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.     

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

The use of recombinant thyrotropin in the follow-up of patients with differentiated thyroid cancer

Many clinicians care for patients who have been treated for differentiated thyroid cancer. Recombinant thyrotropin, which stimulates iodine uptake in thyroid tissue, is a safe and effective diagnostic agent for those patients who require radioiodine scanning for routine follow-up. The combination of a whole body radioiodine scan and a serum thyroglobulin measurement can identify virtually all patients with distant metastatic disease. A serum thyroglobulin >2 ng/mL and/or a positive whole body scan after recombinant thyrotropin stimulation suggest residual thyroid tissue or neoplastic disease. The use of recombinant thyrotropin has fewer adverse effects than does the alternative, which is withdrawal of thyroid hormone replacement, although nausea and headache have been reported. However, recombinant thyrotropin is expensive.     

Clinical use of recombinant human TSH in thyroid cancer patients

Recombinant human TSH (rhTSH) is an effective and safe alternative to thyroid hormone withdrawal during the post-surgical follow-up of papillary and follicular thyroid cancer. Its clinical efficiency for the detection of persistent and recurrent disease is similar to that of thyroid hormone withdrawal. The main purpose for its use is to avoid hypothyroidism.     

Management of differentiated thyroid carcinoma with radioiodine and recombinant human TSH

Recombinant human TSH (rhTSH) brought revolutionary change in the management of patients with differentiated thyroid cancer since it was first approved for clinical use in the United States and Europe. Follow-up management of differentiated thyroid cancer is based on the detection of recurrent or residual cancer, traditionally achieved by measurement of serum thyroglobulin level and various imaging techniques including 131I whole body scan. Previously, TSH stimulation was achieved only by induction of hypothyroidism following withdrawal of thyroid hormone. However, hypothyroidism is uncomfortable and is association with a reduction in quality of life. RhTSH can provide elevated TSH without making patients hypothyroid. In the United States and Europe, rhTSH is approved for use only in monitoring of differentiated thyroid cancer. In this article, we reviewed the role of rhTSH in the diagnosis and management of differentiated thyroid cancer.     

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.     

Serum thyroglobulin and 131I whole body scan after recombinant human TSH stimulation in the follow-up of low-risk patients with differentiated thyroid cancer

OBJECTIVE: The 'standard' postoperative follow-up of patients with differentiated thyroid cancer (DTC) has been based upon serum thyroglobulin (Tg) measurement and (131)I whole body scan ((131)I-WBS) after thyroid hormone (T(4)) treatment withdrawal. However, (131)I-WBS sensitivity has been reported to be low. Thyroid hormone withdrawal, often associated with hypothyroidism-related side effects, may now be replaced by recombinant human thyroid stimulating hormone (rhTSH). The aim of our study was to evaluate the diagnostic accuracy of (131)I-WBS and serum Tg measurement obtained after rhTSH stimulation and of neck ultrasonography in the first follow-up of DTC patients. DESIGN: Ninety-nine consecutive patients previously treated with total thyroidectomy and (131)I ablation, with no uptake outside the thyroid bed on the post-ablative (131)I-WBS (low-risk patients) were enrolled. METHODS: Measurement of serum Tg and (131)I-WBS after rhTSH stimulation, and ultrasound examination (US) of the neck. RESULTS: rhTSH-stimulated Tg was 1 ng/ml (Tg+) in 21 patients, including 6 patients with Tg levels >5 ng/ml. (131)I-WBS was negative for persistent or recurrent disease in all patients (i.e. sensitivity = 0%). US identified lymph-node metastases (confirmed at surgery) in 4/6 (67%) patients with stimulated Tg levels >5 ng/ml, in 2/15 (13%) with Tg >1<5 ng/ml, and in 2/78 (3%) who were Tg-negative. CONCLUSIONS: (i) diagnostic (131)I-WBS performed after rhTSH stimulation is useless in the first follow-up of DTC patients; (ii) US may identify lymph node metastases even in patients with low or undetectable serum Tg levels.     

The use of recombinant human TSH in a patient with metastatic follicular carcinoma and insufficient endogenous TSH production

We present a case of a patient suffering from metastatic differentiated thyroid carcinoma (DTC) and insufficient endogenous TSH production suspicious of secondary hypothyroidism. The use of recombinant human TSH (rhTSH) enabled us to administer a therapeutic activity of radioactive iodine (RAI) under maximal TSH-stimulation, achieving a marked decrease in thyroglobulin accompanied by a clinical improvement.     

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.     

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.     

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.     

Uses for recombinant human TSH in patients with thyroid cancer and nodular goiter

Recombinant human TSH (rhTSH) has revolutionized the care of patients with differentiated thyroid cancer. Since its approval for clinical use in 2001 in Europe (1998 in the USA), rhTSH has greatly enhanced the surveillance of these patients by allowing the avoidance of hypothyroidism for TSH stimulation. Previously, a hypothyroid state was required for TSH stimulated diagnostic whole-body radio-iodine scans (DxWBS) and thyroglobulin (Tg) levels. Patients generally prefer rhTSH as a mechanism for TSH stimulation because symptoms of hypothyroidism can be completely avoided. Currently, rhTSH is only approved for diagnostic monitoring of differentiated thyroid cancer patients. There are many other potential uses for rhTSH, including facilitation of treatment of patients with thyroid cancer and nodular goiter. The diagnostic and therapeutic role of rhTSH in patients with differentiated thyroid cancer and nodular goiter will be discussed in this review.     

Advances in the follow-up of differentiated or medullary thyroid cancer

The long-term survival of patients with thyroid cancer and the possibility of tumour recurrence up to 30-40 years after the achievement of a disease-free status illustrate the importance of lifelong follow-up in these individuals. This Review discusses the most innovative aspects of follow-up protocols for patients with differentiated thyroid cancer, that is, of papillary or follicular hystotype, and those with medullary thyroid cancer. Particular focus is placed on the relevance of new ultrasensitive assays for thyroglobulin measurement and the option of using recombinant human TSH to stimulate thyroglobulin secretion. Methods to compensate for the loss of diagnostic significance of serum thyroglobulin levels in patients with differentiated thyroid cancer and circulating anti-thyroglobulin antibodies are highlighted, as well as the role of the postoperative calcitonin stimulation test and the clinical relevance of determining the doubling time of calcitonin and carcinoembryonic antigen in patients with medullary thyroid cancer. Moreover, this Review gives some insights into the role of molecular thyroid cancer testing, both for prognostic and for therapeutic purposes. Finally, a general overview of traditional imaging procedures, such as neck ultrasonography, CT, MRI and bone scintigraphy, is provided alongside a comparison with new nuclear imaging tests such as PET.     

Genetic analysis of the TSH receptor gene in differentiated human thyroid carcinomas.

Somatic mutations of the TSH receptor (TSHR) gene have been identified as the major cause of toxic thyroid adenoma. Recently, point mutations of the same gene have also been described in some differentiated thyroid carcinomas. The aim of the present study was to investigate the presence TSHR gene mutations in a series of thyroid specimens obtained from 22 consecutive patients with differentiated thyroid carcinomas (8 follicular and 14 papillary). Genomic DNA was extracted from fresh-frozen or paraffin-embedded tumor and normal surrounding parenchyma. Two fragments corresponding to the entire exon 10 and one fragment corresponding to exon 9 were amplified by PCR using biotinylated primers. PCR products were purified on streptavidin-coated magnetic beads and subjected to direct sequencing with Sequenase and 35(3)-labeled d-ATP-alphaS. Adenyl-cyclase activity in membrane preparations of 10 papillary carcinomas was also determined. No TSHR mutations were detected in these tumors. A polymorphism that encoded a single amino acid change Asp727Glu was identified in two follicular thyroid carcinomas. Adenyl-cyclase activity was normal in the ten papillary thyroid carcinomas we analyzed. In conclusion, our results suggest that clonal somatic mutations of the TSHR gene do not play a role in the pathogenesis of differentiated thyroid carcinoma.     

Using recombinant human TSH in the management of well-differentiated thyroid cancer: current strategies and future directions.

Mortality rates from thyroid cancer have fallen significantly in recent decades, almost certainly as the result of earlier diagnosis and improved treatment of differentiated (papillary and follicular) thyroid cancer. Enhanced survival is likely a result of early diagnosis and therapy applied at a disease stage when treatment is most effective. In the United States and Europe, most patients at high risk for relapse and death from thyroid cancer are treated with total or near-total thyroidectomy and receive radioiodine ablation of residual normal or malignant thyroid tissue, followed by treatment with thyroid hormone, a strategy that cures more than 80% of patients. Still, some die of the disease and nearly 15% have local recurrences, while another 5% to 10% develop distant metastases. Over 50% of recurrences appear in the first five years, but distant metastases may surface years, and sometimes decades, after initial therapy. Much has been learned about risk stratification to predict recurrence and death from thyroid cancer but individual patients continue to have adverse outcomes not always foreseen by a low tumor stage. Follow-up must accordingly be meticulous and prolonged. The National Cancer Center Network (NCCN) has recently established consensus practice guidelines that give explicit advice about the diagnosis and management of benign and malignant thyroid tumors, including paradigms for long-term follow-up and the treatment of recurrent disease. The guidelines confirm that diagnostic scanning with 131I and measurement of serum thyroglobulin (Tg) levels are the mainstay of follow-up, offering the opportunity to detect recurrent or persistent cancer at very early stages. These guidelines advocate TSH-stimulated serum Tg measurements, done either during thyroid hormone withdrawal or stimulation with recombinant human TSH (rhTSH, Thyrogen), that often identify the presence of cancer well before diagnostic whole-body scanning or other imaging studies can spot the tumor, which offers the opportunity to treat recurrent disease at an early stage. The use of rhTSH adds a new dimension to long-term follow-up that avoids putting patients through the symptoms of hypothyroidism, and offers the opportunity to follow some patients with rhTSH-stimulated serum Tg levels without performing 131I whole-body scans. A multicenter international study has shown that serum Tg measurements alone are not as sensitive in the identification of patients with persistent or recurrent tumor as are rhTSH-stimulated serum Tg determinations. Although not yet approved for preparation of patients for 131I therapy, rhTSH has been used successfully in a compassionate use program for this purpose in a relatively large number of patients. Formal clinical investigations now planned to provide guidelines for the use of rhTSH for therapeutic 131I portend a new set of effective therapeutic paradigms for the management of differentiated thyroid cancer.