Recombinant human thyroid stimulating hormone in 2008: focus on thyroid cancer management

OncoTargets and Therapy, Jan 2009

Recombinant human thyroid stimulating hormone in 2008: focus on thyroid cancer management Ann Gramza1, Kathryn G Schuff21Division of Medical Oncology, Oregon Health and Science University, Portland, OR USA; 2Division of Endocrinology, Oregon Health and Science University, Portland, OR USAAbstract: Radioiodine (RAI) ablation following thyroidectomy is standard of care treatment for patients with intermediate or high risk differentiated thyroid cancer. Traditionally, this has been achieved by forgoing thyroid hormone replacement postoperatively, allowing endogenous thyroid stimulating hormone (TSH) levels to rise. This rise in TSH provides the stimulus for RAI uptake by the thyroid remnant, but is associated with clinical hypothyroidism and its associated morbidities. Recombinant human TSH (rhTSH, thyrotropin alfa [Thyrogen®], Genzyme Corporation, Cambridge, MA, USA) was developed to provide TSH stimulation without withdrawal of thyroid hormone and clinical hypothyroidism. Phase III studies reported equivalent detection of recurrent or residual disease when rhTSH was used compared with thyroid hormone withdrawal (THW). These trials led to its approval as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without RAI imaging in the surveillance of patients with differentiated thyroid cancer. Recently, rhTSH was given an indication for adjunctive preparation for thyroid remnant ablation after phase III studies demonstrated comparable outcomes for rhTSH preparation when compared with THW. Importantly, rhTSH stimulation has been found to be safe, well tolerated, and to result in improved quality of life. Here, we review the efficacy and tolerability studies leading to the approval for the use of rhTSH in well-differentiated thyroid cancer management.Keywords: recombinant human thyroid stimulating hormone, thyroid cancer, radioiodine, ablation, Thyrogen®, thyrotropin alfa

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Recombinant human thyroid stimulating hormone in 2008: focus on thyroid cancer management

OncoTargets and Therapy Recombinant human thyroid stimulating hormone in 2008: focus on thyroid cancer management Ann Gramza 1 Kathr yn G Schuff 0 0 Division of Endocrinology, Oregon Health and Science University , Portland, OR USA 1 Division of Medical Oncology, Oregon Health and Science University , Portland, OR USA Radioiodine (RAI) ablation following thyroidectomy is standard of care treatment for patients with intermediate or high risk differentiated thyroid cancer. Traditionally, this has been achieved by forgoing thyroid hormone replacement postoperatively, allowing endogenous thyroid stimulating hormone (TSH) levels to rise. This rise in TSH provides the stimulus for RAI uptake by the thyroid remnant, but is associated with clinical hypothyroidism and its associated morbidities. Recombinant human TSH (rhTSH, thyrotropin alfa [Thyrogen®], Genzyme Corporation, Cambridge, MA, USA) was developed to provide TSH stimulation without withdrawal of thyroid hormone and clinical hypothyroidism. Phase III studies reported equivalent detection of recurrent or residual disease when rhTSH was used compared with thyroid hormone withdrawal (THW). These trials led to its approval as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without RAI imaging in the surveillance of patients with differentiated thyroid cancer. Recently, rhTSH was given an indication for adjunctive preparation for thyroid remnant ablation after phase III studies demonstrated comparable outcomes for rhTSH preparation when compared with THW. Importantly, rhTSH stimulation has been found to be safe, well tolerated, and to result in improved quality of life. Here, we review the efficacy and tolerability studies leading to the approval for the use of rhTSH in well-differentiated thyroid cancer management. - 2) Diagnostic scanning to detect residual/recurrent disease and 3) Treatment of residual/recurrent disease. Radioiodine administration following thyroidectomy (“remnant ablation”) is performed to reduce the risk of thyroid cancer recurrence and improve the accuracy of surveillance strategies. The two goals of treatment are to destroy micrometastatic or residual disease, and ablate remaining normal thyroid tissue to facilitate RAI scanning and use of Tg as a tumor marker. No prospective studies have been done to address the question of which patients benefit from this treatment strategy. However, based on large retrospective series, the published consensus guidelines from both the European Thyroid Association (ETA) and American Thyroid Association (ATA) recommend RAI ablation for patients with higher stage disease and recommend considering ablation in lower risk patients with tumors larger than 1 or 1.5 cm (Cooper et al 2006; Pacini et al 2006b) . The use of RAI for all three purposes relies on the ability of both normal and malignant thyroid tissue to transport iodine for synthesis of thyroglobulin, triiodothyronine and thyroxine in response to TSH. An overview of the procedures for thyroid remnant ablation and diagnostic scanning are shown in Figure 1 and 2, respectively. TSH stimulation historically has been achieved by discontinuation of thyroid hormone replacement for 5 to 6 weeks, (thyroid hormone withdrawal, THW), allowing endogenous TSH levels to rise (Figure 1a and 1b). The optimal TSH level for ablation is felt to be 30 mU/L, based on a study that demonstrated that low TSH levels were more likely to be associated with low iodine uptake, which was more robust on reevaluation with a higher TSH (Edmonds et al 1977) . In addition to high TSH levels, iodine depletion, such as with a low iodine diet for 1 to 2 weeks, is important for optimal RAI uptake. If desired to assist in treatment decisions, diagnostic RAI whole body scans (WBS) are performed with a tracer dose of 74 to 185 MBq (2–5 mCi) 131I and the diagnostic scan obtained 48 to 72 hours later as shown in Figure 1b. Radioiodine at a dose of 1.1 to 3.7 GBq (30–100 mCi) is administered for remnant ablation, with higher doses if residual disease is known or suspected or the tumor has unfavorable histology or if treatment of metastatic disease is planned. The patient is placed back on levothyroxine suppressive therapy, as appropriate, and approximately 1 week after the treatment dose of RAI, a post-therapy WBS is performed to better assess for residual or metastatic disease. Substitution of rhTSH stimulation for TSH stimulation by THW for diagnostic evaluations (shown in Figure 2b and reviewed by Cooper et al (2006) or for thyroid remnant ablation (shown in Figures 1c and 1d), has been published by a number of centers, allowing patients to remain on levothyroxine therapy and avoid the symptoms of hypothyroidism (Robbins et al 2001; Pacini et al 2002; Robbins et al 2002b; Barbaro et al 2003; Barbaro et al 2006; Pacini et al 2006a; Pilli et al 2007; Rosario et al 2008; Taieb et al 2008; Tuttle et al 2008) . Over the last 3 years, thyrotropin alfa (Thyrog (...truncated)


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Ann Gramza, Kathryn G Schuff. Recombinant human thyroid stimulating hormone in 2008: focus on thyroid cancer management, OncoTargets and Therapy, 2009, pp. 87-101, DOI: 10.2147/OTT.S3480