title: Combining progression-free survival and overall survival as a novel composite endpoint for glioblastoma trials.
abstract: BACKGROUND
  The use of auxiliary endpoints may provide efficiencies for clinical trial design, but such endpoints may not have intrinsic clinical relevance or clear linkage to more meaningful endpoints. The purpose of this study was to generate a novel endpoint that considers both overall survival (OS) and earlier events such as progression-free survival (PFS) and determine whether such an endpoint could increase efficiency in the design of glioblastoma clinical trials.
  
  
  METHODS
  Recognizing that the association between PFS and OS varies depending on therapy and tumor type, we developed a statistical model to predict OS based on PFS as the trial progresses. We then evaluated the efficiency of our model using simulations of adaptively randomized trials incorporating PFS and OS distributions from prior published trials in neuro-oncology.
  
  
  RESULTS
  When treatment effects on PFS and OS are concordant, our proposed approach results in efficiency gains compared with randomization based on OS alone while sacrificing minimal efficiency compared with using PFS as the primary endpoint. When treatment effects are limited to PFS, our approach provides randomization probabilities that are close to those based on OS alone.
  
  
  CONCLUSIONS
  Use of OS as the primary endpoint, combined with statistical modeling of the relationship between OS and PFS during the course of the trial, results in more robust and efficient trial designs than using either endpoint alone.
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (L.T., G.P.); Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts (L.T., G.P.); Center for Neuro-Oncology Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts, (P.Y.W., B.M.A.); Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (B.M.A.); Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas (D.A.B.).
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Trippa
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (L.T., G.P.); Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts (L.T., G.P.); Center for Neuro-Oncology Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts, (P.Y.W., B.M.A.); Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (B.M.A.); Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas (D.A.B.).
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (L.T., G.P.); Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts (L.T., G.P.); Center for Neuro-Oncology Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts, (P.Y.W., B.M.A.); Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (B.M.A.); Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas (D.A.B.).
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (L.T., G.P.); Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts (L.T., G.P.); Center for Neuro-Oncology Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts, (P.Y.W., B.M.A.); Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (B.M.A.); Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas (D.A.B.).
authors.forename: Donald A
authors.initials: DA
authors.lastname: Berry
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (L.T., G.P.); Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts (L.T., G.P.); Center for Neuro-Oncology Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts, (P.Y.W., B.M.A.); Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (B.M.A.); Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas (D.A.B.).
authors.forename: Brian M
authors.initials: BM
authors.lastname: Alexander
mesh_terms: D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D023381:Endpoint Determination; D005909:Glioblastoma / Q000401:mortality* / Q000628:therapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic
keywords: adaptive clinical trials; auxiliary endpoints; clinical trial; endpoints; overall survival; progression-free survival