New Treatment Options for Metastatic Thyroid Cancer

of MKIs, which can stabilize progressive metastatic disease. These newer drugs have significant toxicities. Therefore, it is important to limit the use of systemic treatments to patients at significant risk for morbidity or mortality due to progressive metastatic disease. Patients treated with systemic agents should have a good baseline performance status, such as being ambulatory at least 50% (Eastern Cooperative Oncology Group performance score of 2) of the day to tolerate these treatments.

Patients who have disease progression or are unable to tolerate sorafenib and lenvatinib can choose to participate in clinical trials with investigational multitarget inhibitors. Other alternatives include vandetinib, pazopanib, and sunitinib, which finished phase 2 trials and showed some partial responses. ^26-30 If the patients are unable to tolerate MKIs, they can try doxorubicin-based conventional chemotherapy regimens. ³¹

Medullary Thyroid Cancer

Medullary thyroid cancer is a neuroendocrine tumor arising from the thyroid parafollicular cells, accounting for about 4% of thyroid carcinomas, most of which are sporadic. However, some are familial as part of the multiple endocrine neoplasia type 2 (MEN 2) syndromes, which are transmitted in an autosomal dominant fashion. ^32,33 Similar to DTC, the primary treatment option is surgery. Medullary thyroid cancer can be cured only by complete resection of the thyroid tumor and any local and regional metastases. Compared with DTC, metastatic MTC is unresponsive to radioiodine or TSH
suppressive treatment, because this cancer neither concentrates iodine nor is TSH dependent. ^34,35

The 10-year OS rate in MTC is ≤ 40% in patients with locally advanced or metastatic disease. ^32,36,37 In hereditary MTC, germline mutations in the c-ret proto-oncogene occur in virtually all patients. In sporadic MTC, 85% of patients have the M918T mutation, and somatic c-ret mutations are seen in about 50% of patients. ^38-42

Similar to DTC, due to the presence of mutations involving RET receptor tyrosine kinase, molecular targeted therapeutics with activity against RET demonstrate a potential therapeutic target in MTC. ^43-45 Other signaling pathways likely to contribute to the growth and invasiveness of MTC include VEGFR-dependent tumor angiogenesis and epidermal growth factor receptor (EGFR)-dependent tumor cell proliferation. ⁴⁶

In 2011 and 2012, the FDA approved tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib for metastatic MTC. Similar to treatment for DTC, systemic therapy is mainly based on targeted therapies. Patients with progressive or symptomatic metastatic disease who are not candidates for surgery or radiotherapy should be considered for TKI therapy.

Vandetanib

Vandetanib is approved for unresectable, locally advanced or metastatic sporadic or hereditary MTC.47 The daily recommended dose is 300 mg/d. It is an oral MKI that targets VEGFR, RET/PTC, and the EGFR.48

The ZETA trial was an international randomized phase 3 trial involving patients with unresectable locally advanced or metastatic