SAT-158 New Data on High Prevalence and Time of Occurrence of New Onset Hypothyroidism Associated with Mitotane Therapy in a Cohort of Adrenocortical Cancer

Abstract

Context. Mitotane is a steroidogenesis inhibitor and an adrenocorticolytic drug used to treat adrenocortical cancer (ACC). Central hypothyroidism is recognized in mitotane-treated patients and recent data suggested that mitotane could have an inhibitory effect on TSH-secreting cells in the pituitary gland. Moreover, mitotane may lead to induction of thyroid hormone metabolism. Clinical data on hypothyroidism related to mitotane such as prevalence and time of occurrence was described in a limited number of patients. Objective. To better characterize clinically secondary hypothyroidism in patients with ACC treated with mitotane therapy. Methods. We reviewed retrospectively paper charts and electronic records from patients with histologically confirmed diagnosis of ACC evaluated at our center from 1995-2019. We analysed the pattern of TSH and thyroid function, but also mitotane timing and levels at baseline and during treatment of patients under mitotane therapy. Thyroid hormone assessment including TSH, FT4 and FT3 was performed at least every 3 months during follow-up. Results. Our cohort of 104 patients with ACC includes 84 patients that received mitotane therapy. Among them, thyroid function data was incomplete for 39 cases. Complete data was retrieved from 45 patients. Ten out of 45 (22.2%) patients were already known for primary hypothyroidism and were receiving L-T4 replacement before the initiation of mitotane. Two of 45 (4.4%) patients maintained a normal thyroid function during complete follow up (4.5 years) and 33/45 (73.3%) had new onset hypothyroidism requiring levothyroxine treatment. Of these 33 patients, 22 were females and 11 were males, ranging from 22-74 yo with a median of 46 yo. The number of patients with ENSAT stage I, II, III and IV of disease were 1, 8, 11 and 13 respectively. Thyroid profiles were compatible with central hypothyroidism (low T4 with low or inappropriately normal TSH) in 22/33 patients (66.7%). Interestingly, 6/33 patients (18.2%) developed a TSH elevation with a normal lower-limit or low T4 level. The timeline distribution of the occurrence of hypothyroidism was 21.2% (n:7) at <3 months, 15.2% (n:5) between 3-6 months, 21.2% (n:7) between 6-9 months and 15.2% (n:5) between 9-12 months. 9.1% (n:3) occurred within the second year of treatment (between 12-24 months). However, in 5/33 (15.2%) cases, the exact time of new hypothyroidism onset was undetermined. Conclusion. Mitotane therapy is frequently associated with new onset hypothyroidism with a prevalence of 73% in our cohort of exposed patients and is most likely of central etiology. 72.7% of cases occur in the first year of treatment while 9.1% occur in the second year. This study supports the importance of monitoring thyroid function (including a free T4 level) during the complete course of mitotane therapy.

The impact of mitotane therapy on serum-free proteins in patients with adrenocortical carcinoma

“…These results were expected, as central hypothyroidism has been recognised as a side effect of mitotane therapy, meaning that whilst the TSH concentration may appear within the reference range, the fT4 concentrations are generally low. Poirier ( 14 ) concluded that induction of mitotane therapy had been associated with a central hypothyroidism prevalence of 73.3%. This accentuates the importance of regular thyroid function investigations to assess individuals’ needs for levothyroxine therapy ( 7 , 14 ).…”

“…Poirier ( 14 ) concluded that induction of mitotane therapy had been associated with a central hypothyroidism prevalence of 73.3%. This accentuates the importance of regular thyroid function investigations to assess individuals’ needs for levothyroxine therapy ( 7 , 14 ).…”

“…Administration of mitotane may also result in biochemical changes, including a marked increase in hormone-binding globulins and adrenal insufficiency ( 12 , 13 , 14 , 15 , 16 ). Specifically, measurement of total serum cortisol may not accurately reflect the glucocorticoid status of the patient and may lead to unrecognised adrenal insufficiency.…”