Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome

Context: Mitotane is highly effective in the long-term management of Cushing's syndrome but has a slow onset of action. Mitotane combined with fast-acting steroidogenesis inhibitors might avoid the need for emergency bilateral adrenalectomy in patients with severe hypercortisolism. Objective: Our objective was to assess the efficacy and safety of combination therapy with mitotane, metyrapone, and ketoconazole in severe ACTH-dependent Cushing's syndrome. Patients, Design, and Setting: Eleven patients with severe Cushing's syndrome participated in this follow-up study in a tertiary referral hospital. Interventions: High-dose therapy combining mitotane (3.0 -5.0 g/24 h), metyrapone (3.0-4.5 g/24 h), and ketoconazole (400-1200 mg/24 h) was initiated concomitantly. Twenty-four-hour urinary free cortisol (UFC) excretion (normal values 10-65 μg/24 h) was monitored. Results: Data are reported as medians (range). All 11 patients experienced a marked clinical improvement. UFC excretion fell rapidly from 2737μg/24 h (range 853-22,605) at baseline to 50μg/24 h (range 18-298) (P = 0.001) within 24-48 h of treatment initiation and remained low to normal on the combination therapy. Insevenpatients, metyrapone and ketoconazole were discontinued after 3.5 months (range 3.0-6.0) of combination therapy, and UFC excretion remained controlled by mitotane monotherapy (UFC 17 μg/24 h, range 5-85; P = 0.016). Five patients became able to undergo etiological surgeryandare presently in remission. Four ofthemrecovered normal adrenal function after mitotane discontinuation. Adverse effects were tolerable, consisting mainly of gastrointestinal discomfort and a significant rise in total cholesterol and γ-glutamyl transferase levels (P = 0.012 and P = 0.002, respectively). Conclusions: When surgical treatment for severe ACTH-dependent Cushing's syndrome is not feasible, combination therapy with mitotane, metyrapone, and ketoconazole is an effective alternative to bilateral adrenalectomy, a procedure associated with significant morbidity and permanent hypoadrenalism.