Surrogacy of Recurrence-free Survival for Overall Survival as an Endpoint of Clinical Trials of Perioperative Adjuvant Therapy in Hepatobiliary-pancreatic Cancers: A Retrospective Study and Meta-analysis.

Abstract

To assess the correlation between recurrence-free survival (RFS) and overall survival (OS) in the hepatobiliary-pancreatic (HBP) surgical setting to validate RFS as a surrogate endpoint. Reliable surrogate endpoints for OS are still limited in the field of HBP surgery. We analyzed patients who underwent curative resection for HBP disease [986 patients with pancreatic ductal adenocarcinoma (PDAC), 1168 with biliary tract cancer (BTC), 1043 with hepatocellular carcinoma, and 1071 with colorectal liver metastasis] from September 2002 to June 2022. We also conducted meta-analyses of randomized controlled trials of neoadjuvant or adjuvant therapy to validate the surrogacy in PDAC and BTC. Correlation coefficients between RFS and OS were low for hepatocellular carcinoma ( p = 0.67) and colorectal liver metastasis ( p = 0.53) but strong for PDAC ( p = 0.80) and BTC ( p = 0.75). In a landmark analysis, the concordance rates between survival or death at 5 years postoperatively and the presence or absence of recurrence at each time point (1, 2, 3, and 4 years) were 50%, 70%, 74%, and 77% for PDAC and 54%, 67%, 73%, and 78% for BTC, respectively, both increasing and reaching a plateau at 3 years. In a meta-analysis, the correlation coefficients for the RFS hazard ratio and OS hazard ratio in PDAC and BTC were p = 0.88 ( P < 0.001) and p = 0.87 ( P < 0.001), respectively. Three-year RFS can be a reliable surrogate endpoint for OS in clinical trials of neoadjuvant or adjuvant therapy for PDAC and BTC.