Perioperative chemotherapy of oxaliplatin combined with S-1 (SOX) versus postoperative chemotherapy of SOX or oxaliplatin with capecitabine (XELOX) in locally advanced gastric adenocarcinoma with D2 gastrectomy: A randomized phase III trial (RESOLVE trial)

Abstract Background Surgery alone is not sufficient to achieve satisfactory prognosis for locally advanced gastric cancer (LAGC), and perioperative therapies have been proposed to improve survival outcome. However, the optimal modality and regimen of perioperative chemotherapy are yet to be identified. This study compared the efficacy and safety of SOX as perioperative chemotherapy versus SOX or XELOX as postoperative chemotherapy after D2 gastrectomy in patients with LAGC. Methods The RESOLVE Trial is a three-arm, randomized, multicenter, open-label phase III trial. Patients with stage cT4a/N+M0 or cT4bNxM0 gastric or gastro-esophageal junction adenocarcinoma were enrolled. All patients received standard gastrectomy with D2 lymphadenectomy. Arms A and B respectively received 8 cycles of adjuvant XELOX (capecitabine 1000 mg/m2, bid, d1-14, oxaliplatin 130 mg/m2, d1, q3W) or SOX (TS-1: 40-60 mg bid, d1-14, oxaliplatin: 130 mg/m2 d1, q3W). Arm C received 3 cycles of neoadjuvant SOX and 5 cycles of adjuvant SOX followed by 3 cycles of TS-1. The primary endpoint was 3-year disease-free survival rate (3yDFS%) in the mITT population. Results A total of 1094 patients were randomized between 08/2012 and 02/2017, 364/365/365 in arm A/B/C, and 454 recurrences/deaths were observed by 07/2019. Baseline characteristics were similar between arms (overall, male 75.2%; median age 60.0 years; GEJ 36.5%). Peri-operative SOX improved 3yDFS% compared with post-operative XELOX (3yDFS%, 62.0% in Arm C, 54.8% in Arm A; HR 0.79, 95%CI [0.62-0.99]; p = 0.045). Post-operative SOX was non-inferior to post-operative XELOX (3yDFS%, 60.3% in Arm B, 54.8% in Arm A; HR 0.85, 95%CI [0.67-1.07]; p = 0.162). Resection rate was 90.4% in Arm A, 92.7% in Arm B, and 85.5% in Arm C, respectively. Thirty-day mortality rate was all 0.9% for Arms A, B and C. Conclusions Perioperative SOX is superior to post-operative XELOX while post-operative SOX is non-inferior to post-operative XELOX for LAGC after D2 gastrectomy. It provides the evidence of perioperative SOX in LAGC. Clinical trial identification NCT01534546. Legal entity responsible for the study The authors. Funding Taiho Pharmaceutical Co., Ltd. Disclosure All authors have declared no conflicts of interest.