Sunitinib (SU11248) is a multitarget inhibitor of tyrosine-kinases (RTK) recently tested in clinical trials for the treatment of some human cancers. Side effects are mostly represented by asthenia and appear in a dose and time correlated manner. After the unexpected observation of a myxedematous coma in a patient affected with GIST and treated with Sunitinib, we evaluated the effect of this drug on thyroid function in 24 patients treated for GISTs Imatinib resistant. Patients received the following cycles of therapy: 4 weeks of daily treatment at the dose of 50 mg/day orally (ON) and 2 weeks of withdrawal (OFF). On days 1 and 28 of each cycle TSH, FT3, FT4, thyroglobulin, anti-Tg and anti-TPO autoantibodies were measured. Eleven patients (46%) treated with SU11248 developed a transient hypothyroidism between the 1st and the 6th cycle of treatment (median 3rd cycle). Hypothyroidism was subclinical in 10 cases and overt in 1 patient. During the OFF periods TSH normalized, but a progressive increase of TSH levels was observed. After a variable number of cycles, the lack of normalization during the OFF periods was observed. In order to elucidate the possible mechanism underlying Sunitinib-induced hypothyroidism, in vivo morpho-functional examinations were performed. Neither ultra-sonographic alterations (in particular destructive-like), nor variations in thyroglobulin and anti-thyroid autoantibodies, were observed during the ON and OFF phases even after several cycles. On the contrary, 123I uptake was normal in basal conditions and largely reduced after the 4 weeks of treatment, with partial or total normalization after the 2 weeks of withdrawal. In conclusion, SU11248 determines hypothyroidism in the 46% of patients. The absence of anti-thyroid autoantibodies and the normal echographic pattern allow to exclude autoimmune and/or destructive mechanisms. Interestingly, hypothyroidism seems to be correlated with a defect in the uptake of iodine. The possibility to perform a selective and temporary block of thyroid function could be useful in the treatment of some thyroid diseases.
28 Apr - 02 May 2007
European Society of Endocrinology