Perioperative Therapy Versus Surgery-First Strategy for Resectable Pancreatic Ductal Adenocarcinoma: Current Evidence, High-Risk Stratification, and Future Directions

Background/Objectives: Long-term survival in pancreatic ductal adenocarcinoma (PDAC) remains poor. Although neoadjuvant therapy (NAT) has been increasingly investigated in resectable disease, its benefit compared with upfront surgery remains uncertain. This review evaluates evidence from randomized and prospective trials and explores clinical and molecular factors that may refine patient selection. Methods: We reviewed key randomized and prospective clinical trials evaluating NAT in resectable PDAC, including NORPACT-1, PANACHE01/PRODIGE-48, PREP-02/JSAP05, NEONAX, PREOPANC-1, PREOPANC-2, and CASSANDRA (PACT-21), the last two of which directly compared different NAT regimens head-to-head in the neoadjuvant setting, whereas PREOPANC-1 compared neoadjuvant chemoradiotherapy with upfront surgery. Outcomes of interest included overall survival (OS), resection rates, and treatment-related differences across resectable and borderline resectable populations. We also examined emerging clinical and biomarker-driven stratification strategies. Results: Trials in strictly resectable PDAC have demonstrated mixed results. NORPACT-1 reported inferior OS with neoadjuvant FOLFIRINOX compared to upfront surgery (median OS 25.1 vs. 38.5 months; HR 1.52). PANACHE01/PRODIGE-48 showed comparable OS despite higher R0 resection rates with NAT. In contrast, PREP-02/JSAP05 demonstrated improved OS with neoadjuvant gemcitabine plus S-1 (37.0 vs. 26.6 months; HR 0.73). PREOPANC-1 showed a survival advantage with neoadjuvant chemoradiotherapy, although pooled analyses suggest this benefit is primarily driven by borderline resectable disease, with no statistically significant OS improvement in strictly resectable cohorts. PREOPANC-2 demonstrated no OS difference between neoadjuvant FOLFIRINOX and gemcitabine-based chemoradiation. Conclusions: The benefit of NAT in resectable PDAC is not uniform and appears to depend on underlying tumor biology and risk features. High-risk characteristics, including elevated CA19-9, large tumor size, and nodal involvement, may identify patients most likely to benefit from upfront systemic therapy. Integration of molecular biomarkers such as SMAD4, GATA6, and homologous recombination deficiency into prospective trial design is critical. Ongoing phase III trials will further define optimal treatment strategies in this population.