Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease.

CONTEXT: Although transsphenoidal surgery remains the first-line treatment in Cushing's disease (CD), recurrence is observed in about 20% of cases. Adjunctive treatments each have specific drawbacks. Despite its inhibitory effects on steroidogenesis, the antifungal drug ketoconazole was only evaluated in series with few patients and/or short-term follow-up.
OBJECTIVE: Analysis of long-term hormonal effects and tolerance of ketoconazole in CD.
DESIGN: A total of 38 patients were retrospectively studied with a mean follow-up of 23 months (6-72).
SETTING: All patients were treated at the same Department of Endocrinology in Marseille, France. PATIENTS: The 38 patients with CD, of whom 17 had previous transsphenoidal surgery. INTERVENTION: Ketoconazole was begun at 200-400 mg/day and titrated up to 1200 mg/day until biochemical remission. MAIN OUTCOME MEASURES: Patients were considered controlled if 24-h urinary free cortisol was normalized.
RESULTS: Five patients stopped ketoconazole during the first week because of clinical or biological intolerance. On an intention to treat basis, 45% of the patients were controlled as were 51% of those treated long term. Initial hormonal levels were not statistically different between patients controlled or uncontrolled. Ketoconazole was similarly efficacious as a primary or postoperative treatment. Among 15 patients without visible adenoma at initial evaluation, subsequent follow-up allowed identification of the lesion in five cases. No adrenal insufficiency was observed. Adverse effects were rare in patients treated long term.
CONCLUSIONS: Ketoconazole is a safe and efficacious treatment in CD, particularly in patients for whom surgery is contraindicated, or delayed because of the absence of image of adenoma on magnetic resonance imaging.