KETOCONAZOLE IN THE MANAGEMENT OF PARANEOPLASTIC CUSHINGS-SYNDROME SECONDARY TO ECTOPIC ADRENOCORTICOTROPIN PRODUCTION

Purpose: To evaluate the safety and efficacy of ketoconazole treatment in the management of patients with paraneoplastic Gushing's syndrome (CS) secondary to ectopic adrenocorticotropin (ACTH) production by mal ignant neoplasms (ECS). Patients and Methods: A retrospective chart re view was undertaken for 15 consecutive patients with ECS treated with ketoconazole. Strict criteria were defined for diagnosis of ECS and fo r clinical, biochemical, and hormonal responses.Results: There were fo ur women and 11 men with a median age of 59 years (range, 44 to 84). E leven patients had primary lung cancer (nine small-cell [SCLC], one mi xed SCLC/non-SCLC, and one non-SCLC); two had carcinoid tumors (one br anchial, one pancreatic); one had hepatocellular carcinoma; and one ha d medullary carcinoma of the thyroid. Eight patients had ECS diagnosed at tumor presentation. Clinical findings included proximal muscle wea kness (n = 10), peripheral edema (n = 8), and hypertension (n = 8). Bi ochemical abnormalities included hypokalemia (n = 14), metabolic alkal osis (n = 13), and new or worsened diabetes mellitus (n = 10). patient s received ketoconazole in dosages of 400 to 1,200 mg/d titrated by ch anges in urinary free-cortisol (UFC) levels for a median duration of 2 6 days (range, 3 to 1,059), and nine also received chemotherapy with k etoconazole. Hypokalemia, metabolic alkalosis, diabetes mellitus, and hypertension improved in the majority of patients. Ten patients had a hormonal response, with seven complete responses (median duration, 25 days; range, 6 to 989). The occurrence of symptomatic hypoadrenalism w as definite in three patients and probable in one. Most patients died of progressive malignant disease accompanied by escape from hormonal c ontrol by ketoconazole. The median survival duration of the group was 19 weeks (range, 1 to 154). Conclusion: Ketoconozole results in bioche mical and hormonal improvement for most patients with ECS. It has few adverse effects, but may impair the cortisol response to stress. For t hat reason, replacement corticosteroids should be considered for patie nts with hormonal response, and moderate- to high-dose corticosteroids should be given for any potential stress situations. The ultimate con trol of the syndrome is dependent on successful treatment of the under lying tumor. (C) 1995 by American Society of Clinical Oncology.