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 mu g/24 h) was monitored. Results: Data are reported as medians (range). All 11 patients experienced a marked clinical improvement. UFC excretion fell rapidly from 2737 mu g/24 h (range 853-22,605) at baseline to 50 mu g/24 h (range 18-298) (P = 0.001) within 24-48 h of treatment initiation and remained low to normal on the combination therapy. In seven patients, 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 mu g/24 h, range 5-85; P = 0.016). Five patients became able to undergo etiological surgery and are presently in remission. Four of them recovered normal adrenal function after mitotane discontinuation. Adverse effects were tolerable, consisting mainly of gastrointestinal discomfort and a significant rise in total cholesterol and gamma-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. (J Clin Endocrinol Metab 96: 2796-2804, 2011)