Predicting the Unpredictable: Prognostic Role of Systemic Inflammatory Indices and Tumor Biology of Neoadjuvant Chemotherapy Response in Gastric and Gastroesophageal Junction Cancer—Insights from a Systematic Review and Real-World Experience

TL;DR

This study finds that tumor biology and immune response, not chemotherapy type, are key to predicting survival in gastric cancer patients.

Contribution

The study identifies systemic inflammatory indices and tumor biology as stronger prognostic factors than chemotherapy regimen choice in gastric cancer.

Findings

Lymphovascular invasion and pan-cytokeratin are independent prognostic markers for poor survival.

Monocyte-to-lymphocyte ratio is an independent adverse factor in survival outcomes.

FLOT chemotherapy regimen did not show statistically significant survival benefit over non-FLOT.

Abstract

Background/Objectives: Perioperative chemotherapy is the standard treatment for locally advanced gastric and gastroesophageal junction adenocarcinoma; however, substantial uncertainty remains regarding the optimal management of non-responding patients and the prognostic relevance of biological and inflammatory biomarkers. This study aimed to determine, using real-world data integrated with a comprehensive literature review, whether long-term survival is driven primarily by the choice of chemotherapy regimen or by the tumor’s intrinsic biological aggressiveness and the host’s systemic inflammatory response. Methods: A retrospective analysis was performed of 43 patients with locally advanced gastric cancer who received neoadjuvant chemotherapy. Survival outcomes were stratified by regimen (FLOT versus non-FLOT) and analyzed using Kaplan–Meier methods. The prognostic value of clinicopathological features and systemic inflammatory indices was assessed using multivariate Cox regression models to identify independent predictors of mortality. Results: Although FLOT showed a trend toward improved overall survival (OS) (median not reached vs. 18.9 months), this difference did not reach statistical significance. Univariate analysis linked lymphovascular invasion (LVI) (HR = 4.17; p = 0.003), pan-cytokeratin (panCK) (HR = 2.44; p = 0.032), and monocyte-to-lymphocyte ratio (MLR) (HR = 1.73; p = 0.027) with survival. To minimize overfitting, two multivariate models were constructed. The first confirmed LVI (HR = 7.32; p < 0.001) and panCK (HR = 4.30; p = 0.006) as independent prognostic markers. The second identified MLR (HR = 1.65; p = 0.033) and panCK (HR = 2.42; p = 0.034) as independent adverse factors. Conclusions: Our findings suggest a paradigm shift in prognostic assessment for locally advanced gastric cancer: therapeutic success appears to depend more on underlying tumor biology and the immune microenvironment than on any specific neoadjuvant regimen. High MLR and LVI serve as strong surrogate markers of a biologically aggressive, chemotherapy-resistant phenotype. Consequently, future clinical strategies should move beyond a “one-size-fits-all” chemotherapy approach and prioritize these biomarkers for risk stratification and personalization of multimodal therapy.

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