Conclusion
These are promising data suggesting efficacy of vandetanib, motesanib, cabozantinib, sorafenib, and sunitinib in the treatment of MTC. The RET-inhibitory effect of these multitargeted agents in RET mutation-driven MTC and their antiangiogenic effect in wild-type RET cases could explain the effectiveness of these agents in these patients. A comparable low partial response rate, but a high rate of stable disease, was observed in all of these phase II studies. However, the same results may not be replicable in phase III studies, as MTC is a clinically heterogeneous disorder. Many challenges remain in selecting appropriate TKIs for MTC.
Correlative studies are required to identify RET genotypes and markers in MTC that could predict the patterns of response or resistance to these TKIs. It would be more challenging to identify these markers and regulatory signaling pathways in wild-type RET MTC. The observation made by the authors that patients without identifiable RET mutations had responses raises the question of whether VEGFR2 inhibition contributes to the treatment effect. We should also be cautious about selecting targeted agents and stepping forward from a phase I study to a randomized phase III trial without having sufficient knowledge of the biology that directs the disease phenotype.
Disclosures
Dr. Mirshahidi is on the speakers’ bureau of Genentech and on the advisory boards of Celgene and Genentech.
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How I treat medullary thyroid cancer
Hamid Mirshahidi, MD
Medullary thyroid carcinoma (MTC) develops from the neuroendocrine parafollicular C cells of the thyroid. These cells secrete neuroendocrine peptides, including calcitonin and carcinoembryonic antigen (CEA). The hereditary form presents as inherited tumor syndromes; they include multiple endocrine neoplasia type 2A (MEN 2A), which is the most common type; MEN 2B; and familial MTC. Typically, patients develop sporadic disease in their 50s or 60s, and those with familial forms of the disease tend to be younger.
Total thyroidectomy with or without central neck dissection is the primary treatment of locoregional disease. Ipsilateral or bilateral modified neck dissection is recommended if ipsilateral or contralateral cervical lymph nodes are clinically or radiologically evident. Adjuvant external-beam radiotherapy (EBRT) may be considered in selected cases, such as for patients with extrathyroidal disease or extensive nodal metastases. Postoperative surveillance of patients with MTC consists of measurement of calcitonin levels, which should be checked preoperatively as a baseline as well. Following thyroidectomy, the calcitonin level reaches a new steady state in about 72 hours. In patients with undetectable calcitonin levels and a normalized CEA level, annual measurement of both markers should still be checked and annual cervical ultrasonography should be considered.
MTC most commonly metastasizes to the liver, bones, and lungs. Palliative resection, EBRT, radiofrequency ablation, or chemoembolization should be considered for patients with locoregional symptoms and distant metastasis to maintain locoregional disease control. Radioiodine treatment and conventional cytotoxic chemotherapy, such as doxorubicin- and dacarbazine-based chemotherapies, are not effective in these patients. Clinical trial enrollment and novel small molecule tyrosine kinase inhibitors targeting the RET and vascular endothelial growth factor receptor should be considered as alternative therapies.