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

Figure 1 The precision timing framework for adjuvant chemotherapy in gastric cancer. This conceptual framework integrates three core pillars to guide individualized timing of adjuvant chemotherapy: (1) Tumor biology: Molecular subtyping (e.g., microsatellite instability, Epstein-Barr virus, and chromosomal instability) and detection of postoperative circulating tumor DNA (ctDNA) define the risk of recurrence and potential therapeutic sensitivity; (2) Patient recovery: Objective metrics from Enhanced Recovery After Surgery protocols, including functional recovery (QoR-15) and nutritional status, determine patient readiness for early chemotherapy; and (3) Dynamic monitoring: Real-time assessment of ctDNA clearance and immune status allows for adaptive treatment decisions, including dose adjustment or treatment de-escalation. The intersection of these pillars enables a shift from a fixed-timing paradigm to a biologically informed, personalized treatment sequence. MSI: Microsatellite instability; EBV: Epstein-Barr virus; CIN: Chromosomal instability; ctDNA: Circulating tumor DNA; ERAS: Enhanced Recovery After Surgery; AC: Adjuvant chemotherapy.

Figure 2 Proposed roadmap for future research on precision timing in gastric cancer. This schematic outlines the key steps and priorities required to transition from feasibility studies to clinical implementation. The roadmap is divided into three phases: (1) Discovery & validation: Focuses on mechanistic studies to define the optimal biological window, identification and validation of robust biomarkers [e.g., circulating tumor DNA (ctDNA) and immune profiles], and the establishment of standardized Enhanced Recovery After Surgery protocols; (2) Clinical development: Encompasses prospective, biomarker-enriched randomized controlled trials with adaptive designs to evaluate the efficacy of ctDNA-guided timing, alongside dose optimization studies to maintain relative dose intensity; and (3) Implementation & standardization: Involves the development of clinical guidelines, incorporation of patient-reported outcomes and cost-effectiveness analyses, and the establishment of standardized, blinded endpoints for trials. ERAS: Enhanced Recovery After Surgery; ctDNA: Circulating tumor DNA; RCT: Randomized controlled trial; RDI: Relative dose intensity.