VICTORIA, British Columbia — Patients with advanced nonthyroid cancers who experience the common side effect of hypothyroidism during cancer treatment with tyrosine kinase–inhibitor (TKI) therapy show significantly increased survival compared with those who have normal thyroid levels.
“In this largest cohort analysis of its kind to date, we found that tyrosine kinase inhibitor–induced hypothyroidism occurred in 40% of [initially] euthyroid patients…and incident overt but not subclinical hypothyroidism was associated with greater overall survival,” first author Trevor E Angell, MD, of the division of endocrinology, diabetes, and hypertension, at Brigham and Women’s Hospital, in Boston, Massachusetts, said in presenting the findings here at the 2017 Annual Meeting of the American Thyroid Association.
Thyroid dysfunction is known to occur with TKI treatment, and while there have been some reports of potential survival benefits with resulting hypothyroidism, data on the issue have been lacking.
Angela M Leung, MD, an assistant professor of medicine with the division of endocrinology, diabetes, and metabolism at the University of California, Los Angeles David Geffen School of Medicine, who comoderated the session, gave her views.
“Tyrosine kinase–inhibitor therapies are increasingly being used in the treatment of various cancers, [and] it is recognized that the development of different types of endocrine dysfunction are associated with use of these agents, in part due to immune destruction,” she told Medscape Medical News.
“This study adds further understanding to the available literature on this topic, specifically examining the incidence of thyroid dysfunction and survival rates following use of a tyrosine-kinase inhibitor among patients with malignancy.”
Women More Likely to Develop Hypothyroidism After TKI Treatment
To explore the relationship, Dr Angell and colleagues evaluated 1120 adult patients with advanced nonthyroid cancer who were treated with tyrosine-kinase inhibitors between 2000 and 2017 and had available thyroid-function testing results.
After exclusions for factors including thyroid cancers and preexisting thyroid disease, 538 patients were included in the study.
Among the patients, 321 had normal thyroid levels; 144 (27%) developed overt hypothyroidism with TKI therapy, defined as thyroid-stimulating hormone (TSH) levels of 10 mIU/L or higher and low free T4; and 71 (13%) developed subclinical hypothyroidism, defined as TSH levels of 5 to 10 mIU/L or higher TSH if free T4 was normal.
The majority of patients (>95%) had advanced disease (stage III and IV), and there were no differences between the groups in terms of cancer stage, Eastern Cooperative Oncology Group (ECOG) performance score, or race.
There was a statistically significant increase in overall survival over 14 years among those who developed hypothyroidism compared with those who remained euthyroid, with the survival benefit after adjustment for variables predominantly seen in the overt hypothyroidism group (P < .0001) rather than in the subclinical hypothyroidism group (P = .16).
In terms of factors associated with the development of hypothyroidism, no significant link was observed between cumulative TKI exposure, the number of tyrosine-kinase inhibitors received, age, or race.
The leading factor that was independently associated with a risk of hypothyroidism was female sex (odds ratio [OR], 1.99; P < .01), while factors associated with a decreased risk included treatment with a non-TKI — for example, a vascular endothelial growth factor (VEGF) inhibitor (OR, 0.43; P < .01).
Patients treated with multiple tyrosine-kinase inhibitors were more likely to develop hypothyroidism while on their initial drug than a subsequent drug, and patients developed hypothyroidism after a median of 85 exposure days with exposure to one tyrosine-kinase inhibitor and after a median of 74 days with multiple agents.
Factors associated with an increased risk of death included older age at baseline and certain cancer types, such as gastrointestinal stromal tumors (GIST) or sarcoma.
Results Provide Better Understanding of Hypothyroidism With TKI Treatment
The findings provide a better understanding of hypothyroidism in relation to TKI treatment, Dr Angell told Medscape Medical News.
“Previous studies had demonstrated hypothyroidism occurring during treatment with tyrosine-kinase inhibitors, but our understanding of clinical risk factors and the survival benefit in initially euthyroid subjects when accounting for other variables has been limited,” he explained.
He noted that mechanisms speculated to play a role in the development of hypothyroidism with TKI treatment include direct toxicity to the thyroid gland, destructive thyroiditis, and increased thyroid-hormone clearance.
Dr Angell speculated that hypothyroidism during TKI treatment could also be an indication of efficacy of this class of drugs.
“While we do not have answers yet, it may be that the drug effects on the thyroid are a reflection of how much the drug is also affecting the cancer cells,” he suggested.
And he noted that treatment of the TKI-related hypothyroidism did not appear to change the results.
“More than 90% of patients with overt hypothyroidism were treated, but in our evaluation of those who were and were not treated, we found no difference in survival,” he said.
More Research Needed
Dr Leung said these latest results should prompt additional research into the issue.
“The findings showing that incident overt hypothyroidism in this sample was associated with increased overall survival is interesting.”
Further research is needed to look at this and to “better understand the mechanism of increased overall survival in patients who develop overt hypothyroidism following tyrosine kinase–inhibitor use, whether this may involve immune activation or other pathways,” she concluded.
The authors and Dr Leung had no relevant financial relationships.
2017 Annual Meeting of the American Thyroid Association. October 19, 2017; Victoria, British Columbia. Abstract 1.