Neoadjuvant therapy versus upfront surgery for resectable/borderline resectable pancreatic ductal adenocarcinoma: Systematic review and meta-analysis of randomized controlled trials.

Abstract

e16461 Background: Neoadjuvant strategies are becoming increasingly popular in resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC), but randomized evidence has been inconsistent. This updated RCT-only meta-analysis incorporates phase III data (CISPD-1) and the finalized Prep-02/JSAP05 report. We aim to compare neoadjuvant therapy (NAT) versus upfront surgery (UFS) in resectable/borderline resectable PDAC regarding efficacy and safety. Methods: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched for RCTs enrolling patients with resectable/borderline resectable PDAC and comparing NAT followed by surgery vs UFS (with adjuvant therapy as planned in each trial). Overall survival (OS) was the primary endpoint. Disease-control endpoints including disease-free survival (DFS), recurrence-free survival (RFS), event-free survival (EFS), or progression-free survival (PFS) were pooled as a single time-to-event outcome (HRs); binary outcomes were pooled as RRs using random-effects inverse-variance models; heterogeneity was assessed with I². Results: Five RCTs (n = 1,121) were included. NAT did not significantly improve OS, HR 0.80 (95% CI 0.61-1.05; I² = 67.2%). Across four RCTs reporting disease-control endpoints including DFS, RFS, EFS or PFS, NAT was associated with improved disease control HR 0.80 (95% CI 0.64-0.99; I² = 55.5%). Among patients who underwent resection, NAT increased margin-negative (R0) resection rates RR 1.26 (95% CI 1.06-1.49; I² = 74.9%) but reduced the likelihood of reaching resection overall RR 0.93 (95% CI 0.88-0.98; I² = 14.4%). NAT was associated with higher severe adverse events RR 1.39 (95% CI 1.15-1.67; I² = 0%). Conclusions: NAT for resectable/borderline resectable PDAC improved disease-control outcomes and margin-negative resection rates, but was associated with a reduction in patients ultimately undergoing resection. Moreover, NAT was associated with an increased risk of severe adverse events and no clear OS benefit. Substantial heterogeneity suggests effects may differ by regimen and baseline resectability; longer follow-up is needed. Trial-level counts (trial-defined denominators). Notes: R0 denominators are resected/pathology sets (PREOPANC reports R0 among PDAC resections). AE denominators are trial-defined safety sets (PREOPANC reports serious AEs). NR=not reported. Trial Randomized NAT/UFS ResectedNAT/UFS R0 (n/N) Grade ≥3/serious AEs (n/N) Jang 2018 27/23 17/18 14/17 vs 6/18 NR PREOPANC 2022 119/127 72/92 49/68 vs 35/82 62/119 vs 52/127 NORPACT-1 2024 77/63 63/56 35/63 vs 22/56 42/73 vs 19/47 Prep-02/JSAP05 2026 182/179 157/156 143/157 vs 134/156 NR CISPD-1 2025 162/162 135/149 118/135 vs 119/149 68/143 vs 35/114 Total 567/554 444/471 359/440 vs 316/461 172/335 vs 106/288