Systemic treatment of advanced, metastatic, medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a rare endocrine tumor, which arises from thyroid parafollicular C cells. Through its ability to metastasize by blood and lymphatic vessels, it can show a more aggressive clinical behavior than differentiated thyroid cancers. Mutation of RET gene is the main molecular alteration involved in MTC origin. In the case of germline RET mutation, MTC can be inherited in an autosomal dominant way and show three different phenotypes: familial medullary thyroid carcinoma and multiple endocrine neoplasia types IIA and IIB. In addition, in sporadic cases, somatic RET mutation remains the key molecular alteration in most of cases. Total thyroidectomy with prophylactic or therapeutic central compartment lymph nodes dissection is the surgical treatment of choice. Further surgical treatments and local therapies should be used in the case of single or few local or distant metastasis. However, in cases with large metastatic spread of the disease, particularly in those with significant tumor progression, additional systemic treatments are needed. In this review, we discuss the key points of systemic treatment in advanced, metastatic MTC. We provide an update on the main aspects (from biological rationale to clinical experience) of each treatment, focusing our attention on the drugs used in clinical practice in the last years. Finally, we give insights about the emerging treatments from highly selective RET inhibitors to new radionuclide therapy.