BACKGROUND: The optimal treatment strategy for resectable pancreatic ductal adenocarcinoma (R-PDAC) remains controversial. In this study, we aimed to evaluate the impact of neoadjuvant chemotherapy (NAC) using gemcitabine plus nab-paclitaxel (GnP) or modified FOLFIRINOX (mFFX) compared with upfront surgery (UFS) in patients with R-PDAC. METHODS: This retrospective cohort study included 125 patients diagnosed with R-PDAC at a single institution between 2010 and 2022. The patients were divided into UFS (n = 57) and NAC (n = 68) groups. Survival outcomes, perioperative factors, and prognostic variables were analyzed. Subgroup analysis was performed based on high-risk features, defined as elevated carcinoembryonic antigen (CEA) levels >6 ng/mL and tumor size ≥25 mm. RESULTS: No significant differences were observed in overall survival (OS) and progression-free survival (PFS) between the entire UFS and NAC groups. However, in patients with high-risk features, NAC significantly improved OS compared with UFS (median survival 29.0 months vs. 10.6 months, respectively; P < 0.0001). NAC was associated with reduced intraoperative blood loss and a lower lymph node positivity rate without increasing postoperative morbidity or mortality. CONCLUSIONS: While NAC did not universally improve survival outcomes in R-PDAC, it significantly benefitted patients with poor prognostic indicators. These findings support a selective approach to NAC based on biological risk stratification rather than anatomical criteria alone. Future prospective studies are warranted to validate these observations and optimize individualized treatment strategies.
