Patients taking sunitinib at risk for hypothyroidism

Given the high frequency of thyroid dysfunction, careful monitoring of TSH levels is recommended.

Issue: December 2006

Sunitinib has been recently shown to cause hypothyroidism, possibly due to drug-induced thyroiditis.

Sunitinib (Sutent, Pfizer) is a tyrosine kinase inhibitor and is used to treat gastrointestinal stromal tumors and renal cell carcinoma. It is the only drug that improves survival in patients with GIST resistant to treatment with imatinib. It is generally well-tolerated and highly effective in patients with advanced renal cell carcinoma.

Researchers evaluated thyroid function in patients enrolled in a phase-1/phase-2 study of sunitinib for treatment of GIST at Brigham & Women’s Hospital and the Dana Farber Cancer Institute, Boston, between April 2002 and December 2004. Their findings appear in the Annals of Internal Medicine.

Forty-two patients with normal baseline thyroid function were treated with sunitinib for at least three rounds of 50-mg sunitinib per day for four-week cycles (two weeks with treatment, two weeks without) or six-week cycles (four weeks with treatment, two weeks without). Patients were resistant to previous therapy with imatinib. Treatment lasted a median of 37 weeks (range, 10 to 167 weeks).

Patients’ serum thyroid-stimulating hormone concentration was measured; TSH concentrations greater than 7.0 mU/L was deemed consistent with hypothyroidism and included for evaluation. considered abnormal.

After an average of 50 weeks of therapy (range, 12 to 94 weeks), 15 of 42 patients (36%) developed hypothyroidism. Nine of these had TSH concentrations of more than 20 mU/L (mean maximum serum TSH concentration, 100 mU/L); six had TSH concentrations between 7.0 mU/L and 20 mU/L. Seven more patients (17%) had at least one TSH concentration between 5.0 mU/L and 7.0 mU/L, which later reached normal levels. Altogether, abnormal serum TSH concentrations were reported in 26 of 42 (62%) patients.

Six of the 15 (40%) patients who developed hypothyroidism had one or more serum TSH concentration measurements less than 0.5 mU/L before developing hypothyroidism, suggesting that sunitinib may cause a cytotoxic thyroiditis, the researchers wrote.

Sonograms of two patients being treated with sunitinib revealed no thyroid tissue, suggesting possible atrophy. “It will be interesting to see if this finding is seen in future studies, since this finding of apparent follicular cell atrophy has not been seen with any other drug” said Leila Yassa, MD, from the division of endocrinology, diabetes and hypertension at Brigham & Women’s Hospital. “This would suggest that there may be potential for using this or similar drugs to fight certain thyroid cancers.”

Longer treatment duration resulted in increased risk for hypothyroidism. Four of 22 (18%) patients taking sunitinib for 36 weeks developed hypothyroidism, whereas nine of 10 (90%) patients taking sunitinib for more than 96 weeks developed increased TSH levels.

The researchers suggested that patients taking sunitinib should be screened frequently for hypothyroidism. Mild symptoms and a low serum TSH concentration may indicate thyrotoxicosis, which may precede the development of hypothyroidism. Treatment with L-thyroxine should be considered for patients with clinical and subclinical hypothyroidism.

The researchers said that patients being treated with kinase inhibitors should be carefully observed for signs of adverse effects on unrelated organ systems.

According to Yassa, “We were struck by how easily the symptoms of hypothyroidism could be missed in these patients who were already ill and often had other reasons to explain signs of thyroid problems, such as fatigue, constipation, diarrhea, weight loss or anxiety. Serial thyroid function testing during sunitinib therapy was important to allow identification of affected patients. A return to normal thyroid function can have a large, positive impact on a patient who is fighting cancer.” – by Carey Cowles

For more information:

Desai J, Yassa L, Marqusee E, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med. 2006;145:660-664.