Recovery of adrenal function after stopping mitotane in patients with adrenocortical carcinoma.

Mitotane is the standard therapy of adrenocortical carcinoma (ACC) due to its relative selectivity of its cytotoxic effects towards adrenocortical cells. Therefore, it virtually always leads to adrenal insufficiency. Frequency and characteristics of hypothalamic-pituitary-adrenal (HPA) axis recovery after discontinuation are ill-defined. Retrospective study of patients with ACC adjuvantly treated with mitotane for ≥12 months who were disease-free at mitotane stop, and had a minimum follow-up ≥1 year. Primary endpoint: adrenal recovery. Cox regression analyses were used to identify predictive factors. Moreover, mitotane plasma elimination rate and hormonal changes after mitotane stop were investigated. 56 patients (36 women) treated with mitotane for a median time of 25 months and an average daily dose of 2.8 g were included. Median time after discontinuation until mitotane levels dropped below 5, 2 mg/L, and the detection limit was 152 days (interquartile range:114-202), 280 days (192-370), and 395 days (227-546), respectively. Full adrenal recovery was documented in 32 (57%) patients after a median time of 26 months (95%CI = 19.6-32.4). In four patients (7.1%) adrenal insufficiency persisted >5 years after discontinuation. Mitotane peak ≥27 mg/L significantly correlated with longer time to adrenal recovery (HR = 0.2, 95%CI = 0.1-0.8, p = 0.03). 27/38 patients (71%) followed in reference centers achieved adrenal recovery compared to only 5/18 (28%) followed-up in non-reference centers (HR = 4.51, 95%CI = 1.71-11.89, p = 0.002). Other investigated factors were not associated with adrenal function after discontinuation. Our study demonstrates that adrenal recovery occurs in most patients after stopping mitotane, particularly when followed-up in specialized centers, but not in all. Elimination time of mitotane after treatment discontinuation is very long, but individually quite variable.

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© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.