title: Validation of Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials.
abstract: The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma.
  
  
  
  Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)-log HROSand log HRPFS-measured inR2from a weighted least-square (WLS) regression model and the CBCS model.
  
  
  
  The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8-3.5 months) and the median OS was 7.2 months (95% CI, 6.5-8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The CopulaR2ranged from 0.51 for PS to 0.78 for histology. The WLSR2ranged from 0.26 for EORTC and PS to 0.67 for age.
  
  
  
  The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma.The Oncologist2017;22:189-198Implications for Practice:For better disease management and for more efficient clinical trial designs, it is important to know if progression-free survival (PFS) is a good surrogate endpoint for overall survival in malignant mesothelioma. With a relatively large database of 17 phase II trials and 716 patients from Cancer and Leukemia Group B and North Central Cancer Treatment Group, we conducted statistical analyses and found that there is no evidence to suggest that PFS is a valid surrogate endpoint for OS for malignant mesothelioma. Future research work is needed to find alternative surrogate endpoints for OS.
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA xiaofei.wang@duke.edu.|Alliance Statistics and Data Center, Duke University, Durham, North Carolina, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Alliance Statistics and Data Center, Duke University, Durham, North Carolina, USA.
authors.forename: Lydia
authors.initials: L
authors.lastname: Hodgson
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: George
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Nate R
authors.initials: NR
authors.lastname: Foster
authors.affiliation: Department of Internal Medicine, Veterans Affairs Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Apar Kishor
authors.initials: AK
authors.lastname: Ganti
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Stinchcombe
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Crawford
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Kratzke
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA.|School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
authors.forename: Herbert
authors.initials: H
authors.lastname: Pang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000401:mortality* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D016019:Survival Analysis; D055815:Young Adult
keywords: Malignant mesothelioma; Overall survival; Progression‐free survival; Risk factors; Surrogate endpoint