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Depending on the postoperative risk stratification of the individual patient, the primary goal of postoperative admin- istration of RAI after total thyroidectomy may include (i) RAI remnant ablation (to facilitate detection of recurrent disease and initial staging by tests such as Tg measurements or whole-body RAI scans), (ii) RAI adjuvant therapy (in- tended to improve disease-free survival by theoretically destroying suspected, but unproven residual disease, es- pecially in patients at increased risk of disease recurrence), or (iii) RAI therapy (intended to improve disease-specific and disease-free survival by treating persistent disease in higher risk patients). Additional considerations in RAI decision-making may include patient comorbidities (and the potential impact of therapeutic doses of RAI or prepa- ration for the procedure), feasible or preferred disease surveillance procedures, patient preferences (the latter be- ing particularly important when clear data on therapeutic
efficacy are lacking), or others. It is important to note that in patients with low-risk DTC, disease surveillance may be accomplished without RAI ablation using neck US and Tg with Tg antibody measurements while on thyroid hormone therapy.
We categorized the results of our review according to the ATA Risk of Recurrence Risk stratification (outlined in a preceding section of these guidelines). However, given that the ATA risk classification is relatively new and the majority of studies examining therapeutic efficacy of postsurgical RAI remnant ablation or therapy (adjuvant or for persistent dis- ease) have been performed with attention to traditional mortality risk stratification systems such as the AJCC/TNM system, MACIS, National Thyroid Cancer Treatment Co- operative Study Group (NTCTCSG), or others, it was nec- essary to extrapolate the results of many studies according to estimated ATA risk level. We have also categorized some of the results of our evidence review according to the AJCC/ TNM risk of mortality stratification system because this system has been in use longer in our field (Table 14). Eva- luation of postoperative disease status and recommendations for RAI remnant ablation and adjuvant therapy can be found in algorithms in Figs. 5–8. | 497 |
ATA low risk. Studies examining the impact of RAI remnant ablation/adjuvant therapy on long-term thyroid cancer outcomes in ATA low-risk patients are subject to limitations due to their observational nature (and potential for bias), as well as limited statistical power to detect relatively uncommon events (such as disease-related mortality). By definition, the risk of disease-specific mortality is low, the risk of persistent/recurrent disease is low (around 3%), and there is no evidence that delayed discovery and treatment of persistent disease may decrease the chance of cure in these patients. In a retrospective multicenter registry study, 1298 DTC patients categorized as being in the ATA low-risk level, were followed for a median of 10.3 years, and there was no significant effect of RAI adjuvant therapy on overall or disease-free survival, using respective multivariate and stratified propensity analysis techniques (544). Prospective data from the NTCTCSG suggest that overall disease-specific and disease-free survival are not improved by RAI treatment in NTCTCSG stage I and II patients (i.e., patients aged <45
years with no distant metastases or patients aged ‡45 years with a primary tumor <4 cm in diameter, no extrathyroidal
extension, and no nodal metastases), also using multivariate analyses and propensity analyses (671,672). In two system- atic reviews examining results of multivariate adjusted ana- lyses, with a focus on low-risk DTC using classic clinic- pathologic staging systems such as TNM/AJCC, the majority of studies did not show a significant effect of RAI adjuvant therapy in reducing thyroid cancer–related death, and con- flicting findings of studies relating to outcomes of disease recurrence (673,674). A more recent systematic review of the literature supported the findings of the earlier systematic reviews (675). It is important to note that in the studies summarized in this section on ATA low-risk disease (or equivalent), patients with multifocal PTC were generally included (if no other adverse features meeting criteria for upstaging were noted). To date, there is little evidence to suggest that RAI may improve disease-specific mortality in low-risk DTC patients, and there is some conflicting evidence | 498 |
Table 14. Characteristics According to the American Thyroid Association Risk Stratification System and AJCC/TNM Staging System That May Impact Postoperative Radioiodine Decision-Making | 499 |
ATA low risk T1b,T2
N0, Nx M0,Mx
Tumor size
>1–4 cm
No Conflicting
observational data
Not routineb—May be considered for patients with aggressive histology or vascular invasion (ATA intermedi- ate risk). | 500 |
ATA low to in- termediate risk T3
N0,Nx M0,Mx
Tumor size >4 cm Conflicting data Conflicting
observational data
Considerb—Need to consider presence of other adverse features. Advancing age may favor RAI use in some cases, but specific age and tumor size cutoffs subject to some uncertainty.a | 501 |
ATA low to in- termediate risk T3
N0,Nx M0,Mx
Microscopic ETE, any tumor size
No Conflicting
observational data
Considerb—Generally favored based on risk of recurrent disease. Smaller tumors with microscopic ETE may not require RAI. | 502 |
ATA low to in- termediate risk T1-3
N1a M0,Mx | 503 |
ATA low to in- termediate risk T1-3
N1b M0,Mx | 507 |
ATA high risk T4
Any N Any M
Central compart- ment neck lymph node metastases | 508 |
Lateral neck or mediastinal lymph node metastases | 512 |
Any size, gross ETE
No, except possi- bly in subgroup of patients ‡45 years of age (NTCTCSG
Stage III) | 514 |
No, except possi- bly in subgroup of patients ‡45 years of age | 517 |
Yes,
observational data
Conflicting observational data | 519 |
Conflicting observational data | 524 |
Yes,
observational data
Considerb—Generally favored, due to somewhat higher risk of persistent or recurrent disease, especially with increasing number of large
(>2–3 cm) or clinically evident lymph nodes or presence of extra- nodal extension. Advancing age may also favor RAI use.a However, there is insufficient data to mandate RAI use in patients with few (<5) microscopic nodal metastases in central compartment in absence of other adverse features.
Considerb—Generally favored, due to higher risk of persistent or recurrent disease, especially with increasing number of macroscopic or clinically evident lymph nodes or presence of extranodal extension. Advancing age may also favor RAI use.a
Yes | 526 |
ATA high risk M1
Any T Any N
Distant metastases Yes,
observational data
Yes,
observational data
Yes | 527 |
aRecent data from the NTCTCSG (National Thyroid Cancer Treatment Cooperative Study Group) have suggested that a more appropriate prognostic age cutoff for their and other classification systems could be 55 years, rather than 45 years, particularly for women.
bIn addition to standard clinicopathologic features, local factors such as the quality of preoperative and postoperative US evaluations, availability and quality of Tg measurements, experience of the operating surgeon, and clinical concerns of the local disease management team may also be considerations in postoperative RAI decision-making. | 529 |
on effect on recurrence, with newer data using the ATA risk system suggesting the lack of a significant effect. Further- more, the majority of the best available observational evi- dence suggests that RAI adjuvant therapy is unlikely to improve disease-specific or disease-free survival in papillary microcarcinoma (<1 cm, uni- or multifocal), in the absence of other higher risk features (146,676–680). In a recent retro- spective analysis of 704 papillary microcarcinoma patients whose initial risk level was ATA low or intermediate who were followed for a median of 64 months, there was no sig- nificant reduction in recurrence rates in patients treated with RAI compared to those not treated with RAI using a pro- pensity score analysis (677). With respect to microcarcinomas of follicular cancer and Hu¨rthle cell cancer, a recent SEER registry secondary data analysis suggested no disease-specific survival benefit in patients treated with RAI in a multivariate analysis adjusted for age, histology, disease extent, type of surgery, and external beam radiation therapy (the total num- ber of patients in this study was 564) (681). A limitation of interpreting these data on follicular and Hu¨rthle cell micro- carcinomas is that some of the patients in the study had some adverse features and were not all considered low risk; how- ever, the authors adjusted for relevant variables in their multivariate analysis (681). The role of RAI adjuvant therapy in ATA low-risk DTC should be clarified in the future, fol- lowing completion of RCTs, such as the Iodine or Not (IoN) trial for low- and intermediate-risk patients (682) and ESTI- MABL2 for low-risk patients. | 531 |
ATA intermediate risk. Multivariate adjusted analyses from SEER suggest that postsurgical RAI treatment is as- sociated with improved overall survival for aggressive PTC histologies such as tall cell, diffuse sclerosing, and insular variants (683,684). Furthermore, multivariate adjusted an- alyses from SEER suggest that RAI treatment is associated with improved overall survival in node-positive adult pa- tients with PTC or pT3 node-negative PTC, in which the primary tumor is >4 cm or there is evidence of microscopic extrathyroidal extension (685). It is important to note, however, that in this SEER study the overall survival rate was very high in node-positive or pT3-node negative PTC patients aged <45 years, such that 99% and 98% of such individuals were alive after a median follow-up period of
years, with or without RAI treatment, respectively. The clinical significance of this approximately 1% absolute risk difference could be questioned. In contrast, in the same study, for individuals aged ‡65 years, assuming the same median study follow-up period of 6.8 years, 73% of T3-node negative or node-positive PTC patients treated with RAI and 69% of those not treated with RAI were alive (685); in this older subgroup, the absolute risk difference would be estimated to be about 4%.
There is some supportive evidence from multivariate and propensity analyses that there may be a benefit of adjuvant RAI treatment in improving overall and disease-specific survival as well as disease-free survival in patients with nodal metastases aged ‡45 years, as such patients would be in- cluded in the NTCTCSG stage III category (671). Further- more, in a single-center retrospective study from Hong Kong examining data from a subgroup of 421 patients with node- positive PTC, lymph node failure-free survival was improved with postsurgical RAI treatment, with the greatest treatment
benefits observed in patients with N1b disease, as well as with lymph nodes >1 cm in diameter (686). RAI therapeutic effi- cacy in patients <45 years of age with nodal metastases are unclear because such patients are categorized as stage I by the NTCTCSG system and no significant benefit of RAI treat- ment was observed for the stage I group in that study, with no specific subgroup analysis reported according to node posi- tivity (671). A single-center retrospective study from the Mayo Clinic examining 20-year cause-specific mortality and recurrence rate, suggested no significant benefit in PTC patients with a MACIS score of <6 who had positive lymph nodes, using respective univariate analyses (278). Given that age is incorporated in the MACIS score, it is possible that age was a contributing factor in the results of that analysis. In a subgroup of 352 patients with microscopic extrathyroidal extension from a single-center retrospective study, postsurgical RAI treatment was associated with a reduction in rate of local relapse (686). However, in the NTCTCSG study, microscopic extraglandular invasion would be classified as NTCTCSG stage I for patients <45 years of age and II for those ‡45 years of age, and those stages were associated with lack of clear benefit of RAI. In a recent systematic review, Lamartina et al. (675) reported conflicting results on the impact of RAI treatment on disease recurrence, specifically indicating that 11 nonrandomized studies suggested a benefit, whereas 13 studies did not show a significant benefit. For patients with ATA intermediate-risk DTC, limited risk-group specific data examining RAI efficacy is available, but existing data suggest that the greatest po- tential benefit may be observed with adverse thyroid cancer histologies, increasing volume of nodal disease, lymph node disease outside the central neck, and advancing patient age. Benefits regarding survival or recurrence can be expected pri- marily in patients with higher risk of recurrent or persis- tent disease that is iodine avid. More studies are needed, including RCTs, to characterize RAI treatment efficacy in ATA intermediate-risk patients. The adjuvant therapeutic efficacy of RAI treatment in improving long-term thyroid cancer outcomes in the situation of isolated microscopic central neck nodal dis- ease in the absence of other adverse features is unknown, so the relatively good overall prognosis of this group (as outlined in the preceding section of these guidelines) as well as the un-
certain RAI therapeutic efficacy for this subgroup, are important considerations in RAI decision-making. Clearly more research is needed to understand the therapeutic efficacy in various subgroups of patients in the ATA intermediate-risk category. | 532 |
ATA high risk. A prospective multicenter study reported a significant improvement in overall and disease-specific mor- tality, as well as disease-free survival in NTCTCSG stage III and IV patients, after statistical adjustment using multivariate and propensity stratified analyses (671). Furthermore, pro- spectively collected data from the SEER cancer registry sug- gest that postsurgical RAI therapy is associated with improved overall survival in patients with PTC with distant metastases (when distant metastases were combined with age >45 years, tumor size >2 cm, and positive lymph nodes at primary diag- nosis) (687). Data from SEER also suggest that overall sur- vival in patients with FTC with distant metastases more than doubled in patients receiving postsurgical RAI treat- ment (687). Thus, routine postsurgical RAI treatment is re- commended in patients with ATA high-risk DTC. | 533 |
[B37] What is the role of molecular marker status in therapeutic RAI decision-making? | 535 |
RECOMMENDATION 52
The role of molecular testing in guiding postoperative RAI use has yet to be established; therefore, no molecular test- ing to guide postoperative RAI use can be recommended at this time.
(No recommendation, Insufficient evidence) | 536 |
Preclinical studies show that the presence of the BRAFV600E mutation significantly reduces sodium-iodide symporter expression and RAI uptake (688). There are currently in- sufficient clinical data, however, to know whether the pres- ence or absence of the BRAFV600E mutation or other genetic alterations in PTC may impact the success of adjuvant therapy or remnant ablation in PTC, or if adjustments in administered activity are warranted for any planned treat- ments. In a recent subgroup analysis of 134 PTC patients with T1aN0M0 disease, the rate of macroscopic structural disease recurrence was 0% in the no RAI group (24% of whom were BRAF positive), 2.6% in 39 BRAF-positive pa- tients who received RAI, and 1.7% in BRAF-negative pa- tients who received RAI (mean follow-up of 5.3 years for the entire study) (565). Of the 97 T1aN0M0 patients who re- ceived postoperative RAI, the rate of biochemical persis- tence of disease (defined by a stimulated Tg of >1 ng/mL), was 13% in the 39 BRAF-positive patients and 1.7% in the BRAF-negative patients; the standard activity for remnant ablation in this study was 30 mCi in most cases (565). The relatively small number of patients who did not receive postoperative RAI and the relatively small number of structural disease recurrences in the T1aN0M0 subgroup of PTC patients and lack of randomization in this study may preclude meaningful analysis of RAI therapeutic efficacy. The ESTIMABL2 study will analyze the relevance of BRAF status on outcome (registration number NCT01837745). There are no studies examining therapeutic efficacy of RAI in ATA high-risk patients, but the presence or absence of a BRAFV600E mutation in that situation would be unlikely to alter RAI decision-making at present. Thus, the role of mo- lecular testing in guiding postoperative RAI use has yet to be established, and more research in this area is clearly needed. Moreover, in general, RCTs examining RAI therapeutic ef- ficacy are needed, and ideally these should be appropriately stratified for ATA recurrence risk level and other important prognostic variables. | 537 |
[B38] How long does thyroid hormone need to be withdrawn in preparation for RAI remnant ablation/ treatment or diagnostic scanning? | 538 |
RECOMMENDATION 53
If thyroid hormone withdrawal is planned prior to RAI therapy or diagnostic testing, LT4 should be withdrawn for 3–4 weeks. Liothyronine (LT3) may be substituted for LT4 in the initial weeks if LT4 is withdrawn for 4 or more weeks, and in such circumstances, LT3 should be with- drawn for at least 2 weeks. Serum TSH should be measured prior to radioisotope administration to evaluate the degree of TSH elevation.
(Strong recommendation, Moderate-quality evidence)
A goal TSH of >30 mIU/L has been generally adopted in preparation for RAI therapy or diagnostic testing, but there is uncertainty relating to the optimum TSH level associated with improvement in long-term outcomes.
(Weak recommendation, Low-quality evidence) | 539 |
Thyrotropin stimulation before RAI remnant ablation/ therapy or scanning has been a long-established standard of care because early observational research suggested that a TSH >30 mIU/L was required for incompletely resected thyroid tumors to significantly concentrate 131I (689). There have been two RCTs comparing various thyroid hormone withdrawal protocols prior to therapeutic or diagnostic iodine radioisotope administration (690,691). Lee et al. (691) re- ported on an open-label, single-center study, in which 291 patients with well-differentiated thyroid cancer (TNM stage T1–T3, N0/N1a,M0) were randomized to either (a) with- drawal LT4 for 4 weeks (n = 89), (b) withdrawal of LT4 for 4 weeks with substitution of LT3 for the first 2 weeks (n = 133), or (c) recombinant human TSH (rhTSH; with withdrawal of LT4 for a few days from the time of the first rhTSH injection to radioisotope administration) (n = 69) (691). In this trial, all patients received 30 mCi of 131I for remnant ablation and were prescribed a 2-week low-iodine diet (LID) pre-ablation. Although the randomization method was unclear, the base- line characteristics (including pre-ablation urinary iodine measurements) were well balanced among groups. Further- more, the pre-ablation TSH was >30 in all patients in all groups in this trial, with no significant difference in mean pre- ablation TSH levels. Moreover, the primary outcome, which was the rate of successful remnant ablation at 12 months, was not significantly different among groups (range 91.0%– 91.7% among groups). Upon administration of question- naires in a double-blind fashion, there was no significant difference in quality of life during preparation for RAI ab- lation, between the LT4 withdrawal group and the LT4 withdrawal with LT3 substitution group; however, quality of life in both withdrawal groups prior to remnant ablation was significantly worse than after rhTSH preparation (691). Long-term outcome data from this trial were not reported. In a single-center trial, Leboeuf et al. (690) randomized 20 in- dividuals with well-differentiated thyroid cancer awaiting RAI remnant ablation or diagnostic scanning to LT4 with- drawal and either (a) substitution of LT3 (50 lg/d, divided as two capsules) for 21 days, followed by 2 weeks off LT3, or
identical-appearing placebo for LT3 (two pills per day) for
21 days. In both groups, either the LT3 or placebo was with- drawn for another 2 weeks, and weekly measurements were performed for serum TSH, free thyroxine, and free triiodothy- ronine (690). The primary outcome was the hypothyroidism symptom score (Billewicz scale), which was ascertained in a double-blind fashion at time of LT4 withdrawal and every 2 weeks until the end of the study. The randomization method was a computer-generated number sequence; the LT3 group was significantly older than the placebo group (mean age 64 com- pared to 46), suggesting imbalance in the randomization (690). Disease stage of participants was not reported. Approximately 15% of participants withdrew from this trial (two in the placebo group and one in the LT3 group). Leboeuf et al. (690) reported no significant differences between the two thyroid hormone | 540 |
withdrawal protocol groups for hypothyroid symptom scores at any time point in the trial in a protocol-based analysis. At the time of ablation or whole-body scanning, the mean TSH was not significantly different between groups. In summary, available evidence from recent RCTs suggests that either direct LT4 withdrawal or LT4 withdrawal with substitution of LT3 in initial weeks is associated with similar short-term quality of life and hypothyroidism symptom scores; moreover, the remnant abla- tion success rate appears comparable.
There is some conflicting observational evidence on whether any specific pre-RAI administration TSH level is associated with success of remnant ablation (692–696). For example, in a secondary analysis of a RAI remnant ablation activity RCT, Fallahi et al. (692) reported that a pre-RAI TSH of >25 fol- lowing (LT4 and LT3) thyroid hormone withdrawal was sig- nificantly associated with increased likelihood of successful remnant ablation (odds ratio 2.36, [95% CI 1.28–4.35], p = 0.006), after adjustment for RAI activity, baseline serum Tg, on-LT4 TSH level, sex, age, histology, baseline RAI up- take, and extent of surgery). In two retrospective studies, each including several hundred DTC patients who underwent thy- roid hormone withdrawal, no significant association was ob- served between pre-RAI TSH and rate of successful remnant ablation, in respective multivariate analyses adjusted for rele- vant variables such as disease extent, 131I activity, and sex (695,696). However, results of these two studies may not necessarily be extrapolated to TSH levels below 30 mU/L, gi- ven that patients with such TSH thresholds were not generally considered eligible for RAI ablation in these studies. Pre–RAI ablation TSH was not a significant predictor of becoming dis- ease free without further treatment in a secondary subgroup analysis of 50 patients who underwent thyroid hormone with- drawal, but the small number of patients in this subgroup may have limited the statistical power for a multivariate analysis (694). In summary, there is some uncertainty on the optimal level pre–RAI treatment TSH following thyroid hormone withdrawal in considering long-term outcome effects. | 542 |
[B39] Can rhTSH (Thyrogen) be used as an alternative to thyroxine withdrawal for remnant ablation or adjuvant therapy in patients who have undergone near-total or total thyroidectomy? | 543 |
RECOMMENDATION 54
In patients with ATA low-risk and ATA intermediate- risk DTC without extensive lymph node involvement (i.e., T1–T3, N0/Nx/N1a, M0), in whom RAI remnant ablation or adjuvant therapy is planned, preparation with rhTSH stimu- lation is an acceptable alternative to thyroid hormone with- drawal for achieving remnant ablation, based on evidence of superior short-term quality of life, noninferiority of remnant ablation efficacy, and multiple consistent observations sug- gesting no significant difference in long-term outcomes.
(Strong recommendation, Moderate-quality evidence)
In patients with ATA intermediate-risk DTC who have extensive lymph node disease (multiple clinically involved LN) in the absence of distant metastases, preparation with rhTSH stimulation may be considered as an alternative to thyroid hormone withdrawal prior to adjuvant RAI treatment.
(Weak recommendation, Low-quality evidence)
In patients with ATA high-risk DTC with attendant higher risks of disease-related mortality and morbidity, more controlled data from long-term outcome studies are needed before rhTSH preparation for RAI adjuvant treat- ment can be recommended.
(No recommendation, Insufficient evidence)
In patients with DTC of any risk level with signifi- cant comorbidity that may preclude thyroid hormone withdrawal prior to iodine RAI administration, rhTSH preparation should be considered. Significant comorbidity may include (a) a significant medical or psychiatric con- dition that could be acutely exacerbated with hypothy- roidism, leading to a serious adverse event, or (b) inability to mount an adequate endogenous TSH response with thyroid hormone withdrawal.
(Strong recommendation, Low-quality evidence)
Recombinant human thyrotropin (trade name Thyrogen) is currently approved by many international authorities including the United States Food and Drug Administration (FDA) and Health Canada for use in preparation for RAI remnant ablation in patients who have undergone a near-total or total thyroid- ectomy for well-differentiated thyroid cancer and who do not have evidence of distant metastases (FDA, www.accessdata. fda.gov; Health Canada, http://webprod.hc-sc.gc.ca). Data from a compassionate use observational study suggest that rhTSH raises serum TSH measurements in patients who are unable to mount an endogenous TSH rise and appears to re- duce the risk of hypothyroid-related complications in patients with significant medical or psychiatric comorbidity (697). Some of the complications that were reported to be avoided by use of rhTSH included worsening of psychiatric illness, respiratory compromise, central nervous system (CNS) com- promise, aggravation of congestive heart failure, and aggra- vation of coronary artery disease (697).
Multiple RCTs have focused on short-term remnant abla- tion outcomes in low and intermediate risk DTC with lower risk features, using rhTSH compared to thyroid hormone withdrawal. In six RCTs of patients with well-differentiated thyroid cancer without distant metastases undergoing RAI remnant ablation (T1–T3, N1 or N0, all M0), the rate of successful remnant ablation, was not significantly different after rhTSH preparation compared to thyroid hormone withdrawal, using 131I dose activities ranging from 30 to 100 mCi (691,698–702). Patients with resected cervical lymph node metastases were included in five of these trials (691,699–702), and these may be assumed to be confined to the central neck, given the extent of primary surgery de- scribed in these studies. In one trial, a further inclusion re- striction was fewer than five positive nodes at the time of the primary surgery (702). Some potential limitations of the ex- isting RCTs in this area include lack of blinding of patients and treating physicians (because it was not feasible). In five of the RCTs that examined health-related quality of life around the time of remnant ablation, this outcome was sig- nificantly worse in patients who underwent thyroid hormone withdrawal compared to rhTSH preparation, and this was attributed to hypothyroid symptoms (691,699–702). How- ever, in three of these RCTs, which examined longer term | 544 |
quality of life, there was no significant difference in mea- surements between patients who had received rhTSH com- pared to those who had thyroid hormone withdrawal preparation, 3 or more months after RAI remnant ablation (699,701,702). A smaller RCT including a total of 25 indi- viduals who had incidentally discovered PTC in the course of thyroidectomy for multinodular goiter, showed that mean Tg measurements were similar at various time points out to about 20 months in 13 individuals who were prepared for remnant ablation using rhTSH within a week after thyroid- ectomy, compared to those prepared by LT4 withdrawal for 4–6 weeks postoperatively (703). A meta-analysis pooling data from 1535 patients in all seven trials described herein, suggested that the rates of remnant ablation success were not significantly different using rhTSH compared to thyroid hormone withdrawal (risk ratio 0.97 [95% CI 0.94–1.01]) (704). Furthermore, a pooled analysis suggested that quality- of-life measures were superior on the day of remnant ablation in the rhTSH group, with no significant difference between groups 3 months later (704). Another meta-analysis including six of the previously mentioned RCTs, also suggested that the success of remnant ablation was not significantly different between patients prepared with rhTSH or thyroid hormone withdrawal, and this result was robust using a variety of definitions of remnant ablation success (705). In summary, the use of rhTSH for preparation for remnant ablation is as- sociated with superior short-term quality of life and similar rates of successful remnant ablation compared to traditional thyroid hormone withdrawal.
There are some limited long-term outcome data following rhTSH preparation for RAI treatment compared to thyroid hormone withdrawal. In one aforementioned RCT in ATA low- and intermediate-risk patients (700), follow-up data were reported at a median of 3.7 years later for 51 of the original 63 patients, and rates of reoperation for cervical neck recurrence were essentially identical between groups (4% of patients), with no deaths (706). In the same study, repeat treatment with 131I for detectable Tg or imaging evidence of disease was performed in 4 of the 28 patients in the rhTSH group and 5 of the 23 patients in the hypothyroid group in this study (706). The low number of thyroid cancer–related deaths and recurrences in this small trial limit the ability to make meaningful statistical comparisons of long-term out- comes. In another RCT including 44 mixed risk–level DTC patients, who were subjected to either rhTSH preparation
(n = 24) for RAI treatment within a week after surgery or 4–6 weeks of LT4 withdrawal (n = 20), after a mean follow-up period of about 52 months, only one individual in the rhTSH group was histologically proven to have recurrent disease (lymph nodes and bone) (707). However, this study was likely underpowered to detect meaningful differences in this outcome, and the final data analysis would be limited by lack of data available at the final follow-up (i.e., in progress) for 18% of the trial participants (707). In one prospective (694) and two retrospective (708,709) observational studies in- cluding largely ATA low- and intermediate-risk DTC pa- tients, no significant difference was observed in the long-term presence of clinically significant disease, regardless of whe-
ther rhTSH or thyroid hormone withdrawal was used in preparing for therapeutic RAI for DTC patients). In a sub- group analysis of 183 DTC patients with level N1b nodal disease from one of the aforementioned retrospective studies,
the rate of NED at last follow-up was not significantly dif- ferent in patients prepared with thyroid hormone withdrawal (26.8%) compared to those prepared with rhTSH (33.7%) (708). In a smaller retrospective, multicenter study, Pitoia et al. (710) reported that in 45 consecutive Tg antibody- negative patients with T3-T4 /N1-Nx/M0 disease, the ab- sence of persistence or recurrence of disease after a mean follow-up of about 3 years was 72% in patients pretreated with rhTSH and 59% in those pretreated with thyroid hor- mone withdrawal ( p = 0.03). In a multicenter retrospec- tive analysis of patients with T4 disease with or without nodal or distant metastases (T4, N0/N1, M0/M1), the rate of stimulated Tg <2 ng/mL Tg among antibody-negative pa- tients was 67.7% (42 of 62) in patients prepared for RAI treatment with rhTSH, compared to 57.8% (37 of 64) in those prepared with thyroid hormone withdrawal (6-month follow- up) (711). In a retrospective analysis of 175 patients with RAI-avid metastatic disease to lungs and/or bone, the authors observed no significant difference in overall survival after a mean follow-up period of 5.5 years, among patients prepared prior to RAI treatment with rhTSH alone for all RAI treat- ments, thyroid hormone withdrawal for all RAI treatments, or thyroid hormone withdrawal for initial treatments followed by rhTSH for subsequent treatment(s) (712). In this study, whole-body and blood dosimetry studies were performed in all patients; therefore, the results may not be extrapolated to RAI fixed dosing. Some important differences among groups in this study that could have impacted the findings included differences in cumulative RAI activities received and longer follow-up in groups who had thyroid hormone withdrawal (712). Although the authors performed a multivariable analysis examining for predictors of overall survival, and method of TSH stimulation was not significant, this model did not adjust for these variables. In a two-center retrospective analysis comparing responses to treatment using RECIST 1.1 criteria in 56 patients with distant metastatic disease pretreated with ei- ther rhTSH or thyroid hormone withdrawal prior to RAI, there were no differences in outcomes between groups after a mean follow-up period of about 6 years (713). Also in this study, there were important baseline differences among groups, such as rates of use of dosimetry and mean cumulative RAI activity. Rates of xerostomia, leukopenia, or thrombocytopenia were not significantly different between treatment groups in this study. The overall mortality rate was 20% in the rhTSH group (3 of 15) and 7.3% in the thyroid hormone withdrawal group (3 of 41) ( p = 0.188) (713), although the study was likely not sufficiently large to examine differences in this important outcome. The findings of the latter study cannot be readily extrapolated to fixed-dosing RAI treatment regimens because 80% of the individuals in the rhTSH group and 46% in the thyroid hormone withdrawal group had dosimetry-based RAI treatment. RCTs comparing rhTSH to thyroid hormone with- drawal preparation pre–RAI treatment, are clearly needed to guide clinical care in higher risk DTC patients.
[B40] What activity of 131I should be used for remnant ablation or adjuvant therapy? | 546 |
RECOMMENDATION 55
If RAI remnant ablation is performed after total thyroidectomy for ATA low-risk thyroid cancer or intermediate-risk disease with lower risk features (i.e., low- | 547 |
volume central neck nodal metastases with no other known gross residual disease or any other adverse features), a low administered activity of approximately of 30 mCi is gener- ally favored over higher administered activities.
(Strong recommendation, High-quality evidence)
Higher administered activities may need to be con- sidered for patients receiving less than a total or near-total thyroidectomy in which a larger remnant is suspected or in which adjuvant therapy is intended.
(Weak recommendation, Low-quality evidence) | 549 |
RECOMMENDATION 56
When RAI is intended for initial adjuvant therapy to treat suspected microscopic residual disease, administered ac- tivities above those used for remnant ablation up to 150 mCi are generally recommended (in absence of known distant metastases). It is uncertain whether routine use of higher administered activities (>150 mCi) in this setting will re- duce structural disease recurrence for T3 and N1 disease.
(Weak recommendation, Low-quality evidence) | 550 |
Successful remnant ablation can be defined by an undetect- able stimulated serum Tg, in the absence of interfering Tg an- tibodies, with or without confirmatory nuclear or other imaging studies. An alternative definition in cases in which Tg antibodies are present is the absence of visible RAI uptake on a subsequent diagnostic RAI scan. In this section, we only included published original RCTs or systematic reviews/meta-analyses of such studies examining the impact of various 131I dose activities on the rate of successful remnant ablation or thyroid cancer out- comes (including thyroid cancer–related deaths or recurrences) in adult patients with well-differentiated thyroid carcinoma who had been treated with total or near-total thyroidectomy and who were not known to have any gross residual disease following surgery. Our search yielded six RCTs (692,699,701,714–716), the majority of which had had no blinding of patients and health care providers (699,701,714–717).
In the trial by Fallahi et al. (692), the randomization pro- gram was prepared and executed by a technologist in the laboratory where the 131I activities were prepared for dis- pensing in coded vials, without revealing the administered activity to participants and health care providers. The path- ologic stage of disease of patients included was TNM stage pT1 to pT3 in four trials (699,714,715,717), whereas only pT1 or pT2 patients were eligible in one trial (701), and primary tumor size or tumor size staging was not reported in two trials (692,716). Some patients with known small- volume lymph node disease were included in five of the trials (699,701,714,715,717), but patients with known lymph node disease were excluded from one trial (692), and lymph node staging was not reported in another trial (716). Although the specific levels and size of lymph node metastases at baseline were not clearly reported, data reported on surgical extent suggested that these were consistent with relatively nonbulky central neck nodal metastases resected in the course of thy- roidectomy with or without central neck dissection (699,701, 714,715,717).
The 131I activities compared were as follows: 30 mCi compared to 100 mCi in four trials (692,699,701,714), 50 mCi compared to 100 mCi in two trials (715,716), or 30 mCi
compared to 60 mCi or 100 mCi in one study comprising pooled long-term outcome data from two staged smaller trials from the same group (717).
The rate of successful remnant ablation was reported to be not inferior using an administered activity of 30 mCi as compared to 100 mCi in three trials after preparation with thyroid hormone withdrawal (699,701,714) and in two trials after preparation with rhTSH (699,701), including data from the two large factorial design trials in both comparisons (699,701). Pilli et al. (715) reported that an administered activity of 50 mCi was not inferior to 100 mCi in achieving successful remnant ablation, following preparation with rhTSH. In contrast, Zaman et al. (716) suggested that 100 mCi may be superior to 50 mCi following thyroid hormone withdrawal, but the small size (40 patients) and lack of re- porting of statistical comparisons are important limitations of this study. The third largest trial (341 patients random- ized) by Fallahi et al. (692) reported that an administered activity of 100 mCi was superior to 30 mCi in achieving successful remnant ablation after thyroid hormone with- drawal. The rate of initial successful remnant ablation (as defined by the primary authors) was highly variable among trials, and the following rates were reported following initial administration of 100 mCi of 131I: 64% in the trial from Fallahi et al. (692), 56% in the trial from Maenpaa et al. (714), 89% in the trial from Mallick et al. (699), 67% in the trial from Pilli et al. (715), 94% in the trial from Schlum- berger et al. (701), and 60% in the trial from Zaman et al. (716). The reasons explaining variability in the rates of successful RAI remnant ablation among trials are not completely understood but could potentially be due to dif- ferences in study populations, completeness of surgery (including size of the remaining remnant), or sensitivity of techniques used to evaluate outcomes (such as Tg assays or diagnostic imaging studies).
Short-term side effects in the weeks following remnant ablation have been reported to be more frequent in patients treated with 100 mCi as compared to 30 mCi activities by Mallick et al. (699), and a similar trend was reported by Maenpaa et al. (714). Repeat treatment with additional 131I has been reported to be more frequent in patients treated with
30 mCi as compared to higher activities in three trials (692,699,717), but not in one trial (714). Long-term outcome data from randomized trials in this area are limited by rela- tively low event rates, potentially underpowering statistical analyses. Kukulska et al. (717) followed 390 patients that had been randomized to either 30, 60, or 100 mCi administered activities for remnant ablation, and reported the following event rates after a median period of 10 years following treatment: local relapse in 2% following an initial 30 mCi activity com- pared to 3% for initial administered activities of 60 or 100 mCi (reported to be not significantly different), and distant meta- static recurrence in 0% of the patients in all of the treatment groups. Maenpaa et al. (714) followed 160 patients who were randomized to either 30 or 100 mCi for a median of 51 months, and they reported the following outcomes: reoperation for re- section of thyroid cancer in lymph nodes in 7% and 8% of patients who were treated with activities of 30 and 100 mCi, respectively; distant metastatic recurrence in 0% and 4% of patients treated with activities of 30 and 100 mCi, respectively; and no thyroid cancer–related deaths in any of the treatment groups. | 551 |
Overall, the rate of successful remnant ablation in patients who have undergone total or near-total thyroidectomy ap- pears to be not inferior in patients treated with 30 mCi compared to 100 mCi in the majority of studies comparing these activities and particularly in studies achieving the highest successful ablation rates. Rates of short-term adverse effects may be higher after administration of 100 mCi 131I compared to 30 mCi, in a small number of trials examining these outcomes. Limited long-term RCT data on the impact of various activities for remnant ablation or adjuvant therapy are available, but thyroid cancer–related recurrences or deaths do not appear to be higher with the use of lower initial activities for remnant ablation, compared to higher admin- istered activities. Four recent systematic reviews and meta- analyses reported results that are supportive of these con- clusions (718–721), although some of the predefined study inclusion criteria in these reviews were generally not as strict as defined in our review (particularly for variables such as the extent of primary surgery or the stringency of Tg threshold in the definition of success of remnant ablation); it is also im- portant to note that in some of these meta-analyses, statisti- cally significant heterogeneity (variability) of treatment effect was noted for the pooled analyses on successful rem- nant ablation (718,720,721). A recent retrospective database analysis by Verburg et al. (722) with longer follow-up than most earlier studies adds a note of caution for the use of lower administered activities in older low-risk patients. They fol- lowed 698 patients with low-risk DTC (pT1 or pT2 and no involved LN) for at least 5 years. There were no long-term (10–15 year) overall survival or disease-specific survival
differences in younger patients (<45 years old) who received lower administered activities of 131I (£54 mCi) compared with those receiving higher administered activities. The older patients (‡45 years old), however, who received lower administered activities of 131I (£54 mCi) did have a lower disease-specific survival compared with those receiving higher administered activities. Disease was defined as ab- normal structural or functional imaging or a detectable serum Tg after TSH stimulation. The absolute disease-specific survival remained high even in the patients receiving lower administered activities of 131I, and there were no differences in overall survival in these older patients.
In 2009, the ATA guidelines task force recommended a fixed administered activity of between 100 and 200 mCi for adjuvant RAI treatment if residual microscopic disease is suspected) or if an aggressive histologic variant of DTC was present (25). Since that time, at least five retrospective, single institution studies have compared clinical outcomes following various adjuvant RAI fixed activities in ATA intermediate-risk and ATA higher risk patients, without distant metastases (723–726). In comparing rates of disease persistence or recurrence in 225 ATA intermediate-risk DTC patients treated with 30 to 50 mCi compared to ‡100 mCi of adjuvant RAI, Castagna et al. (723) reported no significant difference in rates of successful remnant ablation or in long- term disease persistence/recurrence between groups. How- ever, there were some statistically significant differences between the treatment groups that may have influenced these results, including higher numbers of men and individuals with lateral neck nodal disease and a longer follow-up period (which may increase the rate of detection) in the higher ad- ministered activity group of this study (723). In another study
including 176 DTC patients with a primary tumor size £2 cm in diameter and microscopic extrathyroidal extension, no significant differences were found in a comparison of rates of successful remnant ablation and long-term recurrences in patients treated with 30 mCi 131I compared with 149 mCi (724). In this study, no recurrences were noted in either group after a median follow-up of 7.2 years. Although the mean primary tumor size was higher in the group treated with higher activities compared with the lower activity group in this study ( p < 0.001), the difference in mean tumor di- ameter was only 2 mm, so it may be of questionable clinical significance (724). Kruijff et al. (725) reported the results of multiple secondary subgroup analyses on data from 341 pa- tients with T3 PTC, in which a postsurgical 131I administered activity of £75 mCi was compared to >75 mCi. In this study, the respective rates of disease recurrence, mortality, and stimulated Tg >2 ng/mL were not significantly different in the lower administered activity group (i.e., 7%, 3%, 72%),
compared to the higher activity group (12%, 1.7%, 64%)
(respective p-values of 0.55, 0.43, 0.40). Furthermore, in this study, a multivariate analysis using data from 1171 mixed- risk DTC patients without distant metastases suggested that there was no significant difference in risk of disease recur- rence with the use of >75 mCi of 131I postoperatively com- pared to £75 mCi (higher administered activity hazard ratio 1.57 ([95% CI 0.61–3.98], p = 0.341), after adjustment for age, sex, primary tumor size, presence of vascular invasion, multifocality, and lymph node positivity, with a mean follow- up period of 60 months) (725). In another study comparing rates of disease structural recurrence/persistence in 181 pa- tients with positive N1b lymph nodes, Sabra et al. (726) re- ported no statistically significant difference between the following approximate fixed administered activity cate- gories: 75–139 mCi with a median of 102 mCi (31%), 140–
169 mCi with a median of 150 mCi (32%), and 170–468 mCi with a median of 202 mCi (23%) ( p = 0.17). Consistent with this finding, no significant correlation between RAI activity and best clinical response was observed in this study. In re- spective secondary subgroup analyses, a dose response was apparent in individuals ‡45 years of age, but not younger individuals, and the authors cautioned about the use of fixed RAI activities exceeding 150 mCi because of concerns about potential toxicity in the context of renal impairment (726). In the three studies utilizing either thyroid hormone withdrawal or rhTSH for RAI treatment preparation (723,725,726), in- sufficient data were reported to make any meaningful inter- pretation on any relationship between administered activity in the context of preparation method. In one study, RAI ad- juvant treatment was performed postoperatively, presumably without initiation of thyroid hormone because rhTSH was not reported to be used (724). None of the aforementioned studies (723–726) reported on RAI toxicity or quality of life out- comes; furthermore, T4 disease was not included in these studies. Overall, there is little evidence to suggest that in- creasing administered activities of adjuvant RAI is neces- sarily associated with improvement of clinical outcomes for patients with ATA intermediate- and high-risk disease without evidence of persistent disease. There is an important unmet need for RCTs examining thyroid cancer–related outcomes, quality of life, and toxicities in patients with ATA intermediate or higher level thyroid cancer, in the absence of gross residual disease or distant metastases. | 553 |
[B41] Is a low-iodine diet necessary before remnant ablation? | 555 |
RECOMMENDATION 57
A low iodine diet (LID) for approximately 1–2 weeks should be considered for patients undergoing RAI remnant ablation or treatment.
(Weak recommendation, Low-quality evidence)
It is important for health care providers to inquire about a history of possible high-dose iodine exposure (e.g., IV con- trast, amiodarone, or others) in considering timing of scheduling RAI therapy or imaging. There are no studies examining whether the use of a LID in preparation for RAI remnant ablation or treatment impacts long-term disease- related recurrence or mortality rates. In a recent systematic review of observational studies in this area, the most com- monly studied LIDs allowed for £50 lg/d of iodine for 1–2 weeks and that the use of LIDs appeared to be associated with reduction in urinary iodine excretion as well as increase in 131I uptake, compared to no LID (727). There is conflicting evidence on the impact of a LID on the outcome of remnant ablation success (727), with the best available evidence lar- gely restricted to retrospective analyses, using historical controls (728,729). In a study including a total of 120 pa- tients, the use of a 4-day LID (with seafood restriction for 1 week) was associated with a higher rate of remnant ablation success (defined by absent neck activity and stimulated Tg
<2 ng/mL) compared to no LID (728). In a study including a
total of 94 patients, comparing a more stringent LID to a less stringent diet of restricted salt/vitamins/seafood, each for 10 to 14 days, there was no significant difference in rate of successful remnant ablation, using a visually negative 131I scan to define that outcome (729). The optimal stringency and duration of LID (if any) prior to therapeutic RAI is not known. In a RCT including 46 patients, the increase in 131I uptake and reduction in urinary iodine excretion was not significantly different between patients who followed a LID for 2 weeks compared to 3 weeks prior to RAI scanning (730), suggesting that there may be little reason to extend the LID past 2 weeks. However, a lack of association between urinary iodine excretion and rate of successful thyroid abla- tion has been reported in patients not specifically prescribed a LID (731); the absence of a specific LID comparison group in this study may limit the generalizability of the findings to situations in which a specific LID is prescribed. Such findings may suggest, however, that the routine measurement of uri- nary iodine excretion, outside of possibly a research setting or suspected iodine contamination, may not be necessary. Although LIDs may be cumbersome or unpalatable, serious side effects are relatively infrequent (727), with case re- ports of potentially life-threatening hyponatremia occur- ring largely in elderly patients who were subject to thyroid hormone withdrawal, often in the presence of metastatic disease, sometimes concurrently treated with thiazide di- uretics, and with a LID duration of longer than a week in the majority of cases (732). It is important to avoid restriction of noniodized salt during the LID, since this may be asso- ciated with hyponatremia, especially in patients undergo- ing thyroid hormone withdrawal. Some examples of LID descriptions for patients, may be found at the following
websites: ATA (www.thyroid.org/faq-low-iodine-diet/), ThyCa: Thyroid Cancer Survivors’ Association, Inc. (http:// thyca.org/rai.htm#diet), Light of Life Foundation (www
.checkyourneck.com/About-Thyroid-Cancer/Low-Iodine- Cookbook), and Thyroid Cancer Canada (www.thyroid cancercanada.org/userfiles/files/LID_English_Aug_2013_ final.pdf). | 556 |
[B42] Should a posttherapy scan be performed following remnant ablation or adjuvant therapy? | 557 |
RECOMMENDATION 58
A posttherapy WBS (with or without SPECT/CT) is rec- ommended after RAI remnant ablation or treatment, to inform disease staging and document the RAI avidity of any structural disease.
(Strong recommendation, Low-quality evidence) | 558 |
The literature on the utility of posttherapy RAI scans is largely based on single-center retrospective studies (643,733–736), many of which included a relatively large proportion of ATA intermediate- and high-risk DTC patients (643,733,734). In a comparison of the results of pretherapy 131I scans to posttherapy scans, the rate of newly discovered lesions on posttherapy scans was reported to be between 6% and 13%. In a study examining post–remnant ablation scans in 60 DTC patients, the disease stage was altered in 8.3% of individuals (735). In older literature, it had been reported that posttherapy scanning demonstrated new findings in 31% of 39 cases studied, but the detection of thyroid foci was in- cluded in that outcome, whereas almost a third of the patients (12 of 39) had a sizeable portion of their thyroid remaining following primary surgery (736). In the recent posttherapy scan literature, the 131I activities ranged from 30 to 300 mCi (733–735), and the timing of scans was between 2 and 12 days following therapeutic RAI (643,733–735,737,738), with some studies prescribing a preparatory LID (643,735,738) and others not prescribing such a diet (733,734). In one study, posttherapy scan images were compared on the third and seventh day following ablative or therapeutic RAI adminis- tration for mixed-risk DTC (following thyroid hormone withdrawal) (738). The authors of this study reported that the concordance of lesions detected on both scans was 80.5% (108 of 135 patients), with 7.5% of early scans providing more information than late scans, and 12% of late scans providing more information than early scans (738). A limi- tation in interpreting the posttherapy scan literature is that all of the lesions identified on posttherapy scans were not always confirmed to represent structural disease (i.e., using cross- sectional imaging, histopathology, or long-term outcome data), and readers of posttherapy scans were generally not specifically blinded to the results of other investigations, such as pretherapy RAI scans.
The potential utility of the combination of RAI post- therapy scanning in conjunction with SPECT/CT has been examined in multiple prospective (737,739,740) and retro- spective studies (741–743). The majority of these studies (737,739–742) have independently confirmed the presence of disease by means such as alternative imaging studies, histopathology, or clinical follow-up. In a single-center | 559 |
study of 170 patients with mixed risk level well- differentiated thyroid cancer, the combination RAI post- therapy scanning and neck/thorax SPECT/CT, was esti- mated to have a sensitivity of 78% [95% CI 60%–90%], with a specificity of 100% (negative or indeterminate scans were grouped as negative), for the outcome of persistent/ recurrent disease (median study follow-up period of 29 months) (737). Furthermore, in a multivariate analysis re- ported in this study, posttherapy RAI scanning with SPECT/ CT significantly independently predicted an increased risk of future disease persistence/recurrence (HR 65.2 [95% CI 26.0–163.4) (737). In a single-center study of 81 DTC pa- tients who underwent 131I posttherapy scanning in con- junction with SPECT-spiral CT of the neck, 1.6% of the 61 patients with negative cervical scintigraphy–SPECT/CT had evidence of abnormal cervical scintigraphy 5 months later, whereas 3 of the 20 patients (15%) with positive or in- determinate cervical posttherapy scintigraphy–SPECT/CT, had abnormal cervical scintigraphy 5 months later (741). The incremental value of SPECT/CT in impacting thera- peutic planning appears to be greatest in studies in which its use was reserved for situations of posttherapy scan diagnostic uncertainty (impacted therapy in 24.4% [8 of 33] of cases, all of which went on to surgery) (739), or when disease was advanced and WBS was inconclusive (impacted management in 35% [8 of 23] of such patients in another study) (740). The routine addition of neck/chest SPECT/CT to all posttherapy scans was estimated to alter postsurgical ATA recurrence risk estimate in 6.4% (7 of 109) of patients (743), impact therapeutic planning in about 2% of cases (742), and reduce the need for addi- tional cross-sectional imaging in 20% of cases (29 of 148). In one study examining the use of routine cervical/ thoracic SPECT/CT in conjunction with posttherapy scanning, the SPECT/CT portion identified non–iodine avid lesions in 22% of patients (32 of 148), although the underlying pathologic diagnosis or long-term clinical significance of these lesions was not clearly reported (i.e., ‘‘tiny’’ lung nodules in 19 patients, mediastinal lymph nodes <5 mm in 10 patients, and osteolytic bone metas- tases in three patients) (743). In situations in which SPECT/CT may not be feasible to perform in conjunction with a posttherapy RAI scan, clinical judgment needs to prevail on the utility of alternative cross-sectional imag- ing studies, considering factors such as clinical-pathologic stage, the completeness of surgery, inappropriate thyr- oglobulinemia, and, if performed, the posttherapy RAI scan result. | 561 |
[B43] Early management of DTC after initial therapy | 562 |
[B44] What is the appropriate degree of initial TSH suppression? | 563 |
RECOMMENDATION 59
For high-risk thyroid cancer patients, initial TSH suppression to below 0.1 mU/L is recommended.
(Strong recommendation, Moderate-quality evidence)
For intermediate-risk thyroid cancer patients, initial TSH suppression to 0.1– 0.5 mU/L is recommended.
(Weak recommendation, Low-quality evidence)
For low-risk patients who have undergone remnant ab- lation and have undetectable serum Tg levels, TSH may be maintained at the lower end of the reference range (0.5– 2 mU/L) while continuing surveillance for recurrence. Si- milar recommendations hold for low-risk patients who have not undergone remnant ablation and have undetectable serum Tg levels.
(Weak recommendation, Low-quality evidence)
For low-risk patients who have undergone remnant ablation and have low-level serum Tg levels, TSH may be maintained at or slightly below the lower limit of normal (0.1–0.5 mU/L) while surveillance for recurrence is con- tinued. Similar recommendations hold for low-risk pa- tients who have not undergone remnant ablation, although serum Tg levels may be measurably higher and continued surveillance for recurrence applies.
(Weak recommendation, Low-quality evidence)
For low-risk patients who have undergone lobectomy, TSH may be maintained in the mid to lower reference range (0.5–2 mU/L) while surveillance for recurrence is continued. Thyroid hormone therapy may not be needed if patients can maintain their serum TSH in this target range.
(Weak recommendation, Low-quality evidence) | 564 |
DTC expresses the TSH receptor on the cell membrane and responds to TSH stimulation by increasing the expression of several thyroid specific proteins (Tg, sodium-iodide symporter) and by increasing the rates of cell growth (744). Suppression of TSH, using supraphysiologic doses of LT4, is used commonly to treat patients with thyroid cancer in an effort to decrease the risk of recurrence (275,671,745–747). A meta-analysis supported the efficacy of TSH suppression therapy in preventing major adverse clinical events (RR = 0.73 [CI = 0.60–0.88], p < 0.05) (745). A large RCT from Japan (748) showed that disease-free survival was equivalent in patients with normal TSH (0.4– 5 mU/L) compared with those on LT4 suppression therapy (TSH
<0.01 mU/L). Extent of residual disease is uncertain in these patients in that most did not undergo total thyroidectomy or RAI ablation and Tg levels were not monitored or reported, making direct comparisons to a North American approach difficult.
Retrospective and prospective studies have demonstrated that TSH suppression to below 0.1 mU/L may improve out- comes in high-risk thyroid cancer patients (275,749), though no such evidence of benefit has been documented in low-risk pa- tients. Higher degrees of suppression to <0.03 mU/L may offer no additional benefit (746). A prospective, nonrandomized co- hort study (671) of 2936 patients found that overall survival improved significantly when the TSH was suppressed to un- detectable levels in patients with NTCTCSG stage III or IV disease and suppressed to the subnormal to undetectable range in patients with NTCTCSG stage II disease; however, in the latter group there was no incremental benefit from suppressing TSH to undetectable levels. Patients in the NTCTCSG stage II classification are somewhat different from AJCC/UICC stage II patients. Suppression of TSH was not beneficial in patients with NTCTCSG stage I disease. In another study, there was a positive association between serum TSH levels and the risk for recurrent | 565 |
disease and cancer-related mortality (750). Adverse effects of TSH suppression may include the known consequences of subclinical thyrotoxicosis, including exacerbation of angina in patients with ischemic heart disease, increased risk for atrial fibrillation in older patients (751), and increased risk of osteo- porosis in postmenopausal women (748,752–754). Therefore, optimal TSH goals for individual patients must balance the potential benefit of TSH suppression with the possible harm from subclinical thyrotoxicosis especially in patients with medical conditions that can be exacerbated with aggressive TSH suppression.
There is little evidence to guide TSH targets or the use of thyroid hormone in ATA low-risk patients who have undergone lobectomy. Most of the studies evaluating lobectomy for these patients do not discuss TSH targets or the use of thyroid hor- mone therapy or note that these data were unavailable in the databases studied (318,323–327). Vaisman et al. (328) noted that ‘‘levothyroxine was often not given after lobectomy if the patient maintained thyroid function tests within the reference range,’’ while Matsuzu et al. (322) noted that ‘‘TSH suppression therapy was performed in most of the cases postoperatively, but the patients’ TSH levels were not analyzed in this study.’’ A recent study by Ebina et al. (755) retrospectively analyzed low- risk patients who had undergone lobectomy and had not re- ceived thyroid hormone therapy. After a mean follow-up of 8.3 years, only 13% of the 674 patients undergoing lobectomy be- came overtly hypothyroid. The 10-year cause-specific and disease-specific survivals were not different between the pa- tients who underwent thyroidectomy versus a lesser operation, although it was common for the patients undergoing lobectomy to also receive an ipsilateral central neck dissection. More re- search is needed in this area to help guide management of those patients undergoing lobectomy for low-risk DTC. | 567 |
[B45] Is there a role for adjunctive external beam radiation therapy or chemotherapy?
[B46] External beam radiation therapy | 568 |
RECOMMENDATION 60
There is no role for routine adjuvant EBRT to the neck in patients with DTC after initial complete surgical removal of the tumor.
(Strong recommendation, Low-quality evidence)
The application of adjuvant neck/thyroid bed/loco-regional radiation therapy in DTC patients remains controversial. In particular, the use of radiation therapy within the context of initial/primary surgery/thyroidectomy has no meaningful liter- ature support. There are reports of responses among patients with locally advanced disease (756,757) and improved relapse- free and cause-specific survival in patients over age 60 with extrathyroidal extension but no gross residual disease (758), and selective use can be considered in these patients. It remains unknown whether external beam radiation therapy might re- duce the risk for recurrence in the neck following adequate primary surgery and/or RAI treatment in patients with ag- gressive histologic subtypes (759). However, in the context of certain individual patients undergoing multiple and frequent serial neck re-operations for palliation of loco-regionally re- current disease, adjuvant EBRT may be considered. In such contexts, the risks of anticipated additional serial re-operations
versus the risks of EBRT must be carefully weighed to arrive at optimal decisions for individual patients. The approach to pa- tients with gross incomplete surgical resection of disease is addressed in another section (Recommendation 72). | 569 |
[B47] Systemic adjuvant therapy | 570 |
RECOMMENDATION 61
There is no role for routine systemic adjuvant therapy in patients with DTC (beyond RAI and/or TSH suppressive therapy using LT4).
(Strong recommendation, Low-quality evidence) | 571 |
There are no clinical trial data to indicate that any adjuvant therapy beyond RAI and/or TSH suppressive therapy using LT4 has a net beneficial role in DTC patients. Furthermore, as the prognosis of DTC patients in complete remission and without any indication of active systemic disease is very good—and as toxicities, and even the risk of death, from use of kinase inhibitor therapies are appreciable—toxicities/risks have strong potential to exceed expected therapeutic benefit in the adjuvant context in most patients with DTC.
Whether populations of DTC patients might be identifiable who have sufficiently great future risks from recurrent dis- ease to justify the corresponding risks attendant to the ap- plication of adjuvant systemic therapy (beyond RAI and/or TSH suppressive therapy using LT4) remains uncertain. Doxorubicin may act as a radiation sensitizer in some tumors of thyroid origin (760) and could be considered for patients with locally advanced disease undergoing external beam ra- diation therapy. It is unproven whether patients with rising Tg in the setting of no identifiable progression of anatomical disease have sufficiently high future risks from disease to justify the application of adjuvant systemic therapy beyond RAI and/or TSH suppressive therapy using LT4. | 572 |
[C1] DTC: LONG-TERM MANAGEMENT AND ADVANCED CANCER MANAGEMENT GUIDELINES
[C2] What are the appropriate features of long-term management?
Accurate surveillance for possible recurrence in patients thought to be free of disease is a major goal of long-term follow-up. Tests with high specificity allow identification of patients unlikely to experience disease recurrence, so that less aggressive management strategies can be used that may be more cost effective and safe. Similarly, patients with a higher risk of recurrence are monitored more aggressively because it is believed that early detection of recurrent disease offers the best opportunity for effective treatment. A large study (761) found that the residual life span in disease-free patients treated with total or near-total thyroidectomy, 131I for remnant abla- tion, and in some cases high-dose 131I for residual disease was similar to that in the general Dutch population. In contrast, the life expectancy for patients with persistent disease was re- duced to 60% of that in the general population but varied widely depending upon tumor features. Age was not a factor in disease-specific mortality in a comparison of patients with age-matched individuals in the Dutch population. Treatment thus appears safe and does not shorten life expectancy. Al- though an increased incidence of second tumors in thyroid | 573 |
cancer patients has been recognized after the administration of high cumulative activities of 131I (762,763), this elevated risk was not found to be associated with the use of 131I in another study (764). RAI therapy in low-risk patients did not affect median overall survival in one study (765), but did increase second primary malignancies in another study (766). This risk of second primary malignancies after RAI therapy is dis- cussed in more detail in section C33. Patients with persistent or recurrent disease are offered treatment to cure or to delay future morbidity or mortality. In the absence of such options, therapies to palliate by substantially reducing tumor burden or preventing tumor growth are utilized, with special attention paid to tumors threatening critical structures.
A second goal of long-term follow-up is to monitor thy- roxine suppression or replacement therapy to avoid under- replacement or overly aggressive therapy (767).
[C3] What are the criteria for absence of persistent tumor (excellent response)?
In patients who have undergone total or near-total thy- roidectomy and RAI treatment (remnant ablation, adjuvant therapy or therapy), disease-free status comprises all of the following (summarized in Table 13):
No clinical evidence of tumor
No imaging evidence of tumor by RAI imaging (no uptake outside the thyroid bed on the initial posttreat- ment WBS if performed, or if uptake outside the thyroid bed had been present, no imaging evidence of tumor on a recent diagnostic or posttherapy WBS) and/or neck US
Low serum Tg levels during TSH suppression (Tg
<0.2 ng/mL) or after stimulation (Tg <1 ng/mL) in the absence of interfering antibodies
[C4] What are the appropriate methods for following patients after initial therapy? | 575 |
[C5] What is the role of serum Tg measurement in the follow-up of DTC? | 576 |
RECOMMENDATION 62
Serum Tg should be measured by an assay that is calibrated against the CRM457 standard. Thyroglobulin antibodies should be quantitatively assessed with every measurement of serum Tg. Ideally, serum Tg and anti-Tg antibodies should be assessed longitudinally in the same laboratory and using the same assay for a given patient.
(Strong recommendation, High-quality evidence)
During initial follow-up, serum Tg on thyroxine therapy should be measured every 6–12 months. More frequent Tg measurements may be appropriate for ATA high-risk patients.
(Strong recommendation, Moderate-quality evidence)
In ATA low- and intermediate-risk patients that achieve an excellent response to therapy, the utility of subsequent Tg testing is not established. The time interval between serum Tg measurements can be lengthened to at least 12–24 months.
(Weak recommendation, Low-quality evidence)
Serum TSH should be measured at least every 12 months in all patients on thyroid hormone therapy.
(Strong recommendation, Low-quality evidence)
ATA high-risk patients (regardless of response to therapy) and all patients with biochemical incomplete, structural incomplete, or indeterminate response should continue to have Tg measured at least every 6–12 months for several years.
(Weak recommendation, Low-quality evidence) | 577 |
RECOMMENDATION 63
In ATA low-risk and intermediate-risk patients who have had remnant ablation or adjuvant therapy and nega- tive cervical US, serum Tg should be measured at 6–18 months on thyroxine therapy with a sensitive Tg assay (<0.2 ng/mL) or after TSH stimulation to verify absence of disease (excellent response).
(Strong recommendation, Moderate-quality evidence)
Repeat TSH-stimulated Tg testing is not recommended for low- and intermediate-risk patients with an excellent response to therapy.
(Weak recommendation, Low-quality evidence)
Subsequent TSH-stimulated Tg testing may be con- sidered in patients with an indeterminate, biochemical incomplete, or structural incomplete response following either additional therapies or a spontaneous decline in Tg values on thyroid hormone therapy over time in order to reassess response to therapy.
(Weak recommendation, Low-quality evidence) | 578 |
Subsequent stimulated testing is rarely needed for those with NED, because there are rarely benefits seen in this pa- tient population from repeated TSH-stimulated Tg testing (590,594,597,768). The use of sensitive methods for serum Tg may obviate the need for rhTSH stimulation in low-risk patients with a Tg on LT4 treatment below 0.1–0.2 ng/mL (393,587,595,601,606,769). | 579 |
[C6] Serum Tg measurement and clinical utility
Measurement of serum Tg levels is an important modality to monitor patients for residual or recurrent disease. Most laboratories currently use immunometric assays to measure serum Tg, and it is important that these assays are calibrated against the CRM-457 international standard. Despite im- provements in standardization of Tg assays, there is still a two-fold difference between some assays (316,770), leading to the recommendation that measurements in individual pa- tients be performed with the same assay over time. Im- munometric assays are prone to interference from anti-Tg autoantibodies, which commonly cause falsely low serum Tg measurements. Moreover, variability in Tg autoantibody as- says may result in falsely negative antibody levels associated with a misleadingly undetectable serum Tg due to the anti- bodies that are present but not detected (771). Assays for anti- Tg autoantibodies suffer from a similar variance and lack of concordance as do Tg assays (608,772), and both Tg and Tg autoantibody assays may be affected by heterophilic anti- bodies (773,774). The presence of Tg autoantibodies should be suspected when the surgical pathology indicates the pres- ence of background Hashimoto thyroiditis (775). While there | 580 |
is no method that reliably eliminates Tg antibody interfer- ence, radioimmunoassays for Tg may be less prone to anti- body interference, which can occasionally result in falsely elevated Tg levels (776–778). However, radioimmunoassays for Tg are not as widely available, may be less sensitive than immunometric assays in detecting small amounts of residual tumor, and their role in the clinical care of patients is un- certain. In the absence of antibody interference, serum Tg has a high degree of sensitivity and specificity to detect thyroid cancer, especially after total thyroidectomy and remnant ablation. In patients with low risk for recurrence, serum Tg measurement at the time of remnant ablation/adjuvant ther- apy may be useful for prediction of subsequent disease-free status (605).
Most data come from studies using methods with a func- tional sensitivity of 1 ng/mL. Functional sensitivity of many contemporary assays is £0.1 ng/mL, which may lead to greater reliance of Tg on thyroid hormone therapy instead of performing Tg determination following TSH stimulation. Because TSH stimulation generally increases basal serum Tg by 5- to 10-fold, significant serum Tg levels (>1–2 ng/mL) found after TSH stimulation when using an assay with a functional sensitivity of 0.5–1 ng/mL may already be pre- dicted in patients on LT4 treatment without TSH stimulation by a highly sensitive Tg assay when Tg levels are above
0.2 ng/mL.
The highest degrees of sensitivity for serum Tg are noted following thyroid hormone withdrawal or stimulation us- ing rhTSH (779). Serum Tg measurements obtained during thyroid hormone suppression of TSH and less commonly following TSH stimulation may fail to identify patients with relatively small amounts of residual tumor (583,649, 780,781). These minimal amounts of residual disease are often located in the neck, and performing neck US in these patients offers the best opportunity to recognize or exclude neoplastic disease even when serum Tg is undetectable (297,782,783). Conversely, even TSH-stimulated Tg mea- surement may fail to identify patients with clinically signif- icant tumor because of anti-Tg antibodies or less commonly because of defective or absent production and secretion of immunoreactive Tg by tumor cells (649,780). Tg levels should be interpreted in light of the pretest probability of clinically significant residual tumor. An aggressive or poorly differentiated tumor may be present despite low basal or stimulated Tg; in contrast, a minimally elevated stimulated Tg may occur in patients at low risk for clinically significant morbidity (784). Nevertheless, a single rhTSH-stimulated serum Tg <0.5–1.0 ng/mL in the absence of anti-Tg antibody has an approximately 98%–99.5% likelihood of identifying patients completely free of tumor on follow-up (590,591,593,597,768). Repeating rhTSH-stimulated Tg measurements may not be necessary in most cases when surveillance includes an undetectable basal serum Tg and negative ultrasonography (604,617). However, 0.5%–3% of patients may manifest clinical or biochemical recurrence in spite of an initial rhTSH-stimulated Tg of <0.5 ng/mL (592). Initial follow-up for low-risk patients (about 85% of postoperative patients) who have undergone total or near- total thyroidectomy and 131I remnant ablation should be based mainly on TSH-suppressed Tg and cervical US, fol- lowed by TSH-stimulated serum Tg measurements if the TSH-suppressed Tg testing is undetectable (583,785). How-
ever, a Tg assay with a functional sensitivity of 0.1–0.2 ng/ mL may reduce the need to perform TSH-stimulated Tg measurements during the initial and long-term follow-up of some patients. In one study using such an assay, a T4- suppressed serum Tg <0.1 ng/mL was only rarely (2%) as- sociated with an rhTSH-stimulated Tg >2 ng/mL; however, 42% of the patients had baseline rhTSH-stimulated Tg ele- vation >0.1 ng/mL, but only one patient was found to have residual tumor (606). In another study using the same assay (787), a TSH-suppressed serum Tg level was >0.1 ng/mL in 14% of patients, but the false-positive rate was 35% using an rhTSH-stimulated Tg cutoff of >2 ng/mL, raising the possi- bility of unnecessary testing and treatment. In low-risk pa- tients not undergoing ablation, an ultrasensitive Tg was
<1 ng/mL in 91% and <2 ng/mL in 96% of patients at 9 months after thyroidectomy (644). In a second-generation assay, a cutoff of 0.15 ng/mL was shown to have a NPV of 98.6% and 91% specificity for residual disease or poten- tial recurrence (587). The only prospective study also docu- mented increased sensitivity of detection of disease at the expense of reduced specificity (770), and receiver operating curves have shown that a Tg level on thyroid hormone therapy around 0.2–0.3 ng/mL portends the best sensitivity and specificity for detecting persistent disease. With the use of these sensitive Tg assays, it was concluded that an annual serum Tg on LT4 treatment with periodic neck US is adequate for detection of recurrence without need for rhTSH stimu- lation testing in those patients with a serum Tg <0.2–0.3 ng/ mL on thyroid hormone therapy (606). In patients at low to intermediate risk of recurrence, the utility of an undetectable postoperative nonstimulated Tg level is uncertain and may depend upon the functional sensitivity of the Tg assay, with some studies (632,646) observing RAI-avid metastatic foci (usually in neck lymph nodes) in 8.5%–12% of such patients, while another study (630) noted negative scans in 63 of 63 patients when the baseline Tg was <0.2 ng/mL. The different results likely relate to both the degree of intermediate versus higher risk patients in the respective cohorts, the amount of residual thyroid tissue, the elapsed time since surgery, the cutoff for functional sensitivity of the Tg assays, as well as the sensitivity of the post-RAI imaging techniques.
Approximately 20% of patients who are clinically free of disease with serum Tg levels <1 ng/mL during thyroid hor- mone suppression of TSH (785) will have a serum Tg level
>2 ng/mL after rhTSH or thyroid hormone withdrawal at 12 months after initial therapy with surgery and RAI. In this patient population, one-third will have identification of per- sistent or recurrent disease and of increasing Tg levels, and the other two-thirds will remain free of clinical disease and will have stable or decreasing stimulated serum Tg lev- els over time (618,624). However, there may be a low like- lihood of a rise in serum Tg to >2 ng/mL when the basal serum Tg is <0.1 ng/mL if a second-generation Tg im- munochemiluminometric assay (ICMA) with a functional sensitivity of 0.05 ng/mL is employed (788). There is good evidence that a Tg cutoff level above 2 ng/mL following rhTSH stimulation is highly sensitive in identifying patients with persistent tumor (785,789–794). However, the results of serum Tg measurements made on the same serum specimen differ among assay methods (316). Therefore, the Tg cutoff may differ significantly among medical centers and labora- tories. Further, the clinical significance of minimally | 582 |
detectable Tg levels is unclear, especially if only detected following TSH stimulation. However, receiver operating curves have shown that a Tg level on thyroid hormone around 0.2–0.3 ng/mL portends the best sensitivity and specificity for detecting persistent disease. In these patients, the trend in se- rum Tg over time will typically identify patients with clinically significant residual disease. A rising unstimulated or stimu- lated serum Tg indicates disease that is likely to become clinically apparent (618,795). Thyroglobulin doubling time may have utility as a predictor of recurrence, analogous to the use of calcitonin doubling time for MTC (622,796). | 584 |
[C7] Anti-Tg antibodies
The presence of anti-Tg antibodies, which occur in ap- proximately 25% of thyroid cancer patients (797) and 10% of the general population (798), will falsely lower serum Tg determinations in immunometric assays (799). The use of recovery assays in this setting to detect significant interfer- ence is controversial (799,800). Serum anti-Tg antibody should be measured in conjunction with serum Tg assay by an immunometric method. Although assay standardization against the International Reference Preparation 65/93 has been recommended (608), wide-ranging variability in assay results and analytical sensitivity of the assay remains (801,802). Use of recovery methods for anti-Tg antibody may suffer variable interferences (608). Anti-Tg antibody may rise transiently postoperatively as an apparent immune re- action to the surgery itself and may also rise after ablation therapy (611). Anti-Tg antibodies should be measured in a different assay if the routine anti-Tg antibody assay is neg- ative in a patient with surgically proven Hashimoto thy- roiditis (775). It may be useful to measure anti-Tg antibodies shortly after thyroidectomy and prior to ablation because high levels may herald the likelihood of recurrence in patients without Hashimoto thyroiditis (801). Similarly, recurrent or progressive disease is suggested in those patients initially positive for anti-Tg antibodies who then become negative but subsequently have rising levels of anti-Tg antibodies. Falling levels of anti-Tg antibodies may indicate successful therapy (614,801). Thus, serial serum anti-Tg antibody quantification using the same methodology may serve as an imprecise surrogate marker of residual normal thyroid tissue, Ha- shimoto thyroiditis, or tumor (608,609,615). Following total thyroidectomy and RAI remnant ablation, anti-Tg antibodies usually disappear over a median of about 3 years in patients without evidence of persistent disease (611,615,616). Several studies demonstrate an increased risk of recurrence/persistent disease associated either with a new appearance of anti-Tg antibodies or rising titers (609–614). From a clinical per- spective, anti-Tg antibody levels that are declining over time are considered a good prognostic sign, while rising antibody levels, in the absence of an acute injury to the thyroid (release of antigen by surgery or RAI treatment), significantly in- creases the risk that the patient will subsequently be diag- nosed with persistent or recurrent thyroid cancer.
The recent development of liquid chromatography-tandem mass spectrometry assay of Tg holds promise for accurate Tg measurement in the presence of Tg autoantibodies (803– 805), but further studies will be required to validate the assays in terms of functional sensitivity, correlations with immu- noassay results, and patient outcomes, reflecting either ex- cellent response or persistent disease (806).
[C8] What is the role of serum Tg measurement in patients who have not undergone RAI remnant ablation? | 585 |
RECOMMENDATION 64
Periodic serum Tg measurements on thyroid hormone therapy should be considered during follow-up of patients with DTC who have undergone less than total thyroidec- tomy and in patients who have had a total thyroidectomy but not RAI ablation. While specific cutoff levels of Tg that optimally distinguish normal residual thyroid tissue from persistent thyroid cancer are unknown, rising Tg values over time are suspicious for growing thyroid tissue or cancer.
(Strong recommendation, Low-quality evidence) | 586 |
In low- and intermediate-risk patients who underwent a total thyroidectomy without remnant ablation or adjuvant therapy, the same strategy of follow-up is used, based on serum Tg determination on LT4 treatment and on neck US at 9–12 months. In most of these patients, neck US does not reveal any suspicious findings and the serum Tg is <1 ng/mL on LT4 treatment, is low (<2 ng/mL) and will remain at a low level, or will decrease without any additional therapy over time (545). There is no need for rhTSH stimulation because Tg will increase to a value above 1 ng/mL in 50% of the cases, even in individuals without residual cancer, with the magnitude of increase being related to the size of normal thyroid remnants (783). These patients are followed on an annual basis with serum TSH and Tg determination.
In the few patients with a serum Tg that remains elevated over time, especially for those with a rising Tg, remnant ab- lation or adjuvant therapy with 131I may be considered with a posttherapy WBS if neck US is negative. There is no evidence in these low-risk patients that a delayed treatment over the postoperative treatment may adversely affect the outcome.
A cohort of 80 consecutive patients with very low-risk PTMC who had undergone near-total thyroidectomy without postoperative RAI treatment were studied over 5 years (783). The rhTSH-stimulated serum Tg levels were £1 ng/mL in 45 patients (56%) and >1 ng/mL in 35 (44%) patients in whom rhTSH-stimulated Tg levels were as high as 25 ng/mL. The diagnostic WBS revealed uptake in the thyroid bed but showed no pathological uptake in any patient, and thyroid bed uptake correlated with the rhTSH-stimulated serum Tg levels ( p < 0.0001). Neck ultrasonography identified lymph node metastases in both Tg-positive and Tg-negative patients. The authors concluded that for follow-up of this group of patients:
diagnostic WBS was ineffective at detecting metastases;
neck ultrasonography as the main surveillance tool was highly sensitive in detecting lymph node metastases; and (iii) detectable rhTSH-stimulated serum Tg levels mainly de- pended upon the size of thyroid remnants, which suggests that serum Tg determination should be performed primarily on thyroid hormone therapy when using a sensitive Tg assay (functional sensitivity £0.2 ng/mL). In a series of 290 low-risk patients who had not undergone remnant ablation (545), se- rum Tg levels on LT4 became undetectable (<1 ng/mL) within 5–7 years in 95% of the cohort and was <0.1 ng/mL in 80% of a subset of these patients, using a sensitive assay to confirm the utility of Tg measurements on thyroid hormone treatment | 587 |
for routine follow-up. The frequency of follow-up is uncertain in patients who have not received RAI ablation and have sufficient residual thyroid tissue to produce measurable levels of serum Tg, the magnitude of which will depend upon the mass of residual tissue and the degree of TSH suppression. It appears reasonable to consider periodic measurements of Tg as surveillance for a trend in rising values. | 589 |
[C9] What is the role of US and other imaging techniques (RAI SPECT/CT, CT, MRI, PET-CT)
during follow-up?
[C10] Cervical ultrasonography | 590 |
RECOMMENDATION 65
Following surgery, cervical US to evaluate the thyroid bed and central and lateral cervical nodal compartments should be performed at 6–12 months and then periodically, depending on the patient’s risk for recurrent disease and Tg status.
(Strong recommendation, Moderate-quality evidence)
If a positive result would change management, ultra- sonographically suspicious lymph nodes ‡8–10 mm (see Recommendation 71) in the smallest diameter should be biopsied for cytology with Tg measurement in the needle washout fluid.
(Strong recommendation, Low-quality evidence)
Suspicious lymph nodes less than 8–10 mm in smallest diameter may be followed without biopsy with consider- ation for FNA or intervention if there is growth or if the node threatens vital structures.
(Weak recommendation, Low-quality evidence)
Low-risk patients who have had remnant ablation, negative cervical US, and a low serum Tg on thyroid hormone therapy in a sensitive assay (<0.2 ng/mL) or after TSH stimulation (Tg <1 ng/mL) can be followed primarily with clinical examination and Tg measurements on thyroid hormone replacement.
(Weak recommendation, Low-quality evidence)
Cervical ultrasonography is performed with a high- frequency probe (‡10 MHz) and is highly sensitive in the detection of cervical metastases in patients with DTC (290,783,807). These studies primarily evaluate patients with PTC, and the utility of neck US for monitoring patients with low-risk FTC is not well-established. Neck US should in- terrogate all lymph node compartments and the thyroid bed. Frequently, US does not distinguish thyroid bed recurrences from benign nodules (629,808). When an abnormality is found during the year after surgery in patients without any other suspicious findings, including low serum Tg on thyroid hormone therapy, follow-up may be performed with neck US.
A correlation performed between US findings and pathology at surgery (292) has shown for lymph nodes >7 mm in the smallest diameter that a cystic appearance or hyperechoic punctuations in a context of thyroid cancer should be considered as malignant; lymph nodes with a hyperechoic hilum are re- assuring; the type of vascularization (central: reassuring; pe- ripheral: concerning) has a high sensitivity/specificity; a round
shape, a hypoechoic appearance or the loss of the hyperechoic hilum by themselves does not justify a FNA biopsy (FNAB).
Interpretation of neck US should take into account all other clinical and biological data. In fact, the risk of recurrence is closely related to the initial lymph node status: most lymph node recurrences occur in already involved compartments; the risk increases with a higher number of N1 and a higher number of N1 with extracapsular extension (338) and with macroscopic rather than microscopic lymph node metastases (335,809).
In low- and intermediate-risk patients, the risk of lymph node recurrence is low (<2%) in patients with undetectable serum Tg and is much higher in those with detectable/elevated serum Tg. In fact, 1 g of neoplastic thyroid tissue will increase the serum Tg by *1 ng/mL during LT4 treatment and by approximately 2–10 ng/mL following TSH stimulation (788,800). Neck US can detect N1 as small as 2–3 mm in diameter (in patients in whom serum Tg may be low or undetectable), but benefits of their early discovery (<8–10 mm) is not demonstrated.
FNAB for cytology and Tg measurement in the aspirate fluid is performed for suspicious lymph nodes ‡8–10 mm in their smallest diameter. US guidance may improve the results of
FNAB, in particular for small lymph nodes and those located deep in the neck. However, FNAB cytology misses thyroid cancer in a significant proportion (up to 20%) of patients. The combination of cytology and serum Tg determination in the aspirate fluid increases sensitivity (303,810,811). In cases of lymph node metastases, the Tg concentration in the aspirate fluid is often elevated (>10 ng/mL), and concentrations above this level are highly suspicious (296,298,301). A Tg concentration in the aspirate fluid between 1 and 10 ng/mL is moderately suspi- cious for malignancy, and comparison of the Tg measurement in the aspirate fluid and the serum should be considered in these patients. Also, up to half of the FNAB performed for suspicious US findings are benign, demonstrating that selection of patients for FNAB needs to be improved (296,298,812). Nonsuspicious and small nodes (<8–10 mm in the smallest diameter) can be monitored with neck US. | 591 |
[C11] Diagnostic whole-body RAI scans | 592 |
RECOMMENDATION 66
After the first posttreatment WBS performed following RAI remnant ablation or adjuvant therapy, low-risk and intermediate-risk patients (lower risk features) with an undetectable Tg on thyroid hormone with negative anti- Tg antibodies and a negative US (excellent response to ther- apy) do not require routine diagnostic WBS during follow-up.
(Strong recommendation, Moderate-quality evidence) | 593 |
RECOMMENDATION 67
(A) Diagnostic WBS, either following thyroid hormone withdrawal or rhTSH, 6–12 months after adjuvant RAI therapy can be useful in the follow-up of patients with high or intermediate risk (higher risk features) of persistent disease (see risk stratification system, section [B19]) and should be done with 123I or low activity 131I.
(Strong recommendation, Low-quality evidence)
B) SPECT/CT RAI imaging is preferred over planar im- aging in patients with uptake on planar imaging to better | 594 |
anatomically localize the RAI uptake and distinguish be- tween likely tumors and nonspecific uptake
(Weak recommendation, Moderate-quality evidence) | 596 |
Following RAI ablation or adjuvant therapy, when the posttherapy scan does not reveal uptake outside the thyroid bed, subsequent diagnostic WBSs have low sensitivity and are usu- ally not necessary in low-risk patients who are clinically free of residual tumor and have an undetectable serum Tg level on thyroid hormone and negative cervical US (583,785,813,814). A diagnostic WBS may be indicated in three primary clinical settings: (i) patients with abnormal uptake outside the thyroid bed on posttherapy WBS, (ii) patients with poorly informative postablation WBS because of large thyroid remnants with high uptake of 131I (>2% of the administered activity at the time of WBS) that may hamper the visuali- zation of lower uptake in neck lymph nodes, and (iii) patients with Tg antibodies, at risk of false-negative Tg measurement, even when neck US does not show any suspicious findings. Iodine 123 is preferred over 131I in these rare indications for diagnostic WBS, because it delivers lower radiation doses to
the body and provides better quality images.
Iodine 131 or 123I whole-body scintigraphy includes planar images or images using a dual-head SPECT gamma camera of the whole body and spot images of the neck, mediastinum, and on any abnormal focus of RAI uptake. It may be performed after the administration of either a diagnostic (usually 2–5 mCi) or a therapeutic activity (30–150 mCi) of RAI. Because of the lack of anatomical landmarks on planar images, it is often difficult to differentiate uptake in normal thyroid remnants from lymph node metastases (especially when thyroid rem- nants are large), uptake in lung metastases from rib lesions, or accumulation of RAI in intestine or bladder from a pelvic bone lesion. Hybrid cameras combine a dual-head SPECT gamma camera with a CT scanner in one gantry. This allows direct superimposition of functional and anatomical imaging. The radiation dose delivered to the patient by the low-dose CT scan is 2–5 mSv, a dose that is much lower than the dose delivered by the administration of 100 mCi of 131I (around 50 mSv).
Whole-body SPECT/CT performed after the administra- tion of a diagnostic or a therapeutic activity (30 mCi or more) of RAI is associated with (i) an increased number of patients with a diagnosis of metastatic lymph node and (ii) a de- creased frequency of equivocal findings (739,743,815–818). Furthermore, the CT portion of the SPECT/CT provides ad- ditional information on non–iodine-avid lesions; SPECT-CT changed tumor risk classifications in 25% of the patients according to the International Union Against Cancer classi- fication and in 6% of the patients according to the ATA risk of recurrence classification; the SPECT-CT changed treatment management in 24 to 35% of patients, by decreasing the rate of equivocal findings. Finally, SPECT-CT avoids the need for further cross-sectional imaging studies such as contrast CT or MRI. Neoplastic lesions with low uptake of RAI or without any uptake may be a cause of false negative SPECT-CT.
Iodine 124 emits positrons, allowing PET/CT imaging in DTC patients. It is used as a dosimetric and also as a diagnostic tool to localize disease. In fact, for each neoplastic focus 124I PET/CT permits an accurate measurement of its volume as well as the uptake and half-life of 124I in it, therefore allowing a reliable individual dosimetric assessment for each neoplastic focus.
The sensitivity of 124I-PET for the detection of residual thyroid tissue and/or metastatic DTC was reported to be higher than that of a diagnostic 131I planar WBS (99% vs. 66%) (819–821). Iodine 124 PET/CT has not yet been compared with 131I SPECT/CT in a large series of patients with DTC. Furthermore, 124I is not yet widely available for clinical use and is primarily a research tool at this time. | 597 |
[C12] 18FDG-PET scanning | 598 |
RECOMMENDATION 68
18FDG-PET scanning should be considered in high- risk DTC patients with elevated serum Tg (generally
>10 ng/mL) with negative RAI imaging
(Strong recommendation, Moderate-quality evidence)
18FDG-PET scanning may also be considered as (i) a part of initial staging in poorly differentiated thyroid cancers and invasive Hu¨rthle cell carcinomas, especially those with other evidence of disease on imaging or because of elevated serum Tg levels, (ii) a prognostic tool in pa- tients with metastatic disease to identify lesions and pa- tients at highest risk for rapid disease progression and disease-specific mortality, and (iii) an evaluation of post- treatment response following systemic or local therapy of metastatic or locally invasive disease.
(Weak recommendation, Low-quality evidence) | 599 |
18FDG-PET/CT is primarily considered in high-risk DTC patients with elevated serum Tg (generally >10 ng/mL) with negative RAI imaging. In a meta-analysis of 25 studies that included 789 patients, the sensitivity of 18FDG-PET/CT was 83% (ranging from 50% to 100%) and the specificity was 84% (ranging from 42% to 100%) in non–131I-avid DTC (822). Factors influencing 18FDG-PET/CT sensitivity in- cluded tumor dedifferentiation, larger tumor burden, and to a lesser extent, TSH stimulation.
18FDG-PET is more sensitive in patients with an aggres- sive histological subtype, including poorly differentiated, tall cell, and Hu¨rthle cell thyroid cancer. 18FDG uptake on PET in metastatic DTC patients is a major negative predictive factor for response to RAI treatment and an independent prognostic factor for survival (823,824). It can also identify lesions with high 18FDG uptake (standardized uptake value) that may be more aggressive and should be targeted for therapy or close monitoring. It is complementary to 131I WBS, even in the presence of detectable 131I uptake in metastases, because 18FDG uptake may be present in neoplastic foci with no 131I uptake.
In patients with a TSH-stimulated Tg £10 ng/mL, the sensitivity of 18FDG is low, ranging from <10% to 30%. It is therefore recommended to consider 18FDG-PET only in DTC patients with a stimulated Tg level ‡10 ng/mL. Of course, this level needs to be adapted and lowered in case of aggressive pathological variant of thyroid cancer that may produce low amounts of serum Tg. Furthermore, in patients with unde- tectable Tg levels but with persistent Tg antibodies the level of serum Tg cannot be reliably assessed and 18FDG-PET may localize disease in some of these patients.
The sensitivity of 18FDG-PET scanning may be slightly in- creased with TSH stimulation. A multicentric prospective study on 63 patients showed an increase in the number of lesions | 600 |
detected on the 18FDG-PET/CT performed after rhTSH stimulation compared to the 18FDG-PET/CT performed on thyroid hormone treatment and without TSH stimulation (825). However, the sensitivity for detecting patients with at least one tumor site was not improved by the rhTSH stim- ulation. In this study, the lesions found only by rhTSH-PET contributed adequately to an altered therapeutic plan in four patients (6%), and the clinical benefit of identifying these additional small foci remains to be proven. Its clinical benefit might be higher in patients with normal neck and chest CT scan and normal neck ultrasonography. A meta- analysis on seven studies including the previous study and comprising 168 patients confirmed these results and showed that 18FDG-PET/CT performed following TSH stimulation altered clinical management in only 9% of patients. Fur- thermore, false positives can be seen with 18FDG-PET im- aging with or without TSH stimulation (825).
Results of 18FDG-PET/CT might alter the indications for 131I treatment or the decision for surgical removal of small tumor foci with 18FDG uptake. The frequency of false- positive lesions varies among series from 0% to 39%, and this high number justifies a FNAB with cytology and Tg mea- surement in the aspirate fluid in cases in which surgery is planned, based on 18FDG-PET results. The higher sensitivity of neck ultrasonography for the detection of small metastatic lymph nodes should be noted, with 18FDG-PET being more sensitive for some locations such as the retropharyngeal or the retro-clavicular regions (825).
To date, there is no evidence that TSH stimulation im- proves the prognostic value of 18FDG-PET imaging. | 602 |
[C13] CT and MRI | 603 |
RECOMMENDATION 69
Cross-sectional imaging of the neck and upper chest (CT, MRI) with IV contrast should be considered (i) in the setting of bulky and widely distributed recurrent nodal disease where US may not completely delineate disease, (ii) in the assess- ment of possible invasive recurrent disease where potential aerodigestive tract invasion requires complete assessment, or (iii) when neck US is felt to be inadequately visualizing possible neck nodal disease (high Tg, negative neck US).
(Strong recommendation, Moderate-quality evidence)
CT imaging of the chest without IV contrast (imag- ing pulmonary parenchyma) or with IV contrast (to in- clude the mediastinum) should be considered in high risk DTC patients with elevated serum Tg (generally >10 ng/ mL) or rising Tg antibodies with or without negative RAI imaging.
(Strong recommendation, Moderate-quality evidence)
Imaging of other organs including MRI brain, MR skeletal survey, and/or CT or MRI of the abdomen should be considered in high-risk DTC patients with elevated serum Tg (generally >10 ng/mL) and negative neck and chest imaging who have symptoms referable to those or- gans or who are being prepared for TSH-stimulated RAI therapy (withdrawal or rhTSH) and may be at risk for complications of tumor swelling.
(Strong recommendation, Low-quality evidence)
In patients with elevated or rising Tg or anti-Tg antibodies and NED on neck US or RAI imaging (if performed), CT imaging of the neck and chest should be considered. The frequency of positive anatomic imaging increases with higher serum Tg levels above 10 ng/mL. CT is the most frequently recommended first-line technique to search for lymph node metastases in patients with squamous cell carcinoma of the head and neck, and an injection of contrast medium is man- datory for the analysis of the neck and mediastinum (826). Radioiodine can be administered 4–8 weeks following the injection of contrast medium, because at that time a majority of the iodine contamination has disappeared in most patients (315). If there is a concern, a random urine iodine (and cre- atinine) prior to initiation of a LID and RAI testing or treat- ment can be measured to make sure the urine iodine is not high. Diagnostic CT scan may complement neck US for the detection of macrometastases in the central compartment, in the mediastinum, and behind the trachea (307–309), and it is the most sensitive tool for the detection of micrometastases in the lungs. Before revision surgery is contemplated, pre- sumptive recurrent neck targets must be defined by high- resolution radiographic anatomic studies such as US or spiral axial CT scan to complement 18FDG-PET/CT or RAI im- aging and must be carefully defined to allow for adequate preoperative mapping and definitive surgical localization. In addition to nodal assessment axial scanning, including CT scan with contrast has utility in the evaluation of locally recurrent invasive disease and relationships with vessels. Such patients may present with hoarseness, vocal cord pa- ralysis on laryngeal exam, progressive dysphagia or mass fixation to surrounding structures, respiratory symptoms including stridor or hemoptysis, and lesions with rapid pro- gression/enlargement. Such lesions are incompletely evalu- ated with US alone, and axial CT scanning with contrast medium is indicated.
The use of MRI has also been advocated for imaging the neck and the mediastinum. It is performed with and without injection of gadolinium chelate as a contrast medium and does not require any injection of iodine contrast medium. The performance of MRI for imaging the neck and mediastinum has not been directly compared with CT on large numbers of thyroid cancer patients (827–829). Compared to CT scan, it may better delineate any involvement of the aerodigestive tract (830,831). It is often used as second-line imaging tech- nique in patients with demonstrated or suspicious lesions on CT scan in order to better delineate these lesions. In the lower part of the neck, movements of the aerodigestive axis during the procedure that may last several minutes will decrease the quality of images (414). Endoscopy of the trachea and or esophagus, with or without ultrasonography, looking for ev- idence of intraluminal extension can also be helpful in cases of suspected aerodigestive tract invasion. MRI is less sensitive than CT scan for the detection of lung micronodules.
Finally, whether these imaging techniques (CT and MRI) should be performed for diagnostic purposes or whether an 18FDG-PET/CT scan should be performed as the first-line imaging procedure for diagnosis is still a matter of debate. In the past, CT scan with injection of contrast medium was more sensitive for the detection of lymph node metastases (832), but with modern PET/CT equipment, the CT scan of the PET/ CT is as reliable as a CT scan used for radiology, and many lesions can be found on 18FDG-PET/CT scanning, even if no | 604 |
injection of contrast medium has been performed (833,834). Delineation between lymph node metastases or local recur- rence and vessels or the aerodigestive axis is often not well visualized on 18FDG-PET/CT in the absence of contrast in- jection, and if necessary other imaging techniques (CT and MRI with contrast medium) may be performed especially for a preoperative work-up. As a result, most patients with ex- tensive disease should be considered for 18FDG-PET/CT and CT imaging with contrast, and some patients will also be considered for MRI.
This imaging strategy is applied in patients with elevated serum Tg (>5–10 ng/mL) and no other evidence of disease (neck and chest imaging), starting with a 18FDG-PET/CT (822,833). In the past an empiric treatment was used in such patients, but recent studies have shown that 18FDG-PET/CT imaging is more sensitive and should be performed as the first-line approach, with empiric RAI treatment being con- sidered only for those patients with no detectable 18FDG uptake (833). | 606 |
[C14] Using ongoing risk stratification (response to thera- py) to guide disease long-term surveillance and therapeutic management decisions
Ongoing risk stratification allows the clinician to continue to provide individualized management recommendations as the risk estimates evolve over time. While the specific details of how surveillance and therapeutic strategies should be modified over time as a function of response to therapy re- classification within each ATA risk category remains to be defined, we do endorse the following concepts (more details in Table 13).
Excellent response: An excellent response to therapy should lead to a decrease in the intensity and frequency of follow-up and the degree of TSH suppression (this change in management will be most apparent in ATA intermediate- and high-risk patients).
Biochemical incomplete response: If associated with stable or declining serum Tg values, a biochemical incom- plete response should lead to continued observation with ongoing TSH suppression in most patients. Rising Tg or anti- Tg antibody values should prompt additional imaging and potentially additional therapies.
Structural incomplete response: A structural incomplete response may lead to additional treatments or ongoing ob- servation depending on multiple clinico-pathologic factors including the size, location, rate of growth, RAI avidity, 18FDG avidity, and specific pathology of the structural lesions. Indeterminate response: An indeterminate response should lead to continued observation with appropriate serial imaging of the nonspecific lesions and serum Tg monitoring. Nonspecific findings that become suspicious over time or rising Tg or anti-Tg antibody levels can be further evaluated
with additional imaging or biopsy. | 607 |
[C15] What is the role of TSH suppression during thyroid hormone therapy in the long-term follow-up of DTC? | 608 |
RECOMMENDATION 70
In patients with a structural incomplete response to therapy, the serum TSH should be maintained below
0.1 mU/L indefinitely in the absence of specific contrain- dications.
(Strong recommendation, Moderate-quality evidence)
In patients with a biochemical incomplete response to therapy, the serum TSH should be maintained between 0.1 and 0.5 mU/L, taking into account the initial ATA risk classification, Tg level, Tg trend over time, and risk of TSH suppression.
(Weak recommendation, Low-quality evidence)
In patients who presented with high-risk disease but have an excellent (clinically and biochemically free of disease) or indeterminate response to therapy, consider- ation should be given to maintaining thyroid hormone therapy to achieve serum TSH levels of 0.1–0.5 mU/L for up to 5 years after which the degree of TSH suppression can by reduced with continued surveillance for recurrence.
(Weak recommendation, Low-quality evidence)
In patients with an excellent (clinically and bio- chemically free of disease) or indeterminate response to therapy, especially those at low risk for recurrence, the serum TSH may be kept within the low reference range (0.5–2 mU/L).
(Strong recommendation, Moderate-quality evidence)
In patients who have not undergone remnant ablation or adjuvant therapy who demonstrate an excellent or in- determinate response to therapy with a normal neck US, and low or undetectable suppressed serum Tg, and Tg or anti-Tg antibodies that are not rising, the serum TSH can be allowed to rise to the low reference range (0.5–2 mU/L).
(Weak recommendation, Low-quality evidence) | 609 |
A meta-analysis has suggested an association between thyroid hormone suppression therapy and reduction of major adverse clinical events (745). The appropriate degree of TSH suppression by thyroid hormone therapy is still unknown, es- pecially in high-risk patients rendered free of disease. A con- stantly suppressed TSH (0.05 mU/L) was found in one study to be associated with a longer relapse-free survival than when serum TSH levels were always 1 mU/L or greater, and the degree of TSH suppression was an independent predictor of recurrence in multivariate analysis (749). Conversely, another large study found that disease stage, patient age, and 131I therapy independently predicted disease progression, but the degree of TSH suppression did not (275). A third study showed that during LT4 therapy the mean Tg levels were significantly higher when TSH levels were normal than when TSH levels were suppressed (<0.5 mU/L) but only in patients with local or distant recurrence (835). A fourth study of 2936 patients found that overall survival improved significantly when the TSH was suppressed to <0.1 mU/L in patients with NTCTCSG stage III or IV disease and to a range of 0.1 mU/L to about 0.5 mU/L in patients with NTCTCSG stage II disease; however, there was no incremental benefit from suppressing TSH to undetectable levels in stage II patients, and suppression of TSH was of no benefit in patients with stage I disease (671), and higher de- grees of suppression to TSH of <0.03 mU/L provided no ad- ditional benefit (746). Another study found that a serum TSH | 610 |
threshold of 2 mU/L differentiated best between patients free of disease and those with relapse or cancer-related mortality, which remained significant when age and tumor stage were included in a multivariate analysis (750). A prospective study showed that disease-free survival for low-risk patients without TSH suppression was not inferior to patients with TSH sup- pression (836). No prospective studies have been performed examining the risk of recurrence and death from thyroid cancer associated with varying serum TSH levels, based on the cri- teria outlined above in [C14] for the absence of tumor at 6–12 months post surgery and RAI ablation.
A recent observational study demonstrated increased risk of all-cause and cardiovascular mortality in DTC patients com- pared to a control population (837). The authors also showed that survival in the DTC patients was lower when the serum TSH was <0.02 mU/L, which is particularly relevant in patients with an excellent response to therapy in whom overtreatment should be avoided. An approach to balancing the risks of thy- roxine suppression against the risks of tumor recurrence or progression has been presented in a recent review (747). This review helped to define patients at low, intermediate, and high risk of complications from TSH suppression therapy. Table 15 provides recommendations for TSH ranges based on response to thyroid cancer therapy weighed against risks of LT4 therapy,
which is adapted from the review by Biondi and Cooper (747). In patients at high risk of adverse effects on heart and bone by TSH suppression therapy, the benefits of TSH suppression should be weighed against the potential risks. In peri- and postmenopausal women at risk for bone loss, adjunctive ther- apy with calcium supplements, vitamin D, and other bone- enhancing agents (bisphosphonates, denosumab, etc.) should be considered. b-Adrenergic blocking drugs may be considered in older patients to obviate increases in left ventricular mass and tachycardia (838,839).
There are inadequate data to make a strong recommendation regarding the intensity and duration of TSH suppression in the biochemical incomplete response to therapy category. This category encompasses a variety of patients with low serum Tg levels (median nonstimulated Tg 3.6 ng/mL) having been initially classified as ATA low risk (16%–24%), ATA inter- mediate risk (47%–64%), or ATA high risk (18%–21%) (539,607). Furthermore, the risk of development of structurally identifiable disease within this cohort is not uniform but rather is related to the ongoing behavior of residual disease as re- flected by both the magnitude of the Tg elevation and to the rate of rise of the serum Tg or anti-Tg antibodies. Based on weak data and expert opinion, we recommend a goal TSH of 0.1–0.5 mIU/L for the majority of patients with a biochemical | 612 |
Table 15. Thyrotropin Targets for Long-Term Thyroid Hormone Therapy | 614 |
incomplete response, recognizing that less intense TSH sup- pression (0.5–2.0 mIU/L) may be appropriate for ATA low- risk patients with stable nonstimulated Tg values near the threshold for excellent response (e.g., nonstimulated Tg values in the 1–2 ng/mL range), while more intense TSH suppression (<0.1 mIU/L) may be desired in the setting of more elevated or rapidly rising Tg values. | 617 |
[C16] What is the most appropriate management of DTC patients with metastatic disease?
Metastases may be discovered at the time of initial disease staging or may be identified during longitudinal follow-up. If metastases are found following initial therapy, some patients may subsequently experience a reduction in tumor burden with additional treatments that may offer a survival or palliative benefit (840–844). The preferred hierarchy of treatment for metastatic disease (in order) is surgical excision of loco- regional disease in potentially curable patients, 131I therapy for RAI-responsive disease, external beam radiation therapy or other directed treatment modalities such as thermal ablation, TSH-suppressive thyroid hormone therapy for patients with stable or slowly progressive asymptomatic disease, and sys- temic therapy with kinase inhibitors (preferably by use of FDA-approved drugs or participation in clinical trials), espe- cially for patients with significantly progressive macroscopic refractory disease. Clinical trials or kinase inhibitor therapy may be tried before external beam radiation therapy in special circumstances, in part because of the morbidity of external beam radiation and its relative lack of efficacy. However, lo- calized treatments with thermal (radiofrequency or cryo-) ab- lation (845), ethanol ablation (846), or chemo-embolization (847) may be beneficial in patients with a single or a few metastases and in those with metastases at high risk of local complications; the treatments should be performed in such patients before the initiation of any systemic treatment. These modalities may control treated metastases, may avoid local complications, and may delay initiation of systemic treatment. Additionally, surgical therapy in selected incurable patients is important to prevent complications in targeted areas, such as the CNS and central neck compartment. Conversely, conser- vative intervention with TSH-suppressive thyroid hormone therapy may be appropriate for selected patients with stable asymptomatic local metastatic disease and most patients with stable asymptomatic non-CNS distant metastatic disease. | 618 |
[C17] What is the optimal directed approach to patients with suspected structural
neck recurrence? | 619 |
RECOMMENDATION 71
Therapeutic compartmental central and/or lateral neck dis- section in a previously operated compartment, sparing unin- volved vital structures, should be performed for patients with biopsy-proven persistent or recurrent disease for central neck nodes ‡8 mm and lateral neck nodes ‡10 mm in the smallest dimension that can be localized on anatomic imaging.
(Strong recommendation, Moderate-quality evidence) | 620 |
Persistent or recurrent nodal disease may result in local invasion and is the source of considerable patient and phy-
sician anxiety (848). However, several observational studies suggest that low-volume recurrent nodal disease can be in- dolent and can be managed through active surveillance, al- though not all lesions in these series are documented as malignant (629,849). Bulky or invasive recurrent disease is best treated surgically (319,850–853).
The judgment to offer surgery for recurrent nodal disease in the neck is made with equipoise in two opposing decision elements: (i) the risks of revision surgery (which are typically higher than primary surgery due to scarring from previous surgery (854) balanced with (ii) the fact that surgical resec- tion generally represents the optimal treatment of macro- scopic gross nodal disease over other treatment options. An important element in this decision-making process is the availability of surgical expertise specifically in the perfor- mance of revision thyroid cancer nodal surgery, which is a discrete surgical skill set. The decision to treat cervical nodal recurrence surgically should be made with an appreciation of distant disease presence and progression but may be under- taken even in the setting of known distant metastasis for palliation of symptoms and prevention of aerodigestive tract obstruction. The decision for treatment and surgery specifi- cally is best derived through collaborative team approach involving surgery, endocrinology, and importantly the pa- tient and family (855). Therefore, cytologic confirmation of disease can be deferred if the findings of the FNA will not lead to additional evaluation or treatment. While we gener- ally recommend cytologic confirmation of abnormal radio- graphic findings prior to surgical resection, we recognize that this may not be necessary (or possible) in every case (e.g., radiographic findings with a very high likelihood of malig- nancy, or the specific location of the lymph node makes it difficult/impossible to biopsy). | 621 |
[C18] Nodal size threshold
Surgery is considered with the recognition of clinically apparent, macroscopic nodal disease through radiographic analysis including US (Table 7) and/or axial (CT) scanning rather than through isolated Tg elevation (309,335,856). Given the risks of revision nodal surgery, a clearly defined preoperative radiographic target is mandatory. The risks of surgery relate in part to the exact location of the target node(s) and whether the compartment in question has been previously dissected such as recurrent central neck nodes after primary thyroidectomy. This target must be defined by high-resolution radiographic anatomic studies such as US or spiral CT scan with contrast, as a complement to 18FDG-PET/ CT or RAI-SPECT/CT when performed, to allow for ade- quate preoperative mapping and definitive surgical localiza- tion (309,856). Ultrasound-guided FNA for cytology with Tg measurement in the aspiration sample can be performed in the setting of radiographically suspicious nodal recurrence keeping in mind that Tg rinsing may be positive with thyroid bed persistent benign thyroid remnant tissue if the patient has not been treated with RAI. Charcoal tattooing under US guidance may help the surgeon to localize the lymph node to be removed during surgery (344).
Malignant central neck nodes ‡8 mm and lateral neck nodes ‡10 mm in the smallest dimension that have undergone FNAB and can be localized on anatomic imaging (US with or without axial CT) can be considered surgical targets | 622 |
(309,857–859). Short-axis nodal diameter measurement is optimally employed in surgical decision-making for nodal malignancy. Smaller lesions are probably best managed with active surveillance (observation) with serial cross-sectional imaging, reserving FNA and subsequent intervention for documented structural disease progression. However, multi- ple factors in addition to size should be taken into account when considering surgical options, including proximity of given malignant nodes to adjacent vital structures and the functional status of the vocal cords. Patient comorbidities, motivation, and emotional concerns should also be taken into account along with primary tumor factors (high-grade histology, Tg doubling time, RAI avidity, 18FDG-PET avidity, and presence of molecular markers associated with aggressive behavior). Through thorough patient and multidisciplinary collaborative discussions, metastatic nodes >8–10 mm can be carefully observed in properly selected patients with serial clinical and radiographic follow-up, with surgery being of- fered if they progress during follow-up and conservative follow-up being maintained if they are stable over time. | 624 |
[C19] Extent of nodal surgery
Because of the increased risk of recurrence with focal ‘‘berry-picking’’ techniques, compartmental surgery is rec- ommended (860,861). Planned compartmental dissection should be adjusted and be more limited depending on the surgeon’s judgment of procedural safety as it relates to scarring/distortion of anatomy (from prior surgery and/or past radiation therapy) and the perception of impending complications. Typical revision lateral neck dissection in- volves levels II, III, and IV, while revision central neck dis- section includes at least one paratracheal region with prelaryngeal and pretracheal subcompartments. Bilateral central neck dissection is offered only when dictated by disease distribution because of the risks of bilateral nerve injury and permanent hypoparathyroidism.
Basal Tg decreases by 60%–90% after compartmental dissection for recurrent nodal disease in modern series, but only 30%–50% of patients have unmeasurable basal Tg after such surgery, and it is difficult to predict who will respond to surgery with Tg reduction (627,628,634,858,862–876). However, most series suggest surgery results in a high clearance rate of structural disease in over 80% of patients (859,875). | 625 |
[C20] Ethanol injection
Percutaneous ethanol injection for patients with metastatic lymph nodes is gaining interest as a nonsurgical directed therapy for patients with recurrent DTC. Most of the studies limited PEI to patients who had undergone previous neck dissections and RAI treatment, those who had FNA-proven DTC in the lymph node, and those with no known distant metastases.
One of the first studies examining the effectiveness of local metastatic lymph node control by PEI treated 14 pa- tients with 29 lymph nodes (846). Twelve of the 14 patients had good loco-regional control in this study with short-term follow-up (mean 18 months). The largest study to date treated 63 patients with 109 metastatic lymph nodes be- tween the years 2004 and 2009 (878). Ninety-two lymph nodes (84%) were successfully ablated in this retrospective study with a mean follow-up of 38 months, and most re-
quired one to three treatment sessions. Minor complications included brief discomfort at the PEI site, and there were no major complications.
A recent study retrospectively reviewed 25 patients who had 37 lymph nodes ablated between the years 1994 and 2012, with a relatively long follow-up of a mean of 65 months (879). All lymph nodes were successfully ablated in one to five treatment sessions by lack of flow on US. Most of the lymph nodes decreased in size and 46% completely disappeared. Serum Tg levels were reduced in most patients and brought into an acceptable range (<2.4 ng/mL) in 82% of patients with negative anti-Tg antibodies. There were no serious or long-term complica- tions. Another recent study also demonstrated safety and efficacy of PEI in 21 patients with 41 metastatic lymph nodes (880). These investigators treated patients with only one session, and 24% of patients had a recurrence at the site of the injection.
Limitations of many of the studies included small numbers of patients, relatively short-term follow-up, and many pa- tients with small lymph nodes (<5–8 mm).
A general consensus from studies and reviews is that PEI should be considered in patients who are poor surgical can- didates. Many patients will likely need more than one treat- ment session and lymph nodes >2 cm may be difficult to treat with PEI. Focal PEI treatment does represent a nonsurgical form of berry picking. Formal neck compartmental dissection is still the first-line therapy in DTC patients with clinically apparent or progressive lymph node metastases. When de- ciding for the optimal strategy of care for a patient’s lymph node metastases, previous treatment modalities should also be taken into consideration. | 626 |
[C21] Radiofrequency or laser ablation
The use of radiofrequency ablation (RFA) with local anes- thesia in the treatment of recurrent thyroid cancer has been associated with a mean volume reduction that ranges between approximately 55% and 95% (881,882) and complete disap- pearance of the metastatic foci in 40%–60% of the cases (845,882,883). As with alcohol ablation, multiple treatment sessions are often required. Complications include discomfort, pain, skin burn, and changes in the voice (884). Similar to alcohol ablation techniques, it appears that RFA may be most useful in high-risk surgical patients or in patients refusing additional surgery, rather than as a standard alternative to surgical resection of metastatic disease (883–885). More re- cently, preliminary findings using US-guided laser ablation for treatment of cervical lymph node metastases have been re- ported (886). | 627 |
[C22] Other therapeutic options
Empiric RAI therapy for structurally identifiable disease that is not RAI avid by diagnostic scanning is very unlikely to have a significant tumoricidal effect and is therefore not generally recommended (887). Stereotactic radiotherapy (SBRT) can be successfully used to treat isolated metastatic disease foci, but it has no role in most patients with resectable lymph node metastases. EBRT using modern techniques such as intensity modulated radiotherapy and sterotactic radiation, is considered for loco-regional recurrence that is not surgi- cally resectable or with extranodal extension or involvement of soft tissues, particularly in patients with no evidence of | 628 |
distant disease. Efficacy has been suggested only in retro- spective studies on limited numbers of patients (888,889). Likewise, systemic therapies (such as cytotoxic chemother- apy or kinase inhibitors) for loco-regional disease are con- sidered only after all surgical and radiation therapy options have been exhausted. | 630 |
[C23] What is the surgical management of aerodigestive invasion? | 631 |
RECOMMENDATION 72
When technically feasible, surgery for aerodigestive in- vasive disease is recommended in combination with RAI and/or EBRT.
(Strong Recommendation, Moderate-quality evidence) | 632 |
For tumors that invade the upper aerodigestive tract, surgery combined with additional therapy such as 131I and/or external beam radiation therapy is generally advised (890,891). Patient outcome is related to complete resection of all gross disease with the preservation of function, with techniques ranging from shaving a tumor off the trachea or esophagus for super- ficial invasion, to more aggressive techniques when the trachea is more deeply invaded (e.g., direct intraluminal invasion), including tracheal resection and anastomosis or laryngophar- yngoesophagectomy (892–894). Surgical decision-making can be complex and must balance oncologic surgical completeness with preservation of upper aerodigestive track head and neck function. In some circumstances such surgery represents a possible attempt for cure, and in other circumstances it offers significant regional neck palliation in patients with distant metastasis with impending asphyxiation or significant he- moptysis (414,891). | 633 |
[C24] How should RAI therapy be considered for loco-regional or distant metastatic disease?
For regional nodal metastases discovered on diagnostic WBS, RAI may be employed in patients with low-volume disease or in combination with surgery, although surgery is typically preferred in the presence of bulky disease or disease amenable to surgery. Radioiodine is also used adjunctively following surgery for regional nodal disease or aerodigestive invasion if residual RAI-avid disease is present or suspected. Significant variation exists nationally in the United States in regard to RAI use, irrespective of the degree of disease or risk of recurrence (895,896). However, there are no randomized, controlled clinical trials demonstrating better patient out- comes after RAI therapy. One retrospective analysis indi- cated that a delay in RAI therapy of 6 months or more was associated with disease progression and reduced survival (897). In one study of 45 patients with persistent serum Tg elevation after reoperation for loco-regional recurrence, ad- juvant RAI therapy demonstrated no benefit (898). | 634 |
Subsets and Splits