazolamide and outlines efficient treatment options.
Anamnese
Eine 72-jährige Patientin stellte sich in unserer Klinik als Notfall mit starken Kopfschmerzen, Übelkeit und Erbrechen sowie beidseitig plötzlicher Sehverschlechterung vor. Am späten Vormittag des Tages erhielt sie an ihrem rechten Auge eine elektive ambulante Kataraktoperation unter Lokalanästhesie. Die Kataraktoperation des Partnerauges erfolgte bereits 2 Wochen zuvor. An beiden Augen verliefen die Operationen komplikationslos mit Implantation einer Intraokularlinse in den intakten Kapselsack. Postoperativ wurde der Patientin, neben der antibiotischen und antiinflammatorischen Lokaltherapie eine prophylaktische orale Einmaldosis Acetazolamid 250 mg verordnet, um einem möglichen postoperativen intraokularen Druckanstieg vorzubeugen. Die Patientin nahm die Acetazolamid-Tablette 4 h nach der Operation ein und legte sich schlafen. Etwa 6 h später wachte sie aufgrund starker Kopfschmerzen auf und bemerkte beidseits eine massive Sehverschlechterung, woraufhin sie die Klinik aufsuchte.
Klinischer Befund
Bei der Erstvorstellung betrug die bestkorrigierte Sehschärfe der Patientin rechts 1/35 und links 1/25 bei einer Refraktionskorrektur rechts von −3,0 dpt und links −3,5 dpt. Spaltlampenmikroskopisch zeigten sich beidseits eine Bindehautinjektion, ausgeprägtes Hornhautödem sowie eine flache Vorderkammer mit Anteflexion der Intraokularlinse (Abb. 1a, b). Zur weiteren Diagnostik führten wir eine Ultraschallbiomikroskopie durch (Abb. 1c, d). Hierbei betrug die Vorderkammertiefe rechts 2,08 mm und links 2,74 mm, der Kammerwinkel zeigte sich bei einem iridokornealen Winkelblock zirkulär verschlossen. Der Intraokulardruck betrug initial rechts 62 mm Hg und links 64 mm Hg. Eine Fundoskopie war aufgrund des ausgeprägten Hornhautödems nicht möglich. In der B‑Scan-Sonographie zeigte sich beidseits eine Aderhautschwellung im Sinne einer Aderhautabhebung (Abb. 2c, d). Die Patientin wurde mit der Arbeitsdiagnose sekundäres Engwinkelglaukom mit Pupillarblock stationär aufgenommen.
Therapie und Verlauf
Eine initiale systemisch-intravenöse Drucksenkung erfolgte mit Acetazolamid 500 mg und Mannitol (15 %) 300 ml sowie beidseits lokal mit Timolol 0,5 %, Apraclonidin 5 % und Prednisolon 1 %. Unter der genannten Therapie zeigte sich nur eine unzureichende Drucksenkung bei Zunahme der Aderhautschwellung, sodass die Arbeitsdiagnose überdacht werden musste. Acetazolamid wurde im Weiteren als Ursache für ein bilaterales uveales Effusionssyndrom mit sekundärem iridokornealem Engwinkelglaukom angenommen und daher abgesetzt. Dementsprechend erfolgte die weitere systemische Therapie mit einer erneuten Einmalgabe von Mannitol (15 %) 300 ml intravenös und Prednisolon 100 mg per os täglich. Hierunter verbesserte sich der klinische Befund über 3 Tage allmählich. Der Augeninnendruck konnte rechts auf 7 mm Hg und links 9 mm Hg gesenkt werden. In der Fundoskopie zeigte sich noch eine bilaterale periphere Aderhautabhebung (Abb. 2a, b). Der bestkorrigierte Dezimalvisus stieg auf rechts 0,8 und links 0,9 an, die Konfiguration der Vorderkammer normalisierte sich, und die Myopisierung zeigte sich rückläufig. Die systemische und lokal drucksenkende Therapie wurde beendet.
In der Verlaufskontrolle zeigte sich nach 1 Woche beidseits ein regelrechter sonographischer und fundoskopischer Befund des hinteren Augenabschnitts (Abb. 3). Die Vorderkammertiefe betrug rechts 4,39 mm und links 4,37 mm bei einem Augeninnendruck von rechts 10 mm Hg und links 11 mm Hg. Der unkorrigierte Dezimalvisus betrug nun beidseits 1,0. In der nochmals durchgeführten Ultraschallbiomikroskopie offenbarte sich nun beidseits eine Plateau-Iris-Konfiguration (Abb. 3c, d).
Diagnose
Beidseitiges akutes Engwinkelglaukom bei Acetazolamid-indiziertem Effusionssyndrome nach Kataraktoperation in Plateau-Iris-Konfiguration.
Diskussion
Die Entwicklung eines uvealen Effusionssyndroms ist bei Sulfonamid-haltigen Arzneimitteln, zu denen auch der Carboanhydrasehemmer Acetazolamid gehört, grundsätzlich bekannt [9]. Der vorliegende Fall verdeutlicht allerdings, dass die hierbei eintretende Aderhautschwellung nicht nur Aderhautfalten hervorruft, sondern foudroyant verlaufen und dabei durch eine massive intraokulare Volumenverschiebung zu einem iridokornealen Winkelblock führen kann. Neben Acetazolamid sind aus der Literatur ähnliche Fälle auch durch andere Sulfonamid-haltige Medikamente wie dem als Antiepileptikum verwendeten Carboanhydrasehemmer Topiramat und dem Thiaziddiuretikum Hydrochlorothiazid bekannt [4, 7, 8]. In der Allgemeinbevölkerung wird die Inzidenz von Sulfonamid-Allergien mit 3–8 % angenommen [2]. Die meisten Reaktionen auf Sulfonamide resultieren aus multifaktoriellen immunologischen und toxischen Stoffwechselmechanismen, während über die genauen Reaktionsmechanismen weniger bekannt ist [1]. Immunglobulin E(IgE)-vermittelte Typ-1-Immunreaktionen auf Sulfonamide können Anaphylaxie, Angioödeme und Urtikaria hervorrufen und nehmen darüber auch Einfluss auf die Konstitution der Aderhaut [10]. Über diesen Weg kann u. a. Acetazolamid, wie in dieser Kasuistik geschildert, paradoxe Nebenwirkungen mit ausgeprägtem uvealem Effusionssyndrom hervorrufen. Interessanterweise wurde festgestellt, dass gerade bei IgE-vermittelten Typ-1-Immunreaktionen nicht die Sulfonamid-definierende NH2-SO2-Struktur, sondern der im Molekül enthaltene heterozyklische N‑Ring an IgE bindet [3]. Somit ist auch zu erklären, dass verschiedene Sulfonamid-haltige Arzneimittel mit unterschiedlichen heterozyklischen N‑Ringen sehr variable Immunreaktionen hervorrufen können. In dem vorliegenden Fall war bei der Patientin keine Sulfonamid-Allergie bekannt. Dennoch sollte gerade vor der Verabreichung von Acetazolamid und anderen Sulfonamiden eine allergologische Anamnese erfolgen. Gleichzeitig sollte auch bei Vorliegen einer klaren klinischen Situation wie der eines Winkelblocks durch eine spezifische Anamnese differenzialdiagnostisch an die Unterscheidung zwischen einem primären und sekundären Engwinkelglaukom gedacht werden, da dies für die Therapieentscheidung – wie in diesem Fall – von wesentlicher klinischer Relevanz sein kann. In diesem Kontext wurde in der Literatur das Vorliegen einer Plateau-Iris-Konfiguration als wesentlicher Risikofaktor für die Entwicklung eines Winkelblockglaukoms diskutiert [5]. Während lokale und/oder systemische Carboanhydrasehemmer im Rahmen von Augeninnendruckentgleisungen als First-line-Therapeutika angesehen und verwendet werden können [6], wären diese in dem vorliegenden Fall kontraindiziert. Nicht zuletzt sollte neben der adäquaten Therapie auch daran gedacht werden, den Patienten über das Vorliegen und die Bedeutung einer Sulfonamid-Allergie aufzuklären.
Fazit für die Praxis
Ein beidseitiges sekundäres iridokorneales Engwinkelglaukom auf Grundlage eines uvealen Effusionssyndroms kann als seltene, klinisch schwerwiegende unerwünschte Arzneimittelwirkung von Acetazolamid eintreten.
Die Verordnung von Acetazolamid sollte mit Bedacht erfolgen, und mögliche Sulfonamid-Allergien müssen berücksichtigt werden.
Eine effiziente und sichere Möglichkeit der Akutbehandlung besteht in der Verwendung von Osmodiuretika und Kortikosteroiden.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
M. Anwar, T. Brockmann, M. Walckling und T.A. Fuchsluger geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patienten zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern eine schriftliche Einwilligung vor. | ACETAZOLAMIDE, APRACLONIDINE HYDROCHLORIDE, TIMOLOL | DrugsGivenReaction | CC BY | 32803274 | 18,639,253 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Choroidal effusion'. | Acute angle-closure glaucoma and effusion syndrome after phacoemulsification.
A 72-year-old female patient developed bilateral secondary iridocorneal angle-closure glaucoma with uveal effusion syndrome after uncomplicated cataract surgery. The postoperative intake of acetazolamide was identified as causative for the development of the effusion syndrome. Taking a sulfonamide-free systemic and local intraocular pressure lowering and anti-inflammatory treatment into account, a rapid improvement of the ocular manifestation was achieved. The case illustrates a rare but clinically severe adverse effect of acetazolamide and outlines efficient treatment options.
Anamnese
Eine 72-jährige Patientin stellte sich in unserer Klinik als Notfall mit starken Kopfschmerzen, Übelkeit und Erbrechen sowie beidseitig plötzlicher Sehverschlechterung vor. Am späten Vormittag des Tages erhielt sie an ihrem rechten Auge eine elektive ambulante Kataraktoperation unter Lokalanästhesie. Die Kataraktoperation des Partnerauges erfolgte bereits 2 Wochen zuvor. An beiden Augen verliefen die Operationen komplikationslos mit Implantation einer Intraokularlinse in den intakten Kapselsack. Postoperativ wurde der Patientin, neben der antibiotischen und antiinflammatorischen Lokaltherapie eine prophylaktische orale Einmaldosis Acetazolamid 250 mg verordnet, um einem möglichen postoperativen intraokularen Druckanstieg vorzubeugen. Die Patientin nahm die Acetazolamid-Tablette 4 h nach der Operation ein und legte sich schlafen. Etwa 6 h später wachte sie aufgrund starker Kopfschmerzen auf und bemerkte beidseits eine massive Sehverschlechterung, woraufhin sie die Klinik aufsuchte.
Klinischer Befund
Bei der Erstvorstellung betrug die bestkorrigierte Sehschärfe der Patientin rechts 1/35 und links 1/25 bei einer Refraktionskorrektur rechts von −3,0 dpt und links −3,5 dpt. Spaltlampenmikroskopisch zeigten sich beidseits eine Bindehautinjektion, ausgeprägtes Hornhautödem sowie eine flache Vorderkammer mit Anteflexion der Intraokularlinse (Abb. 1a, b). Zur weiteren Diagnostik führten wir eine Ultraschallbiomikroskopie durch (Abb. 1c, d). Hierbei betrug die Vorderkammertiefe rechts 2,08 mm und links 2,74 mm, der Kammerwinkel zeigte sich bei einem iridokornealen Winkelblock zirkulär verschlossen. Der Intraokulardruck betrug initial rechts 62 mm Hg und links 64 mm Hg. Eine Fundoskopie war aufgrund des ausgeprägten Hornhautödems nicht möglich. In der B‑Scan-Sonographie zeigte sich beidseits eine Aderhautschwellung im Sinne einer Aderhautabhebung (Abb. 2c, d). Die Patientin wurde mit der Arbeitsdiagnose sekundäres Engwinkelglaukom mit Pupillarblock stationär aufgenommen.
Therapie und Verlauf
Eine initiale systemisch-intravenöse Drucksenkung erfolgte mit Acetazolamid 500 mg und Mannitol (15 %) 300 ml sowie beidseits lokal mit Timolol 0,5 %, Apraclonidin 5 % und Prednisolon 1 %. Unter der genannten Therapie zeigte sich nur eine unzureichende Drucksenkung bei Zunahme der Aderhautschwellung, sodass die Arbeitsdiagnose überdacht werden musste. Acetazolamid wurde im Weiteren als Ursache für ein bilaterales uveales Effusionssyndrom mit sekundärem iridokornealem Engwinkelglaukom angenommen und daher abgesetzt. Dementsprechend erfolgte die weitere systemische Therapie mit einer erneuten Einmalgabe von Mannitol (15 %) 300 ml intravenös und Prednisolon 100 mg per os täglich. Hierunter verbesserte sich der klinische Befund über 3 Tage allmählich. Der Augeninnendruck konnte rechts auf 7 mm Hg und links 9 mm Hg gesenkt werden. In der Fundoskopie zeigte sich noch eine bilaterale periphere Aderhautabhebung (Abb. 2a, b). Der bestkorrigierte Dezimalvisus stieg auf rechts 0,8 und links 0,9 an, die Konfiguration der Vorderkammer normalisierte sich, und die Myopisierung zeigte sich rückläufig. Die systemische und lokal drucksenkende Therapie wurde beendet.
In der Verlaufskontrolle zeigte sich nach 1 Woche beidseits ein regelrechter sonographischer und fundoskopischer Befund des hinteren Augenabschnitts (Abb. 3). Die Vorderkammertiefe betrug rechts 4,39 mm und links 4,37 mm bei einem Augeninnendruck von rechts 10 mm Hg und links 11 mm Hg. Der unkorrigierte Dezimalvisus betrug nun beidseits 1,0. In der nochmals durchgeführten Ultraschallbiomikroskopie offenbarte sich nun beidseits eine Plateau-Iris-Konfiguration (Abb. 3c, d).
Diagnose
Beidseitiges akutes Engwinkelglaukom bei Acetazolamid-indiziertem Effusionssyndrome nach Kataraktoperation in Plateau-Iris-Konfiguration.
Diskussion
Die Entwicklung eines uvealen Effusionssyndroms ist bei Sulfonamid-haltigen Arzneimitteln, zu denen auch der Carboanhydrasehemmer Acetazolamid gehört, grundsätzlich bekannt [9]. Der vorliegende Fall verdeutlicht allerdings, dass die hierbei eintretende Aderhautschwellung nicht nur Aderhautfalten hervorruft, sondern foudroyant verlaufen und dabei durch eine massive intraokulare Volumenverschiebung zu einem iridokornealen Winkelblock führen kann. Neben Acetazolamid sind aus der Literatur ähnliche Fälle auch durch andere Sulfonamid-haltige Medikamente wie dem als Antiepileptikum verwendeten Carboanhydrasehemmer Topiramat und dem Thiaziddiuretikum Hydrochlorothiazid bekannt [4, 7, 8]. In der Allgemeinbevölkerung wird die Inzidenz von Sulfonamid-Allergien mit 3–8 % angenommen [2]. Die meisten Reaktionen auf Sulfonamide resultieren aus multifaktoriellen immunologischen und toxischen Stoffwechselmechanismen, während über die genauen Reaktionsmechanismen weniger bekannt ist [1]. Immunglobulin E(IgE)-vermittelte Typ-1-Immunreaktionen auf Sulfonamide können Anaphylaxie, Angioödeme und Urtikaria hervorrufen und nehmen darüber auch Einfluss auf die Konstitution der Aderhaut [10]. Über diesen Weg kann u. a. Acetazolamid, wie in dieser Kasuistik geschildert, paradoxe Nebenwirkungen mit ausgeprägtem uvealem Effusionssyndrom hervorrufen. Interessanterweise wurde festgestellt, dass gerade bei IgE-vermittelten Typ-1-Immunreaktionen nicht die Sulfonamid-definierende NH2-SO2-Struktur, sondern der im Molekül enthaltene heterozyklische N‑Ring an IgE bindet [3]. Somit ist auch zu erklären, dass verschiedene Sulfonamid-haltige Arzneimittel mit unterschiedlichen heterozyklischen N‑Ringen sehr variable Immunreaktionen hervorrufen können. In dem vorliegenden Fall war bei der Patientin keine Sulfonamid-Allergie bekannt. Dennoch sollte gerade vor der Verabreichung von Acetazolamid und anderen Sulfonamiden eine allergologische Anamnese erfolgen. Gleichzeitig sollte auch bei Vorliegen einer klaren klinischen Situation wie der eines Winkelblocks durch eine spezifische Anamnese differenzialdiagnostisch an die Unterscheidung zwischen einem primären und sekundären Engwinkelglaukom gedacht werden, da dies für die Therapieentscheidung – wie in diesem Fall – von wesentlicher klinischer Relevanz sein kann. In diesem Kontext wurde in der Literatur das Vorliegen einer Plateau-Iris-Konfiguration als wesentlicher Risikofaktor für die Entwicklung eines Winkelblockglaukoms diskutiert [5]. Während lokale und/oder systemische Carboanhydrasehemmer im Rahmen von Augeninnendruckentgleisungen als First-line-Therapeutika angesehen und verwendet werden können [6], wären diese in dem vorliegenden Fall kontraindiziert. Nicht zuletzt sollte neben der adäquaten Therapie auch daran gedacht werden, den Patienten über das Vorliegen und die Bedeutung einer Sulfonamid-Allergie aufzuklären.
Fazit für die Praxis
Ein beidseitiges sekundäres iridokorneales Engwinkelglaukom auf Grundlage eines uvealen Effusionssyndroms kann als seltene, klinisch schwerwiegende unerwünschte Arzneimittelwirkung von Acetazolamid eintreten.
Die Verordnung von Acetazolamid sollte mit Bedacht erfolgen, und mögliche Sulfonamid-Allergien müssen berücksichtigt werden.
Eine effiziente und sichere Möglichkeit der Akutbehandlung besteht in der Verwendung von Osmodiuretika und Kortikosteroiden.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
M. Anwar, T. Brockmann, M. Walckling und T.A. Fuchsluger geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patienten zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern eine schriftliche Einwilligung vor. | ACETAZOLAMIDE, APRACLONIDINE HYDROCHLORIDE, TIMOLOL | DrugsGivenReaction | CC BY | 32803274 | 18,639,253 | 2021-08 |
What was the administration route of drug 'ACETAZOLAMIDE'? | Acute angle-closure glaucoma and effusion syndrome after phacoemulsification.
A 72-year-old female patient developed bilateral secondary iridocorneal angle-closure glaucoma with uveal effusion syndrome after uncomplicated cataract surgery. The postoperative intake of acetazolamide was identified as causative for the development of the effusion syndrome. Taking a sulfonamide-free systemic and local intraocular pressure lowering and anti-inflammatory treatment into account, a rapid improvement of the ocular manifestation was achieved. The case illustrates a rare but clinically severe adverse effect of acetazolamide and outlines efficient treatment options.
Anamnese
Eine 72-jährige Patientin stellte sich in unserer Klinik als Notfall mit starken Kopfschmerzen, Übelkeit und Erbrechen sowie beidseitig plötzlicher Sehverschlechterung vor. Am späten Vormittag des Tages erhielt sie an ihrem rechten Auge eine elektive ambulante Kataraktoperation unter Lokalanästhesie. Die Kataraktoperation des Partnerauges erfolgte bereits 2 Wochen zuvor. An beiden Augen verliefen die Operationen komplikationslos mit Implantation einer Intraokularlinse in den intakten Kapselsack. Postoperativ wurde der Patientin, neben der antibiotischen und antiinflammatorischen Lokaltherapie eine prophylaktische orale Einmaldosis Acetazolamid 250 mg verordnet, um einem möglichen postoperativen intraokularen Druckanstieg vorzubeugen. Die Patientin nahm die Acetazolamid-Tablette 4 h nach der Operation ein und legte sich schlafen. Etwa 6 h später wachte sie aufgrund starker Kopfschmerzen auf und bemerkte beidseits eine massive Sehverschlechterung, woraufhin sie die Klinik aufsuchte.
Klinischer Befund
Bei der Erstvorstellung betrug die bestkorrigierte Sehschärfe der Patientin rechts 1/35 und links 1/25 bei einer Refraktionskorrektur rechts von −3,0 dpt und links −3,5 dpt. Spaltlampenmikroskopisch zeigten sich beidseits eine Bindehautinjektion, ausgeprägtes Hornhautödem sowie eine flache Vorderkammer mit Anteflexion der Intraokularlinse (Abb. 1a, b). Zur weiteren Diagnostik führten wir eine Ultraschallbiomikroskopie durch (Abb. 1c, d). Hierbei betrug die Vorderkammertiefe rechts 2,08 mm und links 2,74 mm, der Kammerwinkel zeigte sich bei einem iridokornealen Winkelblock zirkulär verschlossen. Der Intraokulardruck betrug initial rechts 62 mm Hg und links 64 mm Hg. Eine Fundoskopie war aufgrund des ausgeprägten Hornhautödems nicht möglich. In der B‑Scan-Sonographie zeigte sich beidseits eine Aderhautschwellung im Sinne einer Aderhautabhebung (Abb. 2c, d). Die Patientin wurde mit der Arbeitsdiagnose sekundäres Engwinkelglaukom mit Pupillarblock stationär aufgenommen.
Therapie und Verlauf
Eine initiale systemisch-intravenöse Drucksenkung erfolgte mit Acetazolamid 500 mg und Mannitol (15 %) 300 ml sowie beidseits lokal mit Timolol 0,5 %, Apraclonidin 5 % und Prednisolon 1 %. Unter der genannten Therapie zeigte sich nur eine unzureichende Drucksenkung bei Zunahme der Aderhautschwellung, sodass die Arbeitsdiagnose überdacht werden musste. Acetazolamid wurde im Weiteren als Ursache für ein bilaterales uveales Effusionssyndrom mit sekundärem iridokornealem Engwinkelglaukom angenommen und daher abgesetzt. Dementsprechend erfolgte die weitere systemische Therapie mit einer erneuten Einmalgabe von Mannitol (15 %) 300 ml intravenös und Prednisolon 100 mg per os täglich. Hierunter verbesserte sich der klinische Befund über 3 Tage allmählich. Der Augeninnendruck konnte rechts auf 7 mm Hg und links 9 mm Hg gesenkt werden. In der Fundoskopie zeigte sich noch eine bilaterale periphere Aderhautabhebung (Abb. 2a, b). Der bestkorrigierte Dezimalvisus stieg auf rechts 0,8 und links 0,9 an, die Konfiguration der Vorderkammer normalisierte sich, und die Myopisierung zeigte sich rückläufig. Die systemische und lokal drucksenkende Therapie wurde beendet.
In der Verlaufskontrolle zeigte sich nach 1 Woche beidseits ein regelrechter sonographischer und fundoskopischer Befund des hinteren Augenabschnitts (Abb. 3). Die Vorderkammertiefe betrug rechts 4,39 mm und links 4,37 mm bei einem Augeninnendruck von rechts 10 mm Hg und links 11 mm Hg. Der unkorrigierte Dezimalvisus betrug nun beidseits 1,0. In der nochmals durchgeführten Ultraschallbiomikroskopie offenbarte sich nun beidseits eine Plateau-Iris-Konfiguration (Abb. 3c, d).
Diagnose
Beidseitiges akutes Engwinkelglaukom bei Acetazolamid-indiziertem Effusionssyndrome nach Kataraktoperation in Plateau-Iris-Konfiguration.
Diskussion
Die Entwicklung eines uvealen Effusionssyndroms ist bei Sulfonamid-haltigen Arzneimitteln, zu denen auch der Carboanhydrasehemmer Acetazolamid gehört, grundsätzlich bekannt [9]. Der vorliegende Fall verdeutlicht allerdings, dass die hierbei eintretende Aderhautschwellung nicht nur Aderhautfalten hervorruft, sondern foudroyant verlaufen und dabei durch eine massive intraokulare Volumenverschiebung zu einem iridokornealen Winkelblock führen kann. Neben Acetazolamid sind aus der Literatur ähnliche Fälle auch durch andere Sulfonamid-haltige Medikamente wie dem als Antiepileptikum verwendeten Carboanhydrasehemmer Topiramat und dem Thiaziddiuretikum Hydrochlorothiazid bekannt [4, 7, 8]. In der Allgemeinbevölkerung wird die Inzidenz von Sulfonamid-Allergien mit 3–8 % angenommen [2]. Die meisten Reaktionen auf Sulfonamide resultieren aus multifaktoriellen immunologischen und toxischen Stoffwechselmechanismen, während über die genauen Reaktionsmechanismen weniger bekannt ist [1]. Immunglobulin E(IgE)-vermittelte Typ-1-Immunreaktionen auf Sulfonamide können Anaphylaxie, Angioödeme und Urtikaria hervorrufen und nehmen darüber auch Einfluss auf die Konstitution der Aderhaut [10]. Über diesen Weg kann u. a. Acetazolamid, wie in dieser Kasuistik geschildert, paradoxe Nebenwirkungen mit ausgeprägtem uvealem Effusionssyndrom hervorrufen. Interessanterweise wurde festgestellt, dass gerade bei IgE-vermittelten Typ-1-Immunreaktionen nicht die Sulfonamid-definierende NH2-SO2-Struktur, sondern der im Molekül enthaltene heterozyklische N‑Ring an IgE bindet [3]. Somit ist auch zu erklären, dass verschiedene Sulfonamid-haltige Arzneimittel mit unterschiedlichen heterozyklischen N‑Ringen sehr variable Immunreaktionen hervorrufen können. In dem vorliegenden Fall war bei der Patientin keine Sulfonamid-Allergie bekannt. Dennoch sollte gerade vor der Verabreichung von Acetazolamid und anderen Sulfonamiden eine allergologische Anamnese erfolgen. Gleichzeitig sollte auch bei Vorliegen einer klaren klinischen Situation wie der eines Winkelblocks durch eine spezifische Anamnese differenzialdiagnostisch an die Unterscheidung zwischen einem primären und sekundären Engwinkelglaukom gedacht werden, da dies für die Therapieentscheidung – wie in diesem Fall – von wesentlicher klinischer Relevanz sein kann. In diesem Kontext wurde in der Literatur das Vorliegen einer Plateau-Iris-Konfiguration als wesentlicher Risikofaktor für die Entwicklung eines Winkelblockglaukoms diskutiert [5]. Während lokale und/oder systemische Carboanhydrasehemmer im Rahmen von Augeninnendruckentgleisungen als First-line-Therapeutika angesehen und verwendet werden können [6], wären diese in dem vorliegenden Fall kontraindiziert. Nicht zuletzt sollte neben der adäquaten Therapie auch daran gedacht werden, den Patienten über das Vorliegen und die Bedeutung einer Sulfonamid-Allergie aufzuklären.
Fazit für die Praxis
Ein beidseitiges sekundäres iridokorneales Engwinkelglaukom auf Grundlage eines uvealen Effusionssyndroms kann als seltene, klinisch schwerwiegende unerwünschte Arzneimittelwirkung von Acetazolamid eintreten.
Die Verordnung von Acetazolamid sollte mit Bedacht erfolgen, und mögliche Sulfonamid-Allergien müssen berücksichtigt werden.
Eine effiziente und sichere Möglichkeit der Akutbehandlung besteht in der Verwendung von Osmodiuretika und Kortikosteroiden.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
M. Anwar, T. Brockmann, M. Walckling und T.A. Fuchsluger geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patienten zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern eine schriftliche Einwilligung vor. | Oral | DrugAdministrationRoute | CC BY | 32803274 | 18,639,253 | 2021-08 |
What was the administration route of drug 'APRACLONIDINE HYDROCHLORIDE'? | Acute angle-closure glaucoma and effusion syndrome after phacoemulsification.
A 72-year-old female patient developed bilateral secondary iridocorneal angle-closure glaucoma with uveal effusion syndrome after uncomplicated cataract surgery. The postoperative intake of acetazolamide was identified as causative for the development of the effusion syndrome. Taking a sulfonamide-free systemic and local intraocular pressure lowering and anti-inflammatory treatment into account, a rapid improvement of the ocular manifestation was achieved. The case illustrates a rare but clinically severe adverse effect of acetazolamide and outlines efficient treatment options.
Anamnese
Eine 72-jährige Patientin stellte sich in unserer Klinik als Notfall mit starken Kopfschmerzen, Übelkeit und Erbrechen sowie beidseitig plötzlicher Sehverschlechterung vor. Am späten Vormittag des Tages erhielt sie an ihrem rechten Auge eine elektive ambulante Kataraktoperation unter Lokalanästhesie. Die Kataraktoperation des Partnerauges erfolgte bereits 2 Wochen zuvor. An beiden Augen verliefen die Operationen komplikationslos mit Implantation einer Intraokularlinse in den intakten Kapselsack. Postoperativ wurde der Patientin, neben der antibiotischen und antiinflammatorischen Lokaltherapie eine prophylaktische orale Einmaldosis Acetazolamid 250 mg verordnet, um einem möglichen postoperativen intraokularen Druckanstieg vorzubeugen. Die Patientin nahm die Acetazolamid-Tablette 4 h nach der Operation ein und legte sich schlafen. Etwa 6 h später wachte sie aufgrund starker Kopfschmerzen auf und bemerkte beidseits eine massive Sehverschlechterung, woraufhin sie die Klinik aufsuchte.
Klinischer Befund
Bei der Erstvorstellung betrug die bestkorrigierte Sehschärfe der Patientin rechts 1/35 und links 1/25 bei einer Refraktionskorrektur rechts von −3,0 dpt und links −3,5 dpt. Spaltlampenmikroskopisch zeigten sich beidseits eine Bindehautinjektion, ausgeprägtes Hornhautödem sowie eine flache Vorderkammer mit Anteflexion der Intraokularlinse (Abb. 1a, b). Zur weiteren Diagnostik führten wir eine Ultraschallbiomikroskopie durch (Abb. 1c, d). Hierbei betrug die Vorderkammertiefe rechts 2,08 mm und links 2,74 mm, der Kammerwinkel zeigte sich bei einem iridokornealen Winkelblock zirkulär verschlossen. Der Intraokulardruck betrug initial rechts 62 mm Hg und links 64 mm Hg. Eine Fundoskopie war aufgrund des ausgeprägten Hornhautödems nicht möglich. In der B‑Scan-Sonographie zeigte sich beidseits eine Aderhautschwellung im Sinne einer Aderhautabhebung (Abb. 2c, d). Die Patientin wurde mit der Arbeitsdiagnose sekundäres Engwinkelglaukom mit Pupillarblock stationär aufgenommen.
Therapie und Verlauf
Eine initiale systemisch-intravenöse Drucksenkung erfolgte mit Acetazolamid 500 mg und Mannitol (15 %) 300 ml sowie beidseits lokal mit Timolol 0,5 %, Apraclonidin 5 % und Prednisolon 1 %. Unter der genannten Therapie zeigte sich nur eine unzureichende Drucksenkung bei Zunahme der Aderhautschwellung, sodass die Arbeitsdiagnose überdacht werden musste. Acetazolamid wurde im Weiteren als Ursache für ein bilaterales uveales Effusionssyndrom mit sekundärem iridokornealem Engwinkelglaukom angenommen und daher abgesetzt. Dementsprechend erfolgte die weitere systemische Therapie mit einer erneuten Einmalgabe von Mannitol (15 %) 300 ml intravenös und Prednisolon 100 mg per os täglich. Hierunter verbesserte sich der klinische Befund über 3 Tage allmählich. Der Augeninnendruck konnte rechts auf 7 mm Hg und links 9 mm Hg gesenkt werden. In der Fundoskopie zeigte sich noch eine bilaterale periphere Aderhautabhebung (Abb. 2a, b). Der bestkorrigierte Dezimalvisus stieg auf rechts 0,8 und links 0,9 an, die Konfiguration der Vorderkammer normalisierte sich, und die Myopisierung zeigte sich rückläufig. Die systemische und lokal drucksenkende Therapie wurde beendet.
In der Verlaufskontrolle zeigte sich nach 1 Woche beidseits ein regelrechter sonographischer und fundoskopischer Befund des hinteren Augenabschnitts (Abb. 3). Die Vorderkammertiefe betrug rechts 4,39 mm und links 4,37 mm bei einem Augeninnendruck von rechts 10 mm Hg und links 11 mm Hg. Der unkorrigierte Dezimalvisus betrug nun beidseits 1,0. In der nochmals durchgeführten Ultraschallbiomikroskopie offenbarte sich nun beidseits eine Plateau-Iris-Konfiguration (Abb. 3c, d).
Diagnose
Beidseitiges akutes Engwinkelglaukom bei Acetazolamid-indiziertem Effusionssyndrome nach Kataraktoperation in Plateau-Iris-Konfiguration.
Diskussion
Die Entwicklung eines uvealen Effusionssyndroms ist bei Sulfonamid-haltigen Arzneimitteln, zu denen auch der Carboanhydrasehemmer Acetazolamid gehört, grundsätzlich bekannt [9]. Der vorliegende Fall verdeutlicht allerdings, dass die hierbei eintretende Aderhautschwellung nicht nur Aderhautfalten hervorruft, sondern foudroyant verlaufen und dabei durch eine massive intraokulare Volumenverschiebung zu einem iridokornealen Winkelblock führen kann. Neben Acetazolamid sind aus der Literatur ähnliche Fälle auch durch andere Sulfonamid-haltige Medikamente wie dem als Antiepileptikum verwendeten Carboanhydrasehemmer Topiramat und dem Thiaziddiuretikum Hydrochlorothiazid bekannt [4, 7, 8]. In der Allgemeinbevölkerung wird die Inzidenz von Sulfonamid-Allergien mit 3–8 % angenommen [2]. Die meisten Reaktionen auf Sulfonamide resultieren aus multifaktoriellen immunologischen und toxischen Stoffwechselmechanismen, während über die genauen Reaktionsmechanismen weniger bekannt ist [1]. Immunglobulin E(IgE)-vermittelte Typ-1-Immunreaktionen auf Sulfonamide können Anaphylaxie, Angioödeme und Urtikaria hervorrufen und nehmen darüber auch Einfluss auf die Konstitution der Aderhaut [10]. Über diesen Weg kann u. a. Acetazolamid, wie in dieser Kasuistik geschildert, paradoxe Nebenwirkungen mit ausgeprägtem uvealem Effusionssyndrom hervorrufen. Interessanterweise wurde festgestellt, dass gerade bei IgE-vermittelten Typ-1-Immunreaktionen nicht die Sulfonamid-definierende NH2-SO2-Struktur, sondern der im Molekül enthaltene heterozyklische N‑Ring an IgE bindet [3]. Somit ist auch zu erklären, dass verschiedene Sulfonamid-haltige Arzneimittel mit unterschiedlichen heterozyklischen N‑Ringen sehr variable Immunreaktionen hervorrufen können. In dem vorliegenden Fall war bei der Patientin keine Sulfonamid-Allergie bekannt. Dennoch sollte gerade vor der Verabreichung von Acetazolamid und anderen Sulfonamiden eine allergologische Anamnese erfolgen. Gleichzeitig sollte auch bei Vorliegen einer klaren klinischen Situation wie der eines Winkelblocks durch eine spezifische Anamnese differenzialdiagnostisch an die Unterscheidung zwischen einem primären und sekundären Engwinkelglaukom gedacht werden, da dies für die Therapieentscheidung – wie in diesem Fall – von wesentlicher klinischer Relevanz sein kann. In diesem Kontext wurde in der Literatur das Vorliegen einer Plateau-Iris-Konfiguration als wesentlicher Risikofaktor für die Entwicklung eines Winkelblockglaukoms diskutiert [5]. Während lokale und/oder systemische Carboanhydrasehemmer im Rahmen von Augeninnendruckentgleisungen als First-line-Therapeutika angesehen und verwendet werden können [6], wären diese in dem vorliegenden Fall kontraindiziert. Nicht zuletzt sollte neben der adäquaten Therapie auch daran gedacht werden, den Patienten über das Vorliegen und die Bedeutung einer Sulfonamid-Allergie aufzuklären.
Fazit für die Praxis
Ein beidseitiges sekundäres iridokorneales Engwinkelglaukom auf Grundlage eines uvealen Effusionssyndroms kann als seltene, klinisch schwerwiegende unerwünschte Arzneimittelwirkung von Acetazolamid eintreten.
Die Verordnung von Acetazolamid sollte mit Bedacht erfolgen, und mögliche Sulfonamid-Allergien müssen berücksichtigt werden.
Eine effiziente und sichere Möglichkeit der Akutbehandlung besteht in der Verwendung von Osmodiuretika und Kortikosteroiden.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
M. Anwar, T. Brockmann, M. Walckling und T.A. Fuchsluger geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patienten zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern eine schriftliche Einwilligung vor. | Topical | DrugAdministrationRoute | CC BY | 32803274 | 18,639,253 | 2021-08 |
What was the administration route of drug 'TIMOLOL'? | Acute angle-closure glaucoma and effusion syndrome after phacoemulsification.
A 72-year-old female patient developed bilateral secondary iridocorneal angle-closure glaucoma with uveal effusion syndrome after uncomplicated cataract surgery. The postoperative intake of acetazolamide was identified as causative for the development of the effusion syndrome. Taking a sulfonamide-free systemic and local intraocular pressure lowering and anti-inflammatory treatment into account, a rapid improvement of the ocular manifestation was achieved. The case illustrates a rare but clinically severe adverse effect of acetazolamide and outlines efficient treatment options.
Anamnese
Eine 72-jährige Patientin stellte sich in unserer Klinik als Notfall mit starken Kopfschmerzen, Übelkeit und Erbrechen sowie beidseitig plötzlicher Sehverschlechterung vor. Am späten Vormittag des Tages erhielt sie an ihrem rechten Auge eine elektive ambulante Kataraktoperation unter Lokalanästhesie. Die Kataraktoperation des Partnerauges erfolgte bereits 2 Wochen zuvor. An beiden Augen verliefen die Operationen komplikationslos mit Implantation einer Intraokularlinse in den intakten Kapselsack. Postoperativ wurde der Patientin, neben der antibiotischen und antiinflammatorischen Lokaltherapie eine prophylaktische orale Einmaldosis Acetazolamid 250 mg verordnet, um einem möglichen postoperativen intraokularen Druckanstieg vorzubeugen. Die Patientin nahm die Acetazolamid-Tablette 4 h nach der Operation ein und legte sich schlafen. Etwa 6 h später wachte sie aufgrund starker Kopfschmerzen auf und bemerkte beidseits eine massive Sehverschlechterung, woraufhin sie die Klinik aufsuchte.
Klinischer Befund
Bei der Erstvorstellung betrug die bestkorrigierte Sehschärfe der Patientin rechts 1/35 und links 1/25 bei einer Refraktionskorrektur rechts von −3,0 dpt und links −3,5 dpt. Spaltlampenmikroskopisch zeigten sich beidseits eine Bindehautinjektion, ausgeprägtes Hornhautödem sowie eine flache Vorderkammer mit Anteflexion der Intraokularlinse (Abb. 1a, b). Zur weiteren Diagnostik führten wir eine Ultraschallbiomikroskopie durch (Abb. 1c, d). Hierbei betrug die Vorderkammertiefe rechts 2,08 mm und links 2,74 mm, der Kammerwinkel zeigte sich bei einem iridokornealen Winkelblock zirkulär verschlossen. Der Intraokulardruck betrug initial rechts 62 mm Hg und links 64 mm Hg. Eine Fundoskopie war aufgrund des ausgeprägten Hornhautödems nicht möglich. In der B‑Scan-Sonographie zeigte sich beidseits eine Aderhautschwellung im Sinne einer Aderhautabhebung (Abb. 2c, d). Die Patientin wurde mit der Arbeitsdiagnose sekundäres Engwinkelglaukom mit Pupillarblock stationär aufgenommen.
Therapie und Verlauf
Eine initiale systemisch-intravenöse Drucksenkung erfolgte mit Acetazolamid 500 mg und Mannitol (15 %) 300 ml sowie beidseits lokal mit Timolol 0,5 %, Apraclonidin 5 % und Prednisolon 1 %. Unter der genannten Therapie zeigte sich nur eine unzureichende Drucksenkung bei Zunahme der Aderhautschwellung, sodass die Arbeitsdiagnose überdacht werden musste. Acetazolamid wurde im Weiteren als Ursache für ein bilaterales uveales Effusionssyndrom mit sekundärem iridokornealem Engwinkelglaukom angenommen und daher abgesetzt. Dementsprechend erfolgte die weitere systemische Therapie mit einer erneuten Einmalgabe von Mannitol (15 %) 300 ml intravenös und Prednisolon 100 mg per os täglich. Hierunter verbesserte sich der klinische Befund über 3 Tage allmählich. Der Augeninnendruck konnte rechts auf 7 mm Hg und links 9 mm Hg gesenkt werden. In der Fundoskopie zeigte sich noch eine bilaterale periphere Aderhautabhebung (Abb. 2a, b). Der bestkorrigierte Dezimalvisus stieg auf rechts 0,8 und links 0,9 an, die Konfiguration der Vorderkammer normalisierte sich, und die Myopisierung zeigte sich rückläufig. Die systemische und lokal drucksenkende Therapie wurde beendet.
In der Verlaufskontrolle zeigte sich nach 1 Woche beidseits ein regelrechter sonographischer und fundoskopischer Befund des hinteren Augenabschnitts (Abb. 3). Die Vorderkammertiefe betrug rechts 4,39 mm und links 4,37 mm bei einem Augeninnendruck von rechts 10 mm Hg und links 11 mm Hg. Der unkorrigierte Dezimalvisus betrug nun beidseits 1,0. In der nochmals durchgeführten Ultraschallbiomikroskopie offenbarte sich nun beidseits eine Plateau-Iris-Konfiguration (Abb. 3c, d).
Diagnose
Beidseitiges akutes Engwinkelglaukom bei Acetazolamid-indiziertem Effusionssyndrome nach Kataraktoperation in Plateau-Iris-Konfiguration.
Diskussion
Die Entwicklung eines uvealen Effusionssyndroms ist bei Sulfonamid-haltigen Arzneimitteln, zu denen auch der Carboanhydrasehemmer Acetazolamid gehört, grundsätzlich bekannt [9]. Der vorliegende Fall verdeutlicht allerdings, dass die hierbei eintretende Aderhautschwellung nicht nur Aderhautfalten hervorruft, sondern foudroyant verlaufen und dabei durch eine massive intraokulare Volumenverschiebung zu einem iridokornealen Winkelblock führen kann. Neben Acetazolamid sind aus der Literatur ähnliche Fälle auch durch andere Sulfonamid-haltige Medikamente wie dem als Antiepileptikum verwendeten Carboanhydrasehemmer Topiramat und dem Thiaziddiuretikum Hydrochlorothiazid bekannt [4, 7, 8]. In der Allgemeinbevölkerung wird die Inzidenz von Sulfonamid-Allergien mit 3–8 % angenommen [2]. Die meisten Reaktionen auf Sulfonamide resultieren aus multifaktoriellen immunologischen und toxischen Stoffwechselmechanismen, während über die genauen Reaktionsmechanismen weniger bekannt ist [1]. Immunglobulin E(IgE)-vermittelte Typ-1-Immunreaktionen auf Sulfonamide können Anaphylaxie, Angioödeme und Urtikaria hervorrufen und nehmen darüber auch Einfluss auf die Konstitution der Aderhaut [10]. Über diesen Weg kann u. a. Acetazolamid, wie in dieser Kasuistik geschildert, paradoxe Nebenwirkungen mit ausgeprägtem uvealem Effusionssyndrom hervorrufen. Interessanterweise wurde festgestellt, dass gerade bei IgE-vermittelten Typ-1-Immunreaktionen nicht die Sulfonamid-definierende NH2-SO2-Struktur, sondern der im Molekül enthaltene heterozyklische N‑Ring an IgE bindet [3]. Somit ist auch zu erklären, dass verschiedene Sulfonamid-haltige Arzneimittel mit unterschiedlichen heterozyklischen N‑Ringen sehr variable Immunreaktionen hervorrufen können. In dem vorliegenden Fall war bei der Patientin keine Sulfonamid-Allergie bekannt. Dennoch sollte gerade vor der Verabreichung von Acetazolamid und anderen Sulfonamiden eine allergologische Anamnese erfolgen. Gleichzeitig sollte auch bei Vorliegen einer klaren klinischen Situation wie der eines Winkelblocks durch eine spezifische Anamnese differenzialdiagnostisch an die Unterscheidung zwischen einem primären und sekundären Engwinkelglaukom gedacht werden, da dies für die Therapieentscheidung – wie in diesem Fall – von wesentlicher klinischer Relevanz sein kann. In diesem Kontext wurde in der Literatur das Vorliegen einer Plateau-Iris-Konfiguration als wesentlicher Risikofaktor für die Entwicklung eines Winkelblockglaukoms diskutiert [5]. Während lokale und/oder systemische Carboanhydrasehemmer im Rahmen von Augeninnendruckentgleisungen als First-line-Therapeutika angesehen und verwendet werden können [6], wären diese in dem vorliegenden Fall kontraindiziert. Nicht zuletzt sollte neben der adäquaten Therapie auch daran gedacht werden, den Patienten über das Vorliegen und die Bedeutung einer Sulfonamid-Allergie aufzuklären.
Fazit für die Praxis
Ein beidseitiges sekundäres iridokorneales Engwinkelglaukom auf Grundlage eines uvealen Effusionssyndroms kann als seltene, klinisch schwerwiegende unerwünschte Arzneimittelwirkung von Acetazolamid eintreten.
Die Verordnung von Acetazolamid sollte mit Bedacht erfolgen, und mögliche Sulfonamid-Allergien müssen berücksichtigt werden.
Eine effiziente und sichere Möglichkeit der Akutbehandlung besteht in der Verwendung von Osmodiuretika und Kortikosteroiden.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
M. Anwar, T. Brockmann, M. Walckling und T.A. Fuchsluger geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patienten zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern eine schriftliche Einwilligung vor. | Topical | DrugAdministrationRoute | CC BY | 32803274 | 18,639,253 | 2021-08 |
What was the outcome of reaction 'Angle closure glaucoma'? | Acute angle-closure glaucoma and effusion syndrome after phacoemulsification.
A 72-year-old female patient developed bilateral secondary iridocorneal angle-closure glaucoma with uveal effusion syndrome after uncomplicated cataract surgery. The postoperative intake of acetazolamide was identified as causative for the development of the effusion syndrome. Taking a sulfonamide-free systemic and local intraocular pressure lowering and anti-inflammatory treatment into account, a rapid improvement of the ocular manifestation was achieved. The case illustrates a rare but clinically severe adverse effect of acetazolamide and outlines efficient treatment options.
Anamnese
Eine 72-jährige Patientin stellte sich in unserer Klinik als Notfall mit starken Kopfschmerzen, Übelkeit und Erbrechen sowie beidseitig plötzlicher Sehverschlechterung vor. Am späten Vormittag des Tages erhielt sie an ihrem rechten Auge eine elektive ambulante Kataraktoperation unter Lokalanästhesie. Die Kataraktoperation des Partnerauges erfolgte bereits 2 Wochen zuvor. An beiden Augen verliefen die Operationen komplikationslos mit Implantation einer Intraokularlinse in den intakten Kapselsack. Postoperativ wurde der Patientin, neben der antibiotischen und antiinflammatorischen Lokaltherapie eine prophylaktische orale Einmaldosis Acetazolamid 250 mg verordnet, um einem möglichen postoperativen intraokularen Druckanstieg vorzubeugen. Die Patientin nahm die Acetazolamid-Tablette 4 h nach der Operation ein und legte sich schlafen. Etwa 6 h später wachte sie aufgrund starker Kopfschmerzen auf und bemerkte beidseits eine massive Sehverschlechterung, woraufhin sie die Klinik aufsuchte.
Klinischer Befund
Bei der Erstvorstellung betrug die bestkorrigierte Sehschärfe der Patientin rechts 1/35 und links 1/25 bei einer Refraktionskorrektur rechts von −3,0 dpt und links −3,5 dpt. Spaltlampenmikroskopisch zeigten sich beidseits eine Bindehautinjektion, ausgeprägtes Hornhautödem sowie eine flache Vorderkammer mit Anteflexion der Intraokularlinse (Abb. 1a, b). Zur weiteren Diagnostik führten wir eine Ultraschallbiomikroskopie durch (Abb. 1c, d). Hierbei betrug die Vorderkammertiefe rechts 2,08 mm und links 2,74 mm, der Kammerwinkel zeigte sich bei einem iridokornealen Winkelblock zirkulär verschlossen. Der Intraokulardruck betrug initial rechts 62 mm Hg und links 64 mm Hg. Eine Fundoskopie war aufgrund des ausgeprägten Hornhautödems nicht möglich. In der B‑Scan-Sonographie zeigte sich beidseits eine Aderhautschwellung im Sinne einer Aderhautabhebung (Abb. 2c, d). Die Patientin wurde mit der Arbeitsdiagnose sekundäres Engwinkelglaukom mit Pupillarblock stationär aufgenommen.
Therapie und Verlauf
Eine initiale systemisch-intravenöse Drucksenkung erfolgte mit Acetazolamid 500 mg und Mannitol (15 %) 300 ml sowie beidseits lokal mit Timolol 0,5 %, Apraclonidin 5 % und Prednisolon 1 %. Unter der genannten Therapie zeigte sich nur eine unzureichende Drucksenkung bei Zunahme der Aderhautschwellung, sodass die Arbeitsdiagnose überdacht werden musste. Acetazolamid wurde im Weiteren als Ursache für ein bilaterales uveales Effusionssyndrom mit sekundärem iridokornealem Engwinkelglaukom angenommen und daher abgesetzt. Dementsprechend erfolgte die weitere systemische Therapie mit einer erneuten Einmalgabe von Mannitol (15 %) 300 ml intravenös und Prednisolon 100 mg per os täglich. Hierunter verbesserte sich der klinische Befund über 3 Tage allmählich. Der Augeninnendruck konnte rechts auf 7 mm Hg und links 9 mm Hg gesenkt werden. In der Fundoskopie zeigte sich noch eine bilaterale periphere Aderhautabhebung (Abb. 2a, b). Der bestkorrigierte Dezimalvisus stieg auf rechts 0,8 und links 0,9 an, die Konfiguration der Vorderkammer normalisierte sich, und die Myopisierung zeigte sich rückläufig. Die systemische und lokal drucksenkende Therapie wurde beendet.
In der Verlaufskontrolle zeigte sich nach 1 Woche beidseits ein regelrechter sonographischer und fundoskopischer Befund des hinteren Augenabschnitts (Abb. 3). Die Vorderkammertiefe betrug rechts 4,39 mm und links 4,37 mm bei einem Augeninnendruck von rechts 10 mm Hg und links 11 mm Hg. Der unkorrigierte Dezimalvisus betrug nun beidseits 1,0. In der nochmals durchgeführten Ultraschallbiomikroskopie offenbarte sich nun beidseits eine Plateau-Iris-Konfiguration (Abb. 3c, d).
Diagnose
Beidseitiges akutes Engwinkelglaukom bei Acetazolamid-indiziertem Effusionssyndrome nach Kataraktoperation in Plateau-Iris-Konfiguration.
Diskussion
Die Entwicklung eines uvealen Effusionssyndroms ist bei Sulfonamid-haltigen Arzneimitteln, zu denen auch der Carboanhydrasehemmer Acetazolamid gehört, grundsätzlich bekannt [9]. Der vorliegende Fall verdeutlicht allerdings, dass die hierbei eintretende Aderhautschwellung nicht nur Aderhautfalten hervorruft, sondern foudroyant verlaufen und dabei durch eine massive intraokulare Volumenverschiebung zu einem iridokornealen Winkelblock führen kann. Neben Acetazolamid sind aus der Literatur ähnliche Fälle auch durch andere Sulfonamid-haltige Medikamente wie dem als Antiepileptikum verwendeten Carboanhydrasehemmer Topiramat und dem Thiaziddiuretikum Hydrochlorothiazid bekannt [4, 7, 8]. In der Allgemeinbevölkerung wird die Inzidenz von Sulfonamid-Allergien mit 3–8 % angenommen [2]. Die meisten Reaktionen auf Sulfonamide resultieren aus multifaktoriellen immunologischen und toxischen Stoffwechselmechanismen, während über die genauen Reaktionsmechanismen weniger bekannt ist [1]. Immunglobulin E(IgE)-vermittelte Typ-1-Immunreaktionen auf Sulfonamide können Anaphylaxie, Angioödeme und Urtikaria hervorrufen und nehmen darüber auch Einfluss auf die Konstitution der Aderhaut [10]. Über diesen Weg kann u. a. Acetazolamid, wie in dieser Kasuistik geschildert, paradoxe Nebenwirkungen mit ausgeprägtem uvealem Effusionssyndrom hervorrufen. Interessanterweise wurde festgestellt, dass gerade bei IgE-vermittelten Typ-1-Immunreaktionen nicht die Sulfonamid-definierende NH2-SO2-Struktur, sondern der im Molekül enthaltene heterozyklische N‑Ring an IgE bindet [3]. Somit ist auch zu erklären, dass verschiedene Sulfonamid-haltige Arzneimittel mit unterschiedlichen heterozyklischen N‑Ringen sehr variable Immunreaktionen hervorrufen können. In dem vorliegenden Fall war bei der Patientin keine Sulfonamid-Allergie bekannt. Dennoch sollte gerade vor der Verabreichung von Acetazolamid und anderen Sulfonamiden eine allergologische Anamnese erfolgen. Gleichzeitig sollte auch bei Vorliegen einer klaren klinischen Situation wie der eines Winkelblocks durch eine spezifische Anamnese differenzialdiagnostisch an die Unterscheidung zwischen einem primären und sekundären Engwinkelglaukom gedacht werden, da dies für die Therapieentscheidung – wie in diesem Fall – von wesentlicher klinischer Relevanz sein kann. In diesem Kontext wurde in der Literatur das Vorliegen einer Plateau-Iris-Konfiguration als wesentlicher Risikofaktor für die Entwicklung eines Winkelblockglaukoms diskutiert [5]. Während lokale und/oder systemische Carboanhydrasehemmer im Rahmen von Augeninnendruckentgleisungen als First-line-Therapeutika angesehen und verwendet werden können [6], wären diese in dem vorliegenden Fall kontraindiziert. Nicht zuletzt sollte neben der adäquaten Therapie auch daran gedacht werden, den Patienten über das Vorliegen und die Bedeutung einer Sulfonamid-Allergie aufzuklären.
Fazit für die Praxis
Ein beidseitiges sekundäres iridokorneales Engwinkelglaukom auf Grundlage eines uvealen Effusionssyndroms kann als seltene, klinisch schwerwiegende unerwünschte Arzneimittelwirkung von Acetazolamid eintreten.
Die Verordnung von Acetazolamid sollte mit Bedacht erfolgen, und mögliche Sulfonamid-Allergien müssen berücksichtigt werden.
Eine effiziente und sichere Möglichkeit der Akutbehandlung besteht in der Verwendung von Osmodiuretika und Kortikosteroiden.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
M. Anwar, T. Brockmann, M. Walckling und T.A. Fuchsluger geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patienten zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern eine schriftliche Einwilligung vor. | Recovered | ReactionOutcome | CC BY | 32803274 | 18,639,253 | 2021-08 |
What was the outcome of reaction 'Choroidal effusion'? | Acute angle-closure glaucoma and effusion syndrome after phacoemulsification.
A 72-year-old female patient developed bilateral secondary iridocorneal angle-closure glaucoma with uveal effusion syndrome after uncomplicated cataract surgery. The postoperative intake of acetazolamide was identified as causative for the development of the effusion syndrome. Taking a sulfonamide-free systemic and local intraocular pressure lowering and anti-inflammatory treatment into account, a rapid improvement of the ocular manifestation was achieved. The case illustrates a rare but clinically severe adverse effect of acetazolamide and outlines efficient treatment options.
Anamnese
Eine 72-jährige Patientin stellte sich in unserer Klinik als Notfall mit starken Kopfschmerzen, Übelkeit und Erbrechen sowie beidseitig plötzlicher Sehverschlechterung vor. Am späten Vormittag des Tages erhielt sie an ihrem rechten Auge eine elektive ambulante Kataraktoperation unter Lokalanästhesie. Die Kataraktoperation des Partnerauges erfolgte bereits 2 Wochen zuvor. An beiden Augen verliefen die Operationen komplikationslos mit Implantation einer Intraokularlinse in den intakten Kapselsack. Postoperativ wurde der Patientin, neben der antibiotischen und antiinflammatorischen Lokaltherapie eine prophylaktische orale Einmaldosis Acetazolamid 250 mg verordnet, um einem möglichen postoperativen intraokularen Druckanstieg vorzubeugen. Die Patientin nahm die Acetazolamid-Tablette 4 h nach der Operation ein und legte sich schlafen. Etwa 6 h später wachte sie aufgrund starker Kopfschmerzen auf und bemerkte beidseits eine massive Sehverschlechterung, woraufhin sie die Klinik aufsuchte.
Klinischer Befund
Bei der Erstvorstellung betrug die bestkorrigierte Sehschärfe der Patientin rechts 1/35 und links 1/25 bei einer Refraktionskorrektur rechts von −3,0 dpt und links −3,5 dpt. Spaltlampenmikroskopisch zeigten sich beidseits eine Bindehautinjektion, ausgeprägtes Hornhautödem sowie eine flache Vorderkammer mit Anteflexion der Intraokularlinse (Abb. 1a, b). Zur weiteren Diagnostik führten wir eine Ultraschallbiomikroskopie durch (Abb. 1c, d). Hierbei betrug die Vorderkammertiefe rechts 2,08 mm und links 2,74 mm, der Kammerwinkel zeigte sich bei einem iridokornealen Winkelblock zirkulär verschlossen. Der Intraokulardruck betrug initial rechts 62 mm Hg und links 64 mm Hg. Eine Fundoskopie war aufgrund des ausgeprägten Hornhautödems nicht möglich. In der B‑Scan-Sonographie zeigte sich beidseits eine Aderhautschwellung im Sinne einer Aderhautabhebung (Abb. 2c, d). Die Patientin wurde mit der Arbeitsdiagnose sekundäres Engwinkelglaukom mit Pupillarblock stationär aufgenommen.
Therapie und Verlauf
Eine initiale systemisch-intravenöse Drucksenkung erfolgte mit Acetazolamid 500 mg und Mannitol (15 %) 300 ml sowie beidseits lokal mit Timolol 0,5 %, Apraclonidin 5 % und Prednisolon 1 %. Unter der genannten Therapie zeigte sich nur eine unzureichende Drucksenkung bei Zunahme der Aderhautschwellung, sodass die Arbeitsdiagnose überdacht werden musste. Acetazolamid wurde im Weiteren als Ursache für ein bilaterales uveales Effusionssyndrom mit sekundärem iridokornealem Engwinkelglaukom angenommen und daher abgesetzt. Dementsprechend erfolgte die weitere systemische Therapie mit einer erneuten Einmalgabe von Mannitol (15 %) 300 ml intravenös und Prednisolon 100 mg per os täglich. Hierunter verbesserte sich der klinische Befund über 3 Tage allmählich. Der Augeninnendruck konnte rechts auf 7 mm Hg und links 9 mm Hg gesenkt werden. In der Fundoskopie zeigte sich noch eine bilaterale periphere Aderhautabhebung (Abb. 2a, b). Der bestkorrigierte Dezimalvisus stieg auf rechts 0,8 und links 0,9 an, die Konfiguration der Vorderkammer normalisierte sich, und die Myopisierung zeigte sich rückläufig. Die systemische und lokal drucksenkende Therapie wurde beendet.
In der Verlaufskontrolle zeigte sich nach 1 Woche beidseits ein regelrechter sonographischer und fundoskopischer Befund des hinteren Augenabschnitts (Abb. 3). Die Vorderkammertiefe betrug rechts 4,39 mm und links 4,37 mm bei einem Augeninnendruck von rechts 10 mm Hg und links 11 mm Hg. Der unkorrigierte Dezimalvisus betrug nun beidseits 1,0. In der nochmals durchgeführten Ultraschallbiomikroskopie offenbarte sich nun beidseits eine Plateau-Iris-Konfiguration (Abb. 3c, d).
Diagnose
Beidseitiges akutes Engwinkelglaukom bei Acetazolamid-indiziertem Effusionssyndrome nach Kataraktoperation in Plateau-Iris-Konfiguration.
Diskussion
Die Entwicklung eines uvealen Effusionssyndroms ist bei Sulfonamid-haltigen Arzneimitteln, zu denen auch der Carboanhydrasehemmer Acetazolamid gehört, grundsätzlich bekannt [9]. Der vorliegende Fall verdeutlicht allerdings, dass die hierbei eintretende Aderhautschwellung nicht nur Aderhautfalten hervorruft, sondern foudroyant verlaufen und dabei durch eine massive intraokulare Volumenverschiebung zu einem iridokornealen Winkelblock führen kann. Neben Acetazolamid sind aus der Literatur ähnliche Fälle auch durch andere Sulfonamid-haltige Medikamente wie dem als Antiepileptikum verwendeten Carboanhydrasehemmer Topiramat und dem Thiaziddiuretikum Hydrochlorothiazid bekannt [4, 7, 8]. In der Allgemeinbevölkerung wird die Inzidenz von Sulfonamid-Allergien mit 3–8 % angenommen [2]. Die meisten Reaktionen auf Sulfonamide resultieren aus multifaktoriellen immunologischen und toxischen Stoffwechselmechanismen, während über die genauen Reaktionsmechanismen weniger bekannt ist [1]. Immunglobulin E(IgE)-vermittelte Typ-1-Immunreaktionen auf Sulfonamide können Anaphylaxie, Angioödeme und Urtikaria hervorrufen und nehmen darüber auch Einfluss auf die Konstitution der Aderhaut [10]. Über diesen Weg kann u. a. Acetazolamid, wie in dieser Kasuistik geschildert, paradoxe Nebenwirkungen mit ausgeprägtem uvealem Effusionssyndrom hervorrufen. Interessanterweise wurde festgestellt, dass gerade bei IgE-vermittelten Typ-1-Immunreaktionen nicht die Sulfonamid-definierende NH2-SO2-Struktur, sondern der im Molekül enthaltene heterozyklische N‑Ring an IgE bindet [3]. Somit ist auch zu erklären, dass verschiedene Sulfonamid-haltige Arzneimittel mit unterschiedlichen heterozyklischen N‑Ringen sehr variable Immunreaktionen hervorrufen können. In dem vorliegenden Fall war bei der Patientin keine Sulfonamid-Allergie bekannt. Dennoch sollte gerade vor der Verabreichung von Acetazolamid und anderen Sulfonamiden eine allergologische Anamnese erfolgen. Gleichzeitig sollte auch bei Vorliegen einer klaren klinischen Situation wie der eines Winkelblocks durch eine spezifische Anamnese differenzialdiagnostisch an die Unterscheidung zwischen einem primären und sekundären Engwinkelglaukom gedacht werden, da dies für die Therapieentscheidung – wie in diesem Fall – von wesentlicher klinischer Relevanz sein kann. In diesem Kontext wurde in der Literatur das Vorliegen einer Plateau-Iris-Konfiguration als wesentlicher Risikofaktor für die Entwicklung eines Winkelblockglaukoms diskutiert [5]. Während lokale und/oder systemische Carboanhydrasehemmer im Rahmen von Augeninnendruckentgleisungen als First-line-Therapeutika angesehen und verwendet werden können [6], wären diese in dem vorliegenden Fall kontraindiziert. Nicht zuletzt sollte neben der adäquaten Therapie auch daran gedacht werden, den Patienten über das Vorliegen und die Bedeutung einer Sulfonamid-Allergie aufzuklären.
Fazit für die Praxis
Ein beidseitiges sekundäres iridokorneales Engwinkelglaukom auf Grundlage eines uvealen Effusionssyndroms kann als seltene, klinisch schwerwiegende unerwünschte Arzneimittelwirkung von Acetazolamid eintreten.
Die Verordnung von Acetazolamid sollte mit Bedacht erfolgen, und mögliche Sulfonamid-Allergien müssen berücksichtigt werden.
Eine effiziente und sichere Möglichkeit der Akutbehandlung besteht in der Verwendung von Osmodiuretika und Kortikosteroiden.
Funding
Open Access funding provided by Projekt DEAL.
Einhaltung ethischer Richtlinien
Interessenkonflikt
M. Anwar, T. Brockmann, M. Walckling und T.A. Fuchsluger geben an, dass kein Interessenkonflikt besteht.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patienten zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern eine schriftliche Einwilligung vor. | Recovered | ReactionOutcome | CC BY | 32803274 | 18,639,253 | 2021-08 |
What was the administration route of drug 'DULOXETINE'? | Managing dissociative symptoms following the use of esketamine nasal spray: a case report.
Patients with treatment-resistant depression (TRD) treated with esketamine nasal spray commonly experience transient symptoms of dissociation. Manifestations of dissociation, such as feelings of detachment from the environment, can cause considerable anxiety for patients. Nonpharmacologic interventions may help clinicians to manage associated anxiety and confusion due to dissociation following administration of esketamine nasal spray. We present the case of a 64-year-old woman with major depressive disorder who participated in a clinical trial evaluating the efficacy and safety of esketamine nasal spray in conjunction with an oral antidepressant for TRD. The patient received flexible doses of esketamine nasal spray (56 or 84 mg) twice weekly for 4 weeks. On treatment day 1, the patient was administered 56 mg of esketamine nasal spray using two nasal spray devices (28 mg per device). Twenty minutes after the first esketamine nasal spray device was administered, the patient experienced a dissociative episode lasting 40 minutes that caused anxiety and confusion. The patient was encouraged to listen to music during treatment sessions, which resulted in notable improvement of her symptoms. Listening to music of choice immediately following esketamine nasal spray administration along with reassurance from staff may help manage confusion and anxiety associated with dissociation.
Background
Patients with treatment-resistant depression (TRD) who are prescribed esketamine nasal spray may experience side effects that temporarily impair their functioning. In double-blind clinical trials of esketamine nasal spray combined with an oral antidepressant, dissociation was reported as an adverse reaction in 41% of the esketamine plus oral antidepressant group (SPRAVATO, 2020). The group receiving 84 mg of esketamine nasal spray experienced higher rates of dissociative symptoms than the group receiving 56 mg (Fedgchin et al., 2019). While dissociative symptoms generally peaked at 40 minutes following esketamine administration and resolved within 1.5 h (Fedgchin et al., 2019), the associated confusion, loss of awareness of external environment, and other dissociative symptoms can be overwhelming for some patients (Park et al., 2019). Ketamine-associated dissociation typically resolves without pharmacologic intervention, suggesting that nonpharmacologic approaches could play a more central role in its management (Park et al., 2019).
Here, we describe the management of a patient affected by confusion, agitation, and anxiety due to dissociation after receiving an administration of esketamine nasal spray. To our knowledge, this strategy has not been reported in the literature and presents a simple, nonpharmacologic, inexpensive solution to a frequently occurring problem.
Case presentation
A 64-year-old woman with a medical history of hyperthyroidism and irritable bowel syndrome and a psychiatric history of major depressive disorder presented in December 2018 with unresolved symptoms of depression. She had a history of several failed antidepressant treatments (venlafaxine, bupropion, and citalopram) in the current major depressive episode and sought to alleviate her current depressive symptoms. She provided written informed consent to participate in a randomized, double-blind study (NCT03434041) to evaluate the efficacy, pharmacokinetics, safety, and tolerability of flexible doses of esketamine nasal spray in conjunction with an oral antidepressant in adults with TRD. She met trial eligibility criteria and was randomly assigned to receive either esketamine or placebo nasal spray; she also simultaneously began treatment with the oral antidepressant duloxetine. Nasal spray study medication was initiated on treatment day 1 beginning at a dose of 56 mg administered using two nasal spray devices (28 mg per device), with dosing (flexible doses of 56 or 84 mg) thereafter twice weekly for 4 weeks. The patient did not respond to treatment (where response = improvement of ≥50% in the Montgomery-Åsberg Depression Rating Scale total score) and did not experience dissociation while participating in the double-blind trial.
Following the fourth week of treatment and at the end of the study, the patient provided written informed consent to participate in an open-label, long-term extension safety study of esketamine nasal spray for TRD. During the induction phase of the subsequent open-label trial, the patient was administered flexible doses of esketamine nasal spray (56 or 84 mg) twice weekly for 4 weeks. She received 56 mg of esketamine nasal spray on day 1 and was titrated to 84 mg on day 11. On day 1 of treatment, the patient experienced agitation and confusion due to dissociation that began 20 minutes after esketamine nasal spray administration and persisted for 40 minutes (Table 1). The coordinator and doctor who were with the patient reassured her that the dissociative symptoms would soon subside and reminded her that she was safe in the clinic.
Table 1 Timing of dissociative symptoms after administration of first esketamine nasal spray device
Visit (study phase/week) Total dosage administered (mg) Time until onset of symptoms (minutes) Time until resolution of symptoms (minutes)
Phase 1/week 1 56 20 40
Phase 1/week 2 56 30 55
Phase 1/week 2 84 14 76
Phase 2/week 18 84 25 78
Phase 2/week 19 84 18 64
Phase 2/week 20 84 20 25
Phase 2/week 22 84 21 38
Phase 2/week 24 84 35 16
Phase 2/week 25 84 30 5
Phase 2/week 30 84 26 32
Phase 2/week 36 84 15 40
Phase 1 = induction phase (patient dosed twice weekly).
Phase 2 = optimization/maintenance phase.
On average, symptoms of dissociation were reported by the patient approximately 23 minutes after the first device was administered and lasted approximately 43 minutes.
We note that the patient experienced dissociation during the second treatment session, but do not have the timing of onset recorded. During the third treatment session, the patient was apprehensive regarding treatment because of the dissociative symptoms she had experienced during the first and second treatment sessions. The study coordinator and investigator reassured the patient that she was safe in the clinic and would be monitored by staff until her symptoms subsided. The patient continued treatment, and 30 minutes after the second esketamine nasal spray device was administered, the patient again began to exhibit symptoms of dissociation. Her symptoms lasted for a total of 55 minutes (Table 1). The patient suggested that she would like to try listening to music on her iPhone to distract herself from the unpleasant dissociative sensations she was experiencing. The patient proceeded to play music and continued to listen to the music for the duration of her stay at the clinic. Approximately 5 minutes after listening to music, the patient appeared noticeably calmer and was no longer confused or agitated by the dissociation she was experiencing. The patient reported that she was better able to tolerate the dissociative symptoms while listening to music of her choice. This marked a notable improvement from the previous dosing sessions, when the patient did not listen to music while experiencing dissociative symptoms. This strategy continued to be employed to alleviate feelings of confusion or anxiety during all subsequent treatment visits.
While the patient continued to experience dissociative symptoms, after the introduction of music, the associated symptoms of anxiety and agitation were no longer recorded. Subsequent experiences of agitation or anxiety were considered related to an increase in the patient’s dose of esketamine (from 56 to 84 mg) and were not related to the experience of dissociation. Since that time, playing music in addition to providing patients with reassurance has been used to successfully manage confusion and agitation associated with dissociation with other patients at our clinic.
Discussion
Esketamine nasal spray is a noncompetitive N-methyl-D-aspartate receptor antagonist. Unlike currently available oral antidepressants, esketamine nasal spray has rapid onset of antidepressant effects (Daly et al., 2018). However, notable side effects are associated with the use of this drug, such as dissociation (41%), dizziness (29%), nausea (28%), and sedation (23%) (SPRAVATO, 2020). Vertigo and headaches were also commonly reported in phase 3 double-blind esketamine trials (Fedgchin et al., 2019; Popova et al., 2019). In the case of this patient, treatment was aimed at managing dissociation. We identified music as a simple, inexpensive, nonpharmacologic way to reduce the symptoms of dissociation.
Playing music for patients is one of the most effective alternative interventions that we have employed at our clinic. Previous research has suggested that music enhances the quality of recovery and acceptance of dissociative symptoms after ketamine anesthesia (Kumar et al., 1992). Patients who are experiencing dissociative symptoms for the first time may have difficulty accepting these symptoms and may even fear them. Music can help alleviate those fears and anxiety. In addition, research has shown that music may lower stress hormones such as cortisol, adrenaline, and noradrenaline and can stimulate the release of endorphins (McCraty et al., 1998). While the exact physiological mechanism behind the effectiveness of music in allaying the confusion and anxiety due to dissociation is unknown, we hypothesize that music’s ability to lower stress hormones and release endorphins may lead to an alleviation of the symptoms of confusion, agitation, and anxiety resulting from esketamine-induced dissociation.
In addition to encouraging the patient in this case report to listen to music during treatment visits, our site provided the patient with a comfortable environment for all treatment sessions, which included maintaining the room at a cool temperature, minimizing the brightness of the room, and providing the patient with a couch to lay upon (Table 2). Furthermore, both the coordinator and investigator provided the patient with reassurance by informing her that the unpleasant symptoms she was experiencing were normal and would subside within an hour (Table 2). Explaining to the patient that she was safe in the clinic and that staff would not leave the room until her symptoms subsided provided her with feelings of comfort and security while she was experiencing the dissociative symptoms.
Table 2 Managing associated symptoms of dissociation after esketamine dosing
Associated symptoms of dissociation Management approaches
Confusion 1. Patient requested to listen to music on her mobile device when feelings of confusion/agitation arose after dosing and for the duration of her time at the clinic
Agitation 2. Relieved symptoms of agitation and discomfort associated with dissociation within several minutes
Anxiety a. Kept room at cool temperature
b. Had patient lie down/prop up feet on couch
c. Patient asked coordinator to hold her hand
d. Coordinator and investigator spoke to patient in calm, reassuring manner
e. Coordinator and investigator explained to patient that symptoms were normal and that they would subside within an hour
f. Ensured patient’s safety. Investigators and coordinator repeatedly explained that the patient was safe in the clinic
We acknowledge that adverse events such as confusion, agitation, and anxiety cannot be resolved in all patients with dissociation by listening to music and receiving reassurance from staff, but we note that this individual patient’s request to listen to music while having staff present and ensuring her safety helped relieve her symptoms of agitation, confusion, and anxiety that had resulted from dissociation. We also recognize that we did not conduct a controlled experiment of this treatment, and did not try to ‘rechallenge’ the patient by having her subsequently undergo esketamine administration without listening to music to control for the possibility that she tolerated later treatments better simply because she had more experience with them. Nevertheless, given our experience with this patient, we utilized listening to music and offering reassurance to subsequent patients in our clinic experiencing troubling symptoms of dissociation, and found it helpful in these instances as well. In sum, we believe this strategy presents a simple, affordable approach to solving a frequent problem associated with esketamine administration.
Conclusion
Clinicians may consider managing dissociation related to esketamine administration through simple, low-risk, nonpharmacologic interventions. Specifically, listening to music based on patients’ personal preferences and being provided with reassurance successfully controlled confusion, agitation, and anxiety resulting from dissociation.
Other adjustments utilized that varied between patients were temperature and light preference (i.e. cooler, darker rooms).
Acknowledgements
The authors thank ApotheCom (Yardley, PA) for editorial services, which were funded by Janssen Scientific Affairs.
Janssen Scientific Affairs funded editorial support for the preparation of this case report. The studies (NCT03434041 and NCT02782104) that the patient in this case report participated in were conducted at 35 centers across the USA and China. The study protocols and their amendments were approved by the local ethics committees. The studies were conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, consistent with Good Clinical Practice guidelines and applicable regulatory requirements. All participants provided written informed consent before participation.
SP, EB, AP, MM, JW, and MRL were all involved in the conduct of this study, as well as the preparation, review, and final approval of the manuscript. All authors read and approved the final manuscript.
Consent for publication: Not applicable, as the information presented in this case report is fully anonymized.
The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.
Conflicts of interest
S.P., E.B., A.P., and J.W. are all employees of The Medical Research Network. M.M. is a former employee of The Medical Research Network. M.R.L. is the owner and Managing Director of The Medical Research Network. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 32804743 | 20,363,624 | 2021-01 |
What was the administration route of drug 'ESKETAMINE'? | Managing dissociative symptoms following the use of esketamine nasal spray: a case report.
Patients with treatment-resistant depression (TRD) treated with esketamine nasal spray commonly experience transient symptoms of dissociation. Manifestations of dissociation, such as feelings of detachment from the environment, can cause considerable anxiety for patients. Nonpharmacologic interventions may help clinicians to manage associated anxiety and confusion due to dissociation following administration of esketamine nasal spray. We present the case of a 64-year-old woman with major depressive disorder who participated in a clinical trial evaluating the efficacy and safety of esketamine nasal spray in conjunction with an oral antidepressant for TRD. The patient received flexible doses of esketamine nasal spray (56 or 84 mg) twice weekly for 4 weeks. On treatment day 1, the patient was administered 56 mg of esketamine nasal spray using two nasal spray devices (28 mg per device). Twenty minutes after the first esketamine nasal spray device was administered, the patient experienced a dissociative episode lasting 40 minutes that caused anxiety and confusion. The patient was encouraged to listen to music during treatment sessions, which resulted in notable improvement of her symptoms. Listening to music of choice immediately following esketamine nasal spray administration along with reassurance from staff may help manage confusion and anxiety associated with dissociation.
Background
Patients with treatment-resistant depression (TRD) who are prescribed esketamine nasal spray may experience side effects that temporarily impair their functioning. In double-blind clinical trials of esketamine nasal spray combined with an oral antidepressant, dissociation was reported as an adverse reaction in 41% of the esketamine plus oral antidepressant group (SPRAVATO, 2020). The group receiving 84 mg of esketamine nasal spray experienced higher rates of dissociative symptoms than the group receiving 56 mg (Fedgchin et al., 2019). While dissociative symptoms generally peaked at 40 minutes following esketamine administration and resolved within 1.5 h (Fedgchin et al., 2019), the associated confusion, loss of awareness of external environment, and other dissociative symptoms can be overwhelming for some patients (Park et al., 2019). Ketamine-associated dissociation typically resolves without pharmacologic intervention, suggesting that nonpharmacologic approaches could play a more central role in its management (Park et al., 2019).
Here, we describe the management of a patient affected by confusion, agitation, and anxiety due to dissociation after receiving an administration of esketamine nasal spray. To our knowledge, this strategy has not been reported in the literature and presents a simple, nonpharmacologic, inexpensive solution to a frequently occurring problem.
Case presentation
A 64-year-old woman with a medical history of hyperthyroidism and irritable bowel syndrome and a psychiatric history of major depressive disorder presented in December 2018 with unresolved symptoms of depression. She had a history of several failed antidepressant treatments (venlafaxine, bupropion, and citalopram) in the current major depressive episode and sought to alleviate her current depressive symptoms. She provided written informed consent to participate in a randomized, double-blind study (NCT03434041) to evaluate the efficacy, pharmacokinetics, safety, and tolerability of flexible doses of esketamine nasal spray in conjunction with an oral antidepressant in adults with TRD. She met trial eligibility criteria and was randomly assigned to receive either esketamine or placebo nasal spray; she also simultaneously began treatment with the oral antidepressant duloxetine. Nasal spray study medication was initiated on treatment day 1 beginning at a dose of 56 mg administered using two nasal spray devices (28 mg per device), with dosing (flexible doses of 56 or 84 mg) thereafter twice weekly for 4 weeks. The patient did not respond to treatment (where response = improvement of ≥50% in the Montgomery-Åsberg Depression Rating Scale total score) and did not experience dissociation while participating in the double-blind trial.
Following the fourth week of treatment and at the end of the study, the patient provided written informed consent to participate in an open-label, long-term extension safety study of esketamine nasal spray for TRD. During the induction phase of the subsequent open-label trial, the patient was administered flexible doses of esketamine nasal spray (56 or 84 mg) twice weekly for 4 weeks. She received 56 mg of esketamine nasal spray on day 1 and was titrated to 84 mg on day 11. On day 1 of treatment, the patient experienced agitation and confusion due to dissociation that began 20 minutes after esketamine nasal spray administration and persisted for 40 minutes (Table 1). The coordinator and doctor who were with the patient reassured her that the dissociative symptoms would soon subside and reminded her that she was safe in the clinic.
Table 1 Timing of dissociative symptoms after administration of first esketamine nasal spray device
Visit (study phase/week) Total dosage administered (mg) Time until onset of symptoms (minutes) Time until resolution of symptoms (minutes)
Phase 1/week 1 56 20 40
Phase 1/week 2 56 30 55
Phase 1/week 2 84 14 76
Phase 2/week 18 84 25 78
Phase 2/week 19 84 18 64
Phase 2/week 20 84 20 25
Phase 2/week 22 84 21 38
Phase 2/week 24 84 35 16
Phase 2/week 25 84 30 5
Phase 2/week 30 84 26 32
Phase 2/week 36 84 15 40
Phase 1 = induction phase (patient dosed twice weekly).
Phase 2 = optimization/maintenance phase.
On average, symptoms of dissociation were reported by the patient approximately 23 minutes after the first device was administered and lasted approximately 43 minutes.
We note that the patient experienced dissociation during the second treatment session, but do not have the timing of onset recorded. During the third treatment session, the patient was apprehensive regarding treatment because of the dissociative symptoms she had experienced during the first and second treatment sessions. The study coordinator and investigator reassured the patient that she was safe in the clinic and would be monitored by staff until her symptoms subsided. The patient continued treatment, and 30 minutes after the second esketamine nasal spray device was administered, the patient again began to exhibit symptoms of dissociation. Her symptoms lasted for a total of 55 minutes (Table 1). The patient suggested that she would like to try listening to music on her iPhone to distract herself from the unpleasant dissociative sensations she was experiencing. The patient proceeded to play music and continued to listen to the music for the duration of her stay at the clinic. Approximately 5 minutes after listening to music, the patient appeared noticeably calmer and was no longer confused or agitated by the dissociation she was experiencing. The patient reported that she was better able to tolerate the dissociative symptoms while listening to music of her choice. This marked a notable improvement from the previous dosing sessions, when the patient did not listen to music while experiencing dissociative symptoms. This strategy continued to be employed to alleviate feelings of confusion or anxiety during all subsequent treatment visits.
While the patient continued to experience dissociative symptoms, after the introduction of music, the associated symptoms of anxiety and agitation were no longer recorded. Subsequent experiences of agitation or anxiety were considered related to an increase in the patient’s dose of esketamine (from 56 to 84 mg) and were not related to the experience of dissociation. Since that time, playing music in addition to providing patients with reassurance has been used to successfully manage confusion and agitation associated with dissociation with other patients at our clinic.
Discussion
Esketamine nasal spray is a noncompetitive N-methyl-D-aspartate receptor antagonist. Unlike currently available oral antidepressants, esketamine nasal spray has rapid onset of antidepressant effects (Daly et al., 2018). However, notable side effects are associated with the use of this drug, such as dissociation (41%), dizziness (29%), nausea (28%), and sedation (23%) (SPRAVATO, 2020). Vertigo and headaches were also commonly reported in phase 3 double-blind esketamine trials (Fedgchin et al., 2019; Popova et al., 2019). In the case of this patient, treatment was aimed at managing dissociation. We identified music as a simple, inexpensive, nonpharmacologic way to reduce the symptoms of dissociation.
Playing music for patients is one of the most effective alternative interventions that we have employed at our clinic. Previous research has suggested that music enhances the quality of recovery and acceptance of dissociative symptoms after ketamine anesthesia (Kumar et al., 1992). Patients who are experiencing dissociative symptoms for the first time may have difficulty accepting these symptoms and may even fear them. Music can help alleviate those fears and anxiety. In addition, research has shown that music may lower stress hormones such as cortisol, adrenaline, and noradrenaline and can stimulate the release of endorphins (McCraty et al., 1998). While the exact physiological mechanism behind the effectiveness of music in allaying the confusion and anxiety due to dissociation is unknown, we hypothesize that music’s ability to lower stress hormones and release endorphins may lead to an alleviation of the symptoms of confusion, agitation, and anxiety resulting from esketamine-induced dissociation.
In addition to encouraging the patient in this case report to listen to music during treatment visits, our site provided the patient with a comfortable environment for all treatment sessions, which included maintaining the room at a cool temperature, minimizing the brightness of the room, and providing the patient with a couch to lay upon (Table 2). Furthermore, both the coordinator and investigator provided the patient with reassurance by informing her that the unpleasant symptoms she was experiencing were normal and would subside within an hour (Table 2). Explaining to the patient that she was safe in the clinic and that staff would not leave the room until her symptoms subsided provided her with feelings of comfort and security while she was experiencing the dissociative symptoms.
Table 2 Managing associated symptoms of dissociation after esketamine dosing
Associated symptoms of dissociation Management approaches
Confusion 1. Patient requested to listen to music on her mobile device when feelings of confusion/agitation arose after dosing and for the duration of her time at the clinic
Agitation 2. Relieved symptoms of agitation and discomfort associated with dissociation within several minutes
Anxiety a. Kept room at cool temperature
b. Had patient lie down/prop up feet on couch
c. Patient asked coordinator to hold her hand
d. Coordinator and investigator spoke to patient in calm, reassuring manner
e. Coordinator and investigator explained to patient that symptoms were normal and that they would subside within an hour
f. Ensured patient’s safety. Investigators and coordinator repeatedly explained that the patient was safe in the clinic
We acknowledge that adverse events such as confusion, agitation, and anxiety cannot be resolved in all patients with dissociation by listening to music and receiving reassurance from staff, but we note that this individual patient’s request to listen to music while having staff present and ensuring her safety helped relieve her symptoms of agitation, confusion, and anxiety that had resulted from dissociation. We also recognize that we did not conduct a controlled experiment of this treatment, and did not try to ‘rechallenge’ the patient by having her subsequently undergo esketamine administration without listening to music to control for the possibility that she tolerated later treatments better simply because she had more experience with them. Nevertheless, given our experience with this patient, we utilized listening to music and offering reassurance to subsequent patients in our clinic experiencing troubling symptoms of dissociation, and found it helpful in these instances as well. In sum, we believe this strategy presents a simple, affordable approach to solving a frequent problem associated with esketamine administration.
Conclusion
Clinicians may consider managing dissociation related to esketamine administration through simple, low-risk, nonpharmacologic interventions. Specifically, listening to music based on patients’ personal preferences and being provided with reassurance successfully controlled confusion, agitation, and anxiety resulting from dissociation.
Other adjustments utilized that varied between patients were temperature and light preference (i.e. cooler, darker rooms).
Acknowledgements
The authors thank ApotheCom (Yardley, PA) for editorial services, which were funded by Janssen Scientific Affairs.
Janssen Scientific Affairs funded editorial support for the preparation of this case report. The studies (NCT03434041 and NCT02782104) that the patient in this case report participated in were conducted at 35 centers across the USA and China. The study protocols and their amendments were approved by the local ethics committees. The studies were conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, consistent with Good Clinical Practice guidelines and applicable regulatory requirements. All participants provided written informed consent before participation.
SP, EB, AP, MM, JW, and MRL were all involved in the conduct of this study, as well as the preparation, review, and final approval of the manuscript. All authors read and approved the final manuscript.
Consent for publication: Not applicable, as the information presented in this case report is fully anonymized.
The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.
Conflicts of interest
S.P., E.B., A.P., and J.W. are all employees of The Medical Research Network. M.M. is a former employee of The Medical Research Network. M.R.L. is the owner and Managing Director of The Medical Research Network. | Nasal | DrugAdministrationRoute | CC BY-NC-ND | 32804743 | 20,363,624 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Colorectal cancer'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | INFLIXIMAB | DrugsGivenReaction | CC BY-NC | 32806874 | 18,243,187 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus infection'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | INFLIXIMAB | DrugsGivenReaction | CC BY-NC | 32806874 | 18,243,194 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dermatitis psoriasiform'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dizziness'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug specific antibody present'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypersensitivity'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infusion related reaction'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Laboratory test abnormal'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lower respiratory tract infection'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphoma'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | INFLIXIMAB | DrugsGivenReaction | CC BY-NC | 32806874 | 18,243,206 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Musculoskeletal disorder'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nervous system disorder'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use issue'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Prostate cancer'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | INFLIXIMAB | DrugsGivenReaction | CC BY-NC | 32806874 | 18,243,189 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Psoriasis'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Psychiatric symptom'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory tract infection'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin infection'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin reaction'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thyroid cancer'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | INFLIXIMAB | DrugsGivenReaction | CC BY-NC | 32806874 | 18,243,199 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Urinary tract infection'. | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB, METHOTREXATE | DrugsGivenReaction | CC BY-NC | 32806874 | 16,626,515 | 2021-10 |
What was the administration route of drug 'INFLIXIMAB'? | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 32806874 | 18,243,194 | 2021-10 |
What was the outcome of reaction 'Colorectal cancer'? | Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?
OBJECTIVE
The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.
RESULTS
Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/ mL and patients with IFX-TLs < 15 μg/mL.
CONCLUSIONS
IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.
pmcINTRODUCTION
In recent decades, the use of biologics in inflammatory bowel disease (IBD) has proven to be an effective choice to achieve patient remission, to reduce the need for corticosteroids and hospitalizations, to avoid surgery and improve patients’ quality of life [1,2]. Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD for the last 20 years, and the first approved drug was infliximab (IFX). IFX has been established as an effective therapy from moderate to severe IBD, and it is used both as induction and maintenance treatment [3].
Anti-TNF agents are widely used in patients with IBD, both for the induction of remission and maintenance treatment. Sometimes it is necessary to use intensified regimens of therapy to achieve remission. Higher IFX trough levels (IFX-TLs) have been associated with higher rates of remission, but we always consider the probability of toxicity of the drugs when dose adjustment is required [4]. Many adverse events (AEs) have been described. Some of them require further medication or even hospitalization and IFX discontinuation. The most common AEs are infections (up to 45%), with serious infections described in 3% and opportunistic infections in less than 1% of patients with IBD receiving IFX [5]. Dermatological manifestations (up to 40%), such as psoriasis or psoriasiform lesions and eczemas, infusion reactions (5%–10%), systemic lupus, hypersensitivity reactions, cancers and, less frequently, neurological (demyelinating disorders or neuropathies) or musculoskeletal disorders have also been described [5,6]. Worsening of heart failure and the occurrence of autoimmunity or aplastic anemia have also been associated with the use of the drug [6]. General symptoms, such as fatigue or dizziness, and abnormal laboratory tests are also often reported [5-7].
The main therapeutic goal in IBD patients is deep remission, including clinical, biochemical and endoscopic remission. Therapeutic drug monitoring has been suggested as a useful tool for treatment optimization and a helpful way to make therapeutic decisions to achieve the final aim of deep remission. Moreover, monitoring IFX-TLs and antibodies to IFX (ATIs) could be useful for predicting or preventing possible AEs of IFX [8]. Especially when IFX is used in combination with an immunomodulator, the risk of some AEs may be increased [9], and the close monitoring of IFX-TLs could be valuable.
The use of IFX in IBD patients and the development of AEs with IFX treatment have been well described, but data on the association between the AEs of IFX and IFX-TLs or IFX ATIs are limited and rather conflicting. This study aimed to investigate the possible association of IFX-TLs or ATIs with the development of AEs (in total and by AE subgroups) in Greek patients with IBD receiving maintenance treatment with IFX.
METHODS
1. Patients
A retrospective analysis of prospective registry data from consecutive IBD patients receiving maintenance treatment with IFX was conducted. The IBD registry of the University Hospital of Heraklion, where all information and data are available, was used. The study was approved by the Institutional Review Board of University Hospital of Heraklion, Greece (IRB No 9557/13-11-2019) and performed in accordance with the principles of the Declarations of Helsinki. Written informed consents were obtained. An ELISA kit (ELISA; Eagle Biosciences, Nashua, NH, USA) was used for the measurement of IFX-TLs and ATIs in the patients’ serum samples. A first measurement was performed in patients who were under maintenance treatment with IFX for a median time of 27 months (14–72). After the first measurement of IFX-TLs and ATIs, a second measurement was performed after a 10-month interval in patients who continued treatment. The lower limit of quantitation of IFX-TLs was 0.03 μg/mL and ATIs at 10 UA/mL was considered as positive. All IBD patients with 1 or 2 available IFX-TL and ATI measurements for the years 2016 to 2017 were included in this study.
A questionnaire about health status, disease activity and any possible adverse reaction that could be correlated with either the disease or the treatment were completed by a physician before every infusion of IFX. Moreover, routine laboratory blood tests obtained at the same time were recorded. Data from all interviews and laboratory tests were retrospectively analyzed by searching for all possible AEs, including infections (respiratory, urinary, and gastrointestinal), dermatological manifestations (psoriasis, psoriasiform lesions, and eczemas), infusion reactions, solid cancers or lymphomas, neurological or musculoskeletal disorders. The time window chosen was the interval between 4 months before and 4 months after each IFX-TL measurement was available. The rationale to choose the specific time window is that these 8 months were closer to each IFX-TLs measurement, so as to increase the possibility these manifestations to be related or not with the levels of IFX. We divided patients into 2 groups according to the presence or absence of AEs. The IFX-TLs and ATIs of patients with or without AEs (total), with or without infections and with or without dermatological manifestations were compared. Moreover, a cutoff point for IFX-TLs of 15 μg/mL was chosen in accordance to previous reports [10] to examine the safety of IFX in the separate group of the IBD patients who had “extremely” high IFX-TLs.
2. Statistical Analysis
Depending on the normality of the data distribution, which was assessed using the Kolmogorov–Smirnov test, mean (standard deviation, SD) or median (interquartile range, IQR) values were calculated. Student t-test for parametric continuous data and the Mann–Whitney U-test for nonparametric continuous data were used for the evaluation of differences among groups. Cox proportional hazards analysis adjusted by the remission time with IFX demonstrating the relationship of the presence of AEs and characteristics of the IBD patients was performed. We considered a difference to be statistically significant if the P-value was less than 0.05.
RESULTS
A total of 83 IBD patients receiving maintenance treatment with IFX were included in the study (61 Crohn’s disease, 73.5%; 22 ulcerative colitis, 26.5%). Among them, 52 patients (63%) were males, and the mean ± SD age was 43.3 ± 16.0 years. All patients received 5 or 10 mg/kg IFX per 4, 6, or 8 weeks, and the median (IQR) duration of IFX treatment was 27 months (14–72). Six patients (7.2%) were receiving intensified doses of IFX at the first measurement, and 17 (20.5%) were receiving intensified doses of IFX at the second measurement. Eleven patients needed intensification after the first measurement to have better control of their disease. Forty-eight patients (57.8%) were treated with combination therapy with immunomodulators, either azathioprine or methotrexate (AZA/MTX). The majority of patients had responded to the induction treatment with IFX and maintained in clinical remission under, IFX with or without immunomodulator, as defined by Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores for Crohn’s disease and ulcerative colitis respectively, during the study period. All patients’ demographic and clinical data are shown in Table 1.
A total of 147 IFX-TL measurements were available, and the median value was 4.69 μg/mL (1.32–9.16). The presence of AEs (total), recorded 4 months before and 4 months after each IFX-TL measurement, was reported for 99 out of the 147 IFX-TL measurements (67.3%). In most cases, one single AE was reported, but in 36 out of the 99 measurements (36.3%), more than one AE was registered. Among all AEs reported, 48 referred to infections (48.5% of all measurements; 75.0% of respiratory, 12.5% of urinary tract), and 27 were skin reactions (27.2% of all measurements); other causes were reported less frequently (Table 2). It should be noted that the skin manifestations reported did not include infusion skin reactions, which were included in the hypersensitivity/infusion reactions.
The median IFX-TLs of patients with AEs (total) were 5.79 μg/mL (1.36–10.25), which was higher than the median IFX-TLs for those without AEs (3.40 μg/mL [1.30–5.92]), but this difference was not statistically significant (P=0.97). Additionally, patients with infections had higher, but not notably different, IFX-TLs than patients without infections (5.99 μg/mL [1.64–9.09] vs. 3.75 μg/mL [1.28–9.33], P=0.16). There was also no difference in IFX-TLs regarding the presence or absence of dermatologic reactions (5.98 μg/mL [1.26–8.46] vs. 4.55 μg/mL [1.34–9.25], P=0.90) (Fig. 1). Moreover, median ATIs were not different between the patients with or without AEs (3.09 UA/mL [2.52–5.63] vs. 2.97 UA/mL [2.59–4.02], P=0.19).
We used a cutoff of 15 μg/mL to compare the presence of AEs in patients with IFX-TLs. The subgroup with TLs ≥ 15 μg/mL was consisting of the 16% of all patients and almost 10% of all IFX-TLs measurements (13 patients, 14 IFX-TLs measurements). The specific cut off was chosen to investigate whether extremely high levels are associated with the presence of any adverse reactions. The comparison of patients with IFX-TLs ≥ 15 μg/mL to those with IFX-TLs < 15 μg/mL showed no significant difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the AE prevalence by group (infections and skin reactions).
Most of the 83 patients (63 patients, 76% of all patients) had 2 IFX-TL measurements performed within a 10-month interval (126 measurements). The median (IQR) IFX-TL of the 1st measurement (74 available values) was 4.81 μg/mL (1.39–12.10), while the median IFX-TL of the 2nd (73 available values) was 4.20 μg/mL (1.10–7.38). Median ATIs (IQR) was 3.44 UA/mL (2.92–6.32) and 2.59 UA/mL (2.19–3.03), respectively. AEs were reported in 50 out of 74 (67.5%) of the 1st measurements and 49 out of 73 (67.1%) of the 2nd measurements.
Fourteen patients experienced severe AEs; 6 suffered from inferior respiratory infection, 1 from cytomegalovirus (CMV) systemic infection, 5 from cancer (2 colorectal, 1 lymphoma, 1 thyroid, and 1 prostate), 1 from extended skin rash and 1 from demyelinating neuropathy, diagnosed with an electromyography and nerve conduction study and confirmed by a neurologist. All the above reactions required hospitalization and special medication. Regarding the infections (including CMV), patients delayed IFX therapy for 1–2 weeks, but then continued in the same dose. The patient with demyelinating neuropathy and the one with the skin rash changed to other biologic. About cancers, 1 patient died (colorectal cancer), 3 stopped IFX therapy and 1 (prostate cancer) continued IFX in the same dose a while after his surgery. The median IFX-TL in these cases was 7.03 μg/mL (3.21–11.59), which was not significantly different than that in patients without severe AEs (4.32 μg/mL [1.18–9.15], P=0.11).
In the Cox proportional hazards analysis adjusted by the remission time with IFX, only disease duration was significantly correlated with the development of AEs. No other variable, including sex, age, IBD subtype, smoking status, concomitant immunomodulators, IFX-TLs, ATIs, time between measurements, IFX dose intensification and IBD related surgery were found to be associated with the presence of AEs (Table 3).
DISCUSSION
Our study showed that higher IFX-TLs in patients with IBD receiving maintenance treatment with IFX were not associated with a higher prevalence of AEs in comparison with similar patients with lower IFX-TLs. Patients with higher IFX-TLs also did not have a higher prevalence of infections or skin manifestations. Even very high IFX-TLs (> 15 μg/mL) were not found to be toxic for IBD patients.
Although the AEs described above have been associated with the use of IFX, data on the correlation of IFX-TLs with the development of AEs are limited and conflicting. Greener et al. [10] showed that high IFX-TLs are generally associated with a higher prevalence of AEs, but not by subgroup analysis; the AEs reported were mostly infections and dermatological manifestations. On the other hand, a study by Guiotto et al. [11] found a significant association (P=0.009; odds ratio, 0.115) between IFX-TLs and the development of AEs. Huang et al. [12] showed that IFX-TLs were not correlated with the presence of any AE, but low IFX-TLs were associated with infusion reactions. A potential role of the persistence of serum ATIs in those patients, followed by low IFX-TLs, could be suggested. Moreover, it has been reported that high IFX-TLs are associated with the presence of dermatological adverse reactions, but the validity of these results and the possible underlying mechanisms remain unclear [12]. In 2 different studies, Protic et al. [13] and Cleynen et al. [14] found no correlation between IFX-TLs and skin adverse reactions. Drobne et al. [15] primarily studied the rates of infections in patients of different groups regarding IFX-TLs and concluded that there was no difference between the frequencies of infections in the different groups. Coutzac et al. [16], on the other hand, compared patients with or without paradoxical cutaneous and rheumatological manifestations. They found no significant difference in the IFX-TLs between these groups in their analyses, but it seems that patients with paradoxical rheumatological manifestations (mainly arthralgias) while receiving IFX therapy tended to have lower IFX-TLs.
The results of these studies, including our study, should be supported by larger prospective studies due to the significance of these conclusions. Higher IFX-TLs are frequently needed to achieve clinical and endoscopic remission, and it must be clarified whether higher IFX doses or higher IFX-TLs lead to a higher prevalence of AEs. In our study, we showed that higher IFX-TLs were not correlated with more AEs, infections or dermatological manifestations. A higher dose of the drug does not always mean that higher IFX-TLs will be achieved. This makes the monitoring of IFX-TLs necessary for the optimization of patient therapy and to achieve the final goals of clinical and endoscopic remission and mucosal healing. These results can lead to a safer use of higher doses to achieve higher levels or lessen anti-drug antibodies, meaning a greater probability of remission [17].
To obtain safer results, we divided our measurements using a high cutoff (15 μg/mL) to study whether higher levels were correlated with more AEs. Further indirect evidence of no correlation of IFX-TLs and AEs is derived from the fact that the reduction of IF-TLs, which appeared over time in the same sample of patients [18], was not associated with an equivalent reduction in the presence of AEs. Based on these results, we conclude that high IFX-TLs are not associated with the presence of AEs and remain a safe target for our patients. Unfortunately, the small size of our study group does not permit us to have safe results about the prevalence of some unusual AEs recorded (cancers and neurological manifestations) with the use of IFX or the IFX-TLs.
The use of combined treatment of IFX with AZA/6-mercaptopurine or MTX can lessen the probability of autoimmunity and the occurrence of antibodies. As a result, a reduction of infusion reactions can be achieved. In our study, there was no difference between the groups receiving or not receiving combined therapy, which can be explained by the fact that our patients were receiving maintenance IFX therapy, with a median duration of 27 months. Infusion reactions are not expected with the same frequency in patients after the induction period, as our patients were [19,20].
In our study, we found a significant correlation between development of AEs and disease duration. This finding could be partially related to the well-known inverse association between disease duration and response to anti-TNF treatment. Moreover, patients with long disease duration are usually older, have longer duration of IFX treatment, have often a history of use of other medication and disease progression to a more complicated phenotype. All the above could be potential risk factors for the development of the observed AEs in our study population.
Among the strengths of our study is that we had 2 measurements of IFX-TLs available for most patients, and the interval between the 2 measurements was 10 months. Furthermore, we searched for AEs close to each measurement, 4 months before and 4 months after, meaning that the AEs recorded did not overlap and were associated with only the specific measurement. Moreover, we studied not only the correlation between IFX-TLs and infections or cancer, which are the most well-described correlations in the literature, but we also included dermatological manifestations and tried to study other AEs as well.
Some limitations of the study should also be noted. The patient sample studied was rather small. Furthermore, this was a retrospective study, so there may have been AEs during the study period that were not mentioned by the patients. Some of the patients who suffered chronically may have underestimated their symptoms or forget to mention some of the previous events. An infection that was rapidly cured or a skin manifestation not observed and mentioned by the patient are some of the events that may have been missed. Another limitation of our study is the relatively short period of 4 months that we chose to collect safety data for our sample. A longer follow-up period would be more acceptable to draw safer conclusions.
In conclusion, in our study, we showed that higher IFX-TLs did not lead to a greater prevalence of AEs. Higher IFX-TLs were not correlated with a higher proportion of infections or skin adverse reactions. Furthermore, this study shows that even very high IFX-TLs did not lead to a higher prevalence of AEs. These conclusions confirm and strengthen other studies with similar published results. This makes the optimization of IFX therapy, including higher target IFX-TLs to achieve clinical remission, endoscopic remission or even mucosal healing, a safe option for IBD patients treated with IFX.
Fig. 1. Median infliximab trough levels (IFX-TLs) of all measurements and comparison of IFX-TLs between patients with and without adverse events (AEs).
Table 1. Demographic and Clinical Characteristics of the 83 IBD Patients Included in the Study
Characteristics Value
Sex
Male 52 (63)
Female 31 (37)
Age (yr) 43.3 ± 16.0
Disease duration (yr) 9 (6–17)
Smoking
Current 29 (35)
No 22 (27)
Past 30 (36)
BMI (kg/m2) 24.7 (20.7–28.1)
Disease
CD 61 (73)
UC 22 (27)
Montreal classification (at enrollment)
Ileum (L1 CD) 23 (38)
Colon (L2 CD) 13 (21)
Ileum + colon (L3 CD) 25 (41)
Perianal (P CD) 24 (39)
Inflammatory (B1 CD) 23 (38)
Stenotic (B2 CD) 18 (30)
Fistulizing (B3 CD) 20 (32)
Left-sided colitis (E2 UC) 8 (36)
Extensive colitis (E3 UC) 14 (64)
Combination treatment (IMMs) 48 (58)
AZA 40 (48)
MTX 8 (10)
HBI for CD 2 (1–3)
SCCAI for UC 1 (0–3)
Median time of IFX use at 1st measurement (mo) 27 (14–72)
Intensified IFX dose at baseline 6 (7)
5 mg/kg/6 wk 2 (2)
5 mg/kg/4 wk 1 (1)
10 mg/kg/8 wk 3 (4)
Intensified dose after the 1st measurement 17 (21)
5 mg/kg/6 wk 11 (13)
5 mg/kg/4 wk 4 (5)
10 mg/kg/8 wk 2 (2)
Previous IBD related surgery 12 (15)
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; IMMs, immunomodulators; AZA, azathioprine; MTX, methotrexate; HBI, Harvey Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; IFX, infliximab.
Table 2. Frequency of Each Type of AE Reported in All Trough Level Measurements Correlated with AEs (n=99)
Type of AE No. of patients (%)
Infections 48 (48.5)
Respiratory 36 (75.0)
Urinary track 6 (12.5)
Others 6 (12.5)
Skin manifestations 27 (27.2)
Psoriasis or psoriasiform 8 (29.6)
Skin infections 9 (33.3)
Others 10 (37.1)
Hypersensitivity/infusion reactions 14 (14.1)
Musculoskeletal disorders 12 (12.1)
Neurological manifestations 2 (2.0)
Severe AEs 14 (14.1)
Inferior respiratory infections 6 (6.1)
CMV infection 1 (1.0)
Cancers 5 (5.1)
Extended skin rash 1 (1.0)
Demyelinating neuropathy 1 (1.0)
AE, adverse event; CMV, cytomegalovirus.
Table 3. Cox Proportional Hazards Analysis Adjusted by the Remission Time with IFX Demonstrating the Relationship of the Presence of Adverse Events and Characteristics of the IBD Patients
Characteristic HR (95% CI) P-value
Diagnosis (CD) 1.17 (0.63–2.17) 0.62
Age 0.99 (0.97–1.07) 0.31
Female sex 0.82 (0.45–1.48) 0.51
Disease duration 0.89 (0.84–0.93) < 0.001
Smoking 1.04 (0.73–1.49) 0.82
IFX-TLs 0.99 (0.97–1.03) 0.97
ATIs 1.05 (0.98–1.13) 0.19
Use of immunomodulators 1.03 (0.68–1.57) 0.89
IFX dose intensification 1.57 (0.82–3.02) 0.18
Shorter IFX interval 1.69 (0.61–4.73) 0.35
IBD related surgery 0.72 (0.32–1.59) 0.42
Measurement timea 0.99 (0.82–1.22) 0.99
a Time between the 2 measurements.
IFX, infliximab; IBD, inflammatory bowel disease; HR, hazard ratio; CI, confidence interval; CD, Crohn’s disease; IFX-TLs, IFX trough levels; ATIs, antibodies to IFX.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Author Contribution
Conceptualization: Koutroubakis IE. Data curation: Theodoraki E. Formal analysis: Theodoraki E, Orfanoudaki E, Foteinogiannopoulou K. Investigation: Theodoraki E. Methodology: Orfanoudaki E, Foteinogiannopoulou K. Project administration: Koutroubakis IE. Writing - original draft: Theodoraki E. Writing - review & editing: Legaki E, Gazouli M, Koutroubakis IE. Approval of final manuscript: all authors. | Fatal | ReactionOutcome | CC BY-NC | 32806874 | 18,243,195 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Bradycardia Shock Caused by the Combined Use of Carteolol Eye Drops and Verapamil in an Elderly Patient with Atrial Fibrillation and Chronic Kidney Disease.
Ophthalmic carteolol is often used to treat glaucoma. Elderly patients with atrial fibrillation (AF) and chronic kidney disease (CKD) are common among the super-elderly in Japan. Because these patients are exposed to polypharmacy, they are at a high-risk of adverse drug interactions. We herein report an elderly patient with CKD who suffered bradycardia shock after the combined use of carteolol eye drops and verapamil for glaucoma and paroxysmal AF. This case highlights the fact that eye drops have a similar systemic effect to oral drugs, and especially in elderly patients with polypharmacy, drug interactions can unwittingly lead to serious events.
Introduction
Ophthalmic beta blockers, represented by timolol and carteolol, are often used to treat glaucoma in the elderly (1). As the elderly population is dramatically increasing in Japan, we often encounter elderly patients with atrial fibrillation (AF) and chronic kidney disease (CKD) (2). Because such patients tend to have multiple comorbidities, they often visit several medical institutions, and accordingly, they are prescribed multiple medications (i.e. polypharmacy). One clinical issue in those patients is that they may unwittingly experience drug interactions due to their polypharmacy, leading to a potential risk of adverse clinical events (3).
There have been two case reports of bradycardia with the combined use of timolol eye drops and verapamil, with their combined use first reported in the 20th century (4,5). However, the interaction between carteolol eye drops and verapamil has not been reported. We herein report a case of bradycardia shock caused by the combined use of carteolol eye drops and verapamil in an elderly patient with a history of CKD and glaucoma, who suffered from paroxysmal AF (PAF).
Case Report
An 84-year-old woman presented with a 3-day history of shortness of breath and chest discomfort. She was determined to be frail as evaluated by a Canadian Study of Health and Aging Clinical Frailty Scale of 6 on admission. She had a history of glaucoma, hypertension, and CKD (estimated glomerular filtration rate 32.6 mL/min/1.73 m2) from over 10 years earlier and was being treated separately at ophthalmology and internal medicine outpatient clinics. She had blindness in her right eye due to glaucoma, and her left eye had been treated with ophthalmic carteolol and travoprost for the last few years. She had been taking azilsartan and doxazosin in addition to diet therapy for hypertension and CKD. As a result, she had been taking five kinds of internal medications, two kinds of external medications, and four kinds of eye drops a day, resulting in polypharmacy.
Five days before admission, she had been diagnosed with symptomatic PAF, so verapamil [40 mg twice a day (b.i.d.)] had been newly initiated by her internal medicine physician. According to the information from the previous doctor, her heart rate had been about 60-80 beats/minute (bpm) before the start of verapamil. At admission, her heart rate was 29 bpm, and her blood pressure could not be obtained, although her radial artery pulse was palpable. Her respiratory rate and body temperature were 15/min and 36.0 °C, respectively.
Her laboratory data on admission are shown in Table, revealing high serum potassium, high liver enzyme, and high lactate levels. A 12-lead electrocardiogram (ECG) during the initial examination showed a heart rate of 24 bpm and narrow QRS rhythm followed by retrograde P-waves with a Wenckebach phenomenon without significant ST-segment changes (Fig. 1). Transthoracic echocardiography revealed a normal left ventricular function without any asynergy, D-shape, echo-free space, or valvular disease with a normal size of the left atrial diameter (32.0 mm). Chest X-ray revealed pulmonary edema and enlargement of the cardio-thoracic ratio.
Table. Laboratory Data at the Time of Admission.
WBC 5,900 /mm3 Na 139 mEq/L
Hb 11.4 g/dL K 6.5 mEq/L
Plt 14.2×104 /μL Cl 110 mEq/L
BUN 35.6 mg/dL Ca 8.5 mg/dL
Cre 1.21 mg/dL T-Chol 160 mg/dL
eGFR 32.6 HDL-Chol 67 mg/dL
CCR 21.25 LDL-Chol 66 mg/dL
CRP 0.11 mg/dL TG 64 mg/dL
TP 5.2 g/dL UA 6.3 mg/dL
Alb 3.0 g/dL CK 66 U/L
T-Bil 1.20 mg/dL CK-MB 4 U/L
AST 234 U/L Troponin I 0.01 ng/mL
ALT 119 U/L NT-proBNP 3,722 pg/mL
LDH 421 U/L TSH 7.79 μlU/mL
ALP 248 mEq/L Free T3 2.36 pg/mL
BS 157 mg/dL Free T4 1.20 ng/mL
HbA1c 5.3 % Lactate 2.9 mmol/L
Alb: albumin, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BS: blood sugar, BUN: blood urea nitrogen, Ca: serum calcium, CCR: creatinine clearance, CK: creatine kinase, Cl: serum chloride, Cre: serum creatinine, CRP: C-reactive protein, eGFR: estimated glomerular filtration rate, Free T3: free triiodothyronine, Free T4: free thyroxine, Hb: hemoglobin, HbA1c: hemoglobin A1c, HDL-Chol: high density lipoprotein cholesterol, K: serum potassium, LDH: lactate dehydrogenase, LDL-Chol: low density lipoprotein cholesterol, Na: serum sodium, NT-proBNP: N-terminal pro-Brain Natriuretic Peptide, Plt: platelets, T-Bil: total bilirubin, T-Chol: total cholesterol, TG: triglyceride, TP: total protein, TSH: thyroid-stimulating hormone, UA: serum uric acid, WBC: white blood cells
Figure 1. A 12-lead electrocardiogram during the initial examination. A heart rate of 24 bpm and a narrow QRS rhythm followed by retrograde P-waves with a Wenckebach phenomenon without significant ST-segment changes were noted.
Her clinical course is shown in Fig. 2. Because she had bradycardia shock, represented by high serum lactate and liver enzyme levels, with hyperkalemia, a temporary pacing catheter was placed through the right internal jugular vein, and right ventricular pacing was performed at 90 bpm while administrating an intravenous injection of calcium gluconate hydrate and glucose-insulin therapy for hyperkalemia. Anticholinergics could not be used due to glaucoma. With this treatment, the shock immediately resolved, and the symptoms disappeared. The carteolol eye drops, verapamil, and azilsartan were discontinued, and the patient was treated with a pacing rhythm until the next day (Fig. 3). The morning after she was hospitalized, her heart rhythm returned to a normal sinus rhythm with a heart rate of 63 bpm (Fig. 4). The carteolol eye drops were discontinued after consultation with the ophthalmologist, and a different non-beta blocker for glaucoma (dorzolamide hydrochloride) was prescribed to protect her non-blind left eye. The bradycardia no longer appeared after normalization of the potassium level and discontinuing verapamil and the carteolol eye drops.
Figure 2. Clinical course of this case. ALT: alanine aminotransferase, AST: aspartate aminotransferase, Calcicol: calcium gluconate hydrate, GI: glucose-insulin therapy, HR: heart rate, PAF: paroxysmal atrial fibrillation, PMI: pacemaker intubation
Figure 3. A 12-lead electrocardiogram after initiating temporary pacing. A heart rate of 93 bpm, wide QRS rhythm with a left bundle branch block and upper axis pattern, and right ventricular apex origin were noted.
Figure 4. A 12-lead electrocardiogram the day after the hospitalization. A heart rate of 63 bpm with normal sinus rhythm and T-wave flattening in leads III and aVF were observed.
However, she had symptomatic PAF with a rapid ventricular response on the first hospital day. When the PAF stopped, she temporarily had a backup pacing with VVI 50 bpm due to sick sinus syndrome. Based on her clinical course, it was judged that the use of antiarrhythmic drugs alone for PAF carried a risk of bradycardia shock, so it was decided to administer antiarrhythmic drugs after pacemaker implantation. However, pulmonary vein isolation was not selected due to her age and activity of daily living. Pacemaker implantation was performed on the 14th hospital day. Finally, her arrhythmia, blood pressure, and glaucoma were controlled with the pacemaker implantation and adjustment of her medications, as shown in Fig. 2, and she was discharged in good health on the 20th hospital day.
Discussion
Ophthalmic carteolol, as well as timolol, is used as an eye drop beta blocker for glaucoma. Carteolol has been considered to have a lower risk of cardiovascular events than timolol because carteolol generally has a weaker effect on slowing the heart rate than timolol, depending on the characterization of the intrinsic sympathomimetic activity (ISA) (6,7). Although warning clues of cardiovascular events, such as bradycardia, heart block, and hypotension, have been reported due to the use of timolol eye drops (8), there have been no reports of severe cardiovascular events with the use of carteolol eye drops. Because timolol eye drops are absorbed via the nasal mucosa through the nasolacrimal duct, their bioavailability is approximately 50% of that after oral administration, and they have a systemic effect similar to oral administration; however, they are topically administered (9). Furthermore, because both carteolol and timolol are metabolized by cytochrome P450 2D6 (CYP2D6), their effect can be enhanced in elderly people with a weakened CYP2D6 when combined with a drug with a CYP2D6 inhibitory effect and/or verapamil (10).
Verapamil is a commonly used class IV antiarrhythmic medication that blocks calcium-dependent slow channels, depresses the cardiac contractility, slows the myocardial conduction, and relaxes vascular smooth muscle. It serves to decrease sino-atrial (SA) node discharges and slow atrioventricular (AV) conduction, and the concomitant use with beta blockers can potentially cause severe bradycardia (11).
Elderly patients sometimes have both AF and CKD (2). Because carteolol is mainly excreted by the kidneys, it may have a strong cardiac depressant effect in elderly patients with CKD (12). Elderly people tend to have polypharmacy (3,13), and if prescriptions are obtained from multiple medical institutions, it is possible that the same drugs may be prescribed. In addition, as in the present case, when the serum potassium level is increased due to a side effect of an angiotensin II receptor blocker (ARB) (14), a cardiac depressant effect due to hyperkalemia may exacerbate the cardiac function. In the present case, both the SA node and AV node were likely suppressed by the combination of the ophthalmic carteolol, verapamil, and hyperkalemia, resulting in serious bradycardia due to sick sinus syndrome.
Of note, eye drops have a systemic effect similar to oral drugs. Drug interactions are more likely to occur in the elderly, especially when ophthalmic beta blockers are used in glaucoma patients, and careful follow-up in terms of cardiovascular events is needed; furthermore, verapamil should not be used for rate control in patients with AF. Although the mechanism may have involved the interaction between the carteolol eye drops and either verapamil or azilsaltan-related hyperkalemia, it is equally likely that the interaction was between all three drugs under the existence of CKD in this elderly patient.
In conclusion, physicians should always consider the potential risk of adverse drug interactions when prescribing a new medication to a patient, especially in elderly patients with polypharmacy. Even topical medications, such as carteolol eye drops, might have significant systemic absorption, leading to serious side effects through drug interactions in elderly patients.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuo Okumura: Research funding, Boston Scientific Japan.
Acknowledgement
We thank all of the doctors and medical staff who were involved in the treatment of this patient. In particular, Ph. So Iwabuchi and Ph. Takahiro Sekine provided important information about the carteolol eye drops. We also thank Mr. John Martin for his help with the English editing. | AZILSARTAN KAMEDOXOMIL, BISOPROLOL, BROMFENAC SODIUM, CALCIUM GLUCONATE, CARTEOLOL HYDROCHLORIDE, DEXTROSE, DORZOLAMIDE HYDROCHLORIDE, DOXAZOSIN MESYLATE, EDOXABAN TOSYLATE, HEPARIN SODIUM, INSULIN NOS, LANDIOLOL HYDROCHLORIDE, REBAMIPIDE, TRAVOPROST, VERAPAMIL HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32830185 | 18,270,051 | 2021-01-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sinus node dysfunction'. | Bradycardia Shock Caused by the Combined Use of Carteolol Eye Drops and Verapamil in an Elderly Patient with Atrial Fibrillation and Chronic Kidney Disease.
Ophthalmic carteolol is often used to treat glaucoma. Elderly patients with atrial fibrillation (AF) and chronic kidney disease (CKD) are common among the super-elderly in Japan. Because these patients are exposed to polypharmacy, they are at a high-risk of adverse drug interactions. We herein report an elderly patient with CKD who suffered bradycardia shock after the combined use of carteolol eye drops and verapamil for glaucoma and paroxysmal AF. This case highlights the fact that eye drops have a similar systemic effect to oral drugs, and especially in elderly patients with polypharmacy, drug interactions can unwittingly lead to serious events.
Introduction
Ophthalmic beta blockers, represented by timolol and carteolol, are often used to treat glaucoma in the elderly (1). As the elderly population is dramatically increasing in Japan, we often encounter elderly patients with atrial fibrillation (AF) and chronic kidney disease (CKD) (2). Because such patients tend to have multiple comorbidities, they often visit several medical institutions, and accordingly, they are prescribed multiple medications (i.e. polypharmacy). One clinical issue in those patients is that they may unwittingly experience drug interactions due to their polypharmacy, leading to a potential risk of adverse clinical events (3).
There have been two case reports of bradycardia with the combined use of timolol eye drops and verapamil, with their combined use first reported in the 20th century (4,5). However, the interaction between carteolol eye drops and verapamil has not been reported. We herein report a case of bradycardia shock caused by the combined use of carteolol eye drops and verapamil in an elderly patient with a history of CKD and glaucoma, who suffered from paroxysmal AF (PAF).
Case Report
An 84-year-old woman presented with a 3-day history of shortness of breath and chest discomfort. She was determined to be frail as evaluated by a Canadian Study of Health and Aging Clinical Frailty Scale of 6 on admission. She had a history of glaucoma, hypertension, and CKD (estimated glomerular filtration rate 32.6 mL/min/1.73 m2) from over 10 years earlier and was being treated separately at ophthalmology and internal medicine outpatient clinics. She had blindness in her right eye due to glaucoma, and her left eye had been treated with ophthalmic carteolol and travoprost for the last few years. She had been taking azilsartan and doxazosin in addition to diet therapy for hypertension and CKD. As a result, she had been taking five kinds of internal medications, two kinds of external medications, and four kinds of eye drops a day, resulting in polypharmacy.
Five days before admission, she had been diagnosed with symptomatic PAF, so verapamil [40 mg twice a day (b.i.d.)] had been newly initiated by her internal medicine physician. According to the information from the previous doctor, her heart rate had been about 60-80 beats/minute (bpm) before the start of verapamil. At admission, her heart rate was 29 bpm, and her blood pressure could not be obtained, although her radial artery pulse was palpable. Her respiratory rate and body temperature were 15/min and 36.0 °C, respectively.
Her laboratory data on admission are shown in Table, revealing high serum potassium, high liver enzyme, and high lactate levels. A 12-lead electrocardiogram (ECG) during the initial examination showed a heart rate of 24 bpm and narrow QRS rhythm followed by retrograde P-waves with a Wenckebach phenomenon without significant ST-segment changes (Fig. 1). Transthoracic echocardiography revealed a normal left ventricular function without any asynergy, D-shape, echo-free space, or valvular disease with a normal size of the left atrial diameter (32.0 mm). Chest X-ray revealed pulmonary edema and enlargement of the cardio-thoracic ratio.
Table. Laboratory Data at the Time of Admission.
WBC 5,900 /mm3 Na 139 mEq/L
Hb 11.4 g/dL K 6.5 mEq/L
Plt 14.2×104 /μL Cl 110 mEq/L
BUN 35.6 mg/dL Ca 8.5 mg/dL
Cre 1.21 mg/dL T-Chol 160 mg/dL
eGFR 32.6 HDL-Chol 67 mg/dL
CCR 21.25 LDL-Chol 66 mg/dL
CRP 0.11 mg/dL TG 64 mg/dL
TP 5.2 g/dL UA 6.3 mg/dL
Alb 3.0 g/dL CK 66 U/L
T-Bil 1.20 mg/dL CK-MB 4 U/L
AST 234 U/L Troponin I 0.01 ng/mL
ALT 119 U/L NT-proBNP 3,722 pg/mL
LDH 421 U/L TSH 7.79 μlU/mL
ALP 248 mEq/L Free T3 2.36 pg/mL
BS 157 mg/dL Free T4 1.20 ng/mL
HbA1c 5.3 % Lactate 2.9 mmol/L
Alb: albumin, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BS: blood sugar, BUN: blood urea nitrogen, Ca: serum calcium, CCR: creatinine clearance, CK: creatine kinase, Cl: serum chloride, Cre: serum creatinine, CRP: C-reactive protein, eGFR: estimated glomerular filtration rate, Free T3: free triiodothyronine, Free T4: free thyroxine, Hb: hemoglobin, HbA1c: hemoglobin A1c, HDL-Chol: high density lipoprotein cholesterol, K: serum potassium, LDH: lactate dehydrogenase, LDL-Chol: low density lipoprotein cholesterol, Na: serum sodium, NT-proBNP: N-terminal pro-Brain Natriuretic Peptide, Plt: platelets, T-Bil: total bilirubin, T-Chol: total cholesterol, TG: triglyceride, TP: total protein, TSH: thyroid-stimulating hormone, UA: serum uric acid, WBC: white blood cells
Figure 1. A 12-lead electrocardiogram during the initial examination. A heart rate of 24 bpm and a narrow QRS rhythm followed by retrograde P-waves with a Wenckebach phenomenon without significant ST-segment changes were noted.
Her clinical course is shown in Fig. 2. Because she had bradycardia shock, represented by high serum lactate and liver enzyme levels, with hyperkalemia, a temporary pacing catheter was placed through the right internal jugular vein, and right ventricular pacing was performed at 90 bpm while administrating an intravenous injection of calcium gluconate hydrate and glucose-insulin therapy for hyperkalemia. Anticholinergics could not be used due to glaucoma. With this treatment, the shock immediately resolved, and the symptoms disappeared. The carteolol eye drops, verapamil, and azilsartan were discontinued, and the patient was treated with a pacing rhythm until the next day (Fig. 3). The morning after she was hospitalized, her heart rhythm returned to a normal sinus rhythm with a heart rate of 63 bpm (Fig. 4). The carteolol eye drops were discontinued after consultation with the ophthalmologist, and a different non-beta blocker for glaucoma (dorzolamide hydrochloride) was prescribed to protect her non-blind left eye. The bradycardia no longer appeared after normalization of the potassium level and discontinuing verapamil and the carteolol eye drops.
Figure 2. Clinical course of this case. ALT: alanine aminotransferase, AST: aspartate aminotransferase, Calcicol: calcium gluconate hydrate, GI: glucose-insulin therapy, HR: heart rate, PAF: paroxysmal atrial fibrillation, PMI: pacemaker intubation
Figure 3. A 12-lead electrocardiogram after initiating temporary pacing. A heart rate of 93 bpm, wide QRS rhythm with a left bundle branch block and upper axis pattern, and right ventricular apex origin were noted.
Figure 4. A 12-lead electrocardiogram the day after the hospitalization. A heart rate of 63 bpm with normal sinus rhythm and T-wave flattening in leads III and aVF were observed.
However, she had symptomatic PAF with a rapid ventricular response on the first hospital day. When the PAF stopped, she temporarily had a backup pacing with VVI 50 bpm due to sick sinus syndrome. Based on her clinical course, it was judged that the use of antiarrhythmic drugs alone for PAF carried a risk of bradycardia shock, so it was decided to administer antiarrhythmic drugs after pacemaker implantation. However, pulmonary vein isolation was not selected due to her age and activity of daily living. Pacemaker implantation was performed on the 14th hospital day. Finally, her arrhythmia, blood pressure, and glaucoma were controlled with the pacemaker implantation and adjustment of her medications, as shown in Fig. 2, and she was discharged in good health on the 20th hospital day.
Discussion
Ophthalmic carteolol, as well as timolol, is used as an eye drop beta blocker for glaucoma. Carteolol has been considered to have a lower risk of cardiovascular events than timolol because carteolol generally has a weaker effect on slowing the heart rate than timolol, depending on the characterization of the intrinsic sympathomimetic activity (ISA) (6,7). Although warning clues of cardiovascular events, such as bradycardia, heart block, and hypotension, have been reported due to the use of timolol eye drops (8), there have been no reports of severe cardiovascular events with the use of carteolol eye drops. Because timolol eye drops are absorbed via the nasal mucosa through the nasolacrimal duct, their bioavailability is approximately 50% of that after oral administration, and they have a systemic effect similar to oral administration; however, they are topically administered (9). Furthermore, because both carteolol and timolol are metabolized by cytochrome P450 2D6 (CYP2D6), their effect can be enhanced in elderly people with a weakened CYP2D6 when combined with a drug with a CYP2D6 inhibitory effect and/or verapamil (10).
Verapamil is a commonly used class IV antiarrhythmic medication that blocks calcium-dependent slow channels, depresses the cardiac contractility, slows the myocardial conduction, and relaxes vascular smooth muscle. It serves to decrease sino-atrial (SA) node discharges and slow atrioventricular (AV) conduction, and the concomitant use with beta blockers can potentially cause severe bradycardia (11).
Elderly patients sometimes have both AF and CKD (2). Because carteolol is mainly excreted by the kidneys, it may have a strong cardiac depressant effect in elderly patients with CKD (12). Elderly people tend to have polypharmacy (3,13), and if prescriptions are obtained from multiple medical institutions, it is possible that the same drugs may be prescribed. In addition, as in the present case, when the serum potassium level is increased due to a side effect of an angiotensin II receptor blocker (ARB) (14), a cardiac depressant effect due to hyperkalemia may exacerbate the cardiac function. In the present case, both the SA node and AV node were likely suppressed by the combination of the ophthalmic carteolol, verapamil, and hyperkalemia, resulting in serious bradycardia due to sick sinus syndrome.
Of note, eye drops have a systemic effect similar to oral drugs. Drug interactions are more likely to occur in the elderly, especially when ophthalmic beta blockers are used in glaucoma patients, and careful follow-up in terms of cardiovascular events is needed; furthermore, verapamil should not be used for rate control in patients with AF. Although the mechanism may have involved the interaction between the carteolol eye drops and either verapamil or azilsaltan-related hyperkalemia, it is equally likely that the interaction was between all three drugs under the existence of CKD in this elderly patient.
In conclusion, physicians should always consider the potential risk of adverse drug interactions when prescribing a new medication to a patient, especially in elderly patients with polypharmacy. Even topical medications, such as carteolol eye drops, might have significant systemic absorption, leading to serious side effects through drug interactions in elderly patients.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuo Okumura: Research funding, Boston Scientific Japan.
Acknowledgement
We thank all of the doctors and medical staff who were involved in the treatment of this patient. In particular, Ph. So Iwabuchi and Ph. Takahiro Sekine provided important information about the carteolol eye drops. We also thank Mr. John Martin for his help with the English editing. | AZILSARTAN KAMEDOXOMIL, BISOPROLOL, BROMFENAC SODIUM, CALCIUM GLUCONATE, CARTEOLOL HYDROCHLORIDE, DEXTROSE, DORZOLAMIDE HYDROCHLORIDE, DOXAZOSIN MESYLATE, EDOXABAN TOSYLATE, HEPARIN SODIUM, INSULIN NOS, LANDIOLOL HYDROCHLORIDE, REBAMIPIDE, TRAVOPROST, VERAPAMIL HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32830185 | 18,270,051 | 2021-01-01 |
What was the administration route of drug 'AZILSARTAN KAMEDOXOMIL'? | Bradycardia Shock Caused by the Combined Use of Carteolol Eye Drops and Verapamil in an Elderly Patient with Atrial Fibrillation and Chronic Kidney Disease.
Ophthalmic carteolol is often used to treat glaucoma. Elderly patients with atrial fibrillation (AF) and chronic kidney disease (CKD) are common among the super-elderly in Japan. Because these patients are exposed to polypharmacy, they are at a high-risk of adverse drug interactions. We herein report an elderly patient with CKD who suffered bradycardia shock after the combined use of carteolol eye drops and verapamil for glaucoma and paroxysmal AF. This case highlights the fact that eye drops have a similar systemic effect to oral drugs, and especially in elderly patients with polypharmacy, drug interactions can unwittingly lead to serious events.
Introduction
Ophthalmic beta blockers, represented by timolol and carteolol, are often used to treat glaucoma in the elderly (1). As the elderly population is dramatically increasing in Japan, we often encounter elderly patients with atrial fibrillation (AF) and chronic kidney disease (CKD) (2). Because such patients tend to have multiple comorbidities, they often visit several medical institutions, and accordingly, they are prescribed multiple medications (i.e. polypharmacy). One clinical issue in those patients is that they may unwittingly experience drug interactions due to their polypharmacy, leading to a potential risk of adverse clinical events (3).
There have been two case reports of bradycardia with the combined use of timolol eye drops and verapamil, with their combined use first reported in the 20th century (4,5). However, the interaction between carteolol eye drops and verapamil has not been reported. We herein report a case of bradycardia shock caused by the combined use of carteolol eye drops and verapamil in an elderly patient with a history of CKD and glaucoma, who suffered from paroxysmal AF (PAF).
Case Report
An 84-year-old woman presented with a 3-day history of shortness of breath and chest discomfort. She was determined to be frail as evaluated by a Canadian Study of Health and Aging Clinical Frailty Scale of 6 on admission. She had a history of glaucoma, hypertension, and CKD (estimated glomerular filtration rate 32.6 mL/min/1.73 m2) from over 10 years earlier and was being treated separately at ophthalmology and internal medicine outpatient clinics. She had blindness in her right eye due to glaucoma, and her left eye had been treated with ophthalmic carteolol and travoprost for the last few years. She had been taking azilsartan and doxazosin in addition to diet therapy for hypertension and CKD. As a result, she had been taking five kinds of internal medications, two kinds of external medications, and four kinds of eye drops a day, resulting in polypharmacy.
Five days before admission, she had been diagnosed with symptomatic PAF, so verapamil [40 mg twice a day (b.i.d.)] had been newly initiated by her internal medicine physician. According to the information from the previous doctor, her heart rate had been about 60-80 beats/minute (bpm) before the start of verapamil. At admission, her heart rate was 29 bpm, and her blood pressure could not be obtained, although her radial artery pulse was palpable. Her respiratory rate and body temperature were 15/min and 36.0 °C, respectively.
Her laboratory data on admission are shown in Table, revealing high serum potassium, high liver enzyme, and high lactate levels. A 12-lead electrocardiogram (ECG) during the initial examination showed a heart rate of 24 bpm and narrow QRS rhythm followed by retrograde P-waves with a Wenckebach phenomenon without significant ST-segment changes (Fig. 1). Transthoracic echocardiography revealed a normal left ventricular function without any asynergy, D-shape, echo-free space, or valvular disease with a normal size of the left atrial diameter (32.0 mm). Chest X-ray revealed pulmonary edema and enlargement of the cardio-thoracic ratio.
Table. Laboratory Data at the Time of Admission.
WBC 5,900 /mm3 Na 139 mEq/L
Hb 11.4 g/dL K 6.5 mEq/L
Plt 14.2×104 /μL Cl 110 mEq/L
BUN 35.6 mg/dL Ca 8.5 mg/dL
Cre 1.21 mg/dL T-Chol 160 mg/dL
eGFR 32.6 HDL-Chol 67 mg/dL
CCR 21.25 LDL-Chol 66 mg/dL
CRP 0.11 mg/dL TG 64 mg/dL
TP 5.2 g/dL UA 6.3 mg/dL
Alb 3.0 g/dL CK 66 U/L
T-Bil 1.20 mg/dL CK-MB 4 U/L
AST 234 U/L Troponin I 0.01 ng/mL
ALT 119 U/L NT-proBNP 3,722 pg/mL
LDH 421 U/L TSH 7.79 μlU/mL
ALP 248 mEq/L Free T3 2.36 pg/mL
BS 157 mg/dL Free T4 1.20 ng/mL
HbA1c 5.3 % Lactate 2.9 mmol/L
Alb: albumin, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BS: blood sugar, BUN: blood urea nitrogen, Ca: serum calcium, CCR: creatinine clearance, CK: creatine kinase, Cl: serum chloride, Cre: serum creatinine, CRP: C-reactive protein, eGFR: estimated glomerular filtration rate, Free T3: free triiodothyronine, Free T4: free thyroxine, Hb: hemoglobin, HbA1c: hemoglobin A1c, HDL-Chol: high density lipoprotein cholesterol, K: serum potassium, LDH: lactate dehydrogenase, LDL-Chol: low density lipoprotein cholesterol, Na: serum sodium, NT-proBNP: N-terminal pro-Brain Natriuretic Peptide, Plt: platelets, T-Bil: total bilirubin, T-Chol: total cholesterol, TG: triglyceride, TP: total protein, TSH: thyroid-stimulating hormone, UA: serum uric acid, WBC: white blood cells
Figure 1. A 12-lead electrocardiogram during the initial examination. A heart rate of 24 bpm and a narrow QRS rhythm followed by retrograde P-waves with a Wenckebach phenomenon without significant ST-segment changes were noted.
Her clinical course is shown in Fig. 2. Because she had bradycardia shock, represented by high serum lactate and liver enzyme levels, with hyperkalemia, a temporary pacing catheter was placed through the right internal jugular vein, and right ventricular pacing was performed at 90 bpm while administrating an intravenous injection of calcium gluconate hydrate and glucose-insulin therapy for hyperkalemia. Anticholinergics could not be used due to glaucoma. With this treatment, the shock immediately resolved, and the symptoms disappeared. The carteolol eye drops, verapamil, and azilsartan were discontinued, and the patient was treated with a pacing rhythm until the next day (Fig. 3). The morning after she was hospitalized, her heart rhythm returned to a normal sinus rhythm with a heart rate of 63 bpm (Fig. 4). The carteolol eye drops were discontinued after consultation with the ophthalmologist, and a different non-beta blocker for glaucoma (dorzolamide hydrochloride) was prescribed to protect her non-blind left eye. The bradycardia no longer appeared after normalization of the potassium level and discontinuing verapamil and the carteolol eye drops.
Figure 2. Clinical course of this case. ALT: alanine aminotransferase, AST: aspartate aminotransferase, Calcicol: calcium gluconate hydrate, GI: glucose-insulin therapy, HR: heart rate, PAF: paroxysmal atrial fibrillation, PMI: pacemaker intubation
Figure 3. A 12-lead electrocardiogram after initiating temporary pacing. A heart rate of 93 bpm, wide QRS rhythm with a left bundle branch block and upper axis pattern, and right ventricular apex origin were noted.
Figure 4. A 12-lead electrocardiogram the day after the hospitalization. A heart rate of 63 bpm with normal sinus rhythm and T-wave flattening in leads III and aVF were observed.
However, she had symptomatic PAF with a rapid ventricular response on the first hospital day. When the PAF stopped, she temporarily had a backup pacing with VVI 50 bpm due to sick sinus syndrome. Based on her clinical course, it was judged that the use of antiarrhythmic drugs alone for PAF carried a risk of bradycardia shock, so it was decided to administer antiarrhythmic drugs after pacemaker implantation. However, pulmonary vein isolation was not selected due to her age and activity of daily living. Pacemaker implantation was performed on the 14th hospital day. Finally, her arrhythmia, blood pressure, and glaucoma were controlled with the pacemaker implantation and adjustment of her medications, as shown in Fig. 2, and she was discharged in good health on the 20th hospital day.
Discussion
Ophthalmic carteolol, as well as timolol, is used as an eye drop beta blocker for glaucoma. Carteolol has been considered to have a lower risk of cardiovascular events than timolol because carteolol generally has a weaker effect on slowing the heart rate than timolol, depending on the characterization of the intrinsic sympathomimetic activity (ISA) (6,7). Although warning clues of cardiovascular events, such as bradycardia, heart block, and hypotension, have been reported due to the use of timolol eye drops (8), there have been no reports of severe cardiovascular events with the use of carteolol eye drops. Because timolol eye drops are absorbed via the nasal mucosa through the nasolacrimal duct, their bioavailability is approximately 50% of that after oral administration, and they have a systemic effect similar to oral administration; however, they are topically administered (9). Furthermore, because both carteolol and timolol are metabolized by cytochrome P450 2D6 (CYP2D6), their effect can be enhanced in elderly people with a weakened CYP2D6 when combined with a drug with a CYP2D6 inhibitory effect and/or verapamil (10).
Verapamil is a commonly used class IV antiarrhythmic medication that blocks calcium-dependent slow channels, depresses the cardiac contractility, slows the myocardial conduction, and relaxes vascular smooth muscle. It serves to decrease sino-atrial (SA) node discharges and slow atrioventricular (AV) conduction, and the concomitant use with beta blockers can potentially cause severe bradycardia (11).
Elderly patients sometimes have both AF and CKD (2). Because carteolol is mainly excreted by the kidneys, it may have a strong cardiac depressant effect in elderly patients with CKD (12). Elderly people tend to have polypharmacy (3,13), and if prescriptions are obtained from multiple medical institutions, it is possible that the same drugs may be prescribed. In addition, as in the present case, when the serum potassium level is increased due to a side effect of an angiotensin II receptor blocker (ARB) (14), a cardiac depressant effect due to hyperkalemia may exacerbate the cardiac function. In the present case, both the SA node and AV node were likely suppressed by the combination of the ophthalmic carteolol, verapamil, and hyperkalemia, resulting in serious bradycardia due to sick sinus syndrome.
Of note, eye drops have a systemic effect similar to oral drugs. Drug interactions are more likely to occur in the elderly, especially when ophthalmic beta blockers are used in glaucoma patients, and careful follow-up in terms of cardiovascular events is needed; furthermore, verapamil should not be used for rate control in patients with AF. Although the mechanism may have involved the interaction between the carteolol eye drops and either verapamil or azilsaltan-related hyperkalemia, it is equally likely that the interaction was between all three drugs under the existence of CKD in this elderly patient.
In conclusion, physicians should always consider the potential risk of adverse drug interactions when prescribing a new medication to a patient, especially in elderly patients with polypharmacy. Even topical medications, such as carteolol eye drops, might have significant systemic absorption, leading to serious side effects through drug interactions in elderly patients.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuo Okumura: Research funding, Boston Scientific Japan.
Acknowledgement
We thank all of the doctors and medical staff who were involved in the treatment of this patient. In particular, Ph. So Iwabuchi and Ph. Takahiro Sekine provided important information about the carteolol eye drops. We also thank Mr. John Martin for his help with the English editing. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 32830185 | 18,270,051 | 2021-01-01 |
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