Hypothyroidism After TKIs for Cancer Linked to Longer Survival

Hypothyroidism that occurs as an adverse event with tyrosine kinase inhibitors (TKIs) used to treat cancer is, in fact, associated with significantly improved overall survival and may have important prognostic value, according to new research.

"The clinical relevance of these findings is that clinicians should not hesitate to give serial TKI due to concern for development of thyroid dysfunction, which is readily treatable with hormone replacement and may correlate with improved overall survival," first author Melissa Lechner, MD, PhD, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

The study was published in the April issue of Thyroid.

This retrospective study is the largest to date involving patients with nonthyroidal cancers and normal thyroid status at baseline; patients with pre-existing thyroid disease were excluded.

It involved 538 adult patients with advanced nonthyroidal cancer who were treated with TKIs between 2007 and 2017 and had data available on thyroid function testing. The TKIs included axitinib, pazopanib, regorafenib, sorafenib, sunitinib, and vandetanib, and the cancers that were being treated included renal cell carcinoma, gastrointestinal stromal tumors (GIST), hepatocellular carcinoma, neuroendocrine tumors, sarcoma, and primary central nervous system tumors.

Overall, as many as 40% of patients developed hypothyroidism, including 13% (n = 71) with subclinical hypothyroidism and 27% (n = 144) with overt hypothyroidism.

For the study, subclinical hypothyroidism was defined as a thyroid-stimulating hormone (TSH) level of 5 to 10 mIU/L, or a higher TSH if free thyroxine levels were normal. Overt hypothyroidism was defined as TSH greater than 10 mIU/L, low free thyroxine, or need for hormone replacement.

Significantly Longer Survival

The team found that patients with overt hypothyroidism had significantly longer median overall survival duration of 1643 days (confidence interval [CI], 1215 - 1991 days) compared with patients with subclinical hypothyroidism (1005 days; CI, 634 - 1528 days) and those with no thyroid dysfunction (685 days; CI, 523 - 851 days; P < .0001).

The association between overt hypothyroidism and overall survival remained significant after a multivariate adjustment for factors including age, sex, race, cancer type, cancer stage, and checkpoint inhibitor therapy (hazard ratio [HR], 0.561; P < .0001); however, the association with subclinical hypothyroidism was not significant after the adjustments (HR, 0.796; P = .165).

Women were more likely than men to develop hypothyroidism (94 of 178 [52.8%] vs. 121 of 358 [33.7%], respectively; P < .0002). In terms of cancer type, the overt hypothyroidism group had a significantly higher incidence of renal cell carcinoma and GIST (P < .0001).

TKI exposure time did not significantly differ between patients who did and did not develop hypothyroidism, with a median of 215 days (interquartile range [IQR], 95 - 658 days) among those with normal thyroid function, 195 days (IQR, 63 - 586 days) for subclinical hypothyroidism, and 202.5 days (IQR, 61 - 518.5 days) for overt hypothyroidism (P = .46).

There was also no link between the risk for hypothyroidism and the number of TKIs received; 26 different TKIs were included in the study, and 47% of patients in the cohort received more than 1 TKI during their cancer treatment.

The number of non-TKI cancer treatments did not significantly differ between the groups, and while patients who developed hypothyroidism were more likely to have received checkpoint inhibitor therapy, such as nivolumab or ipilimumab, during the entire study (P = .0004), there were no significant differences in the proportion of patients who received those therapies before thyroid abnormalities developed.

Survival Effect Remained Despite Hypothyroidism Treatment

The improved overall survival benefit was also observed in patients with subclinical and overt hypothyroidism even after patients were treated with thyroid hormone replacement.

Lechner said that was not necessarily a surprise and may be related to the mechanisms speculated to explain the link between TKI-induced hypothyroidism and survival.

"Development of thyroid dysfunction in patients treated with TKIs likely mirrors effect of the drug on other parts of the body, including the cancer," she explained.

"These TKI effects on body tissues, rather than thyroid dysfunction itself, likely correlate with improved overall survival, so we were not surprised that improved overall survival persisted after treatment with thyroid hormone replacement."

Other, smaller studies have also shown no influence of levothyroxine hormone replacement on the survival benefit, including one study showing no effect of the replacement on progression-free survival.

The current findings should help provide further confidence when hypothyroidism arises in TKI cancer treatment, Lechner explained.

"Benefits of therapy are often weighed against adverse effects," she said.

"Hopefully this data provides additional evidence to support continuation of TKI cancer treatment in the face of hypothyroidism, which can be readily treated by endocrinologists."

Findings Support Evidence From Smaller Studies

This effect of TKI-induced hypothyroidism is generally recognized within the field of oncology but has mainly been seen in smaller studies, commented Bryan R. Haugen, MD, head of the Division of Endocrinology, Metabolism and Diabetes and Mary Rossick Kern and Jerome H. Kern Chair in Endocrine Neoplasms Research at the University of Colorado School of Medicine, Aurora.

"This effect is fairly well known among cancer specialists, [and] the study adds to the literature based on the number of patients studied," he told Medscape Medical News.

"At our institution, most medical oncologists will treat the hypothyroidism with levothyroxine and not hold or adjust the dose of TKI," he added. "I suspect that most clinicians in the community do the same."

Haugen also noted that good evidence suggests that many patients with thyroid cancer who have had their thyroid removed and are receiving levothyroxine therapy require increased doses of thyroid hormone when initiating TKI treatment.

"This is believed to be from increased metabolism/clearance of thyroid hormone in the liver, so this likely occurs in most to all patients, including those with a normal thyroid, started on TKI therapies," Haugen explained.

Haugen echoed the suggestion that hypothyroidism may indeed represent an indicator of treatment efficacy, possibly explaining the survival benefit.

"The correlation with a better outcome is very interesting," he said. "My leading hypothesis is that hypothyroidism is a sign that tissues — normal tissue like the thyroid and cancer tissues — are getting a good amount of TKI in the tissue and hypothyroidism is simply a marker that the drug is working well in these particular patients," Haugen said.

"There is evidence that other side effects, including rash, hypertension, et cetera, correlate with better outcomes as well."

He noted that the study also supports previous findings linking checkpoint inhibitors with hypothyroidism. "It was also interesting and confirming of other studies to see that patients exposed to the immune checkpoint inhibitors, albeit a small number, also had higher rates of hypothyroidism."

"It is well documented that hypothyroidism is one of the most common side effects of checkpoint inhibitor therapy," he added.

The authors have disclosed no relevant financial relationships. Haugen has consulted for Eisai, maker of lenvatinib, and is the principal investigator on an investigator-initiated multicenter clinical trial of lenvatinib and pembrolizumab in patients with advanced thyroid cancer that is being supported by Eisai and Merck through the International Thyroid Oncology Group.

Thyroid. Published online April 1, 2018. Abstract

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