Central hypothyroidism is frequent during mitotane therapy in adrenocortical cancer (ACC) patients: Prevalence and timeline

Central hypothyroidism was described previously in mitotane-treated patients but data on its prevalence and time of occurrence is limited. To better characterize thyroid hormone insufficiency in ACC patients exposed to mitotane. We reviewed medical records of patients from two academic centers in Montreal and Toulouse with exposure to mitotane therapy for ACC between 1995 and 2020. We analysed the thyroid function parameters during and after treatment. In our cohort of 83 patients, 17 were excluded because of pre-existing primary hypothyroidism or drug-induced hypothyroidism. During mitotane therapy, 63/66 developed central hypothyroidism with low free T4 associated with low, normal or mildly elevated TSH values (n = 60) or normal free T4 level but reduction of > 20% from baseline values (n = 3). Only 3/66 patients maintained a normal thyroid function. The onset of hypothyroidism was: < 3 months in 33.3%, 3–6 months in 19.1%, 6–9 months in 14.3% and 9–12 months in 9.5%. At the onset of hypothyroidism, the mean serum concentration of mitotane was 11.87 mcg/L and the mean and median cumulative doses of mitotane were 593 g and 325 g (range 14 g to 4147 g), respectively. Over time, 27 patients stopped mitotane, and partial (42.3%) or complete (23.1%) recovery from central hypothyroidism was observed mainly in the first 2 years after mitotane discontinuation. No association was observed between frequency of hypothyroidism recovery and total duration or cumulative dose of mitotane therapy. Mitotane therapy is frequently associated with onset of central hypothyroidism with a prevalence of 95.5%. Most cases occurred in the first year of treatment. Partial or full recovery of normal thyroid function occurs in 65.4% of patients. This study supports the importance of systematic monitoring of TSH and free T4 levels during and following discontinuation of mitotane therapy.