Immunotherapy for Metastatic Cancer Linked to Thyroid Disease

Nancy A Melville

November 11, 2014

SAN DIEGO — Novel immunotherapies for the treatment of metastatic cancers are linked to an increased risk for painless thyroiditis syndrome in some patients, according to a new study presented here at the 2014 Annual Meeting of the American Thyroid Association.

"The take-home message from this is that painless thyroiditis syndrome can occur in subgroups of people with these new immunotherapies for metastatic malignancies, and patients getting such therapy should be watched for this syndrome," lead investigator Dr Paul G Walfish (Mount Sinai Hospital, Toronto, Ontario) told Medscape Medical News.

Painless thyroiditis often occurs in association with endogenous thyroid conditions including Graves' and Addison's disease; however, the condition has also been linked to medications including interferon, kinase inhibitors, interleukin 2, and radiation therapy.

Novel immunotherapy approaches for the treatment of metastatic malignancies have targeted cytotoxic T lymphocyte antigen 4 (CTLA-4) and program death 1 (PD-1) receptor, which each act as negative immune regulators, preventing T-cell proliferation, activation, and cytokine release to foreign antigens, Dr Walfish explained.

Recent research has shown a link between treatment with CTLA-4 monoclonal antibodies and adverse endocrinopathies, but the risk with PD-1 antibodies has not been previously established. PD-1 inhibitors already on the market include pembrolizumab (Keytruda, Merck) for advanced melanoma, approved in the United States, and nivolumab (Bristol-Myers Squibb), which is available in Japan. The CTLA-4 monoclonal antibody ipilimumab (Yervoy, Bristol-Myers Squibb) has clinical-trial data showing hypophysitis as an adverse effect, with a mean incidence of 4% (range, 1% – 25%), as previously reported by Medscape Medical News.

Dr Walfish reported on 10 patients receiving treatment for metastatic malignancies as part of a clinical trial of anti-PD-1 monoclonal antibodies who were referred to his clinic for symptoms of thyroid dysfunction. Six of the patients had transient thyrotoxicosis and were successfully treated with just temporary beta-blocker therapy, while the other four showed serological evidence of antithyroid antibodies, and all required thyroid-hormone replacement therapy for a minimum of 6 months

Dr Bryan R Haugen (University of Colorado School of Medicine, Denver) said these findings underscore the increased need to monitor thyroid function in patients receiving these immunotherapies.

"The hypothyroidism is easy to treat. The hyperthyroidism could be a problem in this potentially ill population, which is why we need to increase awareness and identify those who are becoming hyperthyroid early," he told Medscape Medical News.

"I don't think [thyroid monitoring] is commonly done in these patients, but I think it should be to determine whether those patients with antithyroid antibodies who may have early asymptomatic thyroiditis may be at increased risk for this painless thyroiditis. If they are found to be at risk, we would follow them more closely."

Onset of Thyroid Symptoms Not Related to Response to Immunotherapy

Seven of the patients referred to Dr Walfish's tertiary thyroidology clinic for diagnostic confirmation and management had malignant melanomas, and three were being treated for non–small-cell lung cancers. The patients had a mean age of 55, and 60% were female.

In the six patients who had transient thyrotoxicosis and who were successfully treated with just temporary beta-blocker therapy, all tested negative for thyrotropin-binding inhibitory immunoglobulins (TBII), which suggested exclusion of Graves' disease as a cause, although four of them developed antithyroid antibodies.

The thyrotoxicosis resolved spontaneously in these six patients within about 4 to 6 weeks, but they subsequently developed hypothyroidism, which required thyroid-hormone replacement therapy with levothyroxine.

The other four patients presented only with hypothyroidism about 6 to 8 weeks after the initial immunotherapy exposure, without reporting a previous thyrotoxic phase, although Dr Walfish said doctors may have missed a previous occurrence of thyrotoxicity for those patients.

These four patients had serological evidence of antithyroid antibodies, and all required thyroid-hormone replacement therapy for a minimum of 6 months.

The onset of the thyroid symptoms was not associated with the patients' oncological response to the immunotherapy.

"We must recognize that novel immunotherapies that have recently been applied to several malignancies have now been recognized to have selective immunotoxic effects on the thyroid gland and several other endocrine organs," Dr Walfish said.

He speculated that, as has been demonstrated in thyroid responses to CTLA-4, some of the same genetic factors that are associated with an increased risk for thyroid disorders in general may also predispose patients for painless thyroiditis in relation to treatment with anti-PD-1 monoclonal antibodies.

"Since these effects do not occur in all patients exposed to [the immunotherapy], it is likely that affected individuals have an immunogenetic susceptibility to such adverse consequences," he explained.

"We and others have previously shown that polymorphic variants of the CTLA-4-receptor gene can predispose individuals to a variety of autoimmune endocrine disorders such as Graves' disease, Addison's disease, Hashimoto's thyroiditis, and type 1 diabetes mellitus," he said.

"We postulate that similar mechanisms — polymorphic variants of the PD-1–receptor gene — may account for the occurrence of painless thyroiditis in a subgroup of patients treated with anti-PD-1 monoclonal antibodies," he concluded.

Dr Walfish reported he has no relevant financial relationships. Dr Haugen said that he is in negotiations with two companies that make PD-1 inhibitors to develop trials on advanced thyroid cancer, but he has no current relevant financial relationships.

2014 Annual Meeting of the American Thyroid Association; October 30, 2014; San Diego, CA. Abstract 12.

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