Use of recombinant human thyrotropin before radioiodine therapy in patients with advanced differentiated thyroid carcinoma

The use of 131I for radioablative therapy in patients with differentiated thyroid cancer (DTC) requires a sufficient serum concentration of TSH for efficient thyroid tissue uptake of iodine. We describe the use of recombinant human TSH (rhTSH) in conjunction with ablative radioiodine therapy (RIT) in 11 patients (16 total treatments) with advanced and/or recurrent DTC (5 papillary, 6 follicular) for whom withdrawal of thyroid hormone suppression therapy (THST), the standard method to increase serum TSH, was not an option. Indications for rhTSH use in these patients included inability to tolerate withdrawal of thyroid hormones due to very poor physical condition or inability to achieve sufficient serum TSH levels after THST withdrawal. Ten patients had undergone thyroidectomy, and most (9 of 11) had received prior ablative RIT after THST withdrawal. Baseline thyroglobulin levels ranged from 25 to nearly 30,000 ng/mL, reflecting the heterogeneity of the patient population. In 7 cases (5 patients), posttherapy thyroglobulin levels assessed at a mean of 4.3 months (range, 2-10 months) after 131I therapy were decreased by at least 30% compared to pretherapy levels. In follow-up visits, an additional 3 patients showed marked clinical improvement or decreased or stabilized tumor burden in whole body scans compared to pretherapy scans. Three patients died of progressive disease within 2 months of therapy before follow-up assessments occurred. No adverse events were reported among the 8 surviving patients. The results suggest that rhTSH offers a promising alternative to THST withdrawal to allow ablative RIT after effective TSH stimulation in patients with advanced recurrent DTC who would not otherwise be able to receive this treatment. This therapeutic indication extends the clinical potential of this new agent, already demonstrated to be effective for use with 131I for diagnostic purposes.     

重组人促甲状腺素介导分化型甲状腺癌的131I治疗

目的 研究重组人促甲状腺素(rhTSH)介导分化型甲状腺癌131I治疗对内源性TSH、甲状腺球蛋白、FT3、FT4的影响及其清甲成功率.方法 31例(年龄14～70岁,其中女性23例)接受rhTSH介导的131I治疗(甲状腺功能正常组),31例(年龄23～72岁,其中女性22例)停用甲状腺素后的行131I治疗[甲状腺功能减退组(甲减组)]观察注射rhTSH前后血清TSH、FT3、FT4以及甲状腺球蛋白抗体(TGAb)、甲状腺球蛋白浓度变化,以及131I治疗后6～12个月131I全身诊断显像评价其疗效.结果 使用rhTSH前后,血清TSH、甲状腺球蛋白、FT3、FT4的平均浓度分别是(1.08±4.01)和(140.26±27.20)mIU/L(P＜0.05)、(23.75±132.92)和(169.58±178.49)μg/L(P＜0.05)、(4.52±1.16)和(4.42±1.11)pmol/L(P＞0.05)、(15.09±5.83)和(13.66±5.85)pmol/L(P＞0.05).诊断剂量131I-全身显像显示甲状腺功能正常组24/31(77.4%)及甲减组22/31(71.0%)被考虑成功清甲(P＞0.05).以甲状腺球蛋白评价两组131I治疗疗效统计学无显著差异(P＞0.05),甲状腺功能正常组20/31(64.50%)及甲减组18/31(58.06%)被考虑成功清甲.结论 使用rhTSH能有效刺激内源性TSH增高,提高生活质量,获得较高的清甲成功率.使用rhTSH能有效刺激血清甲状腺球蛋白,有利于监测肿瘤残存、复发与转移.

Abstract：

Objective To observe the influence of recombinant human thyrotropin(rhTSH)on serum concentration of endogenous thyrotropin(TSH), free triiodothyronine(FT3), free thyroxine(FT4), thyroglobulin antibody(TGAb), and thyroglobulin(Tg). To evaluate the efficacy of rhTSH-aided radioiodine treatment in patients with differentiated thyroid carcinoma(DTC). Methods The study recruitment took place between November 2007 and March 2009. 62 patients(including 45 females)with biopsy confirmed DTC had undergone total or nearly total thyroidectomy, and received 131I treatment. 31 patients(including 22 females), median age of 45 years(23-72), received radioiodine treatment 4 weeks after L-thyroxine(T4)withdrawal. The other 31 patients(including 23 females), median age of 44 years(14-70), underwent rhTSH-aided radioiodine treatment. Before and after rhTSH injection, serum TSH, FT3, FT4, TGAb, and thyroglobulin were tested. Post-radiotherapy whole body scan was performed 5 to 7 days after radioiodine treatment and qualitatively and blindly evaluated by two nuclear medicine physicians. Follow-up took place 6 to 12 months after radioiodine treatment. The efficacy of rhTSH-aided radioiodine treatment was evaluated by whole body scan with diagnostic dose radioiodine. SPSS 13.0 statistical software was applied. Results (1)Before and after rhTSH-aided radioiodine treatment, the serum TSH was(1.08±4.01)vs(140.26±27.20)mIU/L(P＜0.05), thyroglobulin(23.75±132.92)vs(169.58±178.49)μg/L(P＜0.05), FT3(4.52±1.16)vs(4.42±1.11)pmol/L(P＞0.05), and FT4(15.09±5.83)vs(13.66±5.85)pmol/L(P＞0.05),respectively.(2)rhTSH-aided radioiodine ablation treatment had the same effect as L-T4withdrawal aided. The complete response ratio was 77.4% vs 71.0%(P＞0.05)by radioiodine whole body scan of diagnostic dose. Conclusion rhTSH-aided radioiodine treatment of DTC was effective and safe, and did at least at equivalent degree as did L-T4withdrawal. Furthermore, Serum thyroglobulin level could be effectively stimulated by rhTSH with tumor relapse or metastasis.     

Influence of human body composition on serum peak thyrotropin (TSH) after recombinant human TSH administration in patients with differentiated thyroid carcinoma

OBJECTIVES: In this study, we evaluated the influence of height, weight, body mass index (BMI), body surface area, and body composition [total lean body mass (LBM) and fat body mass] on serum peak TSH levels obtained after recombinant human (rh)TSH. Furthermore, to verify whether the serum peak TSH influenced the efficacy of radioiodine ((131)I), we compared the rate of thyroid remnant ablation according to the patients' BMI. PATIENTS: We studied 105 patients with differentiated thyroid carcinoma who underwent rhTSH stimulation test. Serum TSH measurements were performed before and 24, 48, and 72 h after rhTSH administration. We also compared the rate of thyroid remnant ablation among 70 differentiated thyroid carcinoma patients with different BMI. RESULTS: The serum peak TSH after rhTSH was significantly lower in overweight and obese subjects compared with normal-weight subjects (92.1 +/- 41.8, 82.4 +/- 24.2, and 112.7 +/- 46.3 microU/ml, respectively; P = 0.01) and in males compared with females (74.6 +/- 22.3 and 105.0 +/- 43.0 microU/ml, respectively; P = 0.0002). By univariate analysis, serum peak TSH was negatively related to weight, height, body surface area, BMI, LBM, and fat body mass, but only LBM was independently associated with serum peak TSH levels. Although it was confirmed that overweight and obese patients had a lower serum peak TSH, the rate of ablation did not differ among normal-weight, overweight, and obese patients. CONCLUSIONS: With this study we demonstrated that LBM is the only parameter independently associated with serum peak TSH after rhTSH administration. However, the serum peak TSH does not influence the rate of (131)I remnant ablation.     

Management of paediatric thyroid carcinoma: recent experience with recombinant human thyroid stimulating hormone in preparation for radioiodine therapy

Background: Thyroid carcinoma in children is rare and raises unique management issues. Although metastatic disease is more common in this age group, prognosis remains good with appropriate treatment. The aim of the study was to report recent experience in the management of differentiated thyroid carcinoma in children, especially in the use of radioiodine after recombinant human thyroid stimulating hormone (rhTSH) stimulation. Methods: Eight patients, aged 5–17 years (five were boys) presented following total thyroidectomy for thyroid carcinoma between May 2003 and June 2005. Seven had papillary carcinoma and one had follicular carcinoma. Five had known lymph node metastases and one had pulmonary metastases at presentation. Four patients had previously received therapeutic irradiation for malignancy. All eight underwent diagnostic iodine scans, seven with rhTSH stimulation. Seven went on to receive radioiodine treatment as hospital inpatients, comanaged by the paediatric and nuclear medicine units. The dosage of ¹³¹I ranged from 1.5 to 3.7 × 10⁹ Bq. All except one were prepared by rhTSH stimulation. Results: Seven of eight patients had significant uptake in the neck on diagnostic scan and two had pulmonary abnormalities. Six of seven evaluable patients achieved complete thyroid ablation. Both patients with pulmonary abnormalities had scan resolution, although one of them only after a second radioiodine treatment. All patients had thyroxine replacement in doses to suppress TSH and all remain alive and well at time of carrying out this study. Conclusion: Optimal management of paediatric thyroid carcinoma necessitates a multidisciplinary approach. Radioiodine therapy under rhTSH is an effective and safe adjuvant treatment in this special subgroup.     

Compliance with follow-up and the informative value of diagnostic whole-body scan in patients with differentiated thyroid carcinoma given recombinant human TSH

OBJECTIVE: Protocols for monitoring patients with differentiated thyroid cancer (DTC) include measurement of serum Tg and, for most patients, whole-body scan (WBS) with low radioiodine activities ('diagnostic' WBS). Recently, recombinant human thyroid-stimulating hormone (rhTSH) has become available to provide the TSH stimulation necessary for these procedures, whilst avoiding thyroid hormone withdrawal and hypothyroid complications. In addition, the inclusion of diagnostic WBS in DTC follow-up has recently become controversial. We have assessed the compliance with withdrawal-aided monitoring and the informative value of diagnostic WBS in consecutive tertiary referral center patients. DESIGN: Forty-eight patients received rhTSH (0.9 mg) in two consecutive daily injections, with radioiodine administration 24 h, diagnostic WBS 48 h, and serum Tg testing prior to and 72 h later. METHODS: Compliance with withdrawal-aided monitoring was assessed with a questionnaire provided by the referring physician, patient record analysis, and patient interview. The informative value of diagnostic WBS was assessed by comparing findings against serum Tg measurements in light of physical and other radiological examinations. RESULTS: Forty of the forty-eight patients were female, the mean age was 43.9 years and the median follow-up from diagnosis was 4.5 years (range 1-19 years). Twenty-seven (56%) patients were compliant and 12 (25%) were non-compliant; compliance was not known in nine. Of 17 patients with clinically suspicious or significant findings on any available modality, four had uptake outside the thyroid bed on WBS but stimulated Tg <2.5 ng/ml on immunometric assay, while five had a negative WBS with serum Tg >2.5 ng/ml. CONCLUSIONS: Thyroid hormone withdrawal substantially impairs, and rhTSH administration substantially promotes, compliance with DTC monitoring. rhTSH-aided WBS is informative and should be included in the follow-up of unselected patients with DTC.     

TSH suppression by octreotide in differentiated thyroid carcinoma

OBJECTIVE This study evaluates the addition of octreotide and L-thyroxine to shorten the period of exposure to unduly elevated TSH levels in patients with differentiated thyroid carcinoma undergoing total body scan with ¹³¹I. DESIGN Fourteen thyroidectomized patients were studied after total body scan and the restarting of different doses of thyroxine. After one year a second total body scan and a schedule of the same dose of thyroxine combined with octreotide were performed in each subject. PATIENTS Patients were divided into four groups according to the treatment: seven patients received initially 100 μg of L-thyroxine (Group 1) and after 1 year 100 μg of L-thyroxine plus 300 μg of octreotide/day (Group 3); the other seven received initially 150 μg of L-thyroxine (Group 2) and then 150 μg of L-thyroxine plus 300 μg of octreotide/day (Group 4). MEASUREMENTS Serum TSH, T3 and T4 were measured on the day of radioiodine administration (day 0) and after 14, 21, 30, 45, 60 and 90 days. RESULTS Mean basal TSH levels were elevated in all four groups ranging from 104 to 91 mU/l without significant differences. The patterns of TSH inhibition were however different in the four groups studied. TSH remained very elevated for a long time in Group 1 patients: at day 90 the TSH value was still 2.1±1.2 mU/l (mean ± SEM). Patients in Groups 2 and 3 showed a similar pattern: TSH was suppressed in 45 days. The most rapid TSH inhibition was observed in Group 4 patients with a mean decrease of 88% in 14 days and complete suppression in 30 days. CONCLUSIONS TSH suppression by L-thyroxine is very slow and it can be significantly enhanced by combined octreotide administration. Combined therapy is safe and offers an alternative choice when high dosages of L-thyroxine are inappropriate or in conditions of advanced illness.     

Diagnostic and therapeutic use of recombinant human TSH (rhTSH) in differentiated thyroid cancer

The introduction of rhTSH into clinical practice has changed dramatically the monitoring and treatment of differentiated thyroid cancer patients. In particular, the post-surgical thyroid ablation with radio-iodine and the periodical follow-up are more and more routinely based on the use of rhTSH as the method of choice for patient preparation. Therapeutic results and sensitivity of follow-up when using rhTSH are not inferior to conventional thyroid hormone withdrawal and, in some regard, are superior if one considers the preservation of quality of life. The latter aspect is very well exemplified by the constant observation that patients who have experienced rhTSH will never accept going back to thyroid hormone withdrawal.

• the issue of ultrasensitive measures of serum Tg in basal condition versus rhTSH-stimulated serum Tg

• prospective clinical trial of rhTSH-aided RAI therapy for metastatic disease

• definition of the best activity of radio-iodine to be used for post-surgical thyroid remnant ablation

Lack of efficacy of recombinant human thyrotropin versus thyroid hormone withdrawal for radioiodine therapy imaging in a patient with differentiated thyroid carcinoma lung metastases.

The treatment of lung metastases of thyroid cancer is nearly exclusively limited to the administration of iodine-131. For patients presented with micronodular lesions, the therapeutic response is often excellent, increasing life expectancy. Because of the necessity of multiple iodine-131 treatments in the course of this therapy, and subsequently, the lack of tolerance of hormonal withdrawal, the use of recombinant human thyrotropin (rhTSH) as a method of stimulation could represent an interesting alternative. However, as in the present case, the stimulation by rhTSH can be less effective than hormonal withdrawal, as shown in the posttherapy scan to detect metastatic lesions and thus could be detrimental to the treatment efficiency.     

Pretreatment with recombinant human TSH changes the regional distribution of radioiodine on thyroid scintigrams of nodular goiters.

In a recent study, we demonstrated that pretreatment with a single, low dose of recombinant human TSH (rhTSH) doubles 24-h thyroid radioactive iodine uptake in patients with nodular goiter. The purpose of the present study was to investigate whether rhTSH pretreatment induces changes in the regional distribution of radioiodine as visualized on thyroid scintigrams in these patients. Anterior planar thyroid 123I scintigrams were obtained in 26 patients with a nodular goiter (23 women and 3 men; age, 62 +/- 9 yr, mean +/- SD; thyroid weight, 165 +/- 72 g) 24 h after administration of a diagnostic dose of radioiodine. All patients were studied twice: first, without rhTSH pretreatment (baseline study), and second, after an im injection of 0.01 mg (n = 10) or 0.03 mg rhTSH (n = 16), given 24 h before radioiodine administration (rhTSH study). For quantification of regional differences in radioiodine uptake, a region of interest method was used. Upon visual inspection, baseline scintigrams showed a heterogeneous uptake of radioiodine. In general, rhTSH scintigrams also showed heterogeneous radioiodine uptake. In some patients, the distribution of radioiodine in the rhTSH scintigram was considerably more homogeneous than in the baseline scintigram. In a few patients, originally "cold" areas had changed into "hot" ones, whereas originally hot areas had changed into cold ones. Quantification of regional radioiodine uptake showed that pretreatment with rhTSH caused a larger increase in radioiodine uptake in relatively cold areas and a smaller increase in radioiodine uptake in relatively hot areas, compared with the increase in radioiodine uptake in the entire thyroid. In patients with a baseline serum TSH level of 0.5 mU/liter or lower, the increase in radioiodine uptake in relatively cold areas was significantly larger than in patients with a baseline serum TSH level higher than 0.5 mU/liter. In conclusion, a single, low dose of rhTSH not only doubled 24-h radioactive iodine uptake but also caused a more homogeneous distribution of radioiodine within the thyroid gland in patients with a nodular goiter by stimulating radioiodine uptake in relatively cold areas more than in relatively hot areas. This was most marked in patients with a low baseline serum TSH level. Our data suggest that pretreatment with rhTSH may improve the efficacy of radioiodine treatment for volume reduction of nodular goiters, especially in patients with a low baseline serum TSH level.     

Recombinant human TSH use in differentiated thyroid cancer

Traditionally, the immediate treatment of patients with differentiated thyroid carcinoma (DTC) after total thyroidectomy (TT) is thyroid remnant ablation (TRA) with 131I, during hypothyroidism. Late follow-up of DCT includes suppressive doses of T4, serial measurements of thyroglobulin (Tg), whole body scan (WBS) with 131I and cervical ultrasound (US). In the last years, TRA with the aid of recombinant human TSH (rhTSH) has shown not only to avoid symptoms of hypothyroidism and a lower quality of life, but also to have the same efficacy as TRA during endogenous TSH elevation. Stimulated Tg with endogenous or exogenous TSH, 9 to 12 months after the initial treatment of DTC, associated with cervical US, is able to identify low-risk patients virtually cured of their disease, in whom TSH suppression does not need to be so strict, avoiding the heart and bone complications of prolonged exogenous thyrotoxicosis. Finally, in spite of the absence of randomized studies designed to evaluate the role of rhTSH in metastatic DTC disease, results of the combined treatment of rhTSH and 131I show a clinical benefit in the majority of treated patients.     

Recombinant TSH in ablative therapy and follow-up of patients with differentiated thyroid carcinoma

The studies evaluating the efficacy and safety of recombinant TSH in the ablative therapy and follow-up of patients with differentiated thyroid carcinoma by serum thyroglobulin (Tg) measurement and iodine scanning were reviewed in this article. Recombinant TSH is comparable to hypothyroidism in the generation of Tg and in the execution of iodine-131 whole-body scanning, with the advantage of sparing patients from the symptoms of hypothyroidism and from impaired quality of life induced by levothyroxine withdrawal, in addition to a reduced exposure to elevated TSH and shorter absence from work, with recombinant TSH being the preparation indicated for the diagnosis of metastases in both low risk (Tg after recombinant TSH) and moderate or high risk patients (Tg and iodine-131 scanning after recombinant TSH). In the case of ablative therapy, the results are promising when using a dose of 100 mCi for remnant ablation, but hypothyroidism is still preferred, except for patients in whom the desired TSH elevation after levothyroxine withdrawal is not achieved, patients with base diseases that are aggravated by acute and severe hypothyroidism (severe heart and lung disease, coronary disease, compromised renal function, history of psychosis due to myxedema), patients debilitated by advanced disease, and elderly individuals. The studies also show that the administration of recombinant TSH is safe, with few mild or moderate adverse effects.     

Embolization in combination with radioiodine therapy for bone metastases from differentiated thyroid carcinoma

BACKGROUND: The outcome for patients with bone metastases from differentiated thyroid carcinoma is worse compared to the overall prognosis of patients with differentiated thyroid carcinoma. The aim of this study is to evaluate the effect of embolization with concomitant radioiodine treatment on the serum thyroglobulin (Tg) level, pain and neurological symptoms in patients with large bone metastases from differentiated thyroid carcinoma. PATIENTS AND METHODS: Five symptomatic patients, who presented with a large unresectable bone metastasis of differentiated thyroid carcinoma were treated with radioiodine and embolization. The effect of this combined treatment was compared to the effect of radioiodine without embolization in a previously treated control group of 6 patients. Serum Tg levels, pain and neurological symptoms were scored. Both groups were treated similarly with total thyroidectomy followed by ablation with 5.55 GBq 131I and a second dose of 5.55 GBq 131I three months later, except for embolization in the embolization group, which took place between the 2 radioiodine treatments. RESULTS: In the embolization group, serum Tg at the second 131I therapy had decreased by 88.7% (median, range: 77.1-99.3%), which was significantly more compared to the decrease of serum Tg in the control group (18.6%, range: -4.7-95%, P < 0.05). CT-scanning showed a median volume reduction of the metastasis after radioiodine treatment combined with embolization of 52.5% (range: 39-80%). Both strategies resulted in a rapid relief of pain and neurological symptoms. Embolization was not accompanied with severe complications. CONCLUSIONS: This preliminary study suggests that embolization of bone metastases of differentiated thyroid carcinoma in combination with radioiodine treatment results in a significant initial reduction of serum Tg level compared to radioiodine treatment alone. This suggests a beneficial reduction in tumour burden. In this patient category, embolization appears to be a safe and well tolerated procedure.     

Radioiodine treatment of metastatic differentiated thyroid cancer in patients on L-thyroxine, using recombinant human TSH

OBJECTIVE: This study tested the hypothesis that administration of human recombinant thyroid-stimulating hormone (rhTSH: Thyrogen, thyrotropin alpha) could promote iodine-131 ((131)I) uptake in the therapy for metastatic or locally invasive differentiated thyroid cancer (DTC), obviating L-thyroxine suppressive therapy (L-T4) withdrawal and hypothyroidism in patients with advanced disease. METHODS: Twelve totally (or almost completely) thyroidectomized adults, nine of whom had received earlier therapy after L-T4 withdrawal, underwent (131)I treatment while euthyroid on L-T4, after rhTSH administration. Nine underwent diagnostic whole-body scanning (WBS) after two consecutive daily i.m. injections (0.9 mg) of rhTSH. They then received an identical second course of rhTSH to promote therapeutic (131)I uptake. Post-therapy WBS was performed one week later. Three patients received only rhTSH (131)I therapy. RESULTS: Administration of rhTSH promoted (131)I uptake in all patients, as demonstrated by post-therapy WBS. Administration of rhTSH also promoted a significant increase in serum thyroglobulin (Tg) concentrations. According to the most recent measurements, 3-12 months after therapy, serum Tg levels fell in four, and stabilized in two out of eleven patients. Upon additional rhTSH-WBS 8 months post-study, a reduction in one metastatic site was noted in one patient. The rhTSH was well tolerated, with mild, transient fever and/or nausea occurring in only a minority of patients. Individuals with bone metastases experienced degrees of peritumoral pain and swelling that were similar (though more short-lived) to those seen in the same or other patients after L-T4 withdrawal. CONCLUSIONS: Administration of rhTSH is a safe, successful tool for inducing (131)I uptake in local and metastatic DTC lesions, and avoids L-T4 withdrawal, preserving metabolic homeostasis and preventing the debilitating effects of hypothyroidism.     

Fractionated dosage of radioiodine for the ablation of differentiated thyroid carcinoma.

In some countries with a limited number of specialized hospital beds for radionuclide therapy, ablation therapy (RIT) of differentiated thyroid carcinoma (DTC) is performed using a fractionated dosage of radioiodine. The aim of this study was to evaluate the early clinical outcome of ablation with fractionated doses of RIT in comparison to the ablation with a single dose. A subset of 386 subjects with DTC referred for the initial RIT was selected retrospectively for the study. Of these, 113 patients (29.3%) were treated with one (131)I dose of 2.2 GBq (group 1, RIT between 2001 and 2003) and 273 patients (70.7%) with fractionated doses (1.1 GBq + 1.1 GBq administered in 24 hour intervals) (group 2, RIT between 1999 and 2001). The early outcome of the initial RIT was evaluated 6-8 months later by radioiodine uptake test (RIU), thyroglobulin concentration, whole-body diagnostic scan, and neck ultrasound. On the basis of these results, the patients were classified as: CR, complete remission; NCR, no complete remission. Frequency of CR and NCR outcomes and the parameters measured during the follow-up evaluation in both groups were compared. CR outcome was found in 69 patients (61.1%) of group 1 and in 172 patients (63.0%) of group 2 (p = n.s.). No difference in measured parameters was found in both groups at the follow-up evaluation. In uncomplicated cases of DTC, RIT using a regimen of a fractionated dosage, is equally effective as the therapy with a single dose. No influence of stunning was observed in patients treated with a fractionated dosage, but the time interval between the doses was 24 hours.