FROM THE LITERATURE

Advanced Thyroid Cancer: Is the Targeted Therapy Era
About to Begin?

Thyroid cancer, the most common endocrine malignancy, is the 17th most common cancer worldwide. The vast majority are differentiated thyroid cancers (DTC), including papillary and follicular subtypes, which account for 90% of thyroid malignancies. For these DTCs, standard treatment with primary surgery and thyroid-stimulating hormone (TSH) suppression with thyroid hormone administration is effective. Depending on disease stage, tumor size, and patient age, ablation of the thyroid remnant with radioactive iodine 131I (RAI) is added. This collective treatment strategy is associated with a good prognosis and an overall survival rate of 90% or better at 20 years. Anaplastic thyroid cancer, although rare (2% of thyroid cancers), is usually unresectable at presentation, highly resistant to therapy, uniformly RAI resistant, and associated with a very poor prognosis (median survival less than 1 year). Medullary thyroid cancer originates from parafollicular, calcitonin-producing cells and accounts for 3% to 5% of thyroid cancers but has a worse prognosis and high mortality.

Once, thyroid cancer metastasizes to distant sites, becomes iodine-nonavid, and is no longer amenable to RAI or surgery, the only viable option for treatment is chemotherapy. The only FDA approved agent is doxorubicin which has low response rates (10% to 37%), short duration of responses, and myelo- and cardiotoxicity rendering it a poor option. Fortunately for patients, targeted therapy appears to be a promising option based on data reported from two phase II trials of targeted agents in advanced thyroid cancer.

• Thyroid tumors are highly vascular and overexpress VEGF, and inhibition of VEGF receptor (VEGFR) signaling has been shown to block the growth of these thyroid tumors in vitro. A phase II single-arm trial in 60 patients with advanced, incurable thyroid cancer of all histologic subtypes resistant or not appropriate for RAI was conducted to assess the activity and safety of axitinib (orally 5mg BID), a potent and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3. Primary endpoint was objective response rate (ORR). Results: Partial response (PR) in 18/60 patients, yielding an ORR of 30% and stable disease (SD) lasting ≥16 weeks in another 38%. Objective responses were seen in all histologic subtypes. Median follow-up is 16.6 months. (Median PFS is 18.1 months, 70% of patients are still alive, and median OS has not yet been reached). Axitinib selectively decreased plasma levels of soluble (s) VEGFR2 and sVEGFR3, demonstrating effective targeting of VEGFR. Together with a generally favorable safety profile, the data suggest that axitinib would be a useful option in patients with advanced thyroid cancer.
  
  J Clin Oncol 26: 4708-4713, 2008
  
  
• Early reports of trials with multi-kinase inhibitors have shown promise in patients with metastatic thyroid cancer. The B-type Raf kinase (BRAF) in the mitogen-activated protein (MAP) kinase signaling pathway plays a key role in thyroid cancer (BRAF has been found in 29% to 69% of papillary cancers), therefore RAF signaling is a logical target in thyroid cancer. Sorafenib(Nexavar^®) is an orally active multi-tyrosine kinase inhibitor with multiple targets, including BRAF, VEGFR1, and VEGFR2.
  
  Based on these facts, a phase II, single-arm trial was conducted to determine the efficacy of sorafenib in patients with iodine-refractory metastatic thyroid cancer. A report of a planned analysis after treatment of the first 30 patients was recently published. Patients received sorafenib 400mg orally twice daily. Study endpoints were ORR, PFS, and best response by RECIST criteria. Results: PR rate was 23% and stable disease rate was 53% with an overall clinical benefit rate of 77%. Median overall PFS time was 79 weeks and for the subset differentiated cancers the median PFS time was 84 weeks. In 17 of 19 (95%) patients for whom serial thyroglobulin levels were available, a marked and rapid response in thyroglobulin levels was noted, with a mean decrease of 70% within 4 months of starting treatment. These results represent a significant advance over chemotherapy and suggest that sorafenib warrants further investigation in advanced thyroid cancer.
  
  J Clin Oncol 26: 4714-4719, 2008.
  
  

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