Surgery and neoadjuvant therapy in locally advanced pancreatic cancer: an umbrella review of survival, resection outcomes, and cost-effectiveness

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, particularly for patients with locally advanced pancreatic cancer (LAPC). Neoadjuvant therapy (NAT) has emerged as a promising strategy to improve resectability and survival outcomes in LAPC. This umbrella review aimed to synthesize the available evidence on the effectiveness of NAT and surgical interventions in LAPC, focusing on resection and R0 resection rates and overall survival (OS). Methods: This study was registered with PROSPERO (CRD42024565454). A comprehensive literature search was conducted in June 2024 across four databases. Studies reporting on NAT and/or surgery in LAPC were selected, and the methodological quality of each meta-analysis was assessed using the A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2) tool. A cost-effectiveness analysis (CEA) was performed comparing FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin) and gemcitabine/ nab-paclitaxel as NAT regimens. Results: Nine systematic reviews with meta-analyses published between 2014 and 2023 were included. They covered a variety of treatment strategies, including NAT followed by resection, induction therapy comparing FOLFIRINOX versus gemcitabine/nab-paclitaxel, and different surgical techniques. FOLFIRINOX demonstrated significantly higher R0 resection rates [risk ratio (RR): 0.77, 95% confidence interval (CI): 0.60-0.97, P<0.05] and improved OS compared to gemcitabine/nab-paclitaxel [hazard ratio (HR): 0.68, 95% CI: 0.46-0.99, P<0.05]. Surgical resection following NAT was associated with significantly better survival outcomes than induction therapy alone or palliative treatments. The CEA revealed that FOLFIRINOX, despite its higher cost, yielded an incremental OS benefit of 5.19 months and maintained a 60-63% probability of being cost-effective within a willingness-to-pay (WTP) threshold of $150,000 per additional month of OS gained. Conclusions: This review highlights the superior efficacy of FOLFIRINOX as a NAT regimen for LAPC, particularly in increasing resectability and R0 resection rates. Combining NAT with surgery offers significant survival benefits, making this strategy a standard of care for eligible LAPC patients.