Intraperitoneal and Intravenous Paclitaxel Plus S-1 for Gastric Cancer With Peritoneal Metastasis: A Phase 3 Randomized Clinical Trial.

Importance: Gastric cancer with peritoneal metastasis has a poor prognosis, and survival with commonly used regimens, such as intravenous paclitaxel plus S-1 (an oral fluoropyrimidine), remains limited. Whether intraperitoneal paclitaxel, which achieves high drug concentrations in the peritoneal cavity, can improve survival has not been established in a phase 3 randomized clinical trial. Objective: To determine whether adding intraperitoneal paclitaxel to intravenous paclitaxel plus S-1 improves overall survival in gastric cancer with peritoneal metastasis. Design, Setting, and Participants: This multicenter, open-label, randomized phase 3 superiority clinical trial (DRAGON-01) was conducted in 9 hospitals in China. Enrollment went from May 2017 to March 2022, and the data cutoff was March 11, 2025. The trial included adults with gastric adenocarcinoma and laparoscopically confirmed peritoneal metastasis without extraperitoneal metastases or prior systemic therapy. Interventions: The IP group received paclitaxel, 50 mg/m2, intravenously plus 20 mg/m2, intraperitoneally on days 1 and 8 of each 21-day cycle, with oral S-1, 80 mg/m2, once per day on days 1 to 14. The PS group received paclitaxel, 70 mg/m2, intravenously on days 1 and 8, with S-1 80, mg/m2, once per day on days 1 to 14. Main Outcomes and Measures: The primary end point was overall survival. Secondary end points included progression-free survival and safety. Results: Among 222 treated patients (median [IQR] age, 59 [48-66] years; 104 [46.8%] female individuals and 118 [53.2%] male individuals), median (IQR) follow-up was 72.2 (50.8-80.2) months. Of 246 who were assessed, 238 (96.7%) were randomized 2:1 to receive intraperitoneal and intravenous paclitaxel plus oral S-1 (IP group) or intravenous paclitaxel plus S-1 (PS group); 222 (90.2%) received treatment (primary analysis). Median overall survival was 19.4 months (95% CI, 17.1-22.9) in the IP group and 13.9 months (95% CI, 10.3-16.1) in the PS group (hazard ratio, 0.67; 95% CI, 0.50-0.90; P = .01). Median progression-free survival was 11.2 months (95% CI, 9.3-14.0) vs 7.2 months (95% CI, 5.7-11.6) (hazard ratio, 0.72; 95% CI, 0.54-0.96). Grade 3 or 4 adverse events occurred in 57 (38.5%) in the IP group and 31 (41.9%) in the PS group; no treatment-related deaths occurred. Conclusions and Relevance: The results of this randomized clinical trial of patients with gastric cancer with peritoneal metastasis suggest that adding intraperitoneal paclitaxel to intravenous paclitaxel plus S-1 significantly improved overall survival without increasing severe toxic effects, potentially providing an encouraging signal for IP therapy in first-line treatment of gastric cancer with peritoneal metastasis. Trial Registration: chictr.org.cn Identifier: ChiCTR-IIR-16009802.