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The information presented herein extends our recent study of TTT (Trial for Triplet Antiemetic Therapy). One of our main clinical questions has been whether a 2nd generation serotonin receptor antagonist (5-HT3ra) would be superior to 1st generation 5-HT3ra when administering triplet antiemetic therapy for the prevention of chemotherapy induced nausea & vomiting (CINV), since a prior Japanese trial demonstrated palonosetron to be superior to granisetron for controlling the delayed phase of CINV induced by highly emetogenic chemotherapy (HEC) and to doublet antiemetic therapy including dexamethasone for anthracycline and cyclophosphamide containing regimens (AC). In this study, we assessed the efficacies of 1st and 2nd generation 5-HT3ra agents for use as triplet antiemetic therapy for AC, by monitoring CINV, focusing especially daily CR in the delayed phase. Between 2012 and 2015, 491 women with breast cancer receiving AC were recruited from 11 institutions in Japan, and randomly assigned to either single-dose palonosetron (0.75mg) or granisetron (40μg/kg) prior to chemotherapy on day 1, both with dexamethasone (9.9 mg intravenously) and aprepitant (125mg orally) on day 1 followed by additional doses (80mg orally) on days 2 and 3. Age, institution and habitual alcohol intake were used as stratification factors. The primary endpoint was a complete response (CR). Statistical analysis was done by Mantel-Haenszel Method. This trial was registered with UMIN000007882. All 491 patients were included in efficacy analyses (ITT): 246 patients in the palonosetron group and 245 in the granisetron group. We previously reported that the difference in CR during the delayed phase, i.e. 24 hours after the administration of AC, did not reach statistical significance (53.8% vs 58.5%) in MASCC 2016. However, daily CR in the palonosetron group was much higher than that in the granisetron group after 48 hours. Palonosetron showed better efficacy in controlling CINV during the late period of the delayed phase, i.e. 48 hours after AC administration, than granisetron as triplet antiemetic therapy for AC. The pattern of CINV reportedly shows two peaks including an acute phase caused by serotonin and a delayed phase caused by substance P, though the pattern of CINV with triplet antiemetic therapy administration might be different if the suppression of each of these peaks were to be achieved more efficiently. CINV may not be divided into two phases in the future, or the borderline area between the acute and delayed phases may require revision. The analysis of the late period of the delayed phase was ad hoc in this trial. However, when conducting studies related to CINV, it might be worthwhile to revise the borderline area between the two phases of CINV to facilitate elucidating the mechanisms underlying this potentially debilitating side effect of chemotherapy. Citation Format: Ogata H, Saito M, Tsuneizumi M, Kutomi G, Hosoya K, Kawai Y, Sugizaki K, Katsumata N, Senuma K, Kitabatake T, Suda M, Uomori T, Miura K, Kurata M, Nitta Y, Yonemoto N, Matsuoka J. Difference between 1st and 2nd generation serotonin receptor antagonists in triplet antiemetic therapy for highly emetogenic chemotherapy in breast cancer patients – according to recent multi-institutional double-blind randomized clinical research on the AC regimen [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-03.