Comparative Effectiveness of Neoadjuvant Therapy and Upfront Resection for Patients with Resectable Pancreatic Adenocarcinoma: An Instrumental Variable Analysis

Background: Neoadjuvant therapy (NAT) is increasingly being used in the management of patients with resectable pancreatic ductal adenocarcinoma (PDAC); however, there is a lack of evidence regarding the benefit among these patients. Objective: The aim of this study was to evaluate overall survival (OS) in PDAC patients with resectable disease treated with NAT or upfront resection through instrumental variable (IV) analysis. Design: A national cohort study of resectable PDAC patients in the National Cancer Data Base (2007–2015) treated with either upfront surgery or resection after NAT. Using multivariable modeling and IV methods, OS was compared between those treated with NAT and upfront resection. The IV was hospital-level NAT utilization in the most recent year prior to treatment. Results: The cohort included 16,666 patients (14,012 upfront resection; 2654 NAT) treated at 779 hospitals. Among those treated with upfront resection, 59.9% received any adjuvant therapy. NAT patients had higher median (27.9 months, 95% confidence interval [CI] 26.2–29.1) and 5-year OS (24.1%, 95% CI 21.9–26.3%) compared with those treated with upfront surgery (median 21.2 months, 95% CI 20.7–21.6; 5-year survival 20.9%, 95% CI 20.1–21.7%). After multivariable modeling, NAT was associated with an approximately 20% decrease in the risk of death (hazard ratio [HR] 0.78, 95% CI 0.73–0.84), and this effect was magnified in the IV analysis (HR 0.61, 95% CI 0.47–0.79). Conclusions: In patients with resectable PDAC, NAT is associated with improved survival relative to upfront resection. Given the benefits of multimodality therapy and the challenges in receiving adjuvant therapy, consideration should be given to treating all PDAC patients with NAT.