Total neoadjuvant therapy as a perioperative strategy for pancreatic ductal adenocarcinoma: a systematic review and meta-analysis

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited resectability at diagnosis and poor long-term survival even after curative-intent surgery. Total neoadjuvant therapy (TNT), which consolidates all systemic chemotherapy and/or chemoradiotherapy before resection, has emerged as a potential strategy to improve tumor downstaging, treatment compliance, and early systemic disease control. Increasingly, TNT is being explored as a perioperative strategy to integrate systemic disease control with surgical selection. This meta-analysis aimed to evaluate the perioperative and survival outcomes of TNT followed by surgical resection in patients with PDAC.

Methods: This systematic review and meta-analysis followed the PRISMA and AMSTAR guidelines, with a registered protocol on PROSPERO. A comprehensive search of PubMed, Embase, and the Cochrane Library up to 28 August 2025 identified studies reporting surgical and oncologic outcomes after TNT in PDAC. Eligible studies enrolled patients undergoing resection following TNT; comparators included conventional neoadjuvant therapy (NAT) followed by resection with or without adjuvant therapy. The primary outcomes were R0 resection rate, lymph-node positivity, and overall survival (OS). Pooled estimates were generated using random- or fixed-effects models based on heterogeneity, and analyses were performed using R software (version 4.2.2).

Results: Nine studies comprising 1,028 TNT-treated patients were included, of which two were prospective and seven retrospective. The pooled margin-negative (R0) resection rate was 88% [95% confidence interval (CI): 83–92%; I²=54.9]. In five comparative studies (585 TNT vs. 1,536 NAT), TNT significantly increased the likelihood of R0 resection [relative risk (RR) 1.12; 95% CI: 1.04–1.21; I²=45.3]. The pooled lymph-node positivity rate was 28% (95% CI: 23–34%; I²=49.3), lower than in NAT groups (RR 0.67; 95% CI: 0.59–0.77; I²=0%), indicating enhanced pathological downstaging. Due to heterogeneity in survival starting points, OS was synthesized descriptively rather than quantitatively. Median OS ranged from 32.3 to 58.8 months when measured from diagnosis and from 25.8 to 39.1 months when measured from surgery. Major complications (Clavien-Dindo ≥III) occurred in 18–56% (median 36%), and perioperative mortality was ≤6.7%. No significant publication bias was observed.

Conclusions: Within the limitations of primarily observational evidence, TNT followed by resection appears to improve R0 resection and nodal clearance rates and was associated with favorable survival trends, although survival outcomes were synthesized descriptively rather than quantitatively. TNT may be considered a reasonable perioperative strategy for carefully selected patients, particularly in high-volume centers, but its optimal regimen and indications require confirmation in randomized trials.