Higher lymph node burden predicts greater chemotherapy benefit in resected pancreatic ductal adenocarcinoma: evidence from 22,045 patients

Whether lymph node burden modifies chemotherapy effectiveness in pancreatic ductal adenocarcinoma (PDAC) has not been systematically investigated. We analyzed 22,045 surgically treated PDAC patients from the Surveillance, Epidemiology, and End Results database (2004-2022). Restricted cubic spline analysis examined chemotherapy hazard ratios across positive lymph node counts. Cox models estimated survival associations and interaction effects between N stage and chemotherapy on multiplicative and additive scales, with Fine-Gray competing risk models for sensitivity analyses. Additional sensitivity analyses included the exclusion of neoadjuvant therapy recipients, lymph node ratio (LNR) analysis, and stratification by lymph node examination adequacy. Chemotherapy absence increased disease-specific mortality (adjusted HR 1.72; 95% CI, 1.65-1.79), while N1 and N2 disease conferred additional risk (HR 1.54 and 2.05, respectively; both p < 0.001). Chemotherapy benefit increased progressively with nodal burden: hazard ratios for chemotherapy absence versus receipt were 1.52 (95% CI, 1.42-1.63) in N0, 1.80 (95% CI, 1.70-1.92) in N1, and 1.97 (95% CI, 1.83-2.12) in N2 disease. Adjusted 3-year disease-specific survival with versus without chemotherapy was 55.1% versus 39.3% (N0), 36.5% versus 18.2% (N1), and 26.4% versus 8.7% (N2). Notably, N1 patients receiving chemotherapy achieved better outcomes than N0 patients without chemotherapy. Adjusted interaction tests revealed significant multiplicative interactions (N1: 1.19; N2: 1.28) and additive interactions (RERI: N1: 0.65; N2: 1.29). These interaction patterns were validated in sensitivity analyses. Lymph node burden significantly modifies chemotherapy effectiveness in resected PDAC, with higher nodal burden patients deriving disproportionately greater benefit. These findings support risk-stratified treatment strategies incorporating lymph node status.