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Radioiodine Ablation of Thyroid Remnants after Preparation with Recombinant Human Thyrotropin in Differentiated Thyroid Carcinoma: Results of an International, Randomized, Controlled Study

Section of Endocrinology, Department of Endocrinology and Metabolism (F.P., E.M., R.E., C.Ce., A.P.), University of Pisa, 43-56126 Pisa, Italy; Section of Endocrinology, Department of Internal Medicine, Endocrinology, and Metabolism (F.P.), University of Siena, 46-53100 Siena, Italy; Divisions of Endocrinology and Metabolism (P.W.L., R.L.W.) and Nuclear Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Service de Medicine Nucleaire et de Cancerologie Endocrinienne (M.S., S.L., M.R.), Institut Gustave Roussy, 94805 Villejuif, France; Department of Nuclear Medicine (A.D.), London Health Sciences Centre, London, Ontario, Canada N6A 5W9; Klinik und Poliklinik fur Nuklearmedizin (M.Lu., H.H., R.F., M.La., C.R.), Universitat Würzburg, 97070 Würzburg, Germany; Departments of Internal Medicine and Radiology (R.T.K.), Divisions of Endocrinology and Nuclear Medicine, The Ohio State University, Columbus, Ohio 43210; Departments of Endocrine Neoplasia and Hormonal Disorders (S.S., N.L.B.) and Nuclear Medicine (E.D.), University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Division of Endocrinology (B.H.), University of Colorado Health Sciences Center, Aurora, Colorado 80045; Service de Médecine Nucléaire (C.Co.), Centre René Huguenin, 92210 Saint Cloud, France; and Department of Otolaryngology-Head and Neck Surgery (J.Y.), University of Western Ontario, London, Ontario, Canada N6A 5B8

Address all correspondence and requests for reprints to: F. Pacini, Section of Endocrinology, Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: After surgery for differentiated thyroid carcinoma, many patients are treated with radioiodine to ablate remnant thyroid tissue. This procedure has been performed with the patient in the hypothyroid state to promote endogenous TSH stimulation and is often associated with hypothyroid symptoms and impaired quality of life.

Objective and Intervention: This international, randomized, controlled, multicenter trial aimed to compare the efficacy and safety of recombinant human TSH (rhTSH) to prepare euthyroid patients on L-thyroxine therapy (euthyroid group) to ablate remnant thyroid tissue with 3.7 GBq (100 mCi) ¹³¹I, compared with that with conventional remnant ablation performed in the hypothyroid state (hypothyroid group). Quality of life was determined at the time of randomization and ablation. After the administration of the 131-I dose, the rate of radiation clearance from blood, thyroid remnant, and whole body was measured.

Results: The predefined primary criterion for successful ablation was "no visible uptake in the thyroid bed, or if visible, fractional uptake less than 0.1%" on neck scans performed 8 months after therapy and was satisfied in 100% of patients in both groups. A secondary criterion for ablation, an rhTSH-stimulated serum thyroglobulin concentration less than 2 ng/ml, was fulfilled by 23 of 24 (96%) euthyroid patients and 18 of 21 (86%) hypothyroid patients (P = 0.2341). Quality of life was well preserved in the euthyroid group, compared with the hypothyroid group, as demonstrated by their lower pretreatment scores on the Billewicz scale for hypothyroid signs and symptoms, 27 ± 7 vs. 18 ± 4 (P < 0.0001) and their significantly higher Short Form-36 Health Assessment Scale scores in five of eight categories. Euthyroid patients had a statistically significant one third lower radiation dose to the blood, compared with patients in the hypothyroid group.

Conclusions: This study demonstrates comparable remnant ablation rates in patients prepared for ¹³¹I remnant ablation with 3.7 GBq by either administering rhTSH or withholding thyroid hormone. rhTSH-prepared patients maintained a higher quality of life and received less radiation exposure to the blood.

	Introduction

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INITIAL TREATMENT FOR patients with differentiated epithelial-derived (papillary and follicular) thyroid carcinoma is total or near-total thyroidectomy, which is often followed by ¹³¹I ablation of remnant thyroid tissue (1). The rationale for thyroid remnant ablation is to decrease the risk of clinical tumor recurrence (2) and improve the sensitivity and specificity of follow-up testing with periodic serum thyroglobulin measurement and radioiodine scanning (3, 4). In current medical practice, remnant ablation is performed after thyroid hormone has been withheld, which increases endogenous TSH release to promote radioiodine uptake in remaining thyroid cells. Frequently this is associated with the physical and psychological side effects of hypothyroidism, which can have a profound negative impact on the patient’s quality of life (5).

Recombinant human TSH (rhTSH, TSH, Thyrogen, Genzyme Corp., Cambridge, MA) has been developed as a source of exogenous TSH. Clinical studies have shown that administration of rhTSH to thyroid cancer patients remaining on thyroid hormone therapy promotes radioiodine uptake and thyroglobulin production by thyroid cells with comparable efficacy with hypothyroidism for diagnosing residual cancer and preserving the patient’s quality of life (6). A few uncontrolled pilot studies have been performed exploring the efficacy of 131-I ablation after preparation with rhTSH. Specifically, a lower rate of successful ablation was found using 30 mCi (1.1 GBq) after rhTSH, compared with the same dose after thyroid hormone withdrawal in one study (7). In contrast, another study (8) using a 30-mCi (1.1 GBq) standard activity found that similar rates of ablation were achieved after rhTSH and thyroid hormone withdrawal, although this study protocol included the withdrawal of L-thyroxine for 4 d before ablation, rendering the results difficult to compare directly. A third study (9) found no difference in ablation rate when preparing the patients with thyroid hormone withdrawal or rhTSH using individual doses of radioiodine determined by dosimetric studies. The present prospective, randomized, multicenter study was designed to investigate whether preparation of patients with rhTSH while on L-thyroxine therapy results in a comparable rate of successful postoperative thyroid ablation, compared with preparation by withdrawal of thyroid hormone when using a fixed dose of 100 mCi (3.7 GBq) of 131-I.

	Subjects and Methods

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Aim of the study

This randomized, controlled, open-label study involved four centers in Europe and five in North America. The primary objective of the study was to determine whether thyroid remnant ablation in T₄-treated euthyroid patients after preparation with rhTSH results in a comparable ablation rate to treating patients in the hypothyroid state. To test this hypothesis, the primary criterion for successful ablation was defined as "no visible uptake, or if visible, less than 0.1%" on a whole-body radioiodine scan performed 8 months after radioiodine therapy. A second objective was to evaluate the safety profile of rhTSH when used for thyroid remnant ablation. Other objectives were to compare the quality of life in both groups and the uptake and retention of radioiodine in the remnant thyroid tissue as well as radiation exposure to the blood and whole body in both groups.

Inclusion criteria

Study patients were 18 yr or older with newly diagnosed differentiated papillary or follicular thyroid carcinoma, the sole previous treatment for which had been total or near-total thyroidectomy within 2 wk before enrollment. Patients were all staged T2 or T4 with minor invasion of the thyroid capsule, N0-N1, and M0 or T0-T1, N1, and M0 (10). T4 tumors were no longer eligible after a protocol amendment because concern arose that patients with T4 tumors might alternatively be treated routinely with radioiodine doses higher than 100 mCi or external radiotherapy at some centers. However, six T4 patients already enrolled before the study amendment. For women of child-bearing potential, a negative serum human chorionic gonadotropin pregnancy test was required. As assessed by the principal investigator at each site, patients had no clinically significant abnormalities of hematological or blood chemistry testing for routine analytes, including serum creatinine concentration. No patients had major concurrent medical disorders, including other malignancies within the past 5 yr; and no patient had a recent history of drugs affecting thyroid or renal function, including iodine-containing medications or radiocontrast agents.

Study design

All patients provided written informed consent to participate in the study. The protocol was approved by each site’s institutional review board and/or independent ethics committee.

Within 14 d after thyroidectomy, eligible patients were randomized to either the euthyroid group, which received rhTSH to prepare for radioiodine therapy, or the hypothyroid group, from which thyroid hormone treatment was withheld before radioiodine therapy. Patients in the euthyroid group received L-thyroxine therapy for 4–6 wk until their serum TSH concentration was 5 mU/liter or less. Then 0.9 mg rhTSH (Thyrogen) was administered im on 2 consecutive days; and 24 h later, 3.7 GBq (100 mCi) ¹³¹I was administered. Subsequently whole-body probe measurements and blood collections were conducted at 2, 6, 24, 48, 72–96 h, and 96–168 h to obtain time-activity curves. Patients also underwent whole-body scanning and remnant neck imaging at 48, 72–96 h, and 96–168 h after ablation.

Patients randomized to the hypothyroid group did not receive thyroid hormone therapy postoperatively. The serum TSH concentration was reassessed at 4–6 wk until the patient’s TSH was greater than 25 mU/liter. The patients received a 3.7 GBq (100 mCi) ¹³¹I activity followed by posttreatment imaging and dosimetry measurements at the same intervals as the euthyroid group. Thereafter these patients commenced L-thyroxine therapy.

Dosimetric procedures were developed and assessed centrally by one of the participating centers (University of Würzburg) based on earlier studies (11, 12) and adjusted to the higher activities used in this study. A full description of the technical aspects of the study and the theory of the dosimetry is presented elsewhere (13). A manual with detailed instructions to the dosimetric measurements and the data extraction was distributed to all participating centers before the beginning of the study. All data with respect to dosimetry were transmitted to Würzburg at which the dosimetry calculations were performed using identical evaluation procedures for each patient. The absorbed dose to the blood was calculated using a modified approach described in detail by Hänscheid et al. (13) based on the medical internal radiation dose (MIRD) formalism and S values from Akabani and Poston (14). The remnant uptakes and the corresponding areas were determined by quantitative evaluation of the scintigram remnant counts, applying appropriate background corrections.

Eight (±1) months after ablation, rhTSH-stimulated (0.9 mg/d for two doses) whole-body scan and spot views of the neck (48 h after the administration of 150 MBq ¹³¹I as tracer activity) and serum thyroglobulin testing were performed.

Assessment of outcome

The neck and whole-body scans performed 8 ± 1 months after ablation and 48 h after the administration of the diagnostic activity were evaluated in a blinded manner by three independent readers. If a majority of the readers considered radioiodine uptake to be visible in the thyroid bed, the percentage of ¹³¹I uptake in the thyroid bed was calculated.

Symptoms of hypothyroidism and quality of life were assessed using the Billewicz scale and Short Form-36 (SF-36) scores at baseline, 2 wk after randomization, immediately before ¹³¹I ablation, and 1 month after ablation.

Safety was monitored throughout the study by assessment of vital signs and any changes in medical history or physical examination and by complete blood count (complete blood count, platelet, and differential white blood cell count), routine biochemical parameters (urea nitrogen, creatinine, liver function tests, total cholesterol, and triglycerides), and urinalysis.

Measurement of serum TSH, thyroglobulin, and urinary iodine excretion

TSH determinations were performed at the individual sites using standard immunoassay procedures. Thyroglobulin measurements were performed in a central laboratory (Department of Endocrinology, University of Pisa), using an immunometric assay (Diagnostic Products Corp., Los Angeles, CA) with a functional sensitivity of 0.9 ng/ml, standardized against the certified reference material for human thyroglobulin (15). In the same laboratory antithyroglobulin antibodies were measured using an immunoradiometric assay method (ICN Pharmaceuticals, Inc., Asse Relegem, Belgium). Patients with a potentially interfering level of antithyroglobulin autoantibodies were not considered for statistical analysis of serum thyroglobulin changes.

Urinary iodine excretion over 24 h was determined 2 d before ¹³¹I administration (hypothyroid group) or within 2 d before rhTSH administration (euthyroid group) and at the 8-month assessment. Iodine measurements were performed in a central laboratory (Boston Medical Center, Boston, MA) using a colorimetric method (16).

Biostatistical considerations and sample size

Patients were randomized in 1:1 ratio into the two treatment arms based on a blocked and stratified randomization scheme, with permuted blocks of 4 and stratification by site to ensure balance between the treatment arms in each site. A box was provided to each clinical site that contained a batch of sealed randomization envelopes numbered sequentially. On confirmation that a potential patient met all entry criteria, an envelope would be drawn, starting with the lowest number, and opened to reveal the treatment group to which the patient was assigned.

This study was designed to answer the question whether successful ablation with the euthyroid rhTSH treatment is within 20% of the hypothyroid treatment. The comparison was based on standard noninferiority framework (17) in which difference of 20% in outcome was considered a clinically meaningful difference. For such designs, it is implicit that the 95% confidence interval around the difference in the observed ablation rates is calculated instead of conducting a hypothesis test. If the 95% confidence interval does not include the 20% clinically relevant difference, then the inference is that the euthyroid treatment is not inferior to the hypothyroid treatment by more than the prespecified difference. Assuming a successful ablation rate of 93% in the overall patient population, it was calculated that with 25 patients in each arm, the probability of finding the predefined noninferiority relationship, if such relationship truly exists, was 79%. Although this statistical approach was developed for the analysis of the primary end point (i.e. absence of visible uptake or, if present, less than 0.1%), the same analysis was also used for other ablation endpoints without adjusting the definition of significance, using ² analysis.

Other statistics included Student t test and Wilcoxon rank sum test for difference between groups (for serum TSH, serum thyroglobulin, urinary iodine excretion, and radioiodine kinetics).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patient inclusion

The first patient was enrolled on December 17, 2001. The last patient completed the final study visit on September 26, 2003. Sixty-six patients provided informed consent, three were found ineligible, leaving 63 patients for intent-to-treat analyses. Thirty of these patients were randomized to the hypothyroid group and 33 to the euthyroid group. In the hypothyroid group, two patients were excluded from the final analysis: one due to discovery of lung metastases on the posttherapy whole-body scan and one because the neck scan was uninterpretable due to a positioning error. In the euthyroid group, one patient was ineligible for the final analysis due to a mistake in the reconstitution of one rhTSH dose in preparation for ¹³¹I ablation. As shown in Table 1, patients in the two arms of the study were not significant different in their baseline characteristics.

Immediately before radioiodine ablation in the hypothyroid group and before rhTSH administration in the euthyroid group, the mean (± SD) serum TSH concentration in the euthyroid group was 1.1 ± 1.3 mU/liter, whereas in the hypothyroid group, it was 83 ± 51 mU/liter. At month 8, the median serum TSH concentrations in the euthyroid and hypothyroid groups were not significantly different, 0.0 mU/liter (range 0.0–96.0 mU/liter) and 0.0 mU/liter (range 0.0–1.6 mU/liter), respectively. The extremely high serum TSH level (96.0 mU/liter) in the euthyroid group was due to one patient who mistakenly was not taking their L-thyroxine.

Results of the posttherapy scan at the time of ablation and the control radioiodine scan at 8 months

Thyroid bed uptake was identified in each patient on the postablation scans. Mean (± SD) and median areas in the scans obtained 48 h after ablation were 16 ± 10 and 14 cm² in the hypothyroid group, and 19 ± 17 and 19 cm² in the euthyroid group, and were not significantly different.

Based on the primary end point of no visible uptake, or if visible, less than 0.1% uptake, scans performed 8 months after therapeutic radioiodine administration (Table 2) showed that all patients who had evaluable results in both groups had been successfully ablated. Based on the criterion of no visible uptake alone, 24 of 32 euthyroid patients (75%) and 24 of 28 hypothyroid patients (86%) had their thyroid residues successfully ablated (P = 0.300).

Serum thyroglobulin levels at study entry were comparable in the euthyroid and hypothyroid groups, 11 ± 16 and 34 ± 127 ng/ml, respectively (P = 0.331). Immediately before administering rhTSH to euthyroid patients, their serum thyroglobulin concentrations had fallen to 1.5 ± 1.9 ng/ml on thyroxine therapy, whereas in the hypothyroid group, it remained 22 ± 47 ng/ml (P = 0.025), reflecting their differing states of endogenous TSH stimulation. At 1 and 8 months after radioiodine therapy, serum thyroglobulin levels were low or undetectable, with no significant differences between the two groups. Immediately before diagnostic rhTSH administration at month 8, serum thyroglobulin concentrations were less than 2 ng/ml in all patients in both groups. Three days after the second dose of rhTSH, the serum thyroglobulin was 2 ng/ml or greater in one euthyroid group patient and five hypothyroid group patients. Although the study was not specifically designed to examine the success of ablation based on serum thyroglobulin concentration, these data were also analyzed. When successful ablation was defined as rhTSH-stimulated serum thyroglobulin concentration less than 2 ng/ml in the subset of patients without interfering antithyroglobulin antibodies (Table 3), 23 of 24 euthyroid patients (96%) and 18 of 21 hypothyroid patients (86%) were considered successfully ablated. The 95% confidence interval for difference in ablation rates was –7 to 27%, demonstrating that the response to radioiodine treatment in the euthyroid group was not clinically inferior to that in the hypothyroid group. Furthermore, no difference was found by ² analysis (P = 0.2341). Using a cut-off for rhTSH-stimulated serum thyroglobulin of less than 1 ng/ml, the 95% confidence interval for difference in ablation rates ranged from –24 to 19%, failing to exclude the predefined clinically relevant difference of 20%, but no significant difference was found by ² analysis (P = 0.826).

Urinary iodine concentrations before ablation were not significantly different in the euthyroid and hypothyroid groups, 12 ± 9 and 9 ± 8 µg/dl, respectively (P = 0.157), indicating no significant impact of the additional iodine content of administered L-thyroxine in the euthyroid group. At month 8 before the follow-up scan, mean urinary iodine levels in euthyroid and hypothyroid groups were again comparable, 15 ± 17 and 15 ± 8 µg/dl, respectively (P = 0.837).

Radioiodine kinetics

Analysis of the thyroid remnant tissue radioiodine kinetics showed that the fractional uptake 48 h after the ¹³¹I administration tended to be lower in the euthyroid group than the hypothyroid group (Table 4), although the difference was not statistically significant (P = 0.096). The effective half-life in remnant tissue was significantly shorter in the hypothyroid group (P = 0.011), whereas the mean residence time in remnant tissue was shorter in the euthyroid group (0.9 ± 1.27 h) than the hypothyroid group (1.4 ± 1.51 h), but the difference was not statistically significant (P = 0.109). The dose to the blood was significantly lower in the euthyroid group (0.109 ± 0.028 mGy/MBq administered activity) than in the hypothyroid group (0.167 ± 0.061 mGy/MBq; P < 0.0001).

Mild and transient symptoms around the time of radioiodine ablation were noted in eight patients in each group. The most frequent symptoms in the euthyroid group were nausea (four patients), fatigue (two patients), and taste loss (two patients). In the hypothyroid group, symptoms included fatigue (three patients), nausea (two patients), and skeletal pain (two patients).

There was a highly significant difference (P < 0.0001) at wk 4 between Billewicz scores of the two groups, with patients in the hypothyroid group having higher mean total scores immediately before ablation and 1 month after ablation, compared with baseline (2 wk after randomization). The most common complaints of patients in the hypothyroid group, as opposed to those of the euthyroid group, were cold intolerance (50 vs. 21%), weight increase (60 vs. 21%), constipation (43 vs. 3%), slow movements (50 vs. 12%), cold skin (47 vs. 12%), and periorbital puffiness (50 vs. 0%). One month after ablation, mean Billewicz scores for patients in the hypothyroid group returned to the level seen in the euthyroid group.

The SF-36 scale showed that the status of the euthyroid group improved in seven of eight physical and mental domains between baseline and wk 4, whereas the hypothyroid group experienced a decrease in quality of life in seven of eight SF-36 domains. The change from baseline in the euthyroid group was significantly different from that in the hypothyroid group in five of eight SF-36 domains (Table 5).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The 8-month follow-up scans to assess ablation were performed after rhTSH preparation, based on previous evidence that the results of diagnostic whole-body scans obtained after rhTSH are not significantly different from those obtained after thyroid hormone withdrawal (6, 20, 21). Using the predefined scan criterion of no visible uptake, or if visible, less than 0.1%, all patients in both groups were ablated. Several studies have shown that minimal visible remnants in the thyroid bed have no clinical importance and do not affect the subsequent follow-up and outcome (22, 23). Nevertheless, even using the more restrictive criterion of no visible uptake alone, the difference between ablated patients in the euthyroid or hypothyroid group was marginal (75 and 86%, respectively) and not statistically significant (P = 0.300).

In the absence of circulating antithyroglobulin antibodies, TSH-stimulated serum thyroglobulin measurement, either after hormone withdrawal or after rhTSH stimulation, is well accepted as the most sensitive marker of residual thyroid tissue after surgery and remnant ablation (3, 21). Consequently, we considered a level of rhTSH-stimulated serum thyroglobulin less than 2 ng/ml at the 8-month control as an additional criterion of successful ablation. Using this measure, the rate of successful ablation was not different between the euthyroid (96%) and hypothyroid groups (86%). A similar trend was observed when the thyroglobulin cut-off level was lowered to 1 ng/ml, although the 95% confidence interval for successful ablation did not exclude a clinically significant 20% difference between the two groups. These thyroglobulin findings are clinically relevant because several centers currently assess the success of ablation with only rhTSH-stimulated serum thyroglobulin measurement without diagnostic whole-body scanning, at least in low-risk patients. Indeed, serum thyroglobulin measurements combined with the results of neck ultrasound examination have been reported by several groups to be the best indicator of complete remission/persistent disease in the follow-up after initial treatment (3, 20, 24, 25).

Symptoms and signs of hypothyroidism as well as subjective perceptions of quality of life were, as expected, significantly better in euthyroid than hypothyroid group patients, as assessed by the results of previously validated survey instruments (Billewicz scale and SF-36). Patients were enrolled in this study soon after being diagnosed with thyroid cancer while recovering from thyroidectomy. Such patients can be expected to have a poor perception of their quality of life, as is reflected by the SF-36 scores in both groups at study entry. During withdrawal of thyroid hormones, SF-36 scores decreased even further in patients in the hypothyroid group in seven of the eight SF-36 domains; whereas in patients in the euthyroid group, SF-36 scores improved in seven of the eight SF-36 domains. The difference between the two groups probably resulted from both an amelioration of immediate postoperative symptoms in rhTSH-treated patients and a deterioration in patients withdrawn from thyroid hormones. This confirms that prevention of hypothyroidism by use of rhTSH for remnant ablation avoided the worsening of subjectively experienced quality of life in patients who already were in a fragile psychological condition soon after being diagnosed with thyroid cancer.

The kinetics of thyroid remnant and whole-body kinetics of radioiodine represent another important issue in our study. A detailed presentation of the theoretical and methodological background of the dosimetric investigations goes beyond the scope of this paper and is described elsewhere (13), including a discussion of the observed differences of the iodine kinetics after thyroid hormone withdrawal and stimulation with rhTSH. Fractional remnant uptakes and residence times tended to be higher in the hypothyroid than the euthyroid group, whereas the half-life of tissue residence in remnants was lower. Only the difference of the half-lives was statistically significant. The radiation dose to the blood, a surrogate measure for radiation dose to the bone marrow, was significantly lower (–35%) in the euthyroid group than in the hypothyroid group. These findings suggest that using rhTSH to prepare for thyroid remnant ablation reduces the blood radiation dose and potential risk of radiation-induced malignancies (26, 27).

Our urinary iodine excretion data indicate that the modest additional stable iodine intake before radioiodine treatment in the thyroxine-treated euthyroid patients did not produce a significantly higher urinary iodine level than in the hypothyroid patients. This contrasts with an earlier report of higher mean urinary iodine excretion in patients undergoing thyroid ablation with rhTSH than hypothyroid patients (8). The median urinary iodine levels in both or our groups were well below the approximately 20 µg/dl threshold conventionally considered to have the potential for interference with effective thyroid remnant uptake of radioiodine.

A final important issue that could not be addressed in our study is whether preparation for remnant ablation with rhTSH vs. thyroid hormone withdrawal has an impact on patients’ long-term outcomes, particularly disease recurrence. This can be answered only by following these cohorts of patients in future years.

In conclusion, these study findings demonstrate comparable thyroid remnant ablation rates in thyroid cancer patients without evidence of remaining disease after surgery when prepared for ¹³¹I therapy by either administering rhTSH or withholding thyroid hormone. rhTSH-prepared patients sustained a better quality of life and received less radiation exposure to blood. Thus, the use of rhTSH for postoperative radioiodine thyroid remnant ablation represents an effective and attractive option in the postoperative management of patients with thyroid cancer.

	Acknowledgments

 
The authors thank Dr. L. E. Braverman (Section of Endocrinology, Diabetes, and Nutrition, Boston University Medical Center, Boston, MA), Dr. V. R. McCready (Institute of Cancer Research, Royal Marsden Hospital Foundation Trust, Sutton, UK), and Dr. C. L. Harmer (Thyroid Unit, Royal Marsden Hospital, London, UK) for reviewing the 8-month posttreatment scans; S. R. Thomas (University of Cincinnati College of Medicine, Department of Radiology, Cincinnati, OH) for his support in setting up the dosimetry protocol, and D. Haakimson, N. Leitman, A. Smart (Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, CO), and M. E. Ewertz (Division of Endocrinology and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD) for their assistance. The authors also thank the study patients whose cooperation, sacrifices, and trust were critical to evaluating this advance in management of this increasingly common disease.

	Footnotes

 
This work was supported by the Genzyme Corp. (Cambridge, MA). The study design was the result of independent input from the study investigators, with statistical, safety, and study monitoring support from the Genzyme Corp.

The authors listed in parentheses have received from Genzyme Corp. honoraria for speaking (R.T.K., C.R., M.S., A.D., B.H., P.W.L., S.S., F.P.), research funding (R.T.K., C.R., M.S., A.D., P.W.L., S.S., A.P.), or fees as consultants (R.T.K., P.W.L., F.P.).

First Published Online December 29, 2005

Abbreviations: rhTSH, Recombinant human TSH; SF-36, Short Form-36.

Received July 26, 2005.

Accepted December 20, 2005.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Schlumberger MJ 1998 Medical progress: papillary and follicular thyroid carcinoma. N Engl J Med 338:297–306[Free Full Text]
2. Sawka AM, Thephamongkhol K, Brouwers M, Thabane L, Browman G, Gerstein HC 2004 A systemic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. J Clin Endocrinol Metab 89:3668–3676[Abstract/Free Full Text]
3. Schlumberger M, Pacini F, Wiersinga WM, Toft A, Smit JW, Sanchez Franco F, Lind P, Lambert E, Jarzab B, Jamar F, Duntas L, Cohen G 2004 Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective. Eur J Endocrinol 150:105–112[Abstract]
4. Bal CS, Kumar A, Chandra P, Dwivedi SN, Mukhopadhyaya S 2004 Is chest x-ray or high-resolution computed tomography scan of the chest sufficient investigation to detect pulmonary metastasis in pediatric differentiated thyroid cancer? Thyroid 14:217–225[CrossRef][Medline]
5. Dow KH, Ferrell BR, Anello C 1997 Quality-of-life changes in patients with thyroid cancer after withdrawal of thyroid hormone therapy. Thyroid 7:613–619[Medline]
6. Haugen BR, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, Cooper DS, Graham KE, Braverman LE, Skarulis MC, Davies TF, DeGroot LJ, Mazzaferri EL, Daniels GH, Ross DS, Luster M, Samuels MH, Becker DV, Maxon III HR, Cavalieri RR, Spencer CA, McEllin K, Weintraub BD, Ridgway EC 1999 A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 84:3877–3885[Abstract/Free Full Text]
7. Pacini F, Molinaro E, Castagna MG, Lippi F, Ceccarelli C, Agate L, Elisei R, Pinchera A 2002 Ablation of thyroid residues with 30 mCi 131-I: a comparison in thyroid cancer patients prepared with recombinant human TSH or thyroid hormone withdrawal. J Clin Endocrinol Metab 87:4063–4068[Abstract/Free Full Text]
8. Barbaro D, Boni G, Meucci G, Simi U, Lapi P, Orsini P, Pasquini C, Piazza F, Caciagli M, Mariani G 2003 Radioiodine treatment with 30 mCi after recombinant human thyrotropin stimulation in thyroid cancer: effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation. J Clin Endocrinol Metab 88:4110–4115[Abstract/Free Full Text]
9. Robbins RJ, Larson SM, Sinha N, Divgi C, Pentlow KS, Ghossein R, Tuttle RM 2002 A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation. J Nucl Med 43:1482–1488[Abstract/Free Full Text]
10. International Union Against Cancer (UICC), Sobin LH, Wittekind Ch, eds. 1997 TNM classification of malignant tumours. 5th ed. New York: John Wiley, Sons, Inc.
11. Luster M, Sherman S, Skarulis MC, Reynolds JR, Lassmann M, Hanscheid H, Reiners C 2003 Comparison of radioiodine biokinetics following the administration of recombinant human thyroid stimulating hormone (rhTSH) and after thyroid hormone withdrawal in thyroid carcinoma. Eur J Nucl Med Mol Imaging 30:1371–1377[Medline]
12. Lassmann M, Luster M, Hanscheid H, Reiners C 2004 The impact of I-131 diagnostic activities on the biokinetics of thyroid remnants. J Nucl Med 45:619–625[Abstract/Free Full Text]
13. Hänscheid H, Lassmann M, Luster M, Thomas RT, Pacini F, Ceccarelli C, Ladenson PW, Wahl RL, Schlumberger M, Richard M, Driedger A, Kloos RT, Sherman SI, Haugen B, Carriere V, Corone C, Reiners C, Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: procedures and results of a prospective international controlled study of ablation after rhTSH or hormone withdrawal. J Nucl Med, in press
14. Akabani G, Poston Sr JW 1991 Absorbed dose calculations to blood and blood vessels for internally deposited radionuclides. J Nucl Med 32:830–834[Abstract/Free Full Text]
15. Feldt-Rasmussen U, Profilis C, Colinet E, Black E, Bornet H, Bourdoux P, Carayon P, Ericsson UB, Koutras DA, Lamas de Leon L, DeNayer P, Pacini F, Palumbo G, Santos A, Schlumberger M, Seidel C, Van Herle AJ, De Vijlder JJM 1996 Human thyroglobulin reference material (CRM 457). 2nd part: physicochemical characterization and certification. Ann Biol Clin (Paris) 54:343–348[Medline]
16. Benotti J, Benotti N, Pino S, Gardyna H 1965 Determination of total iodine in urine, stools, diets and tissue. Clin Chem 11:932–936[Abstract]
17. Blackwelder WC 1982 "Proving the null hypothesis" in clinical trials. Control Clin Trials 3:345–353[CrossRef][Medline]
18. Johansen K, Woodhouse NJY, Odugbesan O 1991 Comparison of 1073 MBq and 3700 MBq iodine-131 in postoperative ablation of residual thyroid tissue in patients with differentiated thyroid cancer. J Nucl Med 32:252–254[Abstract/Free Full Text]
19. Bal CS, Kumar A, Pant GS 2004 Radioiodine dose for remnant ablation in differentiated thyroid carcinoma: a randomized clinical trial in 509 patients. J Clin Endocrinol Metab 89:1666–1673[Abstract/Free Full Text]
20. Ladenson PW, Braverman LE, Mazzaferri EL, Brucker-Davis F, Cooper DS, Garber JR, Wondisford FE, Davies TF, DeGroot LJ, Daniels GH, Ross DS, Weintraub BD 1997 Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma. N Engl J Med 337:888–896[Abstract/Free Full Text]
21. Pacini F, Molinaro E, Castagna MG, Agate L, Elisei R, Ceccarelli C, Lippi F, Taddei D, Grasso L, Pinchera A 2003 Recombinant human thyrotropin-stimulated serum thyroglobulin combined with neck ultrasonography has the highest sensitivity in monitoring differentiated thyroid carcinoma. J Clin Endocrinol Metab 88:3668–3673[Abstract/Free Full Text]
22. Pacini F, Capezzone M, Elisei R, Ceccarelli C, Taddei D, Pinchera A 2002 Diagnostic 131-iodine whole-body scan may be avoided in thyroid cancer patients who have undetectable stimulated serum Tg levels after initial treatment. J Clin Endocrinol Metab 87:1499–1501[Abstract/Free Full Text]
23. Cailleux AF, Baudin E, Travagli JP, Ricard M, Schlumberger M 2000 Is diagnostic 131-iodine scanning useful after total thyroid ablation for differentiated thyroid cancer? J Clin Endocrinol Metab 85:175–178[Abstract/Free Full Text]
24. Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L, Haugen BR, Sherman SI, Cooper DS, Braunstein GD, Lee S, Davies TF, Arafah BM, Ladenson PW, Pinchera A 2003 A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 88:1433–1441[Abstract/Free Full Text]
25. Mazzaferri EL, Kloos RT 2002 Is diagnostic iodine-131 scanning with recombinant human TSH useful in the follow-up of differentiated thyroid cancer after ablation? J Clin Endocrinol Metab 87:1490–1498[Abstract/Free Full Text]
26. Maxon III HR, Smith HS 1990 Radioiodine-131 in the diagnosis and treatment of well differentiated thyroid cancer. Endocrinol Metab Clin North Am 19:685–718[Medline]
27. Rubino C, de Vathaire F, Dottorini ME, Hall P, Schvartz C, Couette JE, Dondon MG, Abbas MT, Langlois C, Schlumberger M 2003 Second primary malignancies in thyroid cancer patients. Br J Cancer 89:1638–1644[CrossRef][Medline]

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