title: Surrogate End Points for Overall Survival in Metastatic, Locally Advanced, or Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis of 24 Randomized Controlled Trials.
abstract: BACKGROUND
  Overall survival (OS) has traditionally been the primary end point in studies evaluating the clinical benefit of first-line chemotherapy in metastatic, locally advanced, or unresectable pancreatic cancer (MLAUPC). Given the prolonged follow-up assessment required to obtain OS and its potential to be confounded by second-line treatments, this study sought to determine whether progression-free survival (PFS), response rate (RR), or disease control rate (DCR) can serve as a reliable surrogate for OS.
  
  
  METHODS
  A systematic review and meta-analysis was performed including all phase 3 clinical trials for MLAUPC, with gemcitabine as the control arm of the trial. The hazard ratios (HRs) for OS and PFS and odds ratios (ORs) for RR and DCR were recorded. A weighted Pearson correlation coefficient was estimated for the association between OS and the other outcomes. The primary analysis used a random effects weighting model, whereas the secondary analyses used a fixed effects- or sample size-weighted approach.
  
  
  RESULTS
  For the study, 24 randomized controlled trials were identified. The Pearson correlation coefficient between OS and PFS was 0.86 (95% confidence interval [CI] 0.67-0.94; p < 0.001). Sensitivity analysis of the studies with little to no crossover further showed a correlation coefficient of 0.91 (95% CI 0.76-0.97; p < 0.001). The correlation coefficient between OS and RR was 0.45 (95% CI 0.07-0.72; p = 0.02) and between OS and DCR was 0.74 (95% CI 0.38-0.90; p < 0.001).
  
  
  CONCLUSIONS
  First-line chemotherapy trials for MLAUPC show a robust correlation between OS and PFS, affirming its role as a surrogate of OS.
authors.affiliation: Department of Surgery, Stanford School of Medicine, Stanford, CA, USA.
authors.forename: Eleftherios A
authors.initials: EA
authors.lastname: Makris
authors.affiliation: Department of Biomedical Engineering, University of California Davis, Davis, CA, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: MacBarb
authors.affiliation: Department of Public Health Sciences, University of California Davis, Davis, CA, USA.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Harvey
authors.affiliation: Department of Surgery, Stanford School of Medicine, Stanford, CA, USA. gpoultsides@stanford.edu.
authors.forename: George A
authors.initials: GA
authors.lastname: Poultsides
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D015996:Survival Rate
chemical_list: D015415:Biomarkers