Advances in Chemotherapy of Differentiated Epithelial and Medullary Thyroid Cancers

Abstract

Context: Systemic chemotherapies for advanced or metastatic thyroid carcinomas have been of only limited effectiveness. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, novel therapies are needed to improve disease outcomes.Evidence Acquisition: The PubMed and Google Scholar search engines were used to identify publications and peer-reviewed meeting presentations addressing chemotherapy and targeted therapy for differentiated or medullary carcinoma.Evidence Synthesis: Multiple novel therapies primarily targeting angiogenesis have entered clinical trials for metastatic thyroid carcinoma. Partial response rates up to 30% have been reported in single agent studies, but prolonged disease stabilization is more commonly seen. The most successful agents target the vascular endothelial growth factor receptors, with potential targets including the mutant kinases associated with papillary and medullary oncogenesis. Two drugs approved for other malignancies, sorafenib and sunitinib, have had promising preliminary results reported, and are being used selectively for patients who do not qualify for clinical trials. Randomized trials for several agents are underway that may lead to eventual drug approval for thyroid cancer. thyroid carcinomas have limited effectiveness, with response rates typically 25% or less (1). With such poor outcomes, results from few clinical trials of new therapies for thyroid carcinomas were published during the latter half of the 20th century (2). Plaguing these early trials was the practice of lumping patients with all histologies of thyroid carcinoma (differentiated, medullary, and anaplastic), confounding interpretation of the results. The definitions of response used in these earlier studies varied as well, and none are comparable with the currently used standard RECIST methodology [for detailed description of RECIST, see Refs. 3, 4). Thus, treatment with cytotoxic chemotherapy is generally limited to patients with symptomatic or rapidly progressive metastatic disease unresponsive to or unsuitable for surgery, radioiodine (for tumors derived from differentiated carcinomas), and external beam radiotherapy. ConclusionDuring the past decade, biological discoveries sparked trials testing novel therapies for advanced thyroid carcinomas. Of prime importance has been recognition of key oncogenic mutations in papillary (PTC) and medullary (MTC) carcinomas. BRAF and RAS genes code for kinases that activate signaling through the MAPK pathway, regulating growth and function in many cells both normal and neoplastic. Evidence from various tumor models support the contention that most PTCs arise as a result of single activating somatic mutations in one of three genes: BRAF, RAS, and translocations producing RET/PTC oncogenes (5). The resultant RET/PTC proteins signal upstream from RAS, thus activating the same MAPK pathway. For MTC,

Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes

“…However, it has been demonstrated that this mutation is refractory to many tyrosine kinase inhibitors (TKI) (35), which nowadays are considered the best target therapy under development (36). It is of concern that if Val804Met mutation is so prevalent, some of these patients might develop an aggressive form with no possibility of being treated with TKI.…”

Metastatic Dormancy and Progression in Thyroid Cancer: Targeting Cells in the Metastatic Frontier

“…The specific factors and requirements for angiogenesis and blood vessel formation may vary in different organs. Many of the current treatments that have shown disease-stabilizing effects in metastatic thyroid cancer are thought to inhibit metastasis-related angiogenesis by inhibiting responses to vascular endothelial growth factor (VEGF) (36). However, whether or not VEGF receptors are the primary target of the compounds clinically has not been proven.…”

Molecular Biology of Thyroid Cancer

“…Therefore, such dependency may represent a potential Achilles heel of cancer cells. Since thyroid cancer cells are apparently "addicted" to aberrant MAP kinase signalling, several small molecules that target this pathway are currently being developed (Sherman, 2009). Several lines of evidence suggest that RET/PTC can be a good target.…”