Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma

Abstract

Mitotane is a steroidogenesis inhibitor and adrenolytic drug used for treatment of adrenocortical cancer (ACC). Mitotane therapy causes adrenal insufficiency requiring glucocorticoid replacement in all patients. However, it is unclear whether chronic therapy with mitotane induces complete destruction of zona fasciculata and whether hypothalamic-pituitary-adrenal (HPA) axis can recover after treatment cessation. Our objective was to assess the HPA axis recovery in a cohort of patients after cessation of adjuvant mitotane therapy for ACC. We retrospectively reviewed patient files with stage I-II-III ACC in two referral centers in Canada and Italy. Data on demographics, tumor characteristics, hormonal profile, and HPA axis were collected. Data from 23 patients with pathologically proven ACC treated with adjuvant mitotane for a minimum of two years were analyzed. Eight patients were males and 15 were females and the median age was 41 years old (range 18 to 73). After mitotane cessation, 18/23 (78.3%) patients achieved a complete HPA axis recovery while 3/23 (13.0%) were unable to tolerate glucocorticoid withdrawal despite having normal hormonal test values and 2/23 (8.7%) never achieved recovery. The mean time interval between mitotane cessation and HPA axis recovery was 2.7 years. A high proportion of patients achieved HPA axis recovery following cessation of mitotane adjuvant therapy. However, complete recovery was often delayed up to 2.5 years and regular assessment of the hormonal profile is required.

Metabolic and Endocrine Toxicities of Mitotane: A Systematic Review

“…Only three studies specified the need for increased steroid coverage due to serum ACTH level elevation, or to signs and symptoms of adrenal insufficiency, as an endocrine adverse event (13/53 patients, 24.5%) [ 19 , 22 , 40 ]. Mineralocorticoid replacement was administered in a total of 67 of 182 patients in six studies [ 21 , 29 , 31 , 34 , 40 , 43 ]. Moreover, another study reported the need for fludrocortisone replacement therapy, but the proportion of patients was unclear [ 22 ].…”

Metabolic and hormonal side effects of mitotane treatment for adrenocortical carcinoma: A retrospective study in 50 Danish patients

“…Fifteen of 24 patients tested with ACTH stimulation test regained adrenal function after discontinuation of mitotane. This confirms a recent study by Poirier at al., who found 78% of patients treated with adjuvant mitotane to completely recover their adrenal function and thus discontinue glucocorticoid replacement 24 . Hypotheses explaining prolonged adrenal insufficiency, are a long‐lasting inhibitory effect on secretion of ACTH from the pituitary 25 or that interparenchymal and intraglandular levels of mitotane remain at a sufficient level to inhibit the steroidogenesis long after plasma mitotane concentration become undetectable 7 …”

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

“…In CD men, gynecomastia is also reported (17.6–50%), as mitotane also acts on gonadal steroidogenesis, impairing testicular androgen production ( 4 , 60 ). Moreover, the adrenolytic action of mitotane usually leads to AI, requiring therefore glucocorticoid replacement, although the AI may be reversible after mitotane withdrawal ( 4 , 60 ); particularly, a recent study on ACC patients exposed to mitotane in long-term treatments (at least 24 months) has shown that hypothalamus-pituitary-adrenal axis recovery may be present in around 78% of patients, with a mean time to recovery of 2.7 years ( 104 ). Despite the relevant number of CD patients treated with mitotane, all the available studies on mitotane as a treatment for CD are single-center, non-controlled studies, and two of the oldest studies included also patients undergone pituitary irradiation, potentially biasing the overall results ( 105 , 106 ).…”