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Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India, 110029
Address all correspondence and requests for reprints to: Dr. C. S. Bal, M.B.B.S., M.D., D.N.B., Additional Professor, Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India, 110029. E-mail: csbal{at}hotmail.com.
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Abstract |
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5 cm), adequate surgery (total/near-total thyroidectomy), and radioiodine neck uptake of less than or equal to 10% had odds ratios of 2.4 [confidence interval (CI), 1.3–3.98], 2.6 (CI, 1.6–4.2), and 2.2 (CI, 1.4–3.5), respectively, for successful remnant ablation. Patients receiving at least 25 mCi of 131I had a three times better chance of getting remnant ablation than patients receiving lesser activity of 131I. Any activity of 131I between 25 and 50 mCi appears to be adequate for remnant ablation. |
Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Unfortunately, the optimal 131I activity required to achieve remnant ablation with a single administration remains controversial. Some advocate that a large activity of 100–150 mCi of 131I is required for successful ablation (18, 19, 20), whereas others believe that an activity as small as 30–50 mCi is sufficient to achieve the same goal (21, 22, 23, 24, 25, 26, 27, 28, 29, 30). Most of these studies are retrospective historical descriptions of heterogeneous groups of patients with different criteria used for patient selection, nonuniformity of treatment methodology, and different criteria used to describe remnant ablation. Our institutional policy over the last three decades is to ablate all significant residual thyroid tissue. Our previous pilot work in this field had concluded that administered 131I activity beyond 50 mCi does not give any incremental success rate of ablation but rather increases whole-body radiation absorbed dose (29). However, that study did not give any definitive answer regarding the lower limit of effective administered activity. Hence, there was need of a large randomized trial to settle this issue of small effective activity of 131I for remnant ablation. The argument is not how large an activity of 131I one may/can administer for remnant ablation but rather how small an effective activity of 131I one can administer to get reasonably good ablation (
80%). Equivalence trials are required more than superiority trials when comparing small activity of 131I with higher activities. Therefore, the objective of the present study was to find out how small should a small dose of 131I (administered activity) be to achieve successful remnant ablation in DTC by using a randomized control trial.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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All India Institute of Medical Sciences, New Delhi, India, is a tertiary care teaching hospital serving the approximately one half billion population of Northern India. The Department of Nuclear Medicine has run a specialty thyroid cancer clinic for the last 35 yr. We have blanket institutional ethics committee approval of using 131I activity from 15–250 mCi as a single administration for carcinoma thyroid ablation/therapy. Any single administration beyond the upper limit needs fresh approval on a case-to-case basis with proper justification. The individual informed written consent was obtained from all patients who participated in this randomized clinical trial. Currently, we are treating approximately 250–260 new DTC patients annually. Between July 1995 and January 2002, in a prospective randomized clinical trial, 565 patients with DTC, who fulfilled the inclusion criteria, were randomized into eight treatment groups. The groups were decided according to the amount of 131I, starting at 15 mCi and increasing the activity in increments of 5 mCi until 50 mCi.
Inclusion criteria. Included in the study were patients having disease confirmed to be limited to the thyroid bed only by clinical, radiological, peroperative, and postsurgical 131I scintigraphic examination and having no evidence of extrathyroid or distant metastases at the time of presentation.
Exclusion criteria. If at any time, extrathyroid disease in the form of either nodal or distant metastases was detected before the first-dose outcome, such patients were excluded from the study. Patients with Hurthle cell carcinoma, poorly differentiated carcinoma, insular carcinoma, medullary thyroid carcinoma, and aggressive variant of papillary carcinoma were also excluded, as they need a different management approach.
The minimum required sample size was determined by using an appropriate formula (for equivalence study) by taking the level of significance (
) of 0.05, power of the study (1 – ß) to be 80%, and precision (d) at 20%. Approximately 48 patients were required to be recruited in each group to fulfill the aim of the study. A simple randomization method (1000 random numbers were generated through a random number table) with concealment was used for allocating the patients to different activity groups in this prospective study. We needed only 384 patients to achieve our target. However, the problem with simple randomization is that, although it gives equal probability for each patient to receive any one of the eight dose schedules, it does not ensure that an equal number of patients will be in each group before 1000 patients are recruited. We went on recruiting patients till each group had at least 48 patients treated in a particular regime. That explains the unequal numbers in the eight groups. This inequality will be smaller and smaller as we approach 1000.
In the postrandomization phase, 56 patients were excluded for various reasons. In 19 patients, nodal/distant metastases (nine nodal and 10 pulmonary/skeletal metastases) were revealed in posttherapy 131I whole-body scans (WBSs), and another 37 patients were either lost to follow-up or had incomplete follow-up data. Therefore, the final analysis was done with 509 patients. Figure 1
depicts the trial profile in detail.
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. The histopathological diagnosis was established in all patients and classified according to the World Health Organization criteria (31). Four hundred and ten (80.6%) patients had papillary thyroid carcinoma, and 99 (19.4%) had follicular thyroid carcinoma.
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The absorbed radiation dose to the thyroid gland was calculated using the formula described by Thomas et al. (32):
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i (g-rad/µCi-h) is the equilibrium dose constant, and 
i is the absorbed fraction. For the purpose of simplification and convenience for the large number of patients, we had made the assumption of an effective T1/2 of 5 d as described by Snyder et al. (33). Maxon et al. (34) had reported a similar effective half-life in cases of DTC. Moreover, we also observed the mean value of 118 ± 14 h for effective half-life after calculating it in randomly selected patients; the remaining patients in whom we could not perform T1/2 estimation, we assumed 120 h (5 d) as a reasonable approximation. Remnant mass was estimated by going through the surgical notes and talking to the operating surgeons, as and when required. After 131I therapy, WBS (post-therapy scan) was done in all patients to look for any nodal/distant metastases missed on low-dose WBS. The patients were then advised to take levothyroxine (2 µg/kg body weight) daily on an empty stomach as suppressive therapy. This was continued until 4–6 wk before the repeat diagnostic studies 6 months later. The preparation for the 6-month posttherapy evaluation was similar to that for the preablation scan. No recombinant human TSH was used in this study. All patients were prepared by conventional methods with serum TSH more than 30 µIU/ml. The repeat diagnostic studies consisted of 2–3 mCi 131I WBS, 48-h RAIU, Tg, and anti-Tg antibody assay. The criteria for ablation were as follows: major criterion of negative 131I WBS and minor criteria of 48-h RAIU less than or equal to 0.2% and Tg less than or equal to 10 ng/ml (29). Fulfillment of any two criteria was required to declare successful ablation. If, after the first posttherapeutic evaluation, the patients did not meet the criteria for thyroid ablation, then additional 131I treatment (25–50 mCi) was administered. Repeat 131I doses were administered until thyroid ablation was achieved, after which annual check-ups were planned with Tg estimation.
Tg was estimated by sequential competitive RIA with a double-antibody method using DPC kits from Diagnostic Products Corp. (Los Angeles, CA). The assay had a detection limit (sensitivity) and functional limit of 2.6 and 10.0 ng/ml, respectively. Intraassay and interassay coefficients of variation were 5.7 and 8.7%, respectively. Anti-Tg antibody was estimated by immunoradiometric assay based on a sandwich method using kits from Immunotech A.S. (Prague, Czech Republic). The assay had a sensitivity of 10 IU/ml (normal values < 100 IU/ml). Intraassay and interassay coefficients of variation were 5.7 and 9.7%, respectively.
Statistical analysis
The values are expressed as mean ± SD. Under univariate analysis, t test and 
2 had been applied for quantitative and qualitative variables, respectively. The baseline comparison, i.e. comparison of different demographic and clinical parameters in different groups, was made and reported accordingly. Furthermore, ANOVA was used to compare the various quantitative parameters in the eight dose groups. Under multivariate analysis, multiple stepwise logistic regressions had been applied for independent covariates such as age, sex, histopathology, tumor size, type of gland, first dose, etc. with first-dose outcome as the dependent variable (ablation/nonablation). A P value < 0.05 was considered significant. The statistical packages SAS (version 8.0) and SPSS (version 10.5) were used for the statistical analyses.
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Results |
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and 2.
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).
Under univariate analysis, 2 test for the association of categorical variables, such as sex, type of gland, type of surgery, and histopathology, with first-dose outcome revealed that only type of surgery had influence over the remnant ablation, with adequate surgery (NTT) having a much higher ablation rate (307/367 = 83.2%) than inadequate surgery (HT/STT) (88/142 = 63.3%). The difference was statistically significant (P = 0.0001). Female to male ratio was 2.9 vs. 1.9 (P = 0.052), type of gland (solitary thyroid nodule/multinodular goiter) was 293/102 vs. 75/39 (P = 0.07), and histopathology (papillary/follicular) was 320/75 vs. 90/24 (P = 0.624) in ablated and nonablated groups, respectively. However, unpaired t test applied to assess the relationship between various quantitative variables, such as age, duration of disease, tumor size, interval between surgery and 131I treatment, postsurgical RAIU, and radiation-absorbed dose with first-dose outcome revealed that only tumor size and postsurgical RAIU had any effect on the first-dose outcome. Mean tumor size and mean RAIU was 4.4 ± 1.8 cm and 8.1 ± 6.4%, respectively, in the ablated patients vs. 5.4 ± 3.6 cm and 12.1 ± 8.2%, respectively, in nonablated patients (P = 0.006 and 0.0001, respectively). There was no statistical difference in the rest of the variables, mean age being 37.9 ± 12.5 vs. 35.9 ± 13.2 yr (P = 0.154), mean duration of illness (before surgery) 43.0 ± 49.7 vs. 47.8 ± 49.9 months (P = 0.086), interval between surgery and 131I treatment 5.5 ± 11.4 vs. 6.5 ± 10.6 months (P = 0.375), and radiation-absorbed dose to the thyroid remnant 255 ± 226 vs. 238 ± 227 Gy (P = 0.452) in ablated and nonablated groups, respectively.
When multivariate stepwise logistic regression analysis was applied to the whole group (n = 509), tumor size, type of surgery, postsurgical RAIU, and administered activity of 131I were found to have a statistically significant effect on the first-dose outcome. Patients with less than or equal to 5-cm tumor size had a 2.4 times better chance of having remnant ablation than patients with more than 5-cm tumor size. Similarly, chances of remnant ablation was 2.6 times more in patients with adequate surgery than in patients with STT/HT and 2.2 times more in patients with less than or equal to 10% RAIU. Although there was no statistically significant difference in first-dose outcome between patients receiving 25–50 mCi of 131I, they had a three times better chance of remnant ablation compared with patients receiving less than or equal to 20 mCi of 131I (Table 3).
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). The multivariate stepwise logistic regression analysis among patients having inadequate surgery revealed that only the first dose of 131I was significantly associated with the outcome (ablation). Patients receiving at least 25 mCi of 131I had a four times better chance (95% CI for odds ratio, 1.6–9.8) of remnant ablation in the inadequate surgery group than patients receiving less than 25 mCi administered activity.
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Discussion |
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Remnant ablation can be achieved by either administering an empiric fixed activity of 131I or using dosimetry-guided techniques. The clinical merits of dosimetry-guided 131I therapy have been clearly demonstrated in the literature. Although Benua et al. (38) first introduced the dosimetric approach in thyroid cancer treatment in the early 1960s, it has not gained wide acceptance in routine management of DTC patients. Because of the technical and logistic difficulties, most centers have adapted the fixed-activity or standard-activity technique using 30–200 mCi 131I. However, the most appropriate or effective administered activity of 131I to ablate remnant thyroid tissue remains controversial. Some favor low activity around 30 mCi, and others argue for higher activity up to 200 mCi of 131I for remnant ablation (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30). It was believed for a long time that a higher amount of 131I is more effective in achieving complete ablation with a single administration. The proponents of large-activity 131I remnant ablation argue that large administered activity not only ablates remnants but also ablates possible micrometastatic deposits. They presume that low activity is less effective to ablate the micrometastases not visualized in a posttherapy WBS and thereby will lead to a higher recurrence rate, local as well distant (39). However, this issue is already addressed by Mazzaferri and Kloos (15), who found no difference in 30-yr recurrence rates (4 and 6%, respectively; P = 0.1) between low-activity (29–50 mCi) and high-activity (51–200 mCi) 131I remnant ablation groups.
The interest in administering the smallest effective dose of 131I is the advantage of outpatient treatment (as the radiation exposures to household members of patients given less than 30 mCi is well below the maximum annual limit of 5.0 mSv) with the attended economy and convenience (40). There is also a theoretical advantage of decreasing the risk of leukemogenesis and extrathyroid organ damage from lower whole-body radiation, which has been estimated to be 6.1 roentgen-equivalent-man (rem) for 30 mCi, 8.5 rem for 50 mCi, and 12.2 rem for 60 mCi of 131I, especially in young patients with favorable prognostic factors (23). In 1976, McCowan et al. (21) reported that 80–100 mCi of 131I were not more effective than 30 mCi in achieving remnant ablation. Subsequently, other retrospective and prospective studies confirmed similar findings. Review of the literature, coupled with our previous experience, suggests that remnant ablation in up to 80% of cases could be achieved with 131I activity of 30–50 mCi, which doesn’t change significantly after increasing the activity, provided the surgeon had left a small remnant and ablation is defined by a diagnostic WBS using 2–5 mCi 131I. In our previous randomized study using a fixed amount of 131I ranging from 25–200 mCi for remnant ablation, we observed that increasing the empirical administered activity beyond 50 mCi resulted in a plateau of the dose-response curve (29). Although, the 2 test showed no statistical difference between the 30-mCi group and the 50-mCi group, no final and statistically valid conclusion regarding the lowest possible dose could be drawn because there were only two dose groups with a wide interval and sample size was relatively small. Then we had proposed to have another randomized trial incorporating a larger number of patients and a narrower 131I activity interval to see whether it is possible to reduce the administered activity of 131I without compromising the successful ablation rate less than 50 mCi (41).
Our present study shows that a dose as small as 25 mCi was good enough for remnant ablation after adequate surgery. It was associated with an 81% ablation rate, which did not change even after increasing the dose up to 50 mCi. The strength of the present study, however, is that it is a single institutional trial incorporating a large number of patients with uniform inclusion, exclusion, and ablation criteria. Apart from 131I activity (< or 
25 mCi), tumor size, type of surgery, and postsurgical RAIU were also found to have a statistically significant effect on remnant ablation. Patients with small tumor (5 cm), adequate surgery (TT/NTT), and lower RAIU (10%) had more successful outcome. However, all three factors are somehow interlinked with each other. It is sometimes difficult to remove all tumor mass in patients with large tumor; hence, they will have significant remnant and therefore high RAIU. Similarly, if inadequate surgery had been performed because of some reason or other, again there will be large remnant and high RAIU. The rate of successful ablation would be low in both cases.
There have been some strong suggestions that patients with functioning thyroid remnant should be individualized by careful dosimetry after appropriate tracer studies. It had been proposed that at least 30,000 rad (300 Gy) cumulative absorbed dose should be delivered to the thyroid remnant for successful ablation (42). However, we have made some interesting observations regarding the radiation-absorbed dose vs. the ablation rate in this study. We found that radiation-absorbed doses of 173–374 Gy had similar rates of ablation. The univariate and multivariate stepwise logistic regression analysis did not reveal that radiation-absorbed dose had any influence on remnant ablation. The rationale of using the highest possible administered activity is based on the radiobiological fact that the radiation treatment efficacy is directly related to the radiation dose delivered. However, dosimetric calculations assume a homogeneous 131I distribution throughout a target lesion, which is often not true in reality. The other possible error is the estimation of residual mass and effective half-life of tracer. All these add up to give an error margin in dosimetric calculation of one magnitude or more. The reported cytolethal doses of 131I for normal and neoplastic thyroid tissue show significant variations. Successful ablation was achieved in a patient receiving only 120 Gy of radiation-absorbed dose, whereas a radiation-absorbed dose of 600 Gy could not achieve ablation in another patient. This observation could possibly be explained by varying radiosensitivity of thyroid tissue, measurement of which remains an elusive factor. This biological variable is unknown, undefined, and unpredictable and varies from individual to individual. This could be considered as one of the causes of unpredictable outcome of radioablation in individual patients. Therefore, it appears that although one can aim to deliver roughly 300 Gy to the thyroid remnant to achieve successful remnant ablation, the lesser absorbed dose can do a similar job and needs critical appraisal.
Some authors believe the relationship between extent of surgery and successful remnant ablation may be stronger than that between the radioiodine dose and remnant ablation. To critically assess the influence of surgery in the outcome of 131I therapy in remnant ablation, we separately analyzed the data for the NTT group (n = 367) and the inadequate surgery group (n = 142). The rate of successful ablation in the adequate surgery group was much higher than in the inadequate group, which was statistically significant. However, multivariate stepwise logistic regression analysis revealed that only the first dose of 131I was significantly associated with the outcome in both groups. Patients receiving at least 25 mCi of 131I had 2.8 and 4.0 times better chances of remnant ablation in the adequate and inadequate surgery groups, respectively. In addition to the first dose of 131I, the adequate surgery group had two additional factors, namely tumor size and postsurgery RAIU, also found to significant affect the outcome. However, the inadequate surgery group had no other influencing factor other than 131I administered activity. Because absorbed radiation dose is inversely proportional to residual mass, keeping all other factors constant and assuming equal radiosensitivity, higher activities to be administered to ablate larger masses is logical. In other words, in a meticulously operated patient, it is likely that the benefits of a lower dose gets progressively closer to that of a higher dose and may even be equal to a higher dose if surgery has left behind a less than 5-g remnant or uptake less than 10% at 48 h.
Some thyroidologists may argue that the ablation rate achieved by administering 25 mCi of 131I may not be reproducible by other centers or may be a regional phenomenon that may not be applicable at a global level. With any amount of administered activity of 131I, no group has ever achieved a successful ablation rate of 100% at first dose. Even after performing painstaking individual dosimetry, Maxon et al. (42) and Samuel and her colleagues (43) had achieved an ablation rate of approximately 80%. They had concluded that the vast majority of patients due for remnant ablation require approximately 30 mCi of 131I. Lin et al. (44) from Taiwan, Pacini et al. (45) and Barbaro et al. (46) from Italy, DeGroot et al. (23) from Chicago, and Samuel et al. (43) from Mumbai (another major thyroid cancer treatment center from India) have all observed similar ablation rates. Therefore, it is more of a global than local observation. The environmental iodine distribution is varied in the above mentioned geographical regions, yet the ablation rate is uniform for the given dose of 131I.
Conclusion
Patients with DTC should undergo TT/NTT followed by radioiodine remnant ablation. Twenty-five mCi of 131I appears to be the smallest effective activity for remnant ablation as all patients can be treated on an ambulatory basis with associated low cost, convenience, and low whole-body radiation-absorbed dose to the patients.
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Footnotes |
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Abbreviations: CI, Confidence interval; DTC, differentiated thyroid carcinoma; HT, hemithyroidectomy; NTT, near-total thyroidectomy; RAIU, radioiodine neck uptake; rem, roentgen-equivalent-man; STT, subtotal thyroidectomy; Tg, thyroglobulin; TT, total thyroidectomy; WBS, whole-body scan.
Received July 6, 2003.
Accepted January 6, 2004.
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