Trial sequential analysis of randomized controlled trials on neoadjuvant therapy for resectable pancreatic cancer

Introduction: Meta-analyses of randomized controlled trials (RCTs) provide the highest level of evidence but can suffer from type I (false-positive) and II (false-negative) errors, which can be estimated through trial sequential analysis (TSA) demonstrating eventual credibility of results. Aim of the study was to establish through TSA which strategy between neoadjuvant approach or upfront surgery provides best results when treating potentially resectable pancreatic adenocarcinoma. Materials and methods: RCTs were searched until September 2021. Intention-to-treat (ITT) overall survival, resection rate, ITT R0 and N0 rates and per-protocol R0 and N0 rates were the outcomes considered. Fixed-effect model was applied. TSA assumed an alpha = 5% and a power = 80%. Results: Four RCTs were identified accruing 325 patients for the ITT analyses and 242 for the per-protocol analyses. Neoadjuvant did not improve survival (p = 0.167) and TSA supported that this result was underpowered, requiring additional 1514 patients to prove credibility. Neoadjuvant reduced resection rate (p = 0.044) but type I error was not avoided. Neoadjuvant credibly increased per-protocol R0 and N0 rates (p = 0.003 and p < 0.001), and TSA showed that these were true-positive findings. Neoadjuvant did not increase ITT R0 rate since randomization (p = 0.169) but TSA showed lack of power. Neoadjuvant credibly increased the ITT N0 rate (p < 0.001) and TSA supported that this was a true positive finding. Conclusions: Neoadjuvant strategy credibly demonstrated superiority over upfront surgery in determine per-protocol R0 resection and N0 rates, as well as ITT N0 rate. For the remaining outcomes, TSA suggested the need of larger samples to exclude type I and II errors.