Purpose: To evaluate the safety and efficacy of ketoconazole treatment in the management of patients with paraneoplastic Cushing's syndrome (CS) secondary to ectopic adrenocorticotropin (ACTH) production by malignant neoplasms (ECS).
Patients and methods: A retrospective chart review was undertaken for 15 consecutive patients with ECS treated with ketoconazole. Strict criteria were defined for diagnosis of ECS and for clinical, biochemical, and hormonal responses.
Results: There were four women and 11 men with a median age of 59 years (range, 44 to 84). Eleven patients had primary lung cancer (nine small-cell [SCLC], one mixed SCLC/non-SCLC, and one non-SCLC); two had carcinoid tumors (one bronchial, one pancreatic); one had hepatocellular carcinoma; and one had medullary carcinoma of the thyroid. Eight patients had ECS diagnosed at tumor presentation. Clinical findings included proximal muscle weakness (n = 10), peripheral edema (n = 8), and hypertension (n = 8). Biochemical abnormalities included hypokalemia (n = 14), metabolic alkalosis (n = 13), and new or worsened diabetes mellitus (n = 10). Patients received ketoconazole in dosages of 400 to 1,200 mg/d titrated by changes in urinary free-cortisol (UFC) levels for a median duration of 26 days (range, 3 to 1,059), and nine also received chemotherapy with ketoconazole. 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 was definite in three patients and probable in one. Most patients died of progressive malignant disease accompanied by escape from hormonal control by ketoconazole. The median survival duration of the group was 19 weeks (range, 1 to 154).
Conclusion: Ketoconazole results in biochemical and hormonal improvement for most patients with ECS. It has few adverse effects, but may impair the cortisol response to stress. For that reason, replacement corticosteroids should be considered for patients with hormonal response, and moderate- to high-dose corticosteroids should be given for any potential stress situations. The ultimate control of the syndrome is dependent on successful treatment of the underlying tumor.