A multicentre, randomised trial has shown that single intravenous (IV) doses of dolasetron mesylate, a highly selective serotonin receptor antagonist, are as safe and effective as granisetron in preventing nausea and vomiting in patients receiving highly emetogenic, cisplatin-containing chemotherapy.
Previous dose-ranging studies with dolasetron have confirmed its substantial anti-emetic effect in patients receiving moderately or highly emetogenic cisplatin chemotherapy. These studies have also demonstrated that the minimum effective dosage was a single IV dose of 1.8 mg/kg and that higher single IV doses did not significantly increase the efficacy of the drug.
The current study, carried out by the European Dolasetron Comparative Study Group, is the first large, multicentre trial to compare two different IV doses of dolasetron against granisetron, a drug that is well-established as a safe and effective anti-emetic for patients receiving cisplatin chemotherapy. This study is also the first large, multicentre trial to stratify prospectively patients according to gender and prior history of chemotherapy before randomisation to treatment.
A total of 474 patients in 29 centres were randomised to receive dolasetron at a dose of 1.8 or 2.4 mg/kg, or a single 3-mg IV dose of granisetron, 30 minutes before the start of chemotherapy. Cisplatin was administered intravenously at a dose of 80 mg/m2 or greater over a three-hour period. Patients were then monitored for 24 hours for timing and number of emetic episodes, time to administration of escape anti-emetic medication, severity of nausea, and safety.
All three treatments were effective in controlling nausea and vomiting after cisplatin chemotherapy. The rates of complete response, defined as no emetic episodes and no use of escape anti-emetic medication in the 24-hour observation period, were 54% and 47% in the 1.8 and 2.4 mg/kg dolasetron groups, respectively, and 48% in the granisetron group, according to Dr. B. Audhuy and his colleagues, who reported the results of their study in a 1996 issue of the European Journal of Cancer.
For complete plus major response, defined as two or fewer emetic episodes and no use of escape medication, rates were 62% for both the 1.8 and 2.4 mg/kg dolasetron groups and 63% for the granisetron group.
The investigators said that while there were no significant differences in response rates among the three anti-emetic regimens, the 1.8 mg/kg dolasetron dose produced numerically superior responses for complete response, time to first emetic episode and use of rescue medication. Moreover, for all endpoints, there was no greater efficacy for the 2.4 mg/kg dose of dolasetron over the 1.8 mg/kg dose.
Subgroup analyses revealed that males, patients naïve to chemotherapy and patients with a history of alcohol abuse were more likely to demonstrate a complete anti-emetic response. These findings are similar to those of previous studies.
The most common adverse effect in this study was headache and diarrhea, which were primarily mild to moderate in intensity. The rates of headache were 28% and 22% in the 1.8 and 2.4 mg/kg dolasetron groups, respectively, and 23% in the granisetron group. Diarrhea occurred in 13% and 11% of patients in the 1.8 and 2.4 mg/kg dolasetron groups, respectively, and in 6% of patients in the granisetron group.
Asymptomatic, treatment-emergent electrocardiographic changes, including minor increases in QRS duration, and PR and QTc intervals, were noted in all three treatment groups. None of the ECG changes were associated with any clinically significantly cardiovascular events.
Given the similar efficacy of the three treatment regimens and because there was no additional benefit with the higher dolasetron dose, the invesigators concluded that the 1.8 mg/kg dose appears to optimal for further clinical development.
Audhuy B, Cappelaere P, Martin M, et al. A double-blind, randomised comparison of the anti-emetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high dose cisplatin chemotherapy, Eur J Cancer, vol. 32A, No. 5, pp. 807-813, 196.
