Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial

Abstract

Importance: Perioperative chemotherapy is a potential treatment for locally advanced gastric cancer. However, the optimal chemotherapy regimen remains unknown.

Objective: To investigate the safety and efficacy of S-1 plus oxaliplatin (SOX) vs fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as a perioperative chemotherapy regimen for patients with locally advanced gastric cancer.

Design, setting, and participants: In this phase 3, open-label, multicenter, randomized clinical trial, patients from 12 Chinese hospitals were enrolled between June 2011 and August 2016, with a last follow-up date of September 2019. The primary tumor was evaluated as either invading the serosa or the adjacent structures with or without metastatic lymph nodes, and with no evidence of distant metastases. Data were analyzed from December 2019 to June 2020.

Interventions: Patients were randomly assigned (1:1) to receive either 6 perioperative (2-4 preoperative and 2-4 postoperative) 3-week cycles of 130 mg/m2 oxaliplatin on day 1 and 80 to 120 mg/d S-1 orally daily for 2 weeks (SOX) or 130 mg/m2 oxaliplatin, 400 mg/m2 fluorouracil, 400 mg/m2 leucovorin, and 2400 mg/m2 fluorouracil as 46-hour infusion on day 1 (FOLFOX).

Main outcomes and measures: The primary end point was 3-year overall survival (OS). An absolute noninferiority margin of -8% was chosen.

Results: A total of 583 patients were enrolled; 293 were randomized to the SOX group and 290 were randomized to the FOLFOX group. Twelve patients (2.1%) refused preoperative chemotherapy (5 patients in the SOX group and 7 patients in the FOLFOX group), leaving a total of 288 patients in the SOX group (median [range] age, 61 [24 to 78] years; 197 men [68.4%]) and 283 patients in the FOLFOX group (median [range] age, 62 [24 to 80] years; 209 men [73.9%]) who received preoperative chemotherapy. The 3-year OS rate was 75.2% (95% CI, 70.3% to 80.5%) in the SOX group and 67.8% (95% CI, 62.5% to 73.5%) in the FOLFOX group. The absolute difference of 3-year OS rate between the 2 groups was 7.4% (95% CI, -0.1% to 14.9%), which was greater than the prespecified noninferiority margin (-8%) and showed the noninferiority of perioperative chemotherapy with SOX compared with FOLFOX.

Conclusions and relevance: In this randomized clinical trial, SOX was noninferior to FOLFOX as perioperative chemotherapy for patients with locally advanced gastric cancer and could be recommended as an alternative treatment for these patients in Asia.

Trial registration: ClinicalTrials.gov Identifier: NCT01364376.

Figure 1.. Trial Enrollment Flowchart

FOLFOX indicates fluorouracil, leucovorin, and oxaliplatin; SOX, S-1 plus oxaliplatin.

Figure 2.. Kaplan-Meier Survival Estimates

A, The 3-year overall survival rate was 75.2% for the S-1 plus oxaliplatin (SOX) group and 67.8% for the fluorouracil, leucovorin, and oxaliplatin (FOLFOX) group (hazard ratio, 0.84; 95% CI, 0.63-1.13). B, The 3-year progression-free survival rate was 69.3% for the SOX group and 64.5% for the FOLFOX group (HR, 0.95; 95% CI, 0.72-1.25).

Figure 3.. Subgroup Analysis of Overall Survival (OS) in the S-1 Plus Oxaliplatin (SOX) Group Compared With the Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) Group

Hazard ratios (HRs) for death and P values show no significance of heterogeneity of treatment effect according to the sex, age, Eastern Cooperative Oncology Group (ECOG) status, and primary tumor location.