Context: Recent trial results have revived interest in low-activity initial 131 I therapy (RIT) of differentiated thyroid cancer (DTC).

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1 ORIGINAL ARTICLE Endocrine Care Long-Term Survival in Differentiated Thyroid Cancer Is Worse After Low-Activity Initial Post-Surgical 131 I Therapy in Both High- and Low-Risk Patients Frederik A. Verburg, Uwe Mäder, Christoph Reiners, and Heribert Hänscheid Department of Nuclear Medicine (F.A.V., C.R., H.H.), and Comprehensive Cancer Center Mainfranken (U.M.), University of Wuerzburg, Wuerzburg, Germany; and Department of Nuclear Medicine (F.A.V.), RWTH University Hospital Aachen, Aachen, Germany Context: Recent trial results have revived interest in low-activity initial 131 I therapy (RIT) of differentiated thyroid cancer (DTC). Objective: This study sought to compare different initial 131 I activities for outcome. Design and Setting: A database study was performed in a University hospital. Patients: 1298 DTC patients were included (698 low risk, 434 high risk M0, and 136 M1), grouped according to ablation activity (I, 2000 MBq [54 mci]; II, MBq [54 81 mci]; and III, 3000 MBq [81 mci]), subdivided by age ( 45 and 45 y at diagnosis). Main Outcome Measures: Complete remission (CR, defined as thyroglobulin [Tg] below functional sensitivity combined with visually negative 131 I diagnostic whole-body scintigraphy), recurrence, DTC-specific mortality, and relative survival rates were studied. Results: Low-risk patients: In patients 45 years, a lower median cumulative activity was required to achieve CR in group III (3590 MBq) than in groups I (8050 MBq) and II (6300 MBq). In patients at least 45 years of age, DTC-specific mortality was significantly higher in group I than in groups II and III (15-y: %, %, and %, respectively; P.004). High-risk M0 patients: In patients at least 45 years of age, the recurrence rate (15-y: %, %, and %; P.001) and DTC-specific mortality (15-y: %, %, and %; P.004) were significantly higher in group I than in groups II and III. M1 patients: There were no significant differences in survival results between different activity groups in either age category. Conclusion: Before adopting low initial activity RIT for, especially older, low-risk patients, results of long-term followup should be regarded critically. Low-activity RIT in older, high-risk patients is not to be recommended. (J Clin Endocrinol Metab 99: , 2014) Differentiated thyroid cancer (DTC) treatment usually consists of thyroidectomy, often followed by radioiodine therapy (RIT) for thyroid remnant ablation and adjuvant therapy of microscopic tumor foci (1 3). The addition of RIT after surgery significantly improves prognosis, especially in high-risk patients with DTC (4 8). Although numerous studies have been performed to optimize the outcome of initial RIT, the required amount of ISSN Print X ISSN Online Printed in U.S.A. Copyright 2014 by the Endocrine Society Received March 5, Accepted September 23, First Published Online September 26, I is still controversial, not least because of a comparative lack of long-term data on hard prognostic endpoints such as recurrence or DTC-related mortality rates in the function of the initially administered 131 I activity. Studies suggested that successful 131 I remnant ablation is an indicator of good prognosis in patients with DTC (9 12). In view of the long followup required for conclusive prognostic results in patients with DTC, many studies Abbreviations: CI, confidence interval; CR, complete remission (defined as TSH stimulated Tg functional sensitivity of the assay used in combination with negative diagnostic 131 I scintigraphy and negative neck ultrasound); DTC, differentiated thyroid cancer; DxWBS, diagnostic whole-body scintigraphy; rhtsh, recombinant human thyroid-stimulating hormone; RIT, radioiodine therapy; Tg, thyroglobulin. doi: /jc J Clin Endocrinol Metab, December 2014, 99(12): jcem.endojournals.org 4487

2 4488 Verburg et al Low Activity 131 I Therapy and Prognosis J Clin Endocrinol Metab, December 2014, 99(12): therefore focus on successful ablation as a surrogate measure of outcome of 131 I therapy. Different definitions of successful initial RIT are used in the literature. The more lenient ones, focusing on thyroid remnant ablation, result in high success rates, usually exceeding 90% (13, 14), whereas stricter definitions, which focus on the efficacy of 131 I therapy as adjuvant therapy of potentially remaining tumor foci, result in much lower success rates (9 12). Recently, results from two major trials showing equal remnant ablation success with low (1110 MBq/30 mci) and high (3700 MBq/100 mci) 131 I activities (13, 14) have renewed interest in low activity ablation. However, these studies were not laid out to study the efficacy of initial 131 I therapy as an adjuvant therapy and thus long term results on recurrence and DTC-related mortality rates as a function of the initial 131 I activity are lacking. In our center, a definition of complete remission (CR) that focuses on the efficacy of 131 I therapy as an adjuvant therapy, including undetectable Tg and negative diagnostic 131 I whole-body scintigraphy, was applied in combination with different activities used for 131 I ablation in different time periods. In the present study in we aim to compare different 131 I ablation activities as an adjuvant DTC therapy for outcome in terms of complete remission (CR), DTC recurrence, DTC-related death, and potential loss of life expectancy. Materials, and Methods Definitions Papillary and follicular DTC were classified according to World Health Organization standard at the time of initial treatment. Based on clinical and pathology reports, patients were staged in accordance with version 7 of the UICC/AJCC TNM system (15). Patients with pt1 2 tumors without lymph node or distant metastases were defined as having low risk, and those with pt3 4 tumors or metastases were defined as high-risk patients. CR was defined as a negative ultrasound of the neck, undetectable (ie, below the functional sensitivity of the assay used) TSH-stimulated Tg, and a concurrent absence of 131 I uptake on diagnostic whole-body scintigraphy (dxwbs) during TSH stimulation after 131 I therapy; detectable thyroglobulin and any visually discernible uptake was considered pathologic both in clinical practice and for the purpose of this study. Such uptake triggered an additional 131 I therapy. Any patient who did not fully meet the criteria for CR at any time during followup was considered to have persistent disease and was therefore not included in analyses of recurrence rates. Recurrence was defined as any of the following events occurring during followup after CR (ie, once TSH stimulated Tg and 131 I dxwbs were negative): cytologic/histologic evidence of disease, detectable Tg levels in the absence of anti-tg antibodies during thyroid hormone replacement and/or after endogenous or exogenous TSH stimulation, and new foci of pathologic uptake on 131 I dxwbs. Patients were assumed to have died of DTC if this was stated in their file or if DTC was stated as a main or contributing cause of death on the patient s death certificate. Database The Department of Nuclear Medicine of the University of Würzburg established its Thyroid Cancer Database in This database allows for larger prospective longitudinal scientific population studies in patients with DTC (9, 16 19). Data are recorded by medical documentation specialists for each visit. Collected data include basic pathology data as well as results of diagnostic and therapeutic procedures. The registry is regularly updated through inquiries with the referring physicians as well as until 2008 with the public registration offices. The cause of death was verified through inquiry with the death certificate registry of the Bavarian public health offices. The database, as part of a larger local system of oncologic databases, is updated and analyzed with approval of and continuous monitoring by the local medical ethical committee. At their first visit to our hospital, patients were asked to give written consent for the recording and anonymized analysis of their data. Patients Data from 1602 patients with DTC who were admitted to our database between January 1980 and June 2008 were reviewed. The cut-off date was chosen to allow a possible followup of at least 5 years. Thirty-two patients were excluded as initial treatment took place elsewhere and insufficient data on initial treatment was available in the patients records for the present analysis. Two hundred seventy-two patients did not receive RIT after surgery, mostly because of the presence of papillary microcarcinoma, and were therefore excluded. Thus, the final study population consisted of 1298 patients who underwent total thyroidectomy and one or more courses of 131 I therapy. Details on these patients can be found in Table 1. Treatment After surgery, thyroid bed uptake measurement with less than 5 MBq 131 I and ultrasound of the neck were performed. Patients with 131 I uptake of greater than 10% were usually reoperated on before treatment, as were patients with remaining lymph node metastases found during pre-rit work-up. The 131 I activity typically administered in our hospital for initial postsurgical RIT changed with time: 2600 MBq (70 mci) up to 1990, 1000 MBq (27 mci) was given first in May 1990 and last in October 1997; from June 1996 onward, this overlapped with a protocol using 3500 MBq (95 mci), which was used afterward. The activities were based on physician preference of the responsible nuclear medicine physicians at the time. Variations in activities concerned individualization based on the results of the uptake measurement and initial staging as well as adjustments based on clinical judgment of the responsible physician. Furthermore, patients who were initially treated outside of our hospital but had sufficient information available for the present study were treated with different activities, including both high ( 3000 MBq) in the 1980s and low ( 2000 MBq) after the mid 1990s.

3 doi: /jc jcem.endojournals.org 4489 Table 1. Patient Characteristics at the Time of Diagnosis of the Patients Included in the Study, Divided by 131 I Ablation Activity and Subdivided by Age I II III Group Ablation Activity <2000 MBq Low-Risk Patients MBq >3000 Low-Risk Patients MBq Age Group <45 y >45 y <45 y >45 y <45 y >45 y P Value Patients, n Sex.82 a Male Female Histology.08 a Papillary Follicular Median age (range), y 33.7 ( ) 63.4 ( ) 33.2 ( ) 58.8 ( ) 34.0 ( ) 58.2 ( ).19 b T-stage.10 a pt1a pt1b pt pt pt4a pt4b Unknown Lymph node status.64 a cn cn Distant metastases.024 a cm cm TNM stage.44 a I II III IVa IVb IVc Unknown P values concern tests for differences between the different activity groups. a 2 test. b Kruskall-Wallis test. Reflecting the activities given in different time periods we divided patients into three groups according activity: group I, 2000 MBq (54 mci); group II, (54 81 mci); and group III, 3000 MBq (81 mci). After 131 I ablation, TSH-suppressive levothyroxine treatment was initiated as well as life-long followup at half-yearly intervals for the first 5 years and yearly intervals thereafter by means of Tg measurement. Six to 12 months after initial RIT patients underwent 131 I diagnostic whole-body scintigraphy (dxwbs) and Tg measurement after withdrawal of levothyroxine or, in later years, after exogenous stimulation with recombinant human thyroid-stimulating hormone (rhtsh). Until 2008 this was repeated at least once more within the first 2 years after diagnosis. Ultrasound of the neck was performed at each in-patient treatment and each out-patient follow-up visit. X-rays, computed tomography scans, or magnetic resonance imaging scans and were performed on indication. Initial RIT of patients with known metastases and RIT of persistent or recurrent disease was performed with 7000 MBq (189 mci) or, in selected patients, with a dosimetrically determined (20) activity. 131 I therapy was abandoned if the cancer became 131 I refractory as defined by a failing biochemical and/or structural response or the diagnosis of 131 I negative metastases. Laboratory analysis For the purpose of this study, classification of Tg levels as undetectable was based on the functional sensitivity of the assay used in that particular follow-up examination rather than on a single cut-off value. Assays were purchased from Henning, later called B.R.A.H.M.S. (Thermofisher Scientific B.R.A.H.M.S.). Over time, declared functional sensitivity of these assays improved: 5 g/l until 1989, 1 g/l from 1989 to 1996, 0.3 g/l from 1996 to 2001, and 0.2 g/l from 2001 onward. Statistical analysis Categorical variables were compared using a 2 test. Comparison of multiple categories for a continuous variable was performed using the Kruskall-Wallis test. A Bonferroni correction for multiple testing was not applied. Specific influences on survival were analyzed using univariate Cox regression analysis. DTC-specific survival and recurrencefree survival were analyzed using the Kaplan-Meier method, augmented by a log-rank test for differences between survival curves. DTC-specific survival was calculated from the date of diagnosis. Recurrence-free survival was calculated from the date of the follow-up examination at which CR was ascertained. Analysis of relative survival was performed using SurvSoft version 2.0 (21) (Bavarian Cancer Registry) using the method described by Ederer et al (22) employing standardized mortality rates by birth year and sex as compiled by the German Federal Bureau of Statistics (available through For the purpose of this study, life expectancy was considered reduced when the upper limit of the 95% confidence interval (CI)

4 4490 Verburg et al Low Activity 131 I Therapy and Prognosis J Clin Endocrinol Metab, December 2014, 99(12): of the relative survival at any time during follow-up was lower than 1.0. Results Follow-up and results of treatment The disease status could not be assessed in 125 patients who did not return to our center for TSH stimulated follow-up; these patients were excluded from analysis of CR and recurrence rates. An additional 333 patients never reached CR and were therefore excluded from analyses of recurrence rates. Table 1 shows that aside from a difference in the distribution of the number of patients with distant metastases, there were no significant differences in baseline characteristics between the three activity groups. Furthermore, it is well established that DTC shows considerable differences in clinical behavior between patients below or at least 45 years at diagnosis (15). In Cox regression analyses this turned out to be the case in the present collective as well, with these age categories significantly affecting the risk of recurrence (low risk, P.047; high risk M0, P.004; high risk M1, P.19) as well as DTC-related death (low risk, P.20; high risk M0, P.001; high risk M1, P.001) in most cases. We therefore subdivided the risk categories by age. To compensate for the difference in proportion of patients with distant metastases, we have analyzed these patients separately from other high-risk patients. Results of treatment and follow-up are compiled in Table 2. The most important results are elaborated upon below. Low-risk patients In both younger ( 45 y) and older ( 45 y) patients, the rate of successful initial RIT was significantly higher after a high initial activity. Conversely, the number of RITs required to achieve CR was lower in the group with a high initial activity which in younger patients in median also resulted in a lower cumulative activity required to achieve CR. In older low-risk patients, DTC-specific mortality was low and not significantly different between groups II and III (P.162) but in the long term (10 15 years) was significantly higher in group I (P.002) than in groups II and III (Figure 1). Life expectancy was not significantly impaired in any of the three activity groups in either age category. High-risk patients (M0) In both younger ( 45 y) and older ( 45 y) patients, the rate of successful initial RIT was significantly higher after a high initial activity. Conversely, the number of RITs required to achieve CR was lower in the group with a high initial activity. In older high-risk patients without distant metastases, the recurrence and DTC-specific mortality rates differed significantly between the three activity groups. Whereas the recurrence rates were not significantly different between groups II and III (P.639), the recurrence rate in group I was significantly higher than in the other groups (P.001; Figure 2). In older, low-risk patients, the DTC-specific mortality rate was not significantly different between groups II and III (P.567) but was significantly higher in group I (P.001) than in groups II and III (Figure 3). Although life expectancy was not significantly impaired in any of the three activity groups in younger patients, it was impaired (ie, showed an upper limit of the 95% CI below 1.0) in both group I and group III in patients at least 45 years of age at diagnosis. Patients with distant metastases Neither in older, nor in younger M1 patients were significant differences found between the different activity groups with respect to the total rates of CR, the rates of successful initial RIT, the recurrence rates in the few patients who reached CR and the DTC-specific mortality rates. Furthermore, life expectancy was similarly impaired in all three groups in older patients but remained unimpaired in all three activity groups in younger patients. Discussion The present study provides a new perspective in the discussion on high vs low 131 I activities for initial RIT. Several results obtained in the present study can be interpreted to speak against the use of very low activities for initial 131 I ablation. The most important findings concern the higher DTC-related mortality rates found in group I in both lowand high-risk M0 patients at least 45 years of age at diagnosis and the higher recurrence rate in older high-risk patients without distant metastases. However, the significantly higher cumulative activity required to achieve CR in young, low-risk patients who initially received lower initial 131 I activity RIT can be considered clinically significant as well as these patients, considering their long remaining life expectancy, will especially be at risk of long-term, mostly dose-dependent side effects of radiation exposure. Many studies have endeavored to identify the best activity for initial RIT in DTC (3). Predominantly, these studies focused on the rates of successful thyroid remnant ablation as defined by the guidelines of the American Thy-

5 doi: /jc jcem.endojournals.org 4491 Table 2. Results of Treatment and Follow-Up I II III P Value Low-risk patients 45 y at diagnosis Patients, n Duration of follow-up, y 10.4 ( ) 17.1 ( ) 6.5 ( ).001 a Ablation activity, MBq 1000 ( ) 2600 ( ) 3500 ( ).001 a Overall rate of CR 81.8% 85.4% 83.4%.86 b Rate of CR after first RIT 13.6% 33.6% 65.6%.001 b Median No. of RIT for CR 2 (1 3) 2 (1 4) 1 (1 3).001 a Median cumulative activity for 8050 ( ) 6300 ( ) 3590 ( ).037 a Recurrence rates after CR.62 c 5-y N/A % % 10-y N/A % % 15-y N/A % % DTC-related mortality rates.38 c 5-y N/A 0% N/A 10-y N/A 0% N/A 15-y N/A % N/A 5-y 0.95 ( ) 1.00 ( ) N/A 10-y 0.95 ( ) 1.00 ( ) 0.99 ( ) 15-y 0.87 ( ) 0.99 ( ) 0.99 ( ) Low-risk patients 45 y at diagnosis Patients, n Duration of follow-up, y 11.6 ( ) 13.1 ( ) 6.0 ( ).001 a Ablation activity, MBq 1003 ( ) 2600 ( ) 3500 ( ).001 a Overall rate of CR 77.5% 78.9% 80.6%.87 Rate of CR after first RIT 30.0% 27.0% 64.8%.001 b Median No. of RIT for CR 2 (1 3) 2 (1 5) 1 (1 3).001 a Median cumulative activity for 7950 ( ) 6300 ( ) 3530 ( ).40 Recurrence rates after CR.92 c 5-y % % % 10-y % % % 15-y % % % DTC-related mortality rates.004 c 5-y % 0% 0% 10-y % % % 15-y % % % 5-y 0.99 ( ) 1.02 ( ) 0.99 ( ) 10-y 1.00 ( ) 0.97 ( ) 0.96 ( ) 15-y 0.89 ( ) 1.04 ( ) 0.96 ( ) High-risk patients without distant metastases 45yat diagnosis Patients, n Duration of follow-up, y 14.4 ( ) 17.3 ( ) 6.1 ( ).001 a Ablation activity, MBq 1000 ( ) 2600 ( ) 3520 ( ).001 a Overall rate of CR 69.2% 71.8% 62.4%.39 b Rate of CR after first RIT 30.1% 27.1% 44.6%.043 b Median No. of RIT for CR 1 (1 3) 2 (1 5) 1 (1 6).001 a Median cumulative activity for 1850 ( ) 6300 ( ) 3600 ( ).23 Recurrence rates after CR.56 5-y N/A % N/A 10-y N/A % N/A 15-y N/A % N/A DTC-related mortality rates.64 5-y N/A N/A % 10-y N/A % % 15-y N/A % % (Continued)

6 4492 Verburg et al Low Activity 131 I Therapy and Prognosis J Clin Endocrinol Metab, December 2014, 99(12): Table 2. Continued I II III P Value 5-y N/A N/A 0.98 ( ) 10-y N/A 0.97 ( ) 0.98 ( ) 15-y N/A 0.97 ( ) 0.98 ( ) High-risk patients without distant metastases 45yat diagnosis Patients, n Duration of follow-up, y 7.6 ( ) 12.0 ( ) 6.5 ( ).001 a Ablation activity, MBq 1040 ( ) 2600 ( ) 3480 ( ).001 a Overall rate of CR 43.5% 61.6% 62.2%.22 b Rate of CR after first RIT 8.7% 21.4% 38.7%.001 b Median No. of RIT for CR 2 (1 2) 2 (1 5) 1 (1 5).001 a Median cumulative activity for 8000 ( ) 6300 ( ) 3590 ( ).76 a Recurrence rates after CR.001 c 5-y % % % 10-y % % % 15-y % % % DTC-related mortality rates.004 c 5-y N/A % % 10-y % % % 15-y % % % 5-y 0.94 ( ( ) 0.99 ( ) 10-y 0.73 ( ) 0.98 ( ) 0.84 ( ) 15-y 0.45 ( ) 0.91 ( ) 0.71 ( ) High-risk patients with distant metastases, 45yat diagnosis Patients, n Duration of follow-up, y 9.0 ( ) 12.3 ( ) 6.6 ( ).10 a Ablation activity, MBq 1455 ( ) 2600 ( ) 3500 ( ).001 a Overall rate of CR 12.5% 25.0% 53.8%.10 b Rate of CR after first RIT 0% 12.5% 7.7%.57 b Median No. of RIT for CR Not available (n with 1.5 (1 6) 2 (1 4).60 a CR 1) Median cumulative activity for ( ) ( ).67 a Recurrence rates after CR N/A 5-y N/A N/A N/A 10-y N/A N/A N/A 15-y N/A N/A N/A DTC-related mortality rates.154 c 5-y % % N/A 10-y % % N/A 15-y % % N/A 5-y 0.88 ( ) 0.94 ( ) N/A 10-y 0.75 ( ) 0.94 ( ) N/A 15-y 0.75 ( ) 0.94 ( ) N/A High-risk patients with distant metastases, 45yat diagnosis Patients, n Duration of follow-up, y 2.6 ( ) 5.6 ( ) 5.1 ( ).871 a Ablation activity, MBq 1100 ( ) 2600 ( ) 4035 ( ).001 a Overall rate of CR 27.2% 15.2% 7.1%.18 b Rate of CR after first RIT 0% 4.4% 2.4%.70 b Median No. of RIT for CR 2,5 (1 11) 3,5 (1 10) 1,5 (1 3) 0,55 a Median cumulative activity for ( ) ( ) ( ).18 a (Continued)

7 doi: /jc jcem.endojournals.org 4493 Table 2. Continued I II III P Value Recurrence rates after CR.64 c 5-y % % % 10-y % % % 15-y % % % DTC-related mortality rates.911 c 5-y % % % 10-y % % % 15-y % % % 5-y 0.48 ( ) 0.62 ( ) 0.73 ( ) 10-y 0.42 ( ) 0.51 ( ) 0.49 ( ) 15-y 0.30 (0 0.78) 0.41 ( ) 0.26 (0 0.55) Abbreviation: N/A, not applicable due to lack of events. All values are given as median (range) or as mean SD. a Kruskall-Wallis test. b 2 test. c Log-rank test on survival curves calculated using the Kaplan-Meier method. roid Association (1) and have been performed in low-risk patients. Although the results of meta-analyses of these studies are still controversial (23 25), there is now substantial evidence that 1.1 GBq (30 mci) 131 I is sufficient to bring the post-therapeutic Tg level down to 1 2 ng/ml and to reduce the residual thyroid remnant uptake to below % in most patients (13, 14). This may not be surprising considering that activities as low as 74 MBq are able to reduce the fractional uptake (26). Using more lenient criteria for treatment success, solely aimed at the evaluation of successful thyroid remnant ablation, less activity will be sufficient to fulfill these criteria. Because ablation rates using such criteria are close to 100%, they are already high enough with low activities not to be distinguishable from those obtained using higher activities. The treatment success rates observed with the strict criteria of CR used in our study, which are primarily aimed at the evaluation of RIT success as an adjuvant oncologic therapy, are much lower but in line with results of other studies applying the same criteria on different patient populations (9, 11, 27). It is possible that the strict criteria applied here will designate patients as having persistent disease who will only have some remaining normal thy- Figure 1. DTC-specific survival in low-risk patients 45 years at diagnosis, stratified according to ablation activity. Figure 2. Recurrence-free survival in high-risk patients without distant metastases 45 years at diagnosis, stratified according to ablation activity.

8 4494 Verburg et al Low Activity 131 I Therapy and Prognosis J Clin Endocrinol Metab, December 2014, 99(12): Figure 3. DTC-specific survival in high-risk patients without distant metastases 45 years at diagnosis, stratified according to ablation activity. roid tissue. Conversely, even the present strict criteria are not completely able to exclude the presence of small foci of remaining disease, as shown by a non-negligible number of recurrences, which would almost certainly be higher if less strict criteria had been applied clinically thus also showing the imperfection of surrogate endpoints. It is debatable whether 131 I dxwbs should still be used in the evaluation of success of initial RIT. Whereas some authors consider the combination of TSH-stimulated Tg measurement and ultrasound to suffice (28), others still consider dxwbs essential in therapy evaluation (29). The present criteria are not only associated with lower overall success rates than in studies applying less strict criteria but likely they contribute to our finding of significant differences between lower and higher activities, with optimal results both in the short term (ie, success rate of initial RIT and CR rates) and in the long term (ie, recurrence and DTC-related mortality) being obtained with activities greater than 3000 MBq. Our results with regard to life expectancy are in line with our earlier study, which showed that most patients with DTC have an unimpaired life expectancy, except for those over the age of 45 years who have lateral lymph node metastases, extensive local invasion, and/or distant metastases (19). The present study is to a certain extent hampered by the low recurrence rates because the low number of events reduces the power of statistical examinations of differences in recurrence free survival. Also, the subdivision of patients according to risk and age reduces the statistical power becasue some of the patient groups, especially those with distant metastases less than 45 years of age at diagnosis (n 37 or 3% of the total study population), are very small. In other patient groups the number of patients in group I is low, so the absence of significant findings does not exclude differences but rather implies that any differences found are of potentially clinically relevant magnitude. Over the years, a number of different immunoassay kits were used for Tg measurement. Because Tg levels cannot be reliably compared quantitatively between kits (30), we opted for a qualitative assessment of Tg levels. Although the improved functional assay sensitivity in more recent years might cause a bias against patient groups treated more recently with regard to ablation success and CR rates, the results in more recent years were in fact better than in earlier time periods. It is furthermore possible that the first TSH-stimulated evaluation of RIT success at 6 12 months after initial RIT might have been too early, as it is now known that Tg levels can show a decrease for a considerably longer period of time afterward (31, 32). Also, the evolution of other follow-up methods, which is inherent to the long observational time span, might introduce a bias. For instance, additional high-sensitivity imaging modalities such as computed tomography or magnetic resonance imaging were not available in the earlier part of the study period. Furthermore, the use of thyroid hormone withdrawal vs the use of rhtsh (33) could be of concern. Given that literature has shown that rhtsh produces qualitatively, but not quantitatively equal results to thyroid hormone withdrawal (28, 33), we again opted for the qualitative approach in setting our criteria for successful ablation with regard to Tg levels and the presence of 131 I uptake. Furthermore, other uncontrolled and to a certain extent uncontrollable variables may have influenced the study, such as differences in surgical techniques between the 1980s and the 2000s. It is also possible that thyroid remnant size is a factor influencing the number of RIT and the cumulative activity required patients with uptake rates of 5 10% hardly underwent total thyroidectomy, but in clinical practice this was thought low enough for RIT application. We were, however, unable to analyze this because despite this measurement being performed in patients, record keeping in the database on this point over the years was poor, leading to an insufficient data quality for this variable. Thus it is also not possible for us to ascertain whether all patients with sufficiently large thyroid remnants were reoperated on. Due to the aforementioned, uncontrollable improvements in surgical techniques, such larger remnants tend to

9 doi: /jc jcem.endojournals.org 4495 be less frequent nowadays than in the 1980s and may therefore cause a bias in our results. In the debate surrounding high vs low activities for 131 I ablation the present study is of considerable clinical importance. Whereas successful remnant ablation is a matter of definition, long-term endpoints of 131 I therapy such as DTC-related mortality are not as open for differences in definitions. However, the present study shows that differences between different activities may take a long time to come to light. Medium term results in a similar study by Castagna et al (34) did not find differences with regard to DTC-specific mortality in a smaller intermediate risk population with a shorter follow-up duration. The differences in low-risk patients treated with different activities in the present study arose after years of follow-up. This is in line with earlier retrospective studies examining RIT vs no RIT in patients with DTC. A meta-analysis showed that those studies with a longer follow-up (exceeding 9 10 y) had a significant difference, especially with regard to recurrence rates and/or the incidence of new distant metastases, whereas those with shorter follow-up did tended not to show a significant effect (8), notwithstanding that some recent reports on large series with a long-term follow-up also showed that in younger low-risk (TNM Stage I patients) (35), and even in higher-risk (T3N0) patients, very good long-term recurrence-free survival rates, which are nearly or equally as good as those observed after RIT, are possible when RIT is applied selectively (36). Therefore, before assuming that low 131 I ablation activities are equal to high 131 I activities with regard to adjuvant therapy of possibly remaining smaller tumor foci in terms of both the total cumulative activity required to achieve CR and in terms of recurrence-free as well as disease-specific survival, a long follow-up period ( y) should be observed. Conclusion Before adopting low-activity initial 131 I therapy as the de facto standard for especially older, low-risk patients, it seems wise to await results of long-term follow-up of recently published trials. Furthermore, based on the present results, low-activity ablation in older, high-risk patients is not to be recommended. Acknowledgments Address all correspondence and requests for reprints to: Frederik A. Verburg, MD PhD, Department of Nuclear Medicine, University Hospital Aachen, Pauwelsstraße 30, Aachen, Germany. fverburg@ukaachen.de. 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