Support Care Cancer (1997) 5:22-30 © Springer-Verlag 1997 B. Chevallier A double-blind, multicentre comparison P. Cappelaere T. Splinter of intravenous dolasetron mesilate M. Fabbro J.L. Wendling and metoclopramide in the prevention of L. Cals G. Catimel nausea and vomiting in cancer patients M. Giovannini D. Khayat receiving high-dose cisplatin P. Bastit chemotherapy N. Claverie Abstract The potent serotonin re- ly more effective than metoclo- ceptor (5-HT3) antagonists are new pramide for time to first emetic highly selective agents for the pre- episode, nausea, patient satisfac- vention and control of chemothera- tion, and investigator global assess- B. Chevallier, M.D. • P. Bastit, M.D. (IE~) py-induced nausea and vomiting ment of efficacy. Males, chemo- Service d'Oncologie Médicale, that have been shown to be com- therapy-naive patients, and alco- Centre H. Becquerel, Rue d'Amiens, parable to or more effective than holics had higher response rates. F-76038 Rouen, France traditional metoclopramide regi- Dolasetron was weil tolerated, with mens. This study was designed to mild-to-moderate headache most P. Cappelaere, M.D. Centre Oscar Lambre, Lille, France compare the antiemetic efficacy of commonly reported. Twelve per- dolasetron and metoclopramide in cent of patients receiving metoclo- T. Splinter, M.D. chemotherapy-naive and non-naive pramide reported extrapyramidal University Hospital Dijksigt, Rotterdam, The Netherlands cancer patients receiving high-dose symptoms compared with 0% of cisplatin-containing chemotherapy. patients receiving dolasetron. In M. Fabbro, M.D. Centre Val d'Aurelle, This multicentre, double-blind, ran- conclusion, dolasetron mesilate was Montpellier, France domized trial compared the effica- effective for the prevention of cy and safety of single i.v. doses of CINV with high-dose cisplatin. Sin- J.L. Wendling, M.D. Hôpital Saint-Louis, Toulon, France dolasetron mesilate salt (1.2 or gle i.v. doses of dolasetron mesilate 1.8 mg/kg) and metoclopramide were more effective than 7 mg/kg L. Cals, M.D. (7 mg/kg) in 226 patients for the metoclopramide in preventing nau- Hôpital Coste Boyere, La Garde, Toulon, France prevention of acute emesis and sea and vomiting induced by highly nausea associated with the admin- emetogenic cisplatin-containing G. Catimel, M.D. Centre Léon Bérard, Lyon, France istration of high-dose ( _> 80 mg/m 2) chemotherapy. In addition, 1.8 mg/ cisplatin. Efficacy and safety were kg dolasetron mesilate consistently M. Giovannini, M.D. evaluated for 24 h. Complete re- produced the highest response Institut J. Paoli-Calmettes, Marseille, France sponses were achieved by 57%, rates and appears to be the most 48%, and 35% of patients given effective dose for further clinical D. Khayat, M.D. dolasetron mesilate 1.8 mg/kg development. Groupe Hospitalier de la Pitie-Salpetriere, (P = 0.0009 vs metoclopramide), Paris, France dolasetron mesilate 1.2 mg/kg Key words Dolasetron • N. Claverie, M.D. (P = 0.0058 vs metoclopramide), Antiemetic • Cisplatin • Hoechst Marion Roussel, Inc., and metoclopramide, respectively. Metoclopramide • 5-HT3 receptor Strasbourg, France Overall, dolasetron was significant- antagonist since uncontrolled nausea and emesis can result in seri- Introduction ous medical complications, poor quality of life, and a Chemotherapy-induced nausea and vomiting area pri- potentially life-threatening failure to continue treat- mary concern in the treatment of patients with cancer, ment [9, 28]. 23 High-dose metoclopramide (7-10mg/kg per day) Our study compared two different i.v. doses of dola- has been shown to be effective as a single agent in the setron mesilate with metoclopramide in a three-arm, treatment of cisplatin-induced emesis [16, 17] and has double-blind, randomized parallel study with three ma- been shown to be effective when administered as a con- jor objectives. The first was to determine whether sin- tinuous infusion [40]. Metoclopramide-based combina- gle-dose dolasetron mesilate (1.2 mg/kg or 1.8 mg/kg) tion antiemetic therapies have further improved the was as effective as or more effective than the approved emesis associated with cisplatin-containing chemother- regimen of metoclopramide (3 mg/kg i.v. loading dose apy [14, 25, 36]. However, none of these combination followed by a continuous 8-h infusion of 4 mg/kg) in regimens is fully effective. Furthermore, owing to its preventing emesis caused by high-dose cisplatin. The antidopaminergic properties, metoclopramide is fre- second was to compare the tolerability of dolasetron quently associated with unwanted and disabling extra- and metoclopramide, and the third was to compare pa- pyramidal reactions, and anxiety and depression [2, 4, tient satisfaction with each of the three antiemetic re- 16, 39]. gimens. The potent serotonin receptor (5-HT3) antagonists are new, highly selective agents for the prevention and control of nausea and vomiting after cytotoxic chemo- Patients and methods therapy [15, 22]. These compounds have been shown to be comparable to or more effective than traditional me- Patients toclopramide regimens [1, 18, 30, 37], and their use is not accompanied by distressing extrapyramidal side ef- From January 1992 to February 1994, 226 male and female cancer patients receiving cisplatin-containing chemotherapy were en- fects [19, 22]. Some of these new agents also offer the rolled at 13 centres throughout Europe. At 12 of these centres, convenience of once-daily dosing and can be then ad- patients received cisplatin at a dose of _> 80 mg/m2 over 3 h; at ministered in a single i.v. dose [15]. orte centre, patients received 70 mg/m2 cisplatin over 4 h. Both Dolasetron mesilate (Anzemet, Hoechst Marion chemotherapy-naive patients and those who had previously re- ceived cytotoxic chemotherapy were admitted into the study. The Roussel) is a new pseudopelletierine-derivative that is protocol for this study was approved by the appropriate institu- highly selective for 5-HT» receptors and is a potent 5- tional review boards and all patients gave written informed con- HT3 receptor antagonist [6, 13, 32]. Dolasetron is rap- sent. idly and almost completely metabolized to a more po- Patients were excluded from the study if they had a history of tent and more selective metabolite (MDL 74,156) that significant neurologieal or psychiatric illness (except alcoholism), a history of congestive heart failure, arrhythmias requiring medi- has a longer half-life than the parent compound [5, 7]. cation, heart block greater than first degree, cardiotoxicity from Development of dolasetron dosing was based on the cumulative doses of anthracyclines/anthracenediones, abnormal mesilate salt. Therefore, all references to doses reflect serum potassium or calcium concentrations, or evidence of liver that of the salt and can be adjusted to the equivalent disease. Patients who had received investigationaI drugs within 21 days of the study, chemotherapy in the 72 h before cisplatin, and base by multiplying by 0.74; thus, the dolasetron mesi- treatments that might interfere with the study results were also late doses of 1.8 and 2.4 mg/kg are equivalent to 0.9 and excluded from the trial. In addition, patients were disqualified if 1.3 mg/kg, respectively. Dose-ranging studies have sug- they experienced severe nausea or vomiting (severity of 2-4 ac- gested that i.v. dolasetron has substantial antiemetic ef- cording to the Southwest Oncology Group scale) within 24 h be- fore chemotherapy, as were those who experienced vomiting fects and is well tolerated by patients receiving moder- from any organic aetiology. ately or highly emetogenic chemotherapy [8, 23, 24, 27, 31]. These studies also showed that the dose with maxi- mal antiemetic activity was a single i.v. dose of 1.8 mg/ Study procedures kg, and that efficacy did not increase substantially with higher single i.v. doses. After pretreatment screening, eligible patients were stratified by Double-blind, randomized trials in patients un- gender and prior chemotherapy history (naive, non-naive) and dergoing high-dose cisplatin-containing chemotherapy randomly assigned to treatment. Patients received either 1.2 mg/ kg or 1.8 mg/kg dolasetron mesilate as a single i.v. dose over have confirmed dose-ranging results [3, 21, 41]. Patients 15 min, beginning 30 min before cisplatin, or metoclopramide who received a single 1.8 mg/kg dose of dolasetron me- (3 mg/kg i.v. loading dose over 15 min, 30 min before cisplatin, silate achieved significantly higher rates of complete re- followed by 4 mg/kg as a continuous 8-h infusion beginning at the sponse (no emetic episodes and no escape antiemetic same time as cisplatin). To maintain the blind nature of the study, each test drug was medication), complete or major response (_< 2 emetic diluted with sterile 0.9% NaC1 so that each patient received a to- episodes and no escape antiemetic medication), and tal infusion of 50 ml. In addition, a double-dummy administration significantly longer times to the first emetic episode technique was used. The first administration of metoclopramide than those who received 0.6 mg/kg [41]. Furthermore, (3 mg/kg) or dolasetron mesilate (1.2 or 1.8 mg/kg) began 30 min before the cisplatin infusion and consisted of a 50 ml i.v. infusion another study [21] demonstrated that a single i.v. over a period of 15 min. On the basis of body weight require- 1.8 mg/kg dose of dolasetron mesilate was more effica- ments (_< 100 kg), it was known that not more than two ampules cious than 0.6 mg/kg administered three times per day. of dolasetron or placebo and not more than two ampules of me- 24 toclopramide or placebo would be used for an individual patient. ide group and a 60% complete response rate for the dolasetron The second administration of metoclopramide (4 mg/kg) or place- mesilate 1.8 mg/kg group.