Chronic Inflammatory Comprehensive Signature Predicts Oxaliplatin and 5-Fluorouracil Benefit in Early Colorectal Cancer.

Background: Precision delivery of adjuvant chemotherapy (ACT) improves healthcare efficiency and postoperative quality of life in stage II-III colorectal cancer (CRC). However, there remains an unmet need for identifying biomarkers that can predict therapeutic responses to 5-fluorouracil (5-FU) and oxaliplatin. Methods: We analyzed three independent cohorts (1676 stage II-III surgical cases) to evaluate the prognostic role of 12 inflammatory indices. A novel Chronic Inflammatory Comprehensive Signature (CICS) was developed using multivariable Cox regression. Three-year recurrence-free survival (RFS) and overall survival (OS) were compared between CICS-stratified subgroups (CICS-L vs CICS-H) receiving 5-FU- or oxaliplatin-based ACT. Results: Two novel inflammatory ratios (FPSIIR, FPSIRIR) and six composite scores (FPSIIS, FPSIRIS, FPSIRS, FASIIS, FASIRS, FASIRIS) independently predicted prognosis across all three cohorts (all p log-rank<0.05). The CICS demonstrated an AUC of 0.690 for outcome prediction, increasing to 0.724 when combined with CEA-CA19-9. CICS-H patients exhibited reduced chemosensitivity to both agents, with therapeutic benefits primarily confined to the CICS-L subgroup. Comparable favorable RFS was observed in stage II CICS-L patients undergoing 5-FU monotherapy or oxaliplatin-based ACT versus non-ACT treatments (97.73% vs 91.02% vs 91.46%, p log-rank=0.33). Superior survival outcomes and a lower recurrence rate were observed in stage II CICS-H patients receiving 5-FU compared to those receiving oxaliplatin-based ACT. Consistent oxaliplatin benefits were observed in CICS-H and CICS-L patients compared to 5-FU-treated cases in the stage III subgroup. Optimal ACT regimens for patients with CICS-L and CICS-H differ in different stages. The CICS strategy can help patients select a more optimal ACT regimen (RR=0.47, 95% CI=0.35-0.62, p<0.01) and enhance therapeutic efficacy (HR=0.70, 95% CI=0.53-0.92 for RFS; HR=0.70, 95% CI=0.47-0.97 for OS in stage III CRC). Conclusion: CICS-quantified cancer-derived inflammation inversely correlates with the therapeutic responsiveness to 5-FU/oxaliplatin. A CICS-guided strategy maximizes survival outcomes while precision-deescalating chemotherapy use without compromising outcomes, establishing a biomarker-driven paradigm for personalized postoperative management of CRC.