Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by D2 gastrectomy and adjuvant chemotherapy for locally advanced gastric cancer (Neo-CRAG): A randomized, multicenter, phase 3 trial.

LBA4075 Background: Neoadjuvant chemoradiotherapy (CRT) has been proposed to improve tumor response over neoadjuvant chemotherapy (CT) in patients with locally advanced gastric cancer (LAGC). However, there are limited phase III clinical trials to confirm its survival benefit. Methods: The Neo-CRAG study is a multicenter phase III trial conducted in China. Patients with stage cT3N2/N3M0, cT4aN+M0, or cT4bNanyM0 gastric or esophagogastric junction (EGJ, Siewert type II/III) adenocarcinoma were randomly assigned (1:1) to the CRT or CT group. All patients received 3 cycles of preoperative XELOX, followed by D2 gastrectomy and adjuvant XELOX. In CRT group, radiotherapy (45Gy/25Fx) started after the first CT cycle, dose modifications were made with concurrent CRT (oxaliplatin: 130 to 100 mg/m²; capecitabine: 1000 to 825 mg/m²). The radiation target volume chiefly included moderate mucosal CTV expansion (3cm) beyond primary tumor (fasting state), and comprehensive elective regional lymph node irradiation (station 16a2 as the lower border). The primary endpoint was disease-free survival (DFS). The secondary endpoints were overall survival (OS), pathological complete response (pCR), R0 resection, and safety. Results: Between 2013-2022, 620 patients (310 per group) were enrolled from 13 referral hospitals, including 225 (36.3%) patients with EGJ primary. Median follow-up was 69.7 months (IQR, 49.6–97.4). The primary endpoint of DFS was met (HR 0.750, 95%CI 0.607-0.928; P=0.008). The 3-year DFS rate was 55.6% (95% CI, 50.1 - 61.1) in the CRT group and 42.4% (36.9 - 47.9) in the CT group, and median DFS was 52.7 months with CRT versus 24.4 months with CT. Meanwhile, the 5-year OS rate was 50.1% versus 44.2% (HR 0.781, 95% CI 0.628-0.970; P=0.025) and the median OS was 67.5 months with CRT compared to 37.6 months with CT. Subgroup analyses showed that the survival benefit of CRT over CT was consistent. 448 patients underwent D2 gastrectomy. pCR was achieved in 33/223 (14.8%) of patients in the CRT group and 14/225 (6.2%) in the CT group. ypN0 rates were 125/223 (56.1%) in the CRT group and 82/225 (36.4%) in the CT group. Tumor downstaging (ypT0-2) occurred in 95/223 (42.6%) of CRT group and 53/225 (23.6%) of CT group. In patients who underwent R0 resection, lower locoregional recurrence rate was observed in the CRT group (20/213, 9.4%), compared with the CT group (38/208, 18.3%). The safety population comprised 603 patients. Grade 3+ hematologic toxicity was relatively higher in the CRT group (44/302 [14.6%] vs 31/301 [10.3%]). Grade 3+ postoperative complication rates were comparable (20/223 [9.0%] vs 17/225 [7.6%]). Conclusion: For patients with LAGC, intensifying perioperative CT with preoperative radiotherapy improves survival and is an effective strategy for high-risk cases in need of enhanced locoregional control. Clinical trial information: NCT01815853 .