• Mariëtte H W Kappers, Joep H M van Esch, Frank M M Smedts, Ronald R de Krijger, Karel Eechoute, Ron H J Mathijssen, Stefan Sleijfer, Frank Leijten, A H Jan Danser, Anton H van den Meiracker, and Theo J Visser.
• Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands. m.h.w.kappers@erasmusmc.nl
• J. Clin. Endocrinol. Metab. 2011 Oct 1; 96 (10): 3087-94.

ContextAnticancer treatment with the tyrosine kinase inhibitor sunitinib causes thyroid dysfunction.ObjectiveOur objective was to investigate the time course and underlying mechanisms of sunitinib-induced thyroid dysfunction.DesignThyroid function tests of 83 patients on sunitinib were collected retrospectively for their total treatment duration between January 2006 and November 2009 and prospectively in 15 patients on sunitinib for 10 wk. Additionally, thyroid function and histology were assessed in rats on sunitinib (8 d; n = 10) and after sunitinib withdrawal (11 d; n = 7) and compared with controls (n = 7).SettingPatients were seen at a university outpatient oncology clinic. Patients and Animals: Patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors participated in the clinical study and Wistar Kyoto rats were used in the rat study.InterventionSunitinib was taken according to a 4 wk "on," 2 wk "off" treatment regimen. Blood samples for measurement of thyroid function were collected at baseline and at wk 4 and 10. In rats, blood, liver, and thyroid were collected to assess thyroid hormones, deiodinase activity, and thyroid histology.Main Outcome MeasuresTSH and free T(4) levels, deiodinase activity, and thyroid histology were assessed.ResultsForty-two percent of patients in the retrospective study developed elevated TSH levels. Prospective analysis showed increased TSH levels within 10 wk of treatment, accompanied by a decreased T(3)/rT(3) ratio. In rats, serum T(4) and T(3) decreased, hepatic type 3 deiodinase activity increased, and thyroid histology showed marked capillary regression, which all but thyroid hormones reversed after sunitinib withdrawal.ConclusionSunitinib induces hypothyroidism due to alterations in T(4)/T(3) metabolism as well as thyroid capillary regression.

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