VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.