Should There Be a Preferred Serotonin Antagonist for Antiemetic Use in Chemotherapy for Breast Cancer? Using Two Meta-Analysis Methods To Determine Whether Common Dose Differences Affect Efficacy with the Serotonin Antagonist Palonosetron.
Authors: Carleton J. , Gralla R. , Bria E. , Raftopoulos H. , Napolitano B. , Giannarelli D. , Lesser M. 
Published: December 2010

Abstract
Background: Serotonin antagonists (5-HT3) are the most frequently used antiemetics in breast cancer medical oncology. Efficacy advantages for palonosetron have been reported in 2 large randomized clinical trials (RCTs) in which the majority of patients had breast cancer, when compared with other 5-HT3 agents (ondansetron or dolasetron) in single agent trials. Additionally, in a recent 1100 patient RCT, dexamethasone-containing combination regimens with either palonosetron or granisetron were compared and showed significant efficacy advantages for the palonosetron regimen (Saito, Lancet Oncology 2009). In that this latter trial used 0.75 mg palonosetron doses, controversy remained as to the applicabilty of this trial in terms of recommending palonosetron at the 0.25mg dose as the preferred agent in its class.Objectives: We conducted two meta-analyses to address this dosing issue using 2 meta-analysis methods: individual patient data (IPD) and abstracted data (AD-literature based) involving all patients entered into all RCTs at these doses.Methods: A literature search identified 8 RCTs with palonosetron 0.25mg and 0.75mg treatment arms. The primary endpoint was Complete Response (CR, no vomiting and no rescue) over days 1-5 after chemotherapy. Sensitivity analyses by setting (highly or moderately emetic chemotherapy), and a meta-regression analysis for predictive factors were undertaken. Odds Ratios and Relative Risks with 95% confidence intervals were derived for IPD and AD analyses, respectively. Interaction and Cochrane Q-Heterogeneity tests were performed.Results: 1947 subjects in the 8 RCTs were identified (4 trials with highly emetic chemotherapy "HEC" and 4 trials with moderately emetic chemotherapy "MEC." 6 trials used IV palonosetron; 2 used the oral form). No significant heterogeneity was found for Complete Response or Complete Control. Remarkably similar emetic outcomes were found for all endpoints at both doses. No significant differences were found between palonosetron doses, regardless of: 1) meta-analysis approach (IPD or AD) and for either Complete Response or Complete Control; 2) acute or delayed emesis; 3) HEC or MEC. Results for the primary endpoint are in the table. No significant toxicity differences were found.PALONOSETRON DOSES: 0.25mg versus 0.75mgIPD Meta-Analysis Method: Odds Ratio (95% Confidence Interval)AD Meta-Analysis Method: Relative Risk (95% Confidence Interval)Complete Response (days 1-5, no vomiting or rescue)1.00 (0.83-1.20)0.998 (0.909-1.097) Conclusions: Both palonosetron doses provide very similar efficacy for all endpoints, in HEC and MEC. Both meta-analysis methods yielded the same result, and add confidence to the conclusion of similar efficacy for both palonosetron doses. These findings indicate that either dose is appropriate for antiemetic treatment in many breast cancer settings. In that the randomized trial comparing 5HT3 antagonist + dexamethasone combinations gave a non-standard dose of palonosetron, these meta-analyses support the use of palonosetron as the serotonin antagonist of choice at frequently used doses.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5045.