Possible mechanisms of serotonin and aprepitant actions in chemotherapy induced nausea and vomiting (CINV): Insights into the mechanisms of serotonin and aprepitant actions in CINV—According to recent multi-institutional double-blind randomized clinical research on the AC regimen.

Abstract

6587 Background: One of our interests has been whether palonosetron(P) would be superior to granisetron(G) when administering triplet antiemetic therapy for the prevention of CINV, since a prior trial demonstrated P to be superior to G for controlling CINV induced by highly emetogenic chemotherapy (HEC) in doublet therapy. In this study(TTT; trial for antiemetic therapy), we assessed the efficacies of P and G for use as triplet antiemetic therapy for AC, by monitoring CINV, focusing complete response (CR; no vomiting and no rescue medicine) in the delayed phase. The primary endpoint of TTT was a CR during the delayed phase with 5-HT3ra plus dexamethasone and aprepitant administration for AC. The purpose of gaining insights into the possible mechanism of action of aprepitant and P was to obtain ideas for the next strategy against CINV. Methods: Between 2012 and 2015, 491 breast cancer receiving AC were recruited from 11 institutions, and randomly assigned to either single-dose P(0.75mg) or G(40μg/kg) prior to AC on day 1, both with dexamethasone (9.9 mg) and aprepitant (125mg) on day 1 followed by additional doses (80mg) on days 2 and 3. Age, institution and habitual alcohol intake were used as stratification factors. The primary endpoint was a CR. Results: All 491 patients were included in efficacy analyses: 246 patients in the group P and 245 in the group G. The difference in CR during the delayed phase, i.e. 24 hrs after the administration of AC, did not reach statistical significance, however, there was a remarkable difference between 48 and 72 hrs in the day-to-day analysis(p < 0.02). Conclusions: P showed better efficacy in controlling CINV between 48 to 72 hours after AC, than G as triplet antiemetic therapy for AC. We can reasonably speculate that the influence of serotonin has two peaks (0-24 hrs and 48-72 hrs). For controlling CINV in the delayed phase, not only an NK1 receptor antagonist but also administering a 5-HT3ra with long life should be considered until 72 hrs after HEC. Clinical trial information: UMIN 000007882.