Medullary thyroid cancer (MTC) accounts for 3%–12% of thyroid cancer cases in most series. It arises from the C (parafollicular) cells, and does not occur because of radiation exposure, which has been identified as a risk factor for the development of papillary thyroid cancer.1
The disease was first described in the 1950s.2
Most cases are still sporadic (60%–70%), but the familial syndrome and association with other disorders, including pheochromocytoma and primary hyperparathyroidism,3
have been extensively researched over the last 50 years. Multiple hereditary forms of this disease have since been described, including familial MTC and the multiple endocrine neoplasia syndromes (MEN 2A and MEN 2B).1
MEN 2A accounts for 60% of the hereditary forms, MEN 2B 5%, and FMTC 35%.7
Survival is dependent on the stage of MTC at diagnosis. This is one of the most significant prognostic factors on multivariate analysis. Historically, survival for patients with MTC requiring systemic therapy was 6–22 months.8
A review of more than 1200 cases demonstrated a mean survival time after diagnosis of MTC of 8.6 (range 0–29.6) years. Patients with tumors confined to the thyroid gland had a 10-year survival rate of 95.6%, whereas patients with regional stage disease had an overall survival rate of 75.5%. Patients with distant metastases at diagnosis had a poor prognosis, with only 40% surviving 10 years and an overall survival of around 36 months.9
Chemotherapeutic agents, such as doxorubicin and cisplatin, have been used in the treatment of unresectable MTC with limited success, considerable toxicity, and responses lasting only 9–22 months.10
Recent advances in drug development have led to the synthesis of many new targeted agents that are inhibitors of specific growth factors or cell signaling pathways involved in the pathogenesis of MTC.11
Mutations in specific regions of the rearranged during transfection (RET) proto-oncogene have been described in patients with both familial and sporadic forms of MTC. RET encodes for a transmembrane growth factor receptor that is involved in cell signaling and ultimately the uncontrolled growth of malignant MTC cells. Therefore, RET represents an obvious target for specific drugs to treat unresectable forms of this disease.
Many cancers rely on angiogenesis or the formation of new blood vessels to enable growth of the primary tumor and metastasis to distant sites. Angiogenesis appears to be controlled by a variety of proteins, including vascular endothelial growth factor (VEGF) and its specific receptor (VEGFR) on the cell surface. Because these are often overexpressed in thyroid cancers, antiangiogenesis agents have been developed as targeted treatments. Vandetanib (ZD6474, CaprelsaTM, AstraZeneca) targets both the RET proto-oncogene and the VEGF receptor, and is described in detail in this review.