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Previous Volume 340:190-195 January 21, 1999 Number 3 Next

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ABSTRACT

Background The localization of substance P in brain-stem regions associated with vomiting, and the results of studies in ferrets, led us to postulate that a neurokinin-1–receptor antagonist would be an antiemetic in patients receiving anticancer chemotherapy.

Methods In a multicenter, double-blind, placebo-controlled trial involving 159 patients who had not previously received cisplatin, we evaluated the prevention of acute emesis (occurring within 24 hours) and delayed emesis (occurring on days 2 to 5) after a single dose of cisplatin therapy (70 mg or more per square meter of body-surface area). Before receiving cisplatin, all the patients received granisetron (10 µg per kilogram of body weight intravenously) and dexamethasone (20 mg orally). The patients were randomly assigned to one of three treatments in addition to granisetron and dexamethasone: 400 mg of an oral trisubstituted morpholine acetal (also known as L-754,030) before cisplatin and 300 mg on days 2 to 5 (group 1), 400 mg of L-754,030 before cisplatin and placebo on days 2 to 5 (group 2), or placebo before cisplatin and placebo on days 2 to 5 (group 3). Additional medication was available at any time to treat occurrences of vomiting or nausea.

Results In the acute-emesis phase, 93 percent of the patients in groups 1 and 2 combined and 67 percent of those in group 3 had no vomiting (P<0.001). In the delayed-emesis phase, 82 percent of the patients in group 1, 78 percent of those in group 2, and 33 percent of those in group 3 had no vomiting (P<0.001 for the comparison between group 1 or 2 and group 3). The median nausea score in the delayed-emesis phase was significantly lower in group 1 than in group 3 (P=0.003). No serious adverse events were attributed to L-754,030.

Conclusions The neurokinin-1–receptor antagonist L-754,030 prevents delayed emesis after treatment with cisplatin. Moreover, combining L-754,030 with granisetron plus dexamethasone improves the prevention of acute emesis.

Source Information

From the Simon–Williamson Clinic, Birmingham, Ala. (R.M.N.); Merck Research Laboratories, Rahway, N.J. (R.R.R., A.D.C., B.J.G.); Ochsner Medical Center, New Orleans (R.J.G.); Memorial Sloan-Kettering Cancer Center, New York (M.G.K.); St. Elizabeth's Medical Center, Boston (P.J.H.); Capital Comprehensive Cancer Care Clinic, Jefferson City, Mo. (A.K.); Roswell Park Cancer Institute, Buffalo, N.Y. (H.K.); Salem Research Group, Winston-Salem, N.C. (T.H.G.); Research Medical Center, Kansas City, Mo. (K.P.); and Fletcher Allen Health Center, Burlington, Vt. (S.M.G.).

Address reprint requests to Dr. Gertz at Clinical Pharmacology, Merck Research Laboratories, RY33-600, Rahway, NJ 07065, or at barry_ gertz{at}merck.com.

Full Text of this Article

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Prevention of Cisplatin-Induced Emesis by a Neurokinin-1–Receptor Antagonist
Roila F., Ballatori E., Del Favero A., Navari R. M., Carides A. D., Gertz B. J.
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N Engl J Med 1999; 340:1926-1928, Jun 17, 1999. Correspondence

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