Double-blind, multicenter, randomized trial to compare the effect of two doses of adrenocorticotropic hormone versus placebo in controlling delayed emesis after high-dose cisplatin in adult patients with cancer

PURPOSE: To compare, in a double-blind, placebo-controlled, randomized trial, the efficacy of two different doses of the depot formulation of adrenocorticotropic hormone (ACTH) in controlling delayed emesis after cisplatin. PATIENTS AND METHODS: One hundred fifty-two patients were enrolled onto the study. On day 1, all patients received cisplatin (60 to 120 mg/m2) and a combination of dexamethasone 20 mg plus ondansetron or metoclopramide to prevent acute emesis. On day 2 (24 hours after cisplatin administration), patients were randomized to receive placebo, or ACTH 1 mg intramuscularly (I.M.), or ACTH 2 mg I.M. plus one additional dose of 1 mg on day 4. Details of vomiting, nausea, and adverse effects were recorded daily for every 24-hour period from day 2 to day 6. In a subset of patients, serum cortisol levels were measured between 20 and 72 hours after cisplatin administration. RESULTS: One hundred fifty patients were assessable. Over the 5 days of the study, delayed vomiting occurred less frequently in the patients treated with ACTH 2 mg plus 1 mg than in those treated with ACTH 1 mg or placebo (28%, 38%, and 65%, respectively; P = .001). The greatest observed differences were seen on days 2 (24 to 48 hours; P = .01) and 3 (48 to 72 hours; P = .01). On days 4, 5, and 6 (96 to 144 hours), no significant differences were observed among the three arms. The severity of delayed emesis expressed as the mean number of emetic episodes per day was 0.48, 0.70, and 0.80, respectively (P = .002). Patients treated with the higher dose of ACTH had the least nausea on day 3 (P = .02) and day 4 (P = .03). Adrenal cortisol secretion rapidly increased after ACTH injection, but was suppressed for approximately 44 hours in the placebo group. Toxicity was mild and transient in all groups. CONCLUSION: ACTH reduces the incidence and severity of delayed vomiting and nausea after cisplatin. A dose of 2 mg 24 hours after cisplatin is better than one of 1 mg. Whether the activity of ACTH is mediated only by adrenal corticosteroids needs to be verified.