Upfront Chemotherapy Versus Immediate Surgery for Operable Pancreatic Cancer: An Umbrella Review of Meta-Analyses

Background: Neoadjuvant therapy (NAT) is increasingly investigated in operable pancreatic ductal adenocarcinoma (PDAC), yet its role in strictly resectable disease remains controversial. Randomized trials have been conducted both in borderline resectable and resectable PDAC and have demonstrated survival advantages, while evidence in strictly resectable tumors remains poor. We conducted an umbrella review of systematic reviews and meta-analyses (SRMAs) to comprehensively evaluate the highest level of available evidence on NAT versus upfront surgery in operable PDAC. Methods: We performed an umbrella review of completed SRMAs assessing neoadjuvant chemotherapy (NAC) and/or chemoradiotherapy (NACRT) in resectable and borderline resectable PDAC. MEDLINE/PubMed, Embase, and Cochrane Library were searched from inception through November 2025. Eligible SRMAs reported at least one clinical outcome, including overall survival (OS), disease-free/event-free survival (DFS/EFS), resection rate, R0 resection, nodal status, or perioperative outcomes. Methodological quality was appraised using AMSTAR-2 and ROBIS tools. Overlap among SRMAs was quantified using the Corrected Covered Area (CCA), and RCT-only evidence was prioritized for causal inference. Evidence credibility was graded using an Ioannidis-style classification framework. Results: Thirty-four SRMAs published between 2010 and 2025 were included. In strictly resectable PDAC, RCT-only meta-analyses showed no definitive OS benefit for NAT compared with upfront surgery (pooled HR approximately 0.85, 95% CI 0.68-1.05), although a significant improvement in EFS was observed (HR approximately 0.77, 95% CI 0.65-0.90). Trial sequential analyses suggested insufficient information size for conclusive OS benefit in resectable disease. Conversely, in pooled resectable and borderline resectable populations, NAT significantly improved OS (HR approximately 0.66, 95% CI 0.52-0.85), with subgroup analyses indicating that the survival advantage was primarily driven by borderline resectable tumors. NAT consistently increased R0 resection and node-negative (pN0) rates and reduced non-curative explorations. However, neoadjuvant strategies were associated with treatment-related attrition and, in some analyses, lower overall resection rates. Comparative evidence suggested improved pathological outcomes with chemoradiotherapy versus chemotherapy alone, without a consistent survival advantage. Conclusions: Current high-level evidence supports NAT as the preferred strategy for borderline resectable PDAC, demonstrating consistent survival and pathological benefits. In strictly resectable disease, NAT improves disease-control endpoints and pathological surrogates, but a definitive OS advantage has not been consistently demonstrated in RCT-only syntheses. This should not be interpreted as evidence of equivalence between NAT and a surgery-first strategy, given the heterogeneity, limited power, and therapeutic-era effects of the available literature. Treatment decisions in resectable PDAC should therefore be individualized, balancing potential oncologic benefits against attrition risk. Future adequately powered randomized trials employing contemporary multi-agent regimens are needed to clarify the survival impact of NAT in strictly resectable disease.