Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial

Summary

Background

The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy.

Methods

We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m² on day one of each 21 day cycle plus oral capecitabine 1000 mg/m² twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m² on day one of each 21 day cycle plus oral S-1 40–60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m² on day one of each 21 day plus oral S-1 40–60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546.

Findings

Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5–56·3) in the adjuvant-CapOx group, 56·5% (51·0–61·7) in the adjuvant-SOX group, and 59·4% (53·8–64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61–0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68–1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3–4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported.

Interpretation

Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer.

Funding

National Key Research and Development Program of China, Beijing Scholars Program 2018–2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical.

Translation

For the Chinese translation of the abstract see Supplementary Materials section.

Introduction

Globally, gastric cancer is the fifth most common malignancy, and it is the third deadliest cancer.¹ Most patients with gastric cancer are from east Asia, and 47% of patients are from China. South America and some European countries also have high incidence rates.2, 3, 4, 5, 6 Patients in high-incidence areas are often diagnosed at an advanced stage and have a poor prognosis.7, 8, 9, 10, 11, 12 Improving the prognosis of these patients is necessary but challenging.

The standard treatment for locally advanced gastric cancer is D2 gastrectomy, combined with perioperative chemotherapy.10, 11 Capecitabine combined with oxaliplatin (CapOx) is recommended for postoperative therapy.3, 10, 11, 13 Perioperative therapy with epirubicin, cisplatin, and fluorouracil or fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with cT2–4 or N+ and M0 tumours is also recommended in National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology guidelines;3, 11, 14, 15 however, this approach is not recognised worldwide.10, 13 The optimal sequence and combination of perioperative treatment is under debate (eg, surgery first with postoperative adjuvant chemotherapy vs neoadjuvant chemotherapy first followed by surgery and adjuvant chemotherapy). Furthermore, the clinical benefit of neoadjuvant chemotherapy in patients with obvious local tumour invasion or lymph node metastasis (ie, cT4a N+ M0 or cT4b Nany M0 disease) remains undetermined.

Fluoropyrimidine-based chemotherapies remain the backbone of treatment for gastric cancer, including two oral derivatives: S-1 and capecitabine.16, 17 S-1, widely administered for gastric cancer in Asia,16, 18 is associated with fewer adverse events compared with fluorouracil,¹⁹ and it is increasingly being used in Europe and North America. Different perioperative regimens have been observed in many trials, including adjuvant S-1 with oxaliplatin (SOX) and neoadjuvant S-1 with cisplatin.20, 21, 22 Patients who received S-1 regimens tolerated the drug well, and the regimens showed good efficacy in both perioperative and metastatic trials,²³ whereas 99% of patients who received adjuvant CapOx in the CLASSIC trial²¹ had adverse events. Therefore, the potential benefits of SOX—fewer adverse events and better efficacy—in neoadjuvant or adjuvant chemotherapy is worth exploring in phase 3 studies.

Research in context

Evidence before this study

We searched PubMed and the abstracts of the American Society of Clinical Oncology, European Society for Medical Oncology, and Chinese Society of Clinical Oncology major oncology congresses with the keywords including “D2” OR “locally advanced” AND “gastric cancer” AND “perioperative” for article published between Jan 1, 2000, and Dec 31, 2020. We restricted the results to clinical trials published in English. Different perioperative regimens have been assessed in many trials; however, the optimal modality of perioperative therapy for patients with T4 stage, resectable, locally advanced gastric cancer is unknown. Perioperative administration of S-1 and oxaliplatin have not been reported in patients with resectable locally advanced gastric cancer.

Added value of this study

This study shows the superior 3-year disease-free survival in patients with T4 stage, locally advanced, gastric cancer who were scheduled for D2 gastrectomy and who received perioperative S-1 and oxaliplatin (SOX) compared with adjuvant capecitabine and oxaliplatin (CapOx). Furthermore, in our non-inferiority analysis, adjuvant-SOX was as active as standard treatment with adjuvant-CapOx.

Implications of all the available evidence

Perioperative-SOX is efficacious and has a manageable safety profile, and it could be considered as a new treatment option for patients with resectable locally advanced T4 gastric cancer.

To our knowledge, no large-scale randomised trial has been done to compare perioperative SOX with standard postoperative CapOx, and the efficacy and safety of SOX for adjuvant chemotherapy requires investigation in a prospective trial. The aim of this study was to assess the efficacy of perioperative-SOX versus adjuvant-CapOx, and to identify whether adjuvant-SOX was non-inferior to adjuvant-CapOx with regard to mortality and perioperative complications. The primary hypotheses were that perioperative-SOX would improve the disease-free survival compared with adjuvant-CapOx and that adjuvant-SOX was non-inferior to adjuvant-CapOx.