Time-varying impact of established prognostic factors in resected pancreatic ductal adenocarcinoma

Abstract

Background: Prognostic factors in resected pancreatic ductal adenocarcinoma (PDAC) have been determined under the assumption that hazard ratios (HRs) remain static. However, PDAC is a dynamic disease with evolving conditional survival. The aim of this study was to determine if the impact of prognostic factors in PDAC is time-varying.

Methods: This was a multicenter, retrospective cohort study of the prospectively maintained Dutch Pancreatic Cancer Recurrence Database and New York University and Johns Hopkins Hospital Institutional Databases. Patients with complete macroscopic resection of histopathologically proven PDAC between 2014 and 2019 and available follow-up data were included. The time-varying impact of prognostic factors identified by univariable cox-regression was modelled using Aalen's Additive Regression Models (Aalen's models) and visualized as plots of cumulative hazard.

Results: 3104 patients were included, of whom 938 (30.2%) received neoadjuvant therapy (NAT) while the rest underwent upfront surgery (US). 201 (6.5%) patients achieved observed long-term survival (>5 years). Aalen's models showed that lymphovascular invasion, perineural invasion, and nodal disease were prognostic up to 2 years post-operatively. At varying points thereafter, these variables lost their impact in the NAT but not US patients. Similarly, during the 4th year of follow-up, American Society of Anesthesiology scores became impactful in the NAT but not in the US patients.

Interpretation: The impact of prognostic factors in resected PDAC across NAT and US patients is time-varying. Our results suggest that aggressive disease drives early mortality but, after NAT, tumor-biological factors lose prognostic importance to frailty and comorbidities over time.