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

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.