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had a postoperative TSH-stimulatedTg>1–2 ng/mL at the time of ablation (596,605,630–637). In multivariate analysis, the postoperative Tg is often found to be an independent predictor of persistent or recurrent disease(596,630,631,636,637). Furthermore, the risk of having re- current or persistent disease increases as the postoperative Tg rises (634,636). Using receiver operator curve analyses,thyroid hormone withdrawal postoperative Tg values be-tween 20 and 30 ng/mL achieve the optimal balance of sen- sitivity and speciﬁcity for predicting recurrent or persistent disease (638–640). Furthermore, high postoperative stimu-lated Tg values ( >10–30 ng/mL) are also associated with poorer survival (636,639,641). Conversely, postoperative stimulated Tg values less than 1–2 ng/mL are strong predic-tors of remission (634,636). Even in ATA low- and intermediate-risk patients that did not receive RAI remnant ablation, a nonstimulated postoperative Tg <1 ng/mL was associated with excellent clinical outcomes and recurrence rates<1% (642). The median follow-up in this study was 62 months (2–116 months).
Therefore, a postoperative serum Tgcan provide valuable information with regard to the likeli-hood of achieving remission or having persistent or recurrent disease in response to an initial therapy. A postoperative Tg <10 ng/mL may not distinguish be- tween nodal disease and thyroid remnant, when evaluated using concurrent RAI scans with SPECT/CT (643). In one of the prospective studies mentioned previously, a postop-erative Tg threshold of >5 ng/mL was suggested as an in- dication for RAI treatment (633). However, in a recent retrospective review of consecutive low-risk patients trea-ted with total thyroidectomy without RAI, an unstimulatedTg of ‡2 ng/mL with a concomitant median TSH level of 0.48 mIU/L was reported to detect all patients with disease recurrence (76 patients follow ed for a median of 2.5 years) (644). Thus, there is some uncertainty as to what degree of postoperative stimulated or unstimulated thyroglobulinemia (with or without neck US interpretation) may be
appropriateto prompt RAI treatment. Moreover, detection of unex- plained inappropriate thyroglobulinemia may prompt con- sideration of further investigation for its cause (e.g.,imaging studies). The postoperative Tg can also be used to predict the likelihood of identifying RAI-avid metastatic thyroid canceroutside the thyroid bed on the posttherapy scan at the time ofremnant ablation. No uptake outside the thyroid bed was identiﬁed in 63 low-risk patients with a nonstimulated post- operative Tg of <0.4 ng/mL (630) or in 132 low-risk patients with a thyroid hormone withdrawal Tg of <1 ng/mL (645). However, RAI-avid metastatic foci outside the thyroid bed were detected in 12% of intermediate-risk patients with asuppressed Tg of <0.6 ng/mL (646), 5.6% of intermediate/ high risk patients with a suppressed Tg of <1 .0 ng/mL (647), and 6.3% of intermediate/high-risk patients with a thyroidhormone withdrawal stimulated Tg of <2 ng/mL (648). The likelihood of ﬁnding RAI-avid metastatic disease on the
post- therapy scan is substantially lower (2.8%) if the postoperativeATA THYROID NODULE/DTC GUIDELINES 53
Tg is undetectable in three different Tg assays than if it is undetectable only in a single assay (30%) (649). Con- versely, the likelihood of identifying either loco-regionalor distant metastases on the posttherapy scan increases aseither the suppressed or stimulated Tg values rise above 5–10 ng/mL (631,646,647,650). Therefore, neither a stim- ulated or suppressed postoperative Tg of <1 ng/mL can completely eliminate the possibility that a posttherapy RAI scan will identify me tastatic foci outside the thyroid bed. However, postoperative Tg values greater than 5–10 ng/mLincrease the likelihood of identifying RAI-avid metastatic disease on the posttherapy scan. The postoperative serum Tg value can also be used to predict the likelihood of successful remnant ablation. Post-operative thyroid hormone withdrawal stimulated Tg values >5–6 ng/mL were associated with higher rates of failed ab- lation after administered activities of both 30 mCi (651) and100 mCi (652). A TSH-stimulated Tg >6 ng/mL was asso-
ciated with a 5-fold greater risk of failing ablation after an activity of 30 mCi administered after preparation with thy-roid hormone withdrawal (651). It does appear that a postoperative Tg value (either TSH- stimulated or nonstimulated) is an important prognosticfactor that can be used to guide clinical management. Given a disappearance half-life of 1–3 days (653–658), the postop- erative Tg should reach its nadir by 3–4 weeks postopera-tively in nearly all patients. In low-risk patients, a suppressedor stimulated Tg <1 ng/mL is very reassuring and further conﬁrms classiﬁcation of the patients as being at low risk. In intermediate-risk patients, postoperative Tg values <1 ng/mL are reassuring, but do not completely rule out the presence of small-volume RAI-avid metastatic disease. However, even without RAI ablation, many intermediate risk patients haveexcellent clinical outcomes. Therefore, it is not clear that additional therapy is required in these intermediate-risk pa- tients with postoperative Tg values
<1 ng/mL even though small-volume RAI-avid disease may still be present afterthyroidectomy. On the other hand, postoperative Tg values (stimulated or nonstimulated) greater than 10–30 ng/mL increase the like-lihood of having persistent or recurrent disease, failing initial RAI ablation, having distant metastases, and dying of thyroid cancer. Therefore, postoperative Tg values >10 ng/mL will likely lead to additional evaluations and possibly even ad- ditional therapies. With regard to decision-making on the need for RAI remnant ablation, it appears that the postoperative serum Tg value will be more helpful in identifying patients that may beneﬁt from RAI ablation rather than in identifying patientsthat do not require ablation. For example, a postoperative Tgvalue >5–10 ng/mL may lead to selection of RAI ablation in an ATA low-risk patient or ATA intermediate-risk patient that otherwise would not have required RAI ablation (selectiveuse) in order to improve initial staging and facilitate follow- up. Conversely, in
high-risk patients, a postoperative Tg value <1 ng/mL does not rule out RAI-avid disease and therefore is unlikely to alter the decision to proceed with RAI ablation. [B34] Potential role of postoperative US in conjunction with postoperative serum Tg in clinical decision-making In a prospective study of 218 DTC patients, Lee et al. (659) reported that a stimulated Tg <2 ng/mL after thyroid hormonewithdrawal (with goal TSH of >30 mIU/L), at the time of administration of 100–200 mCi of131I (for remnant ablation or treatment), was associated with the following NPVs forbiochemical or structural recurrence at 6–12 months: 98.4%for ATA low-risk patients, 94.1% for ATA intermediate-risk patients, and 50% in the ATA high-risk group. They further reported that the NPVs increased to 97.2%, and 100% forATA intermediate- and high-risk patients, respectively, when the stimulated Tg values were combined with negative neck US ﬁndings at baseline (with no change in low-risk patients).Similar
signiﬁcant decreases in the risk of recurrence were seen when ATA intermediate- and high-risk patients had a normal postoperative neck US (660). [B35] Role of postoperative radioisotope diagnostic scan- ning in clinical decision-making Iodine radioisotope diagnostic testing may include131Io r 123I diagnostic imaging with or without SPECT-CT, and/or RAI uptake measurements. Postoperative RAI planar imaging (123Io r131I, with or without SPECT-CT) has been reported to yield information that could alter clinical management (such as altering disease status assessment) in 25%–53% of patients, as reported in single-center, retrospective studies (643,661,662).However, in a multivariate analysis of retrospective data, Hu et al. (663) reported that the use of 5 mCi of131Ib e t w e e n4a n d 11 days prior to remnant ablation was independently associatedwith an increased risk of remnant ablation failure. In contrast, ina smaller retrospective study, the administration of 3–5 mCi of 131I for scanning 2–5 days prior
to ablation in 37 patients was not associated with any signiﬁcant reduction in remnant abla-tion success, compared to no pretherapy scanning in 63 patients (131I therapeutic activity of 100–200 mCi used in both groups) (664). A possible relationship between131I diagnostic scan activity on remnant ablation success was suggested in another retrospective study, in which success was lower following the use of 3 mCi as compared to 1 mCi of131I, 9 days before therapeutic administration of 100 mCi (665). In two smallRCTs, there was no signiﬁcant impact of131Is c a n n i n g compared to123I scanning on the rate of successful remnant ablation (666,667). The timing of whole-body diagnosticscans following administration of radioisotopes in reviewed studies ranged from about 24 to 72 hours for131I (643,662, 663,665–667) and was 24 hours for123I (661,662,666). The tailoring of RAI therapeutic activity according to RAI neck uptake (measured 24 hours after administration of
1 mCi of131I) was associated with a lower rate of remnant ablation success than ﬁxed dosing, in another single-center retrospective observational study (668). Furthermore, in a multivariate analysis of retrospective data (adjusted for rel-evant risk factors), Verburg et al. (669) reported that the use o f1m C io f131I for calculation of RAI neck uptake 2 days before remnant ablation was independently associated with an increased risk of remnant ablation failure, although Yapand Murby showed that 1.1 mCi131I diagnostic scans did not adversely affect the success of ablation or recurrence rate at 3 years (670). There continues to be discussion on the utility of postoper- ative iodine radioisotope diagnostic scanning (with or without SPECT/CT) in guiding RAI therapeutic decision-making.Valuable information on disease status, remnant uptake, and the presence of residual RAI-avid disease may be obtained by such testing, which could alter management and potentially54 HAUGEN ET AL.
beneﬁt outcome. Questions regarding the potentially negative impact of such scans with131I on RAI therapeutic efﬁcacy for successful remnant ablation (‘‘stunning’’) may be mitigated oravoided by the use of either low-activity131I (1–3 mCi) or alternative isotopes such as123I. [B36] What is the role of RAI (including remnant ablation, adjuvant therapy, or therapy for persistent disease) after thyroidectomy in the primary management of DTC? &RECOMMENDATION 51 (details in Table 14) (A) RAI remnant ablation is not routinely recommended after thyroidectomy for ATA low-risk DTC patients.Consideration of speciﬁc features of the individual patientthat could modulate recurrence risk, disease follow-up implications, and patient preferences are relevant to RAI decision-making. (Weak recommendation, Low-quality evidence)(B) RAI remnant ablation is not routinely recommended after lobectomy or total thyroidectomy for patients with unifocal papillary microcarcinoma, in the absence of other adverse features. (Strong recommendation, Moderate-quality evidence)(C) RAI remnant ablation is not routinely recommended after thyroidectomy for patients
with multifocal papillarymicrocarcinoma in absence of other adverse features. Consideration of speciﬁc features of the individual patient that could modulate recurrence risk, disease follow-upimplications, and patient preferences are relevant to RAI decision-making. (Weak recommendation, Low-quality evidence)(D) RAI adjuvant therapy should be considered after total thyroidectomy in ATA intermediate-risk level DTCpatients. (Weak recommendation, Low-quality evidence)(E) RAI adjuvant therapy is routinely recommended after total thyroidectomy for ATA high risk DTC patients (Strong recommendation, Moderate-quality evidence) 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 recurrentdisease and initial staging by tests such as Tg measurementsor 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 inhigher 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 diseasesurveillance procedures, patie nt preferences (the latter be- ing particularly important when clear data on therapeuticefﬁcacy 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 Tgwith Tg antibody measurements while on thyroid hormonetherapy. We categorized the results of our review according to the ATA Risk of Recurrence Risk stratiﬁcation (outlined in apreceding section of these guidelines). However, given that the ATA risk classiﬁcation is relatively new and the majority of studies examining therapeutic efﬁcacy of postsurgical RAIremnant ablation or therapy (adjuvant or for persistent dis- ease) have been performed with attention to traditional
mortality risk stratiﬁcation systems such as the AJCC/TNMsystem, 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 ofthe 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. ATA low risk. Studies examining the impact of RAI remnant ablation/adjuvant therapy on long-term thyroidcancer outcomes in ATA low-risk patients are subject tolimitations 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). Bydeﬁnition, 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 ofpersistent 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-risklevel, were followed for a median of 10.3 years, and there wasno signiﬁcant effect of RAI adjuvant therapy on overall or disease-free survival, using respective multivariate and stratiﬁed propensity analysis techniques (544). Prospectivedata 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 multivariateanalyses 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 majorityof 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 diseaserecurrence (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 studiessummarized in this section on ATA low-risk disease (or equivalent), patients with multifocal PTC were generally included (if no other adverse features meeting criteria forupstaging 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 evidenceATA THYROID NODULE/DTC GUIDELINES 55
Table 14.Characteristics According to the American Thyroid Association Risk Stratiﬁcation System and AJCC/TNM Staging System That May Impact Postoperative Radioiodine Decision-Making ATA risk Staging (TNM) DescriptionBody of evidence suggests RAI im- proves disease- speciﬁc survival?Body of evidence suggests RAI im- proves disease- free survival? Postsurgical RAI indicated? ATA low risk T1aN0,NxM0,MxTumor size £1c m (uni-or multi-focal)No No No ATA low risk T1b,T2N0, Nx M0,MxTumor size >1–4 cmNo Conﬂicting observationaldataNot routine b—May be considered for patients with aggressive histology orvascular invasion (ATA intermedi- ate risk). ATA low to in- termediate risk T3N0,NxM0,MxTumor size >4 cm Conﬂicting data Conﬂicting observational dataConsider b—Need to consider presence of other adverse features. Advancing age may favor RAI use in somecases, but speciﬁc age and tumorsize cutoffs subject to some uncertainty. a ATA low to in- termediate risk T3 N0,NxM0,MxMicroscopic ETE, any tumor sizeNo Conﬂicting observational dataConsiderb—Generally favored based on risk of recurrent disease. Smaller tumors
with microscopic ETE may not require RAI. ATA low to in- termediate riskT1-3 N1a M0,MxCentral compart- ment necklymph node metastasesNo, except possi- bly in subgroupof patients ‡45 years of age (NTCTCSGStage III)Conﬂicting observationaldataConsider b—Generally favored, due to somewhat higher risk of persistentor 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. aHowever, there is insufﬁcient data to mandate RAIuse in patients with few ( <5) microscopic nodal metastases in central compartment in absence of other adverse features. ATA low to in- termediate riskT1-3N1b M0,MxLateral neck or mediastinallymph nodemetastasesNo, except possi- bly in subgroupof patients ‡45 years of ageConﬂicting observationaldataConsider b—Generally favored, due to higher risk of persistent or recurrentdisease, especially with increasingnumber of macroscopic or clinically evident lymph nodes or presence of extranodal extension. Advancingage may also favor RAI use. a ATA
high risk T4Any N Any MAny size, gross ETEYes, observationaldataYes, observationaldataYes ATA high risk M1 Any T Any NDistant metastases Yes, observational dataYes, observational dataYes 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.56 HAUGEN ET AL.
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 toimprove 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 microcarcinomasof 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 ofsurgery, 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 theirmultivariate 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. 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 insularvariants (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 theprimary 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 ratewas 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 of6.8 years, with or without RAI treatment, respectively. The clinical signiﬁcance of this approximately 1% absolute risk difference could be questioned. In contrast, in the samestudy, 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 RAIand 69% of those not treated with RAI were alive (685); inthis 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 nodalmetastases 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 Kongexamining 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 treatmentbeneﬁts 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 theNTCTCSG 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 PTCpatients 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 possiblet h a ta g ew a sac o n t r i b u t i n gf a c t o ri nt h er e s u l t so ft h a tanalysis. In a subgroup of 352 patients with microscopic extrathyroidal extension from a single-center retrospective study, postsurgical RAI trea tment 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 asigniﬁcant beneﬁt. For patients with ATA intermediate-riskDTC, 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 cancerhistologies, 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 r isk of recurrent or persis- tent disease that is iodine avid. More studies are needed, including RCTs, to characterize RAI treatment efﬁcacy in ATAintermediate-risk patients. The adjuvant therapeutic efﬁcacy ofRAI 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 therelatively 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-m aking. Clearly more research is needed to understand the therapeutic efﬁcacy in various subgroups of patients in the ATA intermediate-risk category. 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 IIIand 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 thandoubled in patients receiving postsurgical RAI treat- ment (687). Thus, routine postsurgical RAI treatment is re- commended in patients with ATA high-risk DTC.ATA THYROID NODULE/DTC GUIDELINES 57
[B37] What is the role of molecular marker status in therapeutic RAI decision-making? &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) 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 BRAFV600Emutation or other genetic alterations in PTC may impact the success of adjuvanttherapy 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 patientswith 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 ofstructural 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 RAIin
ATA high-risk patients, but the presence or absence of aBRAF V600Emutation 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 beestablished, 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 appropriatelystratiﬁed for ATA recurrence risk level and other important prognostic variables. [B38] How long does thyroid hormone need to be withdrawn in preparation for RAI remnant ablation/treatment or diagnostic scanning? &RECOMMENDATION 53 (A) If thyroid hormone withdrawal is planned prior to RAI therapy or diagnostic testing, LT 4should be withdrawn for 3–4 weeks. Liothyronine (LT 3) may be substituted for LT 4 in the initial weeks if LT 4is withdrawn for 4 or more weeks, and in such circumstances, LT 3should 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) (B) 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) Thyrotropin stimulation before RAI remnant ablation/ therapy or scanning has been a long-established standard ofcare because early observational research suggested that a TSH >30 mIU/L was required for incompletely resected thyroid tumors to signiﬁcantly concentrate131I (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 LT 4for 4 weeks
( n=89), (b) withdrawal of LT 4for 4 weeks with substitution of LT 3for the ﬁrst 2 weeks ( n=133), or (c) recombinant human TSH (rhTSH; with withdrawal ofLT 4for 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 of131I 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, whichwas 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 signiﬁcantdifference in
quality of life during preparation for RAI ab- lation, between the LT 4withdrawal group and the LT 4 withdrawal with LT 3substitution 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. Ina single-center trial, Leboeuf et al. (690) randomized 20 in- dividuals with well-differentiated thyroid cancer awaiting RAI remnant ablation or diagnostic scanning to LT 4with- drawal and either (a) substitution of LT 3(50lg/d, divided as two capsules) for 21 days, followed by 2 weeks off LT 3,o r (b) identical-appearing placebo for LT 3(two pills per day) for 21 days. In both groups, either the LT 3or 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 hypothyroidismsymptom score (Billewicz
scale), which was ascertained in a double-blind fashion at time of LT 4withdrawal and every 2 weeks until the end of the study. The randomization method wasa computer-generated number sequence; the LT 3group 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. Approximately15% of participants withdrew from this trial (two in the placebo group and one in the LT 3group). Leboeuf et al. (690) reported no signiﬁcant differences between the two thyroid hormone58 HAUGEN ET AL.
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 notsigniﬁcantly different between groups. In summary, availableevidence from recent RCTs suggests that either direct LT 4 withdrawal or LT 4withdrawal with substitution of LT 3in initial weeks is associated with similar short-term quality of life andhypothyroidism 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 (LT 4and LT 3) 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-LT 4TSH level, sex, age, histology, baseline RAI up- take, and extent of surgery). In two retrospective studies, eachincluding several hundred DTC patients who underwent thy- roid hormone withdrawal, no signiﬁcant association was ob- served between pre-RAI TSH and rate of successful remnantablation, 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 notnecessarily 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 mayhave 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 hormonewithdrawal in considering long-term outcome effects. [B39] Can rhTSH (Thyrogen) be used as an alternative to thyroxine withdrawal for remnant ablation or adjuvant therapy in patients who haveundergone near-total or total thyroidectomy? &RECOMMENDATION 54 (A) 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 oradjuvant therapy is planned, preparation with rhTSH stimu- lation is an acceptable alternative to thyroid hormone with- drawal for achieving remnant ablation, based on evidence ofsuperior 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)(B) 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 tothyroid hormone withdrawal prior to adjuvant RAI treatment.(Weak recommendation, Low-quality evidence) (C) 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)(D) In patients with DTC of any risk level with signiﬁ- cant comorbidity that may preclude thyroid hormone withdrawal prior to iodine RAI administration, rhTSHpreparation 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) inabilityto 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 includingthe 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 nothave 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 thatrhTSH 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 patientswith 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-differentiatedthyroid cancer
without distant metastases undergoing RAI remnant ablation (T1–T3, N1 or N0, all M0), the rate of successful remnant ablation, was not signiﬁcantly differentafter rhTSH preparation compared to thyroid hormone withdrawal, using 131I dose activities ranging from 30 to 100 mCi (691,698–702). Patients with resected cervical lymphnode 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 patientsand 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 termATA THYROID NODULE/DTC GUIDELINES 59
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 withdrawalpreparation, 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 Tgmeasurements 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 LT 4withdrawal 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 notsigniﬁcantly 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 includingsix of the previously mentioned RCTs, also suggested that the success of remnant ablation was not signiﬁcantly different between patients prepared with rhTSH or thyroid hormonewithdrawal, 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 similarrates 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 datawere 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% ofpatients), with no deaths (706). In the same study, repeattreatment 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 thisstudy (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 LT 4withdrawal ( 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 waslikely 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) for18% 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 inpreparing 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, Pitoiaet 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 meanfollow-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 RAItreatment 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 withRAI-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 preparedprior 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 followedby 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 toRAI ﬁxed dosing. Some important differences among groupsin 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 adjustfor 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, therewere 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, suchas rates of use of dosimetry and mean cumulative RAI activity.
Rates of xerostomia, leukopenia, or thrombocytopenia were not signiﬁcantly different between treatment groups in thisstudy. 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 because80% of the individuals in the rhTSH group and 46% in thethyroid hormone withdrawal group had dosimetry-based RAI treatment. RCTs comparing rhTSH to thyroid hormone with- drawal preparation pre–RAI treatment, are clearly needed toguide clinical care in higher risk DTC patients. [B40] What activity of131I should be used for remnant ablation or adjuvant therapy? &RECOMMENDATION 55 (A) 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-60 HAUGEN ET AL.
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)(B) 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) &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 mCiare generally recommended (in absence of known distantmetastases). 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) 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 subsequentdiagnostic RAI scan. In this section, we only included publishedoriginal 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 whowere 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 healthcare 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 stagepT1 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 intwo 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 nodedisease were excluded from one trial (692), and lymph nodestaging 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 extentsuggested 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), 50mCi compared to 100 mCi in two trials (715,716), or 30 mCicompared 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 tri als after preparation with thyroid hormone withdrawal (699,701,714) and in two trialsafter 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 hormonewithdrawal, 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. ( 6 9 2 )r e p o r t e dt h a ta na d m i n i s t e r e d 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 initialadministration 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 notcompletely understood but could potentially be due to dif- ferences in study populations, completeness of surgery (including size of the remaining remnant), or sensitivity oftechniques 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 patientstreated 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 outcomedata 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-p a r e dt o3 %f o ri n i t i a la d m i n i s t e r e da c t i v i t i e so f6 0o r1 0 0m C i (reported to be not signiﬁcantly different), and distant meta- static recurrence in 0% of the patients in all of the treatmentgroups. 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% ofpatients treated with activities of 30 and 100 mCi, respectively; and no thyroid cancer–related deaths in any of the treatment groups.ATA THYROID NODULE/DTC GUIDELINES 61
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 mCicompared to 100 mCi in the majority of studies comparingthese 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 therapyare 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
strictas 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 loweradministered 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 survivaldifferences in younger patients ( <45 years old) who received lower administered activities of 131I(£54 mCi) compared with those receiving higher administered activities. Theolder patients ( ‡45 years old),
however, who received lower administered activities of131I(£54 mCi) did have a lower disease-speciﬁc survival compared with those receivinghigher 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 loweradministered 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 DTCwas present (25). Since that time, at least ﬁve retrospective, single institution studies have compared clinical outcomes following various adjuvant RAI ﬁxed activities in ATAintermediate-risk and ATA higher risk patients, withoutdistant 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 individualswith 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 studyincluding 176 DTC patients with a primary tumor size £2c m in diameter and microscopic extrathyroidal extension, no signiﬁcant differences were found in a comparison of rates ofsuccessful remnant ablation and long-term recurrences inpatients 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 meanprimary 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 of131I 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 activityand 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). Inthe 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, presumablywithout initiation of thyroid hormone because rhTSH was notreported 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 thesestudies. Overall, there is little evidence to suggest that in- creasing administered activities of adjuvant RAI is neces- sarily associated with improvement of clinical outcomes forpatients with ATA intermediate- and high-risk disease without evidence of persistent disease.
There is an important unmet need for RCTs examining thyroid cancer–relatedoutcomes, 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.62 HAUGEN ET AL.
[B41] Is a low-iodine diet necessary before remnant ablation? &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 studiesexamining 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 systematicreview of observational studies in this area, the most com- monly studied LIDs allowed for £50lg/d of iodine for 1–2 weeks and that the use of LIDs appeared to be associated withreduction 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 remnantablation 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 1week) 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 ofsuccessful 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 in131I 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 tosituations in which a speciﬁc LID is prescribed. Such ﬁndingsmay 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, espe cially in patients undergo- ing thyroid hormone withdrawal. Some examples of LID descriptions for patients, may be found at the followingwebsites: 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). [B42] Should a posttherapy scan be performed following remnant ablation or adjuvant therapy? &RECOMMENDATION 58 A posttherapy WBS (with or without SPECT/CT) is rec- ommended after RAI remnant ablation or treatment, toinform disease staging and document the RAI avidity ofany structural disease. (Strong recommendation, Low-quality evidence) 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 scansin 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% of39 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 remainingfollowing 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 12days following therapeutic RAI
(643,733–735,737,738), withsome 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 andseventh day following ablative or therapeutic RAI adminis- tration for mixed-risk DTC (following thyroid hormone withdrawal) (738). The authors of this study reported that theconcordance 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 scansproviding 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, suchas pretherapy RAI scans. The potential utility of the combination of RAI post-
therapy scanning in conjunction with SPECT/CT has beenexamined in multiple prospective (737,739,740) and retro- spective studies (741–743). The majority of these studies (737,739–742) have independently conﬁrmed the presenceof disease by means such as alternative imaging studies,histopathology, or clinical follow-up. In a single-centerATA THYROID NODULE/DTC GUIDELINES 63
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 29months) (737). Furthermore, in a multivariate analysis re- ported in this study, posttherapy RAI scanning with SPECT/ CT signiﬁcantly independently predicted an increased riskof 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 61patients 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 of33] 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/chestSPECT/CT to all posttherapy scans was esti mated to alter postsurgical ATA r ecurrence risk estimate in 6.4% (7 of 109) of patients (743), impact therapeutic planning inabout 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 theunderlying pathologic diagnosis or long-term clinicalsigniﬁcance 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 top r e v a i lo nt h eu t i l i t yo fa l t e r native cross-sectional imag- ing studies, considering factors such as clinical-pathologic stage, the completeness of surgery, inappropriate thyr-oglobulinemia, and, if perf ormed, the posttherapy RAI scan result. [B43] Early management of DTC after initial therapy [B44] What is the appropriate degree of initial TSH suppression? &RECOMMENDATION 59 (A) For high-risk thyroid cancer patients, initial TSH suppression to below 0.1 mU/L is recommended. (Strong recommendation, Moderate-quality evidence) (B) For intermediate-risk thyroid cancer
patients, initial TSH suppression to 0.1– 0.5 mU/L is recommended.(Weak recommendation, Low-quality evidence) (C) 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 survei llance 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)(D) 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)(E) 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 ifpatients can maintain their serum TSH in this target range. (Weak recommendation, Low-quality evidence) 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 ofTSH, using supraphysiologic doses of LT 4, 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 supportedthe efﬁcacy of TSH suppression therapy in preventing majoradverse 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 LT 4suppression therapy (TSH <0.01 mU/L). Extent of residual disease is
uncertain in these patients in that most did not undergo total thyroidectomy or RAIablation 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 thelatter 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 IIpatients. Suppression of TSH was not beneﬁcial in patients withNTCTCSGstage I disease. In another study, there was a positive association between serum TSH levels and the risk for recurrent64 HAUGEN ET AL.
disease and cancer-related mortality (750). Adverse effects of TSH suppression may include the known consequences of subclinical thyrotoxicosis, including exacerbation of anginain patients with ischemic heart disease, increased risk for atrialﬁbrillation 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 thepotential beneﬁt of TSH suppression with the possible harm from subclinical thyrotoxicosis especially in patients with medical conditions that can be exacerbated with aggressiveTSH suppression. There is little evidence to guide TSH targets or the use of thyroid hormone in ATA low-risk patients who have undergonelobectomy. Most of the studies evaluating lobectomy for thesepatients 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 funct ion 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 anddisease-speciﬁc survivals were not different between the pa- tients who underwent thyroidect omy versus a lesser operation, although it was common for the patients undergoing lobectomyto also receive an ipsilateral ce ntral neck dissection. More re- search is needed in this area to help guide management of those patients undergoing lobectomy for low-risk DTC. [B45] Is there a role for adjunctive external beam radiation therapy or chemotherapy?
[B46] External beam radiation therapy &RECOMMENDATION 60 There is no role for routine adjuvant EBRT to the neck in patients with DTC after initial complete surgical removalof the tumor. (Strong recommendation, Low-quality evidence) The application of adjuvant neck /thyroid bed/loco-regional radiation therapy in DTC patients remains controversial. Inparticular, 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 patientswith locally advanced disease (7 56,757) 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 adequateprimary 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-operationsversus 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 isaddressed in another section (Recommendation 72). [B47] Systemic adjuvant therapy &RECOMMENDATION 61 There is no role for routine systemic adjuvant therapy inpatients with DTC (beyond RAI and/or TSH suppressivetherapy using LT 4). (Strong recommendation, Low-quality evidence) There are no clinical trial data to indicate that any adjuvant therapy beyond RAI and/or TSH suppressive therapy usingLT 4has 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 verygood—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 beneﬁtin 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 LT 4) remains uncertain. Doxorubicin may act as a radiation sensitizer in some tumorsof 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 Tgin the setting of no identiﬁable progression of anatomical disease have sufﬁciently high future risks from disease to justify the application of adjuvant systemic therapy beyondRAI and/or TSH suppressive therapy using LT 4. [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 lessaggressive management strategies can be used that may bemore 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 thebest 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-dose131I 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 variedwidely 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. Treatmentthus appears safe and does not shorten life expectancy. Al- though an increased incidence of second tumors in thyroidATA THYROID NODULE/DTC GUIDELINES 65
cancer patients has been recognized after the administration of high cumulative activities of131I (762,763), this elevated risk was not found to be associated with the use of131I in another study (764). RAI therapy in low-risk patients did not affectmedian 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): 1. No clinical evidence of tumor 2. 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 ona recent diagnostic or posttherapy WBS) and/or neck US 3. 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? [C5] What is the role of serum Tg measurement in the follow-up of DTC? &RECOMMENDATION 62 (A) Serum Tg should be measured by an assay that is calibrated
against the CRM457 standard. Thyroglobulin antibodies should be quantitatively assessed with everymeasurement 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) (B) During initial follow-up, serum Tg on thyroxine therapy should be measured every 6–12 months. More frequent Tgmeasurements may be appropriate for ATA high-risk patients. (Strong recommendation, Moderate-quality evidence)(C) 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)(D) Serum TSH should be measured at least every 12 months in all patients on thyroid hormone therapy.(Strong recommendation, Low-quality evidence) (E) 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 monthsfor several years. (Weak recommendation, Low-quality evidence) &RECOMMENDATION 63 (A) 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)(B) 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)(C) Subsequent TSH-stimulated Tg testing may be con- sidered in patients with an indeterminate, biochemicalincomplete, or structural incomplete response following either additional therapies or a spontaneous decline in Tg values on thyroid hormone therapy over time in order toreassess response to therapy. (Weak recommendation, Low-quality evidence) 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-riskpatients with a Tg on LT 4treatment below 0.1–0.2 ng/mL (393,587,595,601,606,769). [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 calibratedagainst 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), leadingto 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-Tgautoantibodies, which commonly cause falsely low serum Tgmeasurements. 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 Tgautoantibody 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 there66 HAUGEN ET AL.
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 falselyelevated Tg levels (776–778). However, radioimmunoassaysfor 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 remnantablation. 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-freestatus (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 Tgby 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 commonlyfollowing TSH stimulation may fail to identify patients with relatively small amounts of residual tumor (583,649, 780,781). These minimal amounts of residual disease areoften 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 ofimmunoreactive 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 poorlydifferentiated 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 signiﬁcantmorbidity (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 ofidentifying 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 andnegative 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 ofsome patients. In one study using such an assay, a T 4- 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 of98.6% 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 theexpense 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 sensitivityand speciﬁcity for detecting persistent disease. With the use of these sensitive Tg assays, it was concluded that an annual serum Tg on LT 4treatment 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 undetectablepostoperative 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 versushigher 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 asthe 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 thispatient 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 andwill 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 followingrhTSH stimulation is highly sensitive in identifying patients with persistent tumor (785,789–794). However, the results of serum Tg measurements made on the

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