## Systemic Therapy for Advanced Medullary Thyroid Carcinoma **Key Point:** Vandetanib, a multi-targeted tyrosine kinase inhibitor (TKI), is the FDA-approved first-line targeted therapy for advanced or metastatic medullary thyroid carcinoma (MTC). ### Why Vandetanib? #### Mechanism of Action Vandetanib inhibits multiple receptor tyrosine kinases critical to MTC pathogenesis: - **RET (Rearranged during Transfection)** — the primary oncogenic driver in MTC (~50% of sporadic MTC and nearly 100% of hereditary MTC) - **EGFR (Epidermal Growth Factor Receptor)** - **VEGFR (Vascular Endothelial Growth Factor Receptor)** — provides anti-angiogenic activity #### Clinical Evidence Vandetanib demonstrated: - Improved progression-free survival (PFS) in the ZETA trial (median PFS 30.5 months vs. 19.3 months with placebo) - Objective response rate of ~45% in advanced MTC - Durable disease control in RET-mutant MTC **High-Yield:** Vandetanib is the **standard-of-care first-line TKI** for advanced MTC. Cabozantinib (another multi-targeted TKI) is an alternative if vandetanib is not tolerated. ### MTC-Specific Pathophysiology Unlike papillary and follicular thyroid cancers (which are TSH-responsive), MTC arises from parafollicular C cells and is driven by RET mutations. This is why TSH suppression and radioactive iodine are ineffective. **Clinical Pearl:** MTC does not concentrate radioactive iodine because C cells do not take up iodine. Calcitonin and CEA are the tumor markers used for surveillance, not thyroglobulin.
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