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A Novel Tyrosine-Kinase Selective Inhibitor, Sunitinib, Induces Transient Hypothyroidism by Blocking Iodine Uptake

Department of Medical Sciences (D.M., G.V., P.B.-P., L.F.), University of Milan and Endocrine Unit, and Nuclear Medicine Division (M.C.), Fondazione Policlinico Istituto di Ricovero e Cura a Carattere Scientifico, 20122 Milan, Italy; and Department of Oncology (P.Co., R.B., P.Ca.), Istituto Nazionale dei Tumori, 20133 Milan, Italy

Address all correspondence and requests for reprints to: Laura Fugazzola, M.D., Endocrine Unit, Department of Medical Sciences, Fondazione Policlinico Istituto di Ricovero e Cura a Carattere Scientifico, Via F. Sforza, 35, 20122 Milan, Italy. E-mail: l.fugazzola{at}policlinico.mi.it.

Context: Sunitinib (sunitinib malate; SU11248; Sutent; Pfizer Inc., New York, NY) is a multitarget inhibitor of tyrosine kinases for the treatment of some human cancers. A myxedematous coma in a patient treated with sunitinib for a gastrointestinal stromal tumor was unexpectedly observed.

Objective: Our objective was to evaluate the effect of sunitinib on thyroid function in 24 patients with gastrointestinal stromal tumors.

Design: This was a prospective, observational cohort study.

Setting: The study was performed at two tertiary care hospitals.

Patients: A total of 24 patients receiving the following cycles of therapy were included in the study: 4-wk daily treatment at the dose of 50 mg orally (ON) and 2-wk withdrawal (OFF).

Interventions: Thyroid function tests, ultrasonography, and iodine-123 (¹²³I) thyroidal uptake were performed at the end of several ON and OFF periods.

Results: After one to six cycles of treatment, 46% of patients developed hypothyroidism. Initially, TSH levels were elevated at the end of ON periods and normalized at the end of OFF periods, but a worsening in following cycles was always observed. Neither echographic alterations nor variations in thyroglobulin and antithyroid autoantibodies were found during the ON and OFF periods. On the contrary, ¹²³I uptake was significantly reduced at the end of ON periods, with partial or total normalization at the end of OFF periods.

Conclusions: A high prevalence of hypothyroidism, very severe in some cases, was observed during sunitinib. Significant variations in ¹²³I uptake strongly suggest that the underlying mechanism is an impaired iodine uptake. The absence of thyroid autoimmunity, the lack of a preceding transient hyperthyroidism, and the normal echographic pattern exclude autoimmune and/or destructive mechanisms. Patients on sunitinib should be strictly monitored for the appearance of hypothyroidism and promptly treated.

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