Neoadjuvant chemotherapy in resectable gastric cancer: An international propensity-matched analysis of 23,805 patients from high-volume centers across three continents.

413 Background: The role of neoadjuvant chemotherapy (NAC) in resectable, locally advanced gastric cancer is debated, with wide variation in adoption between Asian and Western countries. The impact of these diverse practices on perioperative and long-term outcomes is not well defined. Methods: We analyzed 23,805 patients who underwent resection from 10 high-volume gastric cancer centers across Asia, Europe and North America from January 3, 2005 to March 11, 2024. Patients with ≥T2 tumors undergoing radical gastrectomy with or without NAC were compared. Propensity score matching (3:1) adjusted for age, comorbidity, clinical stage, and histology. Results: After matching 1,017 patients (353 NAC, 664 non-NAC) were evaluated. In the West FLOT was the most common regimen (56.3%), while the East had more variability but overall used a combination of taxane and platinum agent (63.5%), with SOX being most common (17.9%). NAC patients more often underwent total gastrectomy (31.2% vs 23.5%, p<0.001), a more extensive lymph node dissection with D2 (62.7% vs 51.9%, p<0.001), and conversion to open surgery (2.93% vs 0.7%, p=0.008). NAC down staged tumors, with fewer pT4a tumors (14.0% vs 20.7%, p<0.001), and more T0 tumors (4.58% vs 0%, p<0.001). Despite these effects, pathologic nodal stage and margin status were similar; and the perioperative-hospital mortality (0.34% vs 0%, p=0.182) and complication rates did not differ. Moreover, overall recurrence rates (19.9% vs 16.4%, p=0.176) also did not differ. Interestingly, NAC patients more often recurred in the peritoneum (57.1% vs 36.4%, p=0.03) and less often in distant sites (8.2% vs 25.85%, p=0.03). Median follow up was 36.4 months (range 0.16 to 144.4 months). Median disease-free survival (10.1 vs 10.6 months, p=0.29) and overall survival (14.5 vs 17.8 months, p=0.61) were similar. Conclusions: In one of the largest and most ethnically diverse international propensity-matched analyses to date, NAC achieved tumor downstaging but did not improve disease-free or overall survival compared to upfront surgery. Distinct recurrence patterns after NAC highlight biological heterogeneity, underscoring the need for tailored strategies to optimize timing systemic therapy in locally advanced gastric cancer. Global real-life oncologic outcomes of NAC versus non-NAC in locally advanced gastric cancer patients at high-volume centers. Non-NACn = 664 NACn = 353 p-value Recurrence, n (%) 106 (16.4) 68 (19.9) 0.176 Recurrence location, n (%) 0.030 Peritoneum 24 (36.4) 28 (57.1) Distant 17 (25.8) 4 (8.2) Local 3 (4.6) 2 (4.1) Distant lymph node 14 (21.2) 7 (14.3) Multiple 5 (7.6) 8 (16.3) Overall survival median, months (IQR) 17.8 (11.5 - 24.4) 14.5 (8.2 - 21.4) 0.613 Disease free survival median, months (IQR) 10.6 (5.7 - 18.8) 10.1 (5.9 - 16.5) 0.286 IQR: Interquartile range, NAC: Neoadjuvant chemotherapy.