Hypothyroidism Risks With MKIs Examined

Eric J. Sherman, MD

Head and Neck Oncology

Memorial Sloan Kettering Cancer Center, New York, NY

A retrospective analysis of the risks of hypothyroidism in patients in Germany who received sunitinib and sorafenib is gaining attention in the field of head and neck cancers, where the drugs are being evaluated for clinical use.

A study published in the European Journal of Cancer earlier this year found that 13.7% of patients on sunitinib and 6.3% of those who took sorafenib were treated with thyroid hormone (TH) therapy typically prescribed to treat hypothyroidism. The study, with findings based on prescription data from 2509 patients, is believed to be the largest database examination of the endocrine disorder among people taking either of the drugs.

Both drugs are multikinase inhibitors (MKIs) that the FDA has approved for the treatment of advanced renal cell carcinoma (RCC). Sunitinib (Sutent) also is approved to treat certain gastrointestinal stromal tumors (GISTs) and pancreatic neuroendocrine tumors while sorafenib (Nexavar) is additionally indicated for hepatocellular carcinoma. A number of phase II trials are under way studying the efficacy of sunitinib and sorafenib in the treatment of thyroid cancer.

In reviewing the study, Eric J. Sherman, MD, said the findings are notable in his field because MKIs represent a promising class of drugs for thyroid patients. “This study is clinically relevant to anyone treating a patient with thyroid cancer,” he said.

Using prescription data from more than 80% of German pharmacies, investigators started with an index of 6444 patients for whom one of the two anticancer therapies had been prescribed from July 1, 2006, through December 31, 2007. Clinical hypothyroidism requiring TH therapy was defined as thyroidstimulating hormone (TSH) levels >10 mIU/L.

Patients who had been prescribed TH before the study period, those who were not registered in the database, and those who received TH within 29 days of the initial index date were excluded. Data for the remaining 2509 patients were examined based on TH prescriptions written during an observation period that began 30 days after the initial index date through August 31, 2009.

In all, 178 of 1295 patients taking sunitinib (13.7%) and 77 of 1214 patients taking sorafenib (6.3%) received TH therapy. Incidence rates were 24.2 per 100 person-years for sunitinib patients and 12.1 per 100 person-years for sorafenib patients, with the unadjusted hazard ratio for TH therapy calculated as 2.0 (95% confidence interval [CI], 1.5-2.6) for sunitinib as compared with sorafenib.

Sherman said hypothyroidism has been observed in patients, but that the study marks the first time that there are enough concrete data to make the necessary recommendations.

The German research team suggested clinicians exercise caution in prescribing TH for cancer patients with slightly increased serum-TSH levels who are not displaying symptoms. “If clinical hypothyroidism occurs, it can be treated with TH, which leads to fast and complete correction of increased TSH values and should not restrict the use of sunitinib and sorafenib in malignant diseases in general,” they concluded.

The FDA-approved prescribing information (PI) for Sutent includes a recommendation for a baseline laboratory measurement of thyroid function prior to the start of treatment and advice about monitoring patients for signs of such problems. In May 2011, the PI was updated to include reports of higher rates of hypothyroidism than with placebo among small groups of patients.

The PI for Nexavar describes hypothyroidism as an “uncommon” adverse drug reaction and does not include it among the most serious reactions.

Sherman said that while hypothyroidism does pose a serious risk to the patient, it is also a very treatable condition. TH can be started as soon as hypothyroidism is identified, and dose rates are monitored throughout treatment. If a patient is taken off sorafenib or sunitinib, it is possible for thyroid levels to return to normal.

“It’s very easy to treat,” Sherman said. “It’s just one of those things that you want to make sure you don’t miss.”

Feldt S, Schüssel K, Quinzler R, et al. Incidence of thyroid hormone therapy in patients treated with sunitinib or sorafenib: a cohort study [published online ahead of print February 28, 2012]. Eur J Cancer. doi:10.1016/j.ejca.2012.01.036.