According to a new study, the researcher examined 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. The clinical relevance of these findings is that clinicians should not hesitate to give serial TKI due to concern for the development of thyroid dysfunction, which is readily treatable with hormone replacement and may correlate with improved overall survival. The study was published in 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.

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).

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

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. 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.

The current findings should help provide further confidence when hypothyroidism arises in TKI cancer treatment. Benefits of therapy are often weighed against adverse effects. Hopefully, this data provides additional evidence to support the continuation of TKI cancer treatment in the face of hypothyroidism, which can be readily treated by endocrinologists.

Findings Support Evidence From Smaller Studies

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 of thyroid hormone in the liver, so this likely occurs in most to all patients, including those with normal thyroid, started on TKI therapies. They suggested that hypothyroidism may indeed represent an indicator of treatment efficacy, possibly explaining the survival benefit. A well documented that hypothyroidism is one of the most common side effects of checkpoint inhibitor therapy.