title: Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Eleven patients with severe Cushing's syndrome participated in this follow-up study in a tertiary referral hospital.
  
  
  METHODS
  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 2737 μg/24 h (range 853-22,605) at baseline to 50 μg/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 μg/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 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.
authors.affiliation: Faculté de Médecine Paris-Sud, Unité Mixte de Recherche S693, and Institut National de la Santé et de la Recherche Médicale Unité 693, Université Paris-Sud, Le Kremlin Bicêtre F-94276, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Kamenický
authors.forename: Céline
authors.initials: C
authors.lastname: Droumaguet
authors.forename: Sylvie
authors.initials: S
authors.lastname: Salenave
authors.forename: Anne
authors.initials: A
authors.lastname: Blanchard
authors.forename: Christel
authors.initials: C
authors.lastname: Jublanc
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gautier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Brailly-Tabard
authors.forename: Sophie
authors.initials: S
authors.lastname: Leboulleux
authors.forename: Martin
authors.initials: M
authors.lastname: Schlumberger
authors.forename: Eric
authors.initials: E
authors.lastname: Baudin
authors.forename: Philippe
authors.initials: P
authors.lastname: Chanson
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000963:Antimetabolites / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003480:Cushing Syndrome / Q000188:drug therapy* / Q000652:urine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D008797:Metyrapone / Q000627:therapeutic use*; D008875:Middle Aged; D008939:Mitotane / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000963:Antimetabolites; D000970:Antineoplastic Agents; D008939:Mitotane; D007654:Ketoconazole; D006854:Hydrocortisone; D008797:Metyrapone