Recurrence-Free Survival Dynamics Following Adjuvant Chemotherapy for Resected Cancers of the Gastrointestinal Tract: A Systematic Review of Randomized Controlled Trials.

INTRODUCTION: Adjuvant chemotherapy can improve recurrence-free survival (RFS) in gastrointestinal malignancies. Previous review of phase III randomized controlled trials (RCTs) for colorectal cancer observed that RFS improvements were driven by early divergences during active chemotherapy; late recurrences were not influenced by adjuvant therapy. The broader applicability of this finding is unknown. METHODS: PubMed, Cochrane Library (CENTRAL), Embase, Scopus, and Web of Science were queried from database inception to December 31, 2025, for phase III RCTs including pancreatic, gastroesophageal, hepatocellular, and biliary tract malignancies. Trials where significant differences in RFS were observed between experimental (adjuvant chemotherapy) and control (resection alone) arms were included. Summary data were extracted from Kaplan-Meier curves using DigitizeIT, and absolute differences in RFS were compared at matched intervals using Wilcoxon matched-pairs signed rank tests. RESULTS: A total of 14 RCTs were identified, investigating periampullary (n = 4), gastroesophageal (n = 5), hepatocellular (n = 4), and biliary tract (n = 1) carcinomas. Across pooled RCTs, the highest rates of recurrence were observed in the first year following resection. Median RFS event rate was significantly higher with resection alone (0-0.5 y: resection alone 44.9 [IQR 14.2-84.1] versus adjuvant chemotherapy 26.4 [IQR 7.7-41.9], P < 0.001; 0.5-1 y: resection alone 33.2 [22.7-42.1] versus adjuvant chemotherapy 25.0 [13.8-44.5]; P = 0.007). No difference was observed during later intervals from postoperative randomization (1-2 y: P = 0.952; 2-3 y: P = 0.191; 3-4 y: P = 0.999; 4-5 y: P = 0.110). For the subset of trials where ≤6 mo of adjuvant chemotherapy was used (n = 10), improvements in RFS event rates were observed only during and immediately following the treatment interval (0-6 mo: P = 0.001; 6-12 mo: P = 0.037). CONCLUSIONS: Across multiple gastrointestinal malignancies, improvements in RFS associated with active adjuvant chemotherapy regimens are driven by early changes in recurrence dynamics. These data may provide in vivo understanding of residual tumor cell populations after curative-intent resection and how chemotherapy can be best used to prevent recurrence.