Palonosetron is a second-generation 5-hydroxytryptamine 3 (5-HT(3))-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.
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 microg/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.
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.
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.
Taiho Pharmaceutical (Tokyo, Japan).