Perioperative chemotherapy (FLOT 4 + 4) versus total neoadjuvant therapy (TNT; FLOT ×8) for resectable gastric cancer: A systematic review and exploratory meta-analysis

Introduction: Gastric and gastroesophageal junction (GEJ) adenocarcinoma is associated with high recurrence rates despite curative-intent surgery. Standard perioperative chemotherapy (PC) using FLOT (4 preoperative + 4 postoperative cycles) improves survival but is frequently not completed because of postoperative morbidity. Total Neoadjuvant Therapy (TNT), which delivers all eight FLOT cycles preoperatively (FLOT ×8), has been proposed to improve treatment completion. This systematic review and meta-analysis compared TNT with standard perioperative FLOT (FLOT 4 + 4) in resectable gastric cancer. Methods: A systematic search following PRISMA 2020 guidelines was conducted in PubMed, Scopus, EMBASE, ScienceDirect, Cochrane Library, LILACS, and SpringerLink through September 2025. Comparative studies evaluating TNT versus PC in adults with resectable gastric or GEJ adenocarcinoma were included. Primary outcomes were chemotherapy completion and pathological complete response (pCR). Secondary outcomes included R0 resection, postoperative morbidity, treatment-related toxicity, overall survival (OS), and disease-free survival (DFS). Results: Three retrospective comparative studies including 425 patients (136 TNT, 289 PC) were analyzed. TNT was associated with higher completion of planned chemotherapy (OR 4.55; 95% CI 1.13-18.27; p < 0.01) without an increase in major postoperative morbidity (OR 0.96; 95% CI 0.55-1.69; p = 0.50). No significant differences were observed in pCR (OR 1.54; 95% CI 0.65-3.63) or R0 resection rates. Survival outcomes were heterogeneous and could not be reliably pooled. Conclusion: TNT was associated with improved chemotherapy completion without increased perioperative morbidity. However, the current evidence base is insufficient to support conclusions regarding oncologic efficacy or survival benefit.