Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial

Summary

Background

Palonosetron is a second-generation 5-hydroxytryptamine 3 (5-HT₃)-receptor antagonist that has shown better efficacy than ondansetron and dolasetron in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy, and similar efficacy to ondansetron in preventing CINV in patients receiving highly emetogenic chemotherapy. In this phase III, multicentre, randomised, double-blind, double-dummy, stratified, parallel-group, active-comparator trial, we assessed the efficacy and safety of palonosetron versus granisetron for chemotherapy-induced nausea and vomiting, both of which were administered with dexamethasone in patients receiving highly emetogenic chemotherapy.

Methods

Between July 5, 2006, and May 31, 2007, 1143 patients with cancer who were receiving highly emetogenic chemotherapy (ie, cisplatin, or an anthracycline and cyclophosphamide combination [AC/EC]) were recruited from 75 institutions in Japan, and randomly assigned to either single-dose palonosetron (0·75 mg), or granisetron (40 μg/kg) 30 min before chemotherapy on day 1, both with dexamethasone (16 mg intravenously) on day 1 followed by additional doses (8 mg intravenously for patients receiving cisplatin or 4 mg orally for patients receiving AC/EC) on days 2 and 3. A non-deterministic minimisation method with a stochastic-biased coin was applied to the randomisation of patients. Covariates known to effect emetic risk, such as sex, age, and type of highly emetogenic chemotherapy, were used as stratification factors of minimisation to ensure balance between the treatment groups. Primary endpoints were the proportion of patients with a complete response (defined as no emetic episodes and no rescue medication) during the acute phase (0–24 h postchemotherapy; non-inferiority comparison with granisetron) and the proportion of patients with a complete response during the delayed phase (24–120 h postchemotherapy; superiority comparison with granisetron). The non-inferiority margin was predefined in the study protocol as a 10% difference between groups in the proportion of patients with complete response. The palonosetron dose of 0·75 mg was chosen on the basis of two dose-determining trials in Japanese patients. All patients who received study treatment and highly emetogenic chemotherapy were included in the efficacy analyses (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00359567.

Findings

1114 patients were included in the efficacy analyses: 555 patients in the palonosetron group and 559 patients in the granisetron group. 418 of 555 patients (75·3%) in the palonosetron group had complete response during the acute phase compared with 410 of 559 patients (73·3%) in the granisetron group (mean difference 2·9% [95% CI −2·70 to 7·27]). During the delayed phase, 315 of 555 patients (56·8%) had complete response in the palonosetron group compared with 249 of 559 patients (44·5%) in the granisetron group (p<0·0001). The main treatment-related adverse events were constipation (97 of 557 patients [17·4%] in the palonosetron group vs 88 of 562 [15·7%] in the granisetron group) and raised concentrations of serum aminotransferases (aspartate aminotransferase: 24 of 557 [4·3%] vs 34 of 562 [6·0%]; alanine aminotransferase: 16 of 557 [2·9%] vs 33 of 562 [5·9%]); no grade 4 main treatment-related adverse events were reported.

Interpretation

When administered with dexamethasone before highly emetogenic chemotherapy, palonosetron exerts efficacy against chemotherapy-induced nausea and vomiting which is non-inferior to that of granisetron in the acute phase and better than that of granisetron in the delayed phase, with a comparable safety profile for the two treatments.

Funding

Taiho Pharmaceutical (Tokyo, Japan).

Introduction

Nausea and vomiting are among the most problematic symptoms experienced by patients with cancer who are receiving chemotherapy. 5-hydroxytryptamine 3 (5-HT₃)-receptor antagonists are now the standard therapy for preventing chemotherapy-induced nausea and vomiting (CINV), because emesis is caused by stimulation of 5-HT₃ receptors located on vagal afferents by serotonin released from enterochromaffin cells in the small intestine.1, 2 The first-generation 5-HT₃-receptor antagonists, ondansetron, granisetron, dolasetron, and tropisetron, show considerable efficacy in preventing acute CINV, with acute responses for single agents ranging from 50% to 70%.³ However, despite prophylactic treatment with these agents, almost half of patients continue to have both acute and delayed CINV after moderately or highly emetogenic chemotherapy.4, 5, 6, 7, 8, 9 Therefore, control methods of CINV still need to be improved.

The acute responses seen with first-generation 5-HT₃-receptor antagonists after moderately or highly emetogenic chemotherapy are further increased when used in combination with dexamethasone.10, 11, 12, 13, 14 The second-generation 5-HT₃-receptor antagonist palonosetron, a potent and highly selective 5-HT₃-receptor antagonist with strong binding affinity to the receptor and a long plasma-elimination half-life (about 40 h), has shown efficacy as a single-dose treatment in preventing both acute and delayed CINV associated with moderately and highly emetogenic chemotherapy.15, 16, 17, 18

Two phase II studies done in Japan reported that no dose–response relation between 0·075 mg, 0·25 mg, and 0·75 mg of palonosetron was noted for complete response (defined as no emetic episodes and no rescue medication) during the acute phase, which was assessed as a primary endpoint.19, 20 However, a clear dose–response relation (p=0·048) was noted during daily assessment over a 120-h study period when 0·075 mg, 0·25 mg, and 0·75 mg doses of palonosetron were given with dexamethasone to prevent CINV associated with highly emetogenic chemotherapy, such as cisplatin, indicating a significant difference in response with the 0·075 mg dose compared with the two higher doses.¹⁹ As an additional noteworthy finding, a subgroup analysis of the patients receiving anthracyclines (doxorubicin or epirubicin) with a cyclophosphamide-containing regimen (AC/EC) showed non-significant dose-dependent increases in complete response, with more than a 10% difference in the highest complete response recorded in the 0·75 mg dose group compared with the 0·25 mg and 0·075 mg dose groups, both in the delayed and overall phases.²⁰ Three doses of palonosetron were well-tolerated and did not show any increase in adverse effects related to dose. The tendency for better efficacy with the 0·75-mg dose than with the other doses and the excellent safety profile in these trials suggested that palonosetron 0·75 mg could be the recommended dose for use in a trial. A 40 μg/kg dose of granisetron is the approved clinical dose²¹ and the most common therapy in Japan.

We did a phase III trial to assess the efficacy and safety of palonosetron 0·75 mg versus granisetron 40 μg/kg, administered with dexamethasone, for preventing acute and delayed CINV after highly emetogenic chemotherapy. The aim of this trial was to establish the best base regimen for control of CINV, especially in patients receiving highly emetogenic chemotherapy.