Rethinking the timing of adjuvant chemotherapy in advanced gastric cancer: From feasibility to precision sequencing

Abstract

The optimal timing for initiating adjuvant chemotherapy (AC) in stage II/III gastric cancer (GC) remains a critical and unresolved clinical issue. Current guidelines lack definitive recommendations, often relying on traditional paradigms that prioritize postoperative recovery over tumor biology. A recent retrospective study challenged this status quo by evaluating ultra-early AC (initiated 10-13 days postoperatively) within Enhanced Recovery After Surgery (ERAS) protocols, confirming its feasibility and safety with a hypothesis-generating signal of reduced peritoneal recurrence, though no survival benefit was observed. This review critically analyzes the study’s findings and limitations, which include the absence of molecular subtyping, inadequate dose optimization, and a small sample size. We propose a paradigm shift towards “precision timing”, an approach that integrates three core pillars: Tumor biology (including molecular subtypes and circulating tumor DNA dynamics), patient recovery status (leveraging ERAS metrics), and dynamic treatment monitoring. By synthesizing evidence from postoperative immunosuppression biology, the unique pathophysiology of peritoneal recurrence in GC, and emerging biomarkers, we delineate a roadmap for future research. This includes the need for prospective trials with enriched high-risk subgroups, biomarker-integrated adaptive designs, and standardized protocols for dose optimization and endpoint adjudication. Moving from a “one-size-fits-all” timing strategy to a biologically informed, individualized approach is essential to improve outcomes for patients with resected GC.

Keywords: Adjuvant chemotherapy; Gastric cancer; Timing of chemotherapy; Precision oncology; Peritoneal recurrence; Circulating tumor DNA; Enhanced Recovery After Surgery

Core Tip: The optimal timing for adjuvant chemotherapy (AC) in gastric cancer (GC) is undefined. A previous study demonstrated that ultra-early AC (10-13 days post-surgery) is feasible and safe under Enhanced Recovery After Surgery protocols, with a signal for reduced peritoneal recurrence but no survival advantage. The study’s limitations, including a lack of molecular profiling and small sample size, underscore the need for a more sophisticated approach. We propose a “precision timing” framework that integrates tumor biology (e.g., molecular subtypes and circulating tumor DNA), patient recovery, and dynamic monitoring to guide AC initiation. This shift from a traditional feasibility paradigm to biomarker-driven, individualized sequencing holds the key to improving outcomes in high-risk GC.