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

• Published in: The journal of clinical endocrinology and metabolism 2011-09, Vol.96 (9), p.2741-2749
• Main Authors: Brassard, Maryse, Neraud, Barbara, Trabado, Séverine, Salenave, Sylvie, Brailly-Tabard, Sylvie, Borget, Isabelle, Baudin, Eric, Leboulleux, Sophie, Chanson, Philippe, Schlumberger, Martin, Young, Jacques
• Format: Article
• Language: English
• Subjects: Adenocarcinoma, Follicular - blood; Adenocarcinoma, Follicular - drug therapy; Adenocarcinoma, Papillary - blood; Adenocarcinoma, Papillary - drug therapy; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Blood Glucose; Calcium - blood; Cross-Over Studies; Endocrinopathies; Enzyme Inhibitors - therapeutic use; ErbB Receptors - antagonists & inhibitors; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Humans; Male; Malignant tumors; Medical sciences; Middle Aged; Parathyroid Hormone - blood; Piperidines - therapeutic use; Proto-Oncogene Proteins c-ret - antagonists & inhibitors; Quinazolines - therapeutic use; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Testosterone - blood; Thyroid Neoplasms - drug therapy; Thyroid. Thyroid axis (diseases); Treatment Outcome; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Vitamin D - blood
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2010-2771

Purpose: 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. Methods: 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. Results: 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-T4 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. Conclusion: 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.