Extrapancreatic extension modifies chemotherapy benefit in resected pancreatic ductal adenocarcinoma: a population-based cohort study.

The effect of extrapancreatic extension (EPE) on the benefit of chemotherapy remains unclear. We analyzed 22,045 surgically treated patients with resected PDAC from the SEER database (2004–2022). Variable importance was assessed using Random Survival Forest models with SHAP and permutation methods. Cox proportional hazards models evaluated survival associations and EPE-chemotherapy interactions on multiplicative and additive scales, with Fine-Gray competing risk models for sensitivity analyses. Variable importance analysis identified chemotherapy, EPE, and N stage as the most influential prognostic factors. Chemotherapy absence increased disease-specific mortality (adjusted HR 1.45, 95% CI 1.39–1.52, p < 0.001), while EPE conferred additional risk (adjusted HR 1.25, 95% CI 1.19–1.31, p < 0.001). Notably, within the EPE stratum, chemotherapy absence increased mortality risk by 83% (adjusted HR 1.83, 95% CI 1.75–1.91) versus 34% (adjusted HR 1.34, 95% CI 1.23–1.46) in non-EPE patients. EPE patients receiving chemotherapy achieved comparable adjusted 3-year disease-specific survival to non-EPE patients without chemotherapy (39.5% vs 35.0%). Significant multiplicative interaction (HR 1.37, 95% CI 1.24–1.50, p < 0.001) and additive interaction (RERI 0.63, 95% CI 0.51–0.76, p < 0.001) were observed, with consistent patterns across tumor size categories validated in competing risk analyses. This population-based analysis revealed EPE as an independent adverse prognostic factor in resected PDAC and a significant EPE-chemotherapy interaction on both multiplicative and additive scales across tumor size categories. Despite conferring worse prognosis, EPE-positive patients receiving chemotherapy achieved survival comparable to that of EPE-negative patients without chemotherapy, underscoring the importance of ensuring receipt of chemotherapy in EPE-positive disease. These findings support the need to re-evaluate the role of EPE in staging systems; however, prospective validation is warranted.