Neoadjuvant therapy versus upfront surgery in resectable pancreatic cancer: reconstructed patient-level meta-analysis of randomized clinical trials

Abstract

Background: Neoadjuvant treatment has shown promising results in patients with borderline resectable pancreatic ductal adenocarcinoma. The potential benefits of neoadjuvant treatment on long-term overall survival in patients with resectable pancreatic ductal adenocarcinoma have not yet been established. The aim of this study was to compare long-term overall survival of patients with resectable pancreatic ductal adenocarcinoma based on whether they received neoadjuvant treatment or underwent upfront surgery.

Methods: A systematic review including randomized clinical trials on the overall survival outcomes between neoadjuvant treatment and upfront surgery in patients with resectable pancreatic ductal adenocarcinoma was conducted up to 1 August 2023 from PubMed, MEDLINE and Web of Science databases. Patient-level survival data was extracted and reconstructed from available Kaplan-Meier curves. A frequentist one-stage meta-analysis was employed, using Cox-based models and a non-parametric method (restricted mean survival time), to assess the difference in overall survival between groups. A Bayesian meta-analysis was also conducted.

Results: Five randomized clinical trials comprising 625 patients were included. Among patients with resectable pancreatic ductal adenocarcinoma, neoadjuvant treatment was not significantly associated with a reduction in the hazard of death compared with upfront surgery (shared frailty HR 0.88, 95% c.i. 0.72 to 1.08, P = 0.223); this result was consistent in the non-parametric restricted mean survival time model (+2.41 months, 95% c.i. -1.22 to 6.04, P < 0.194), in the sensitivity analysis that excluded randomized clinical trials with a high risk of bias (shared frailty HR 0.91 (95% c.i. 0.72 to 1.15; P = 0.424)) and in the Bayesian analysis with a posterior shared frailty HR of 0.86 (95% c.i. 0.70 to 1.05).

Conclusion: Neoadjuvant treatment does not demonstrate a survival advantage over upfront surgery for patients with resectable pancreatic ductal adenocarcinoma.

Fig. 1

PRISMA flow chart according to guidelines RCT, randomized clinial trial.

Fig. 2

Kaplan–Meier plot and number at risk table for resectable R-PDAC (n = 625) P = 0.1295. R-PDAC, resectable pancreatic ductal adenocarcinoma.

Fig. 3

Kaplan–Meier plot and number at risk table for resectable R-PDAC according to NAT protocol (n = 625) Only the arm involving cisplatin, epirubicin and gemcitabine showed a statistically significant difference in favour of NAT compared with the upfront surgery arm, with a log-rank P value of 0.0059. R-PDAC, resectable pancreatic ductal adenocarcinoma; NAT, neoadjuvant treatment.

Fig. 4

Forest plot of resectable PDAC patients hazard of death fixed-effect meta-analysis PDAC, pancreatic ductal adenocarcinoma.

Fig. 5

Kaplan–Meier OS curves and number at risk table for resectable PDAC after excluding studies with high risk of bias (n = 507) P = 0.2638. PDAC, pancreatic ductal adenocarcinoma; OS, overall survival.