Endocrine Effects of the Tyrosine Kinase Inhibitor Vandetanib in Patients Treated for Thyroid Cancer

Abstract

The purpose of the study was to assess the endocrine effects of vandetanib, a multikinase inhibitor targeting RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor, in 39 patients with progressive thyroid cancer included in two randomized placebo-controlled trials using vandetanib 300 mg/d. Endocrine samplings were performed at baseline and then every 6 months. We compared differences in endocrine parameters between baseline and on vandetanib therapy or placebo. During vandetanib treatment, several changes were observed. 1) Calcium (P = 0.0004) and vitamin D (P = 0.001) mean replacement doses were increased; calcium level remained unchanged, but serum 25(OH) vitamin D level decreased (P = 0.001); and serum PTH (P = 0.01) and 1,25(OH)(2) vitamin D (P = 0.01) levels increased, suggesting a decreased intestinal absorption of vitamin D or lack of sun exposure as a result of photosensitization. 2) l-T(4) doses were increased (P < 0.0001) to maintain serum TSH within the normal range. 3) In male patients, total testosterone (P = 0.048), bioavailable testosterone (P = 0.03), and SHBG (P = 0.02) levels increased. Serum inhibin B decreased (P = 0.02) and stimulated FSH increased (P = 0.006), suggesting a Sertoli cells insufficiency. 4) Cortisol level increased (P = 0.007) as well as ACTH level (P = 0.03) and cortisol-binding globulin (P = 0.02), but free urinary cortisol levels remained in the normal range. None of these changes were observed in patients randomized to the placebo arm. In patients with locally advanced or metastatic thyroid cancer, the tyrosine kinase inhibitor vandetanib has several endocrine effects. Thyroid hormone, calcium, and vitamin D analog requirements increased, but consequences of the biological alterations on phosphocalcic metabolism and gonadotrope and adrenal functions are unknown.