Local Time-to-Event Endpoint Under-Reporting and Variability in Pancreatic Cancer Trials Involving Radiotherapy

Abstract

The role of radiotherapy (RT) for pancreatic adenocarcinoma (PDAC) remains controversial, with recent studies showing conflicting results. Importantly, endpoints used to evaluate efficacy in recent RT trials for PDAC have been highly variable. As variability in time-to-event (TTE) endpoint definitions is demonstrated to influence outcomes in other cancers, it is critical that radiation oncologists develop consensus around optimal endpoint definitions to use in future PDAC trial design. Thus, we conducted a systematic review of PDAC trials involving RT to characterize the frequency and variability in local TTE endpoint reporting. An electronic database search was conducted of PubMed, EMBASE, and Cochrane Library to identify phase 2 and 3 clinical trials published from 2010-2022 of localized PDAC involving RT that reported any TTE endpoint (e.g., local control). After excluding duplicates, two independent reviewers screened full-text manuscripts for inclusion. Trial characteristics and local TTE endpoints/definitions were tabulated. Three hundred twenty references were screened and 79 trials were included, of which 73 (92%) were phase 2 and 26 (33%) were randomized. Twenty (25%) trials reported a local TTE endpoint; these were local control (LC; N = 6), local progression-free survival (LPFS; N = 4), freedom from local progression (N = 6), locoregional progression-free interval (N = 1), cumulative incidence of local recurrence (N = 1), time to failure of sustained LC (N = 1), and local disease-free survival (N = 1). LC (N = 6) had 5 unique definitions and was undefined once; 1 definition included death as an event. LPFS (N = 4) had 3 definitions; 2 did not consider death an event. Among trials with local TTE endpoints, 9 trials specified the definition of a local recurrence/progression. Four trials defined local recurrence based on RT volumes; one counted clinical evidence of recurrence (e.g., tumor bleed); and one counted a rise in tumor markers without evidence of distant metastases. The index time ("time-zero") was defined for local TTE endpoints in 10 trials, including start of RT (N = 4) or chemo (N = 1), end of RT (N = 1), diagnosis (N = 1), enrollment (N = 1), and time of surgery (N = 1). Few pancreatic cancer trials involving RT report local TTE endpoints, with significant heterogeneity in endpoints used and their definitions. Development of consensus endpoint definitions will be critical for future PDAC trial design.