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Background and Objectives: The role of neoadjuvant or perioperative treatment in anatomically resectable pancreatic ductal adenocarcinoma (PDAC) remains intensely debated, in part because prior evidence syntheses have often pooled resectable and borderline-resectable disease. We aim to evaluate the efficacy and safety of neoadjuvant or perioperative treatment versus upfront surgery in trial-defined resectable PDAC using randomized evidence only. Materials and Methods: We performed a systematic review and meta-analysis of parallel-group randomized controlled trials comparing neoadjuvant therapy with upfront surgery in adults with resectable PDAC. PubMed, CENTRAL, Scopus, and Clarivate Web of Science were searched from inception until 30 November 2025. Mixed resectable- and borderline-resectable trials were included only when outcomes for the resectable subgroup were extractable. The primary outcome was overall survival (OS), analyzed on an intention-to-treat basis. Secondary outcomes included time-to-disease-event (TTDE) endpoints, resection rate, R0 resection, pathological node-negative (pN0) status, postoperative morbidity and mortality, and grade ≥3 adverse events. The review protocol was prospectively registered in PROSPERO (CRD420251243805). Results: Eight randomized controlled trials enrolling 1395 patients, including 1184 patients with resectable PDAC, met the eligibility criteria. Overall survival was available for six trials (seven comparisons totaling 1066 randomized patients) and was not significantly different between neoadjuvant treatment and upfront surgery (HR 0.80, 95% CI 0.59–1.08). TTDE was likewise not significantly different between strategies (HR 0.80, 95% CI 0.58–1.11). Neoadjuvant treatment reduced the likelihood of proceeding to resection (RR 0.90, 95% CI 0.85–0.95), while R0 resection and pN0 rates were numerically but not significantly higher among the resected patients. Postoperative morbidity and mortality were comparable between groups. Exploratory analyses suggested favorable survival estimates in trials with higher neoadjuvant treatment deliverability and completion. Conclusions: In trial-defined resectable PDAC, current randomized evidence does not demonstrate a universal survival advantage for neoadjuvant treatment over upfront surgery. Exploratory trial-level analyses suggested that higher neoadjuvant treatment deliverability and completion were associated with more favorable survival estimates. These findings support a selective, individualized rather than routine use of preoperative strategies in resectable PDAC.
Duse et al. (Thu,) studied this question.