Predictive value of the preoperative systemic immune-inflammation index for primary chemotherapy resistance risk in patients with advanced gastric cancer.

Background: First-line systemic chemotherapy is a standard treatment for advanced gastric cancer, yet substantial heterogeneity exists in treatment response, with a considerable proportion of patients developing early resistance. Reliable pre-treatment biomarkers to identify patients at high risk of primary chemotherapy resistance are lacking. The systemic immune-inflammation index (SII) reflects host inflammatory and immune status. This study aimed to investigate the predictive value of pre-treatment SII for primary chemotherapy resistance in patients with advanced gastric cancer and to further evaluate its incremental value for survival risk stratification and exploratory predictive modeling. Methods: This retrospective cohort study enrolled patients with advanced gastric cancer who received first-line systemic chemotherapy at the Affiliated Hospital of North Sichuan Medical College between January 2019 and June 2024. The SII was calculated from the most recent complete blood count obtained within 14 days before chemotherapy initiation. The primary endpoint was primary chemotherapy resistance, defined as disease progression at the first response assessment or progression-free survival (PFS) of less than 3 months. Secondary endpoints included PFS and overall survival (OS). Median follow-up was 18.4 months. Associations were assessed using logistic regression and Cox proportional hazards models, with dose-response relationships explored via restricted cubic splines. Predictive models were constructed, and their performance was evaluated using receiver operating characteristic (ROC) curves, the concordance index (C-index), calibration curves, net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA). Robustness was examined using propensity score weighting. Results: Among 246 enrolled patients, 98 (39.8%) developed primary chemotherapy resistance. The incidence of resistance was significantly higher in the high-SII group compared to the low-SII group. Multivariable analysis suggested that elevated pre-treatment SII was associated with an increased risk of primary chemotherapy resistance after adjustment for multiple clinical and laboratory confounders. Higher SII levels were also associated with shorter PFS and OS. Restricted cubic spline analysis suggested a potential non-linear positive dose-response relationship between SII and both resistance risk and adverse survival outcomes. Adding SII to exploratory predictive models was associated with improved discrimination, calibration, and risk reclassification, with a higher potential net benefit observed in DCA. These findings were generally consistent in propensity score-weighted analyses, but should be interpreted cautiously in the absence of external validation. Conclusions: Pre-treatment SII may be a potentially useful marker associated with primary chemotherapy resistance and poor survival outcomes in patients with advanced gastric cancer. As a simple and readily available hematological parameter, SII may have value for exploratory pre-treatment risk stratification and model improvement. However, its clinical utility should be confirmed in future multicenter prospective studies with external validation before routine application in individualized treatment decision-making.