Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving chemotherapy with doxorubicin or cyclophosphamide

Abstract

Selective 5-HT3 antagonists have proven to be safe and effective for the prevention of chemotherapy-induced nausea and vomiting. Dolasetron is a new highly selective addition to this class of antiemetics that has been shown to have significant antiemetic activity in patients receiving cisplatin-containing regimens. This pilot study was designed to evaluate the antiemetic efficacy of dolasetron in cancer patients receiving doxorubicin and/or cyclophosphamide. This study used an open-label, non-randomized design to evaluate the efficacy and safety of intravenous dolasetron in the prevention of emesis in patients receiving doxorubicin (25-75 mg/m2) and/or cyclophosphamide (400-1200 mg/m2). Sixty-nine patients received a single, intravenous dose of dolasetron over 15-20 min beginning 30 min prior to the start of chemotherapy. Dose levels of dolasetron studied were: 0.3, 0.6, 1.2, 1.8 and 2.4 mg/kg. Patients were monitored for emesis, nausea and adverse events for 24h after the start of chemotherapy. Overall, 61% of patients experienced complete control of emesis. No significant trend towards increased antiemetic efficacy (P = 0.076) or nausea control with increasing dolasetron dose was noted, although the power to detect significant differences was limited by the small number of patients on the 0.3-mg/kg and 2.4-mg/kg dose levels. Age, gender, and type of chemotherapy were significant predictors of complete antiemetic control. Adverse events were generally mild and included headache, chills, lightheadedness, fever, diarrhea, dizziness, and asymptomatic prolongation of ECG intervals. Intravenous dolasetron is safe and effective in the prevention of emesis induced by doxorubicin and/or cyclophosphamide.

Open-label comparison of the antiemetic efficacy of single intravenous doses of dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy

“…As in previous dolasetron studies [14,15,23,30,31] and other 5-HT 3 antagonists trials [32,33], tiredness and headache were the most commonly reported adverse events. As in previous studies with 5-HT 3 receptor antagonists [3,13,15,22,23,31,32,34], we also noted asymptomatic changes in ECG intervals. None was of clinical consequence or required medical treatment.…”

“…Patients in the 2.4-mg/kg group may have been more ill and therefore more difficult to manage. This could explain the poorer results in this dosage level compared to the 1.8-mg/kg group, although a decreased effect with 2.4 mg/kg has also been noted in adults [13,22,23]. As in adults, MDL 74,156, the reduced metabolite of dolasetron, appeared rapidly in the plasma of pediatric cancer patients.…”

“…We concluded that this dose level is inappropriate for the management of nausea and vomiting in children. This dose level is also less effective in adult patients receiving chemotherapy [23]. In the remaining two dose levels studied, treatment failure was noted in approximately half of patients.…”

“…In addition, preliminary data in adults suggest that a single intravenous dose of dolasetron is more effective than multiple smaller doses [14]. Meanwhile, these studies have demonstrated that the safety profile of dolasetron is comparable to other selective 5-HT 3 antagonists such as ondansetron, granisetron, and tropisetron [7,23]. Very little information, however, was available on the potential utility and safety of dolasetron in children [18].…”

Consensus recommendations for the prevention of vomiting and nausea following high-emetic-risk chemotherapy

“…Substantial evidence supports these conclusions, particularly with ondansetron, the first 5-HT 3 receptor antagonist developed. Early clinical trials of intravenous ondansetron with cisplatin explored a variety of schedule-related issues, including variable dosing intervals, number of doses, and schedules incorporating continuous infusion [22,50]. In general, these studies demonstrated that shortening the dosing interval or increasing the number of doses did not improve efficacy.…”