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.

Technical aspects and results of the dosimetric assessments of postoperative radioiodine ablation in the framework of an international, prospective, controlled, randomized, comparative study of the effectiveness of ablation therapy with 3.7 GBq (131)I in differentiated thyroid cancer after stimulation with recombinant human TSH (rhTSH) or by thyroid hormone withdrawal (THW) are presented. METHODS: Sixty-three patients were randomized after thyroidectomy to either the THW or the rhTSH group. Scintigraphic neck images were acquired starting 48 h after radioiodine administration to assess biokinetics in the thyroid remnant. The activity in blood samples was quantified and data from whole-body probe measurements and scintigraphic whole-body scans were combined to deduce retention curves in blood and whole body, respectively. The absorbed dose to the blood was calculated using a modified approach based on the formalism of the MIRD Committee of the Society of Nuclear Medicine. RESULTS: The effective half-time in the remnant thyroid tissue was significantly longer after rhTSH than THW (67.6 +/- 48.8 vs. 48.0 +/- 52.6 h, respectively; P = 0.01), whereas the observed differences of the mean 48-h (131)I uptakes (0.5% +/- 0.7% vs. 0.9% +/- 1.0% after THW; P = 0.1) and residence times (0.9 +/- 1.3 vs. 1.4 +/- 1.5 h after THW; P = 0.1) between the rhTSH and THW groups were not statistically significant. The specific absorbed dose to the blood was significantly (P <0.0001) lower after administration of rhTSH (mean, 0.109 +/- 0.028 mGy/MBq; maximum, 0.18 mGy/MBq) than after THW (mean, 0.167 +/- 0.061 mGy/MBq; maximum, 0.35 mGy/MBq), indicating that higher activities of radioiodine might be safely administered after exogenous stimulation with rhTSH. CONCLUSION: Indication of an influence of the residence time of radioiodine in the blood on the fractional uptake into thyroid remnant was found. A novel regimen is proposed in which therapeutic activities to be administered are determined from the individual specific blood dose.     

Dosimetry of radioiodine therapy in patients with nodular goiter after pretreatment with a single, low dose of recombinant human thyroid-stimulating hormone.

A single, low dose of recombinant human thyroid-stimulating hormone (rhTSH) doubles 24-h RAIU and causes a more homogeneous distribution of radioiodine on thyroid scintigrams of patients with nodular goiter. Pretreatment with rhTSH allows the therapeutic dose of (131)I to be reduced by 50%-60% without compromising the result of thyroid volume reduction. The present study focused on the dosimetric aspects of therapy with a reduced dose of (131)I after pretreatment with rhTSH in patients with nodular goiter. METHODS: Thirty-six patients were treated with (131)I to reduce thyroid volume. Nine patients were pretreated with a single dose of 0.01 mg of rhTSH, and 9 patients, with 0.03 mg of rhTSH. Two control groups of 9 patients, matched for thyroid weight and 24-h radioactive iodide uptake, were not pretreated with rhTSH. The therapeutic dose of (131)I was aimed at being sufficient to result in retention of 3.7 MBq of (131)I per gram of thyroid tissue at 24 h. Thyroid radioactivity after (131)I administration was measured every 24 h for 3 d and on days 7, 10, 14, 21, and 28. A model of iodine biokinetics was used to estimate absorbed doses in organs. Protein-bound (131)I activity was measured at 1, 2, 3, 7, and 10 d and at 2, 3, and 4 wk after (131)I therapy. RESULTS: The administered activities were 1.5 times lower in the 0.01-mg rhTSH group and 1.9 times lower in the 0.03-mg rhTSH group than in the control groups. The absorbed dose in the thyroid was similar in the rhTSH-pretreated groups and in the control groups. In the organs of excretion (bladder) and uptake (stomach) of inorganic iodide, the absorbed doses were 2- to 3-fold lower in the pretreated groups than in the control groups. The effective dose equivalent outside the thyroid was considerably lower in the rhTSH-pretreated groups than in their respective control groups (1.6-fold in the 0.01-mg rhTSH group and 2.3-fold in the 0.03-mg rhTSH group). The time course of protein-bound (131)I activity in serum and the cumulated protein-bound (131)I activity in serum did not differ significantly between rhTSH-pretreated and control groups. CONCLUSION: (131)I therapy after pretreatment with a single, low dose of rhTSH, with the dose reduced according to the rhTSH-induced increase in 24-h radioactive iodide uptake, caused lower radiation-absorbed doses in extrathyroidal organs and tissues, especially bladder and stomach, and no significant increase in the release of (131)I-labeled thyroid hormones into the circulation of patients with nodular goiter. Thus, this mode of therapy can be recommended, especially when the dose of radioiodine to be administered without rhTSH pretreatment is high.     

Bone marrow dosimetry and safety of high 131I activities given after recombinant human thyroid-stimulating hormone to treat metastatic differentiated thyroid cancer.

Recombinant human thyroid-stimulating hormone (rhTSH) recently was introduced as a radioiodine administration adjunct that avoids levothyroxine (LT-4) withdrawal and resultant hypothyroidism. The pharmacokinetics of 131I after rhTSH administration are known to differ from those after LT-4 withdrawal but are largely nondelineated in the radioiodine therapy setting. We therefore sought to calculate the red marrow absorbed dose of high therapeutic activities of 131I given after rhTSH administration to patients with metastatic or inoperable locally recurrent differentiated thyroid cancer. We also sought to evaluate the clinical and laboratory effects of this therapy on the bone marrow. METHODS: Fourteen consecutive patients received in total 17 131I treatments (7.4 GBq). Blood and urine samples were obtained at fixed intervals, and their activities were measured in a well counter. Based on blood activity, renal clearance of the activity, and residence times in red marrow and the remainder of the body, the red marrow absorbed dose was calculated using the MIRD schema. Additionally, we monitored for potential hematologic toxicity and compared platelet counts before and 3 mo after treatment. RESULTS: The mean +/- SD absorbed dose per unit of administered (131)I in the red marrow was 0.16 +/- 0.07 mGy/MBq. The corresponding total red marrow absorbed dose was 1.15 +/- 0.52 Gy (range, 0.28-1.91 Gy). In none of the patients was hematologic toxicity observed. The mean +/- SD platelet count (n = 13 treatments) was 243 +/- 62 x 10(9)/L before treatment and 233 +/- 87 x 10(9)/L 3 mo later, a slight and statistically insignificant decrease. After rhTSH-aided administration of high activities of 131I, the bone marrow absorbed dose remained under 2 Gy, the level long considered the safety threshold for all radioiodine therapy. CONCLUSION: Our specific findings imply that when clinically warranted, rhTSH should allow an increase in the therapeutic radioiodine activity. Such an increase might improve efficacy while preserving safety and tolerability; this possibility should be assessed in further studies.     

重组人促甲状腺激素用于低中危分化型甲状腺癌患者的术后评估:Ⅰ期临床研究报告

目的:评价我国自主研发的重组人促甲状腺激素(rhTSH)在辅助分化型甲状腺癌(DTC)患者¹³¹I治疗前后动态评估中的作用。方法:该Ⅰ期研究采用剂量递增设计,纳入2019年5月至2020年11月就诊于北京协和医院及郑州大学附属肿瘤医院的24例DTC患者(男5例、女19例,中位年龄41岁),根据国产rhTSH(简称rhTSH)使用方法分为4个剂量组[0.9 mg×1 d(A组),0.9 mg×2 d(B组),1.8 mg×1 d(C组),1.8 mg×2 d(D组)],每组6例。每例患者接受2个阶段自身对照研究,依次为rhTSH阶段及停用甲状腺激素(THW)阶段。评估rhTSH的安全性、耐受性、患者生活质量[甲状腺功能减退症(简称甲减)症状体征积分、简式心境状态量表(POMS)]、药效学[促甲状腺激素(TSH)及甲状腺球蛋白(Tg)水平、诊断性全身显像(Dx-WBS)]及药代动力学(达峰时间、峰浓度)特征。采用配对t检验或Wilcoxon符号秩检验进行统计分析。结果:4个剂量组均未观察到剂量限制性毒性事件、严重不良事件或≥3级的不良事件。rhTSH阶段的生活质量相关评分明显优于THW阶段:甲减症状体征积分[-53.00(-53.00,-53.00)与-39.50(-47.00,-23.00)分;S=119.50,P<0.001];简式POMS评分[(91.92±12.06)与(99.67±19.13)分;t=0.95,P=0.025]。rhTSH末次给药后24 h血清TSH水平从基线的0.04(0.02,0.11)mU/L升至150.00(105.20,173.31)mU/L;随着rhTSH剂量增加,各组TSH呈增高趋势。在THW阶段,患者需经中位时间23 d的THW方达TSH≥30 mU/L水平,THW阶段TSH水平为73.51(57.22,106.22)mU/L;Tg在rhTSH给药后从基线[0.10(0.10,0.41)μg/L]逐渐升高,48 h达峰值[0.85(0.12,3.01)μg/L],THW阶段Tg水平为0.88(0.15,8.04)μg/L;2个阶段诊断性全身显像结果一致率为95.8%(23/24)。结论:在辅助DTC术后评估中,国产rhTSH对患者显示出较好的安全性,患者生活质量较好;其可有效升高患者TSH水平,并快速刺激Tg分泌及残余甲状腺摄碘。     

Reproducibility of whole-body <Superscript>131</Superscript>I scan and serum thyrotropin and stimulated thyroglobulin values in patients studied twice after injection of recombinant human thyrotropin

Purpose Recombinant human TSH (rhTSH) is used to increase radioiodine uptake during imaging of thyroid cancer, obviating the need to render the patient hypothyroid. We assessed the reproducibility of radioiodine uptake, serum thyrotropin (TSH), and stimulated serum thyroglobulin (Tg) levels after rhTSH administration. Methods A retrospective review was performed of patients at Stanford who underwent whole-body ¹³¹I scanning for surveillance of thyroid cancer twice after thyroidectomy and ¹³¹I ablation, with rhTSH prior to each scan. Forty-eight hour radioiodine uptake, peak serum TSH, and stimulated serum Tg levels for each study were recorded. Paired t tests and correlation analysis were used to assess interexamination repeatability. Results Twenty-three patients underwent two scintiscans with rhTSH, for a total of 46 exams. There was no significant difference between percent uptake at 48 h in the paired exams (p=0.40). Serum TSH level was measured in 45 of 46 exams; TSH exceeded 50 mIU/l in all cases, and there was no significant difference between paired TSH levels (p=0.93). All patients had stimulated serum Tg levels measured, with no significant difference between paired Tg levels (p=0.40); after excluding one patient whose Tg changed from 15.8 ng/ml to undetectable between scans without interval treatment, the p value rose to 0.95. There was a strong correlation among paired uptake values (r=0.85, p<0.0001), peak serum TSH (r=0.69, p=0.0003), and stimulated Tg levels (r=0.81, p<0.0001). No discordant scan interpretations were reported. Conclusion Forty-eight hour radioiodine uptake, peak serum TSH, and stimulated serum Tg levels after administration of rhTSH are repeatable between studies, demonstrating reproducibility of diagnostic results without rendering patients hypothyroid.     

Tumour dosimetry and response in patients with metastatic differentiated thyroid cancer using recombinant human thyrotropin before radioiodine therapy

The development of recombinant human thyrotropin (rhTSH) has given clinicians new options for diagnostic follow-up and treatment of patients with differentiated thyroid cancer (DTC). This paper evaluates the tumour dosimetry and response following -iodine-131 treatment of metastatic thyroid cancer patients after rhTSH stimulation instead of classical hormone withdrawal-induced hypothyroidism. Nineteen consecutive (131)I treatments in 16 patients were performed after rhTSH stimulation. All patients had undergone a near-total thyroidectomy followed by an ablative dosage of (131)I. They all suffered from metastatic or recurrent disease showing tumoral (131)I uptake on previous post-treatment scintigraphy. Dosimetric calculations were performed using (131)I tumour uptake measurements from post-treatment (131)I scintigrams and tumour volume estimations from radiological images. Response was assessed by comparing pre-treatment serum thyroglobulin (Tg) level with the Tg level 3 months post treatment. In 18 out of 19 treatments, uptake of (131)I in metastatic or recurrent lesions was seen. The median tumour radiation dose was 26.3 Gy (range 1.3-368 Gy), and the median effective half-life was 2.7 days (range 0.5-6.5 days). Eleven of 19 treatments (10/16 patients) were evaluable for response after 3 months. (131)I therapy with rhTSH resulted in a biochemical partial response in 3/11 or 27% of treatments (two patients), biochemical stable disease in 2/11 or 18% of treatments and biochemical progressive disease in 6/11 or 55% of treatments. Our study showed that although tumour doses in DTC patients treated with (131)I after rhTSH were highly variable, 45% of treatments led to disease stabilisation or partial remission when using rhTSH in conjunction with (131)I therapy, without serious side-effects and with minimal impact on quality of life. RhTSH is therefore adequately satisfactory as an adjuvant tool in therapeutic settings and is especially suitable in advanced recurrent or metastatic DTC patients who may be intolerant to TSH stimulation by levothyroxine withdrawal.     

Stimulation test in the follow-up of thyroid cancer: plasma rhTSH levels are dependent on body weight, not endogenously stimulated TSH values

BACKGROUND: Stimulation testing in the first year following thyroid ablation has important prognostic value in thyroid cancer patients. Recombinant human TSH (rhTSH) is better tolerated than thyroid hormone withdrawal but provides only transient stimulation so that the TSH threshold of 30 mIU x l(-1) which defines adequate testing during thyroid hormone withdrawal is not appropriate for rhTSH stimulation. We looked at rhTSH levels after a standard two intramuscular injections of 0.9 mg rhTSH. METHODS: Plasma rhTSH levels were measured 24 h after the second injection in 143 consecutive patients. RESULTS: rhTSH levels showed large inter-patient variation (range: 44-240; mean+/-SD: 131+/-48). There was a strong inverse correlation between TSH levels and body weight (P<0.001). Levels lower than 80 mIU x l(-1) (corresponding to 1 SD below average) were recorded in 24 patients (16.8%). These patients had an average body weight of 79.7 kg, as compared to 67.9 kg for those patients with TSH levels higher than 80 mIU x l(-1). A withdrawal test in the first year after thyroid ablation was available in 64 patients. Only one patient (1.6%) had inadequate endogenous TSH stimulation, and there was no dependence of endogenous plasma TSH levels upon weight. CONCLUSION: Contrary to endogenous stimulation, TSH levels after rhTSH injection vary with body weight. The dosage of rhTSH may need to be adapted in patients with more than 80 kg body weight.     

Recombinant human TSH-aided radioiodine treatment of advanced differentiated thyroid carcinoma: a single-centre study of 54 patients

We sought to evaluate the efficacy, biochemical effects, safety and outcome of recombinant human thyroid-stimulating hormone (rhTSH) as an adjunct to radioiodine treatment of advanced differentiated thyroid carcinoma (DTC). We also sought to determine whether rhTSH is useful as an adjunct to radioiodine treatment following isotretinoin re-differentiation therapy of DTC metastases that have lost function. Therefore, in 54 consecutive patients who had retained bulky metastatic and/or locoregional lesions of DTC despite the exhaustion of other therapeutic options, we gave one to four courses of two consecutive daily intramuscular injections of rhTSH, 0.9 mg, followed by a therapeutic activity of (131)I per os on day 3. Fifty patients had received prior radioiodine treatment aided by l-thyroxine (T(4)) withdrawal. We included in the study 23 patients who had received a trial of isotretinoin therapy for re-differentiation of confirmed de-differentiated metastases. In a blinded, within-patient comparison of post-therapy whole-body scans after the first rhTSH-aided and latest withdrawal-aided treatments in patients with functional metastases at baseline, 18 of 27 (67%) scan pairs were concordant, four (15%) were discordant in favour of the rhTSH-aided scan and five (19%) were discordant in favour of the withdrawal-aided scan. In total, 37 (74%) of 50 paired scans were concordant, eight (16%) favoured rhTSH and five (10%) favoured withdrawal. All differences appeared to be attributable to clinical causes, not to any difference between endogenous and exogenous TSH stimulation. Reflecting the biochemical activity of rhTSH and the release of thyroglobulin (Tg) due to tumour destruction, median serum Tg concentration rose approximately fourfold between baseline and day 6 of the rhTSH-aided treatment course. rhTSH was well tolerated, with mostly minor, transient toxicity, except for neck oedema in three patients with neck infiltrates and pathological spine fracture in one patient with a large vertebral metastasis. At 6 months, complete response occurred in one (2%), partial response in 12 (26%) and disease stabilisation in 19 (40%) of 47 evaluable patients. The rate of complete + partial response was 41% and that of disease stabilisation, 30%, in the 27 evaluable patients with functional metastases at baseline; the corresponding rates were 10% and 55% in the 20 evaluable patients with non-functional metastases at baseline. Although within-patient comparison of early outcome after both modalities is limited by a significantly greater median number of courses and a greater median cumulative activity of radioiodine given under withdrawal, response to rhTSH-aided and withdrawal-aided treatment was similar in 23 (52%) of 44 evaluable patients, superior with rhTSH in 12 (27%) and superior with withdrawal in seven (16%). In two patients, a superior response was obtained after isotretinoin pretreatment and rhTSH and attributed to re-differentiation therapy. In conclusion, our study provides preliminary evidence that rhTSH safely and effectively aids radioiodine treatment of advanced DTC, and does so to an at least equivalent degree as does T(4) withdrawal.     

Recombinant human TSH-assisted radioactive iodine remnant ablation achieves short-term clinical recurrence rates similar to those of traditional thyroid hormone withdrawal.

Recent studies have confirmed that radioactive iodine therapy after recombinant human TSH (rhTSH) stimulation effectively ablates the normal thyroid remnant. However, no published study has determined the effectiveness of rhTSH preparations on the important endpoint of disease recurrence. METHODS: Disease recurrence was retrospectively assessed a median of 2.5 y after radioiodine remnant ablation (RRA) in 394 consecutive thyroid cancer patients (93% papillary, 71% female, 47+/-15 y old [mean +/- SD], median (131)I dose of 3,996 MBq [108 mCi]). RESULTS: Similar rates of clinically evident disease recurrence (4% rhTSH vs. 7% thyroid hormone withdrawal [THW], P=not statistically significant) and residual thyroid bed uptake without other evidence of persistent disease (4% rhTSH vs. 7% THW, P=not statistically significant) were seen in the 320 patients undergoing rhTSH-assisted RRA and the 74 patients prepared for RRA by THW. When the definition of no clinical evidence of disease included a suppressed thyroglobulin level of less than 1 ng/mL and a stimulated thyroglobulin level of less than 2 ng/mL, rhTSH-assisted RRA was associated with significantly higher rates of no clinical evidence of disease (74% rhTSH vs. 55% THW, P=0.02) and significantly lower rates of persistent disease (19% rhTSH vs. 32% THW, P=0.02) than was RRA after THW. Patients selected for rhTSH-assisted RRA were older (48+/-15 vs. 44+/-15 y, P=0.03) and received a slightly higher administered activity of (131)I (median, 4,033 MBq [109 mCi] vs. 3,811 MBq [103 mCi], P=0.01) but did not differ with respect to sex, histology, disease stage, or mean time to recurrence (19+/-9 mo for rhTSH vs. 20+/-16 mo for THW). CONCLUSION: rhTSH-assisted RRA is associated with rates of clinically evident disease recurrence and persistent uptake in the thyroid bed that are similar to those for traditional THW.     

Length and cost of hospital stay of radioiodine ablation in thyroid cancer patients: comparison between preparation with thyroid hormone withdrawal and thyrogen

PURPOSE: Treatment of thyroid cancer consists of thyroidectomy and radioiodine ablation following thyroid-stimulating hormone (TSH) stimulation. Similar ablation rates were obtained with either thyroid hormone withdrawal (THW) or rhTSH. But with rhTSH, the elimination of radioiodine is more rapid, thus reducing its whole-body retention and potentially resulting in a shorter hospital stay. The aim of this study was to assess the financial impact of a reduced length of hospital stay with the use of rhTSH. METHODS: This was a case-control study of thyroid cancer patients treated postoperatively with 3,700 MBq (100 mCi) radioiodine; 35 patients who received rhTSH were matched with 64 patients submitted to THW according to covariates influencing radioiodine retention. The length of hospitalization (LOH) was estimated for each method according to the threshold of radioiodine retention below which the patient can be discharged from the hospital. The economic analysis was conducted from a hospital perspective. Simulations were performed. RESULTS: For a threshold of 400 MBq, the LOH was 2.4 days and 3.5 days with rhTSH and THW, respectively, and the cost for an ablation stay was, respectively, 2,146 and 1,807 . In the French context, 57% of the acquisition cost of rhTSH was compensated by the reduction of the length of hospitalization. CONCLUSION: By increasing the iodine excretion, rhTSH allows a shorter hospitalization length, which partially compensates its acquisition cost.     

Recombinant human thyrotropin (rhTSH) in the management of differentiated thyroid cancer

Recombinant human thyrotropin (rhTSH) has been evaluated in 38 patients with differentiated thyroid cancer. The patients had all been treated previously by operation and 31 had received radioiodine 131I. The patients continued to take thyroid hormone and changed to a low iodine diet for 14 days before and throughout the week of testing. The rhTSH was injected intramuscularly on two consecutive days, 74 MBq 131I was administered on the next day and scintigraphy completed 48 h after that. TSH was measured before administration of 131I, and thyroglobulin after the scan. All patients preferred this method to withdrawal of thyroid hormone, but 45% had mild symptoms including headache and nausea. The average TSH was 127 mU x l(-1), and was inversely related to the weight of the patients. Thirty-four had negative scans with a mean uptake of 0.06%. Thyroglobulin values above 10 ng x ml(-1) were found in seven patients, of whom four had similar findings when scanned after withdrawal of thyroid hormone. Of four with positive scans, two had undetectable thyroglobulin. The rate of clearance of 131I was compared in patients studied at 72 h who were hypothyroid and at 48 h in euthyroid patients given rhTSH and was found to be longer in the latter. We conclude that rhTSH can be used to stimulate thyroid tissue to trap 131I and secrete thyroglobulin. Both scan and thyroglobulin should be obtained. The method is well tolerated.     

Value of recombinant human thyrotropin in high-dose radioiodine therapy: a case report

We report on a high-dose radioiodine therapy after injection of recombinant human thyrotropin (rhTSH) in a 61-y-old woman with compression of the spinal cord caused by metastasis of a follicular thyroid carcinoma. Fourteen years ago, the patient underwent subtotal thyroidectomy because of multinodular goiter without any histologic evidence for malignant disease, and the patient was put on thyroxine substitution (100 micro g/d). In April 2000, she developed paralysis of the right leg. Morphologic imaging revealed spinal compression caused by a space-occupying lesion within the thoracic spine. Subsequent biopsy and histology demonstrated metastasis of a follicular thyroid carcinoma. Therefore, high-dose radioiodine therapy was scheduled after 4 wk of hormone withdrawal. Within a few days of being off thyroxine, the patient's paralytic symptoms worsened rapidly. The patient was again put on thyroxine, 100 micro g/d, and high-dose radioiodine therapy under stimulation with rhTSH was performed without any side effects. The second high-dose radioiodine therapy 3 mo later, again performed under stimulation with rhTSH, showed significantly less iodine avidity, and thyroglobulin levels fell from 1,024 micro g/L to 361 micro g/L, thereby demonstrating therapeutic efficacy. Thus, rhTSH might be used as a tool not only in the diagnostic application but also in the therapeutic application of (131)I.     

Procedure guideline for iodine-131 whole-body scintigraphy for differentiated thyroid cancer (version 2)

The version 2 of the procedure guideline for iodine-131 whole-body scintigraphy for differentiated thyroid cancer is an update of the procedure guideline published in 1999. The following statements are added or modified: The two alternatives of an endogenous TSH-stimulation by the withdrawal of the thyroidal hormone medication and of an exogenous TSH-stimulation by the injection of the recombinant human TSH (rhTSH) have an equal sensitivity for the diagnostic use of radioiodine and for the measurement of thyroglobulin. Image acquisition under rhTSH is obtained approximately 48 h after the radioiodine administration, while an interval of about 72 h is preferred under endogenous TSH-stimulation. If iodine-negative metastases are expected, the feasibility of scintigraphy using (99m)Tc sestamibi or preferably positron emission tomography using (18)F-fluorodeoxyglucose should be considered. The sensitivity of FDG-PET is increased by TSH-stimulation. Before planning the iodine-131 scintigraphy the patient has to avoid iodine-containing medication and the possibility of additives of iodine in vitamin- and electrolyte-supplementation has to be considered.     

Procedure guidelines for radioiodine therapy of differentiated thyroid cancer (version 3)

The procedure guideline for radioiodine therapy (RIT) of differentiated thyroid cancer (version 3) is the counterpart to the procedure guideline for (131)I whole-body scintigraphy (version 3) and specify the interdisciplinary guideline for thyroid cancer of the Deutsche Krebsgesellschaft concerning the nuclear medicine part. Recommendation for ablative (131)I therapy is given for all differentiated thyroid carcinoma (DTC) >1 cm. Regarding DTC < or =1 cm (131)I ablation may be helpful in an individual constellation. Preparation for (131)I ablation requires low iodine diet for two weeks and TSH-stimulation by withdrawal of thyroid hormone medication or by use of recombinant human TSH (rhTSH). The advantages of rhTSH (no symptoms of hypothyroidism, lower blood activity) and the advantages of endogenous TSH-stimulation (necessary for (131)I-therapy in patients with metastases, higher sensitivity of (131)I whole-body scan) are discussed. In most centers standard activities are used for (131)I ablation. If pretherapeutic dosimetry is planned, the diagnostic administration of (131)I should not exceed 1-10 MBq, alternative tracers are (123)I or (124)I. The recommendations for contraception and family planning are harmonized with the recommendation of ATA and ETA. Regarding the best possible protection of salivary glands the evidence is insufficient to recommend a specific setting. To minimize the risk of dental caries due to xerostomia patients should use preventive strategies for dental hygiene.     

Possible explanations for patients with discordant findings of serum thyroglobulin and 131I whole-body scanning.

The long-term monitoring of patients with differentiated thyroid carcinoma (DTC) is essential throughout the patient's life after total or near-total thyroidectomy followed by (131)I remnant ablation and thyroid hormone suppression of thyroid-stimulating hormone (TSH). Sensitive surveillance for DTC recurrence and metastases includes radioiodine diagnostic whole-body scanning (DWBS) and measurement of serum thyroglobulin (Tg) after endogenous or exogenous TSH stimulation. Serum Tg levels during thyroid hormone withdrawal (Tg-off) are usually well correlated with the results of DWBS. In general, undetectable Tg levels with negative DWBS (DWBS(-)) suggest complete remission, whereas detectable or elevated Tg concentrations are suggestive of the presence of (131)I uptake in local or distant metastases. However, DTC patients with discordant results of Tg measurement and (131)I WBS have been observed in the follow-up study. Negative (131)I DWBS and a positive Tg test (DWBS(-) Tg(+)) are found in most of these cases. Positive (131)I DWBS and a negative Tg test (DWBS(+) Tg(-)), though of uncommon occurrence, has also been demonstrated in a small but significant number of cases. With this scenario, one should first attempt to uncover a cause for possibly false-negative or false-positive (131)I WBS or serum Tg. Explanations for the discordance are speculative but should be scrutinized when confronted with discrepant data in a given patient.     

Therapy for non-toxic multinodular goiter: radioiodine therapy as attractive alternative to surgery

The need for therapy for nodular goiter results from the growth of thyroid nodules over decades and from the possibility of tracheal compression and worsening of respiratory function. Given the high prevalence of non-toxic goiter, the epidemiologically low incidence of clinically apparent thyroid cancer justifies non-surgical strategies. Randomised studies have shown that levothyroxine offers limited therapeutic effects and is inferior to radioiodine therapy regarding goiter shrinkage. When indication for a definitive therapy is given, the choice between resection and radioiodine therapy should consider volume of goiter, severity of clinical symptoms, thyroid uptake, patient's age, co-morbidity, previous resection of goiter, patient's profession and patient's wish. Even in large goiters between 100 and 300 ml radioiodine therapy showed consistent results with goiter size reduction from 35-40% one year and 40-60% two years after radioiodine therapy. Thyroid hormones to prevent recurrence of goiter are not necessary. Recurrent goiters were seldom observed after radioiodine therapy and resulted from initially very large goiters or uptake in dominate nodules or from low (131)I activities. Recombinant human TSH (rhTSH) offers the opportunity to enhance the effect of radioiodine therapy. Observational studies have shown that rhTSH increases low (131)I uptake in case of high alimentary iodine-supply by the factor 4, causes a more homogenous (131)I distribution within the goiter and improves goiter reduction. A phase I study for dose finding is running in the USA. Conclusion: Radioiodine therapy for shrinkage of large non-toxic goiter should not be restricted to elderly patients, or to patients with co-morbidity or high operative risk, but is an attractive alternative to surgery in patients with special professions (singer, teacher, speaker) or with the wish for a non-invasive treatment modality.     

Protocol for the combined diagnostic and therapeutic use of recombinant human thyroid-stimulating hormone

Patients may be prepared for radioiodine diagnostic imaging by withdrawal of all thyroid medication or by the administration of extrinsic thyroid-stimulating hormone (TSH). Although purified human and bovine TSHs were used in the past, they are no longer recommended because of their adverse effects. Recently, a new extrinsic TSH called recombinant human TSH (rhTSH) was developed and is commercially available. It is a highly purified, recombinant form of the naturally occurring human TSH. It was introduced to decrease complications associated with temporary hypothyroid states required at times in the follow-up evaluation of patients with thyroid cancer. Although rhTSH is currently used for patient preparation in diagnosis only, its use in preparations for subsequent radioiodine therapy may be helpful in some clinical circumstances. The authors describe a patient with papillary thyroid cancer in whom a 2-day rhTSH protocol was used for diagnosis and extended for therapeutic purposes. The protocol was useful to obtain the diagnostic information needed to determine whether to treat, and it allowed rapid progress to therapy without further patient preparation. Until rhTSH is fully approved for both diagnostic and therapeutic uses, this modified 2-day protocol would allow patients with special clinical circumstances to be evaluated and treated rapidly.     

Comparison of radioiodine biokinetics following the administration of recombinant human thyroid stimulating hormone and after thyroid hormone withdrawal in thyroid carcinoma

Iodine kinetics were studied in patients with differentiated thyroid cancer while euthyroid under exogenous thyroid stimulating hormone (TSH) and while hypothyroid to detect differences in radioiodine uptake, distribution and elimination. Nine patients with total or near-total thyroidectomy on thyroid hormone suppressive therapy received two or three daily doses of 0.9 mg recombinant human TSH (rhTSH) followed by administration of a diagnostic activity of 2 mCi (74 MBq) iodine-131. After the biokinetics assessments had been performed, patients stopped taking thyroid hormones to become hypothyroid. A second 2 mCi (74 MBq) diagnostic activity of ¹³¹I was administered, followed by a second set of biokinetics assessments. One week later the patients underwent remnant ablation with a therapeutic activity of ¹³¹I. A comparison of the ¹³¹I kinetics in the patients while euthyroid and while hypothyroid showed major differences in the doses to the remnant as well as in residence times and radiation exposure to the blood. In the first diagnostic assessment the remnant dose was higher in eight of the nine patients and clearance of the activity from the blood was faster in all of them. The data from this study suggest that radioiodine administration is potent and safe when administered to euthyroid patients following rhTSH administration. Enhanced residence time in the remnant and decreased radiation exposure to the blood were noted when patients were euthyroid compared to when they were rendered hypothyroid. However, all patients received diagnostic activities in the same order: first while euthyroid, followed by hypothyroidism. It is quite possible that "stunning" from the radioiodine administered in the initial uptake study inhibited the subsequent uptake of radioiodine by the remnant lesions in the second uptake study.     

Which thyroid cancer patients need periodic stimulation tests?

PURPOSE: Recurrences are frequent in thyroid cancer patients and long-term follow-up is therefore necessary. We evaluated the yield of rhTSH stimulation in three groups of patients, classified according to the UICC/TNM risk stratification and the results of first follow-up testing. METHODS: The study population comprised 129 patients referred for rhTSH testing. All had undergone first follow-up testing after thyroid hormone withdrawal (off-T4) within 1 year of 131I ablation. Negative first follow-up testing was defined as Tg <2 ng/ml and no neck uptake on 131I diagnostic whole-body scan. Seventy-five patients had stage I thyroid cancer and negative first follow-up testing (group A), 19 had stage I disease and positive first follow-up testing (group B), and 35 had stage II-IV disease (group C). RhTSH stimulation was performed an average of 6 years after first follow-up testing. RESULTS: 131I diagnostic scanning after rhTSH was negative in all 75 group A patients. Only one group A patient had detectable Tg after rhTSH injection (1.5 ng/ml), but Tg had also been detected at baseline in this patient (1.45 ng/ml). Given the absence of a response to stimulation, suggesting an interference, Tg was reassessed with a different technique and proved to be undetectable (<0.1 ng/ml). Stimulation with rhTSH in group B showed residual Tg in seven patients and residual 131I uptake in the thyroid bed in two patients, but none of these patients had signs of disease progression. Five group C patients (14%) had a positive rhTSH test result, and this was suggestive of disease progression in at least two cases. CONCLUSION: The first follow-up testing is essential for prognostic classification after 131I ablation of thyroid cancer. In stage I patients, undetectable Tg and negative 131I scan 1 year after ablation define a large population of subjects who have a very low risk of recurrence and who do not require further stimulation tests. In contrast, periodic rhTSH stimulation tests appear useful in higher-risk patients.     

Lesion dose in differentiated thyroid carcinoma metastases after rhTSH or thyroid hormone withdrawal: 124I PET/CT dosimetric comparisons

Purpose

Renal radioiodine excretion is ~50% faster during euthyroidism versus hypothyroidism. We therefore sought to assess lesion dose/GBq of administered ¹³¹I activity (LDpA) in iodine-avid metastases (IAM) of differentiated thyroid carcinoma (DTC) in athyreotic patients after recombinant human thyroid-stimulating hormone (rhTSH) versus after thyroid hormone withdrawal (THW).

Methods

We retrospectively compared mean LDpA between groups of consecutive patients (N?=?63) receiving ¹²⁴I positron emission tomography/computed tomography (¹²⁴I PET/CT) aided by rhTSH (n?=?27) or THW (n?=?36); we prospectively compared LDpA after these stimulation methods within another individual. Data derived from serial PET scans and one CT scan performed 2–96 h post-¹²⁴I ingestion. A mixed model analysis of covariance (ANCOVA) calculated the treatment groups’ mean LDpAs adjusting for statistically significant baseline intergroup differences: non-IAM were more prevalent, median IAM count/patient lower in cervical lymph nodes and higher in distant sites, median stimulated thyroglobulin higher, mean cumulative radioiodine activity greater and prior diagnostic scintigraphy more frequent in the rhTSH patients.

Results

Mean LDpAs were: rhTSH group (n?=?71 IAM), 30.6 Gy/GBq; THW group (n?=?66 IAM), 51.8 Gy/GBq. The difference in group means (rhTSH less THW), ?21.2 Gy/GBq, was statistically non-significant (p?=?0.1667). However, the 95% confidence interval of that difference (?51.4 to ?+?9 Gy/GBq) suggested a trend favouring THW. The within-patient comparison found 2.9- to 10-fold higher LDpAs under THW.

Conclusion

We found some suggestions, but no statistically significant evidence, that rhTSH administration results in a lower radiation dose to DTC metastases than does THW. A large, well-controlled, prospective within-patient study should resolve this issue.