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.
Highlights
Adrenocortical carcinoma (ACC) is a rare but often aggressive tumor with an incidence of one to two cases per million per year
It was found that mitotane could potentially interfere with pituitary function by comparing adrenocorticotropic hormone (ACTH) levels between patients treated with mitotane for adrenocortical cancer (ACC) and patients with primary adrenal insufficiency [15]
A total of 48 patients with a pathologically proven ACC were identified to have minimally completed a two-year course of adjuvant mitotane therapy (34 and 14 patients from Italian and Canadian centers, respectively)
Summary
Adrenocortical carcinoma (ACC) is a rare but often aggressive tumor with an incidence of one to two cases per million per year. Removable tumors of stages I to III presenting with evidence of loco-regional invasion or aggressive pathologic features such as a high proliferation index (Ki67 > 10%) or a positive margin status are candidates for this therapy [6,7,8] This is highlighted by a recent consensus from the European. In vitro studies showed that mitotane causes interference with cholesterol metabolism and with mitochondrial activity in adrenocortical cells, which often leads to an increase in the apoptosis rate It reduces adrenal steroidogenesis by inhibiting key mitochondrial enzymes like CYP11B, which reduces the conversion of hormone precursors into active hormones such as cortisol [11,12,13,14]. It was found that mitotane could potentially interfere with pituitary function by comparing adrenocorticotropic hormone (ACTH) levels between patients treated with mitotane for ACC and patients with primary adrenal insufficiency (autoimmune or post-adrenalectomy) [15]
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