title: Progression-Free Survival, Response Rate, and Disease Control Rate as Predictors of Overall Survival in Phase III Randomized Controlled Trials Evaluating the First-Line Chemotherapy for Advanced, Locally Advanced, and Recurrent Non-Small Cell Lung Carcinoma.
abstract: Recent improvements in chemotherapy agents have prolonged postprogression survival of non-small cell lung cancer. Thus, primary outcomes other than overall survival (OS) have been frequently used for recent phase III trials to obtain quick results. However, no systematic review had assessed whether progression-free survival (PFS), response rate (RR), and disease control rate (DCR) can serve as surrogates for OS at the trial level in the phase III first-line chemotherapy setting.
  
  
  
  We included phase III randomized clinical trials (RCTs) comparing two arms that were reported as a full article regardless of their primary end point. We included only RCTs that evaluated chemonaive patients with advanced, locally advanced, or metastatic non-small cell lung cancer and were published after January 1, 2005. We systematically searched four public electronic databases. Two investigators independently screened and scrutinized candidate articles. How surrogate outcomes represented hazard ratios (HRs) for OS was examined.
  
  
  
  Among 1907 articles, we ultimately found 44 eligible articles covering 22,709 subjects. HR for PFS, median PFS in the experimental arm minus median PFS in the control arm in months, OR for RR (ORrr), and OR for DCR were evaluated in 34, 35, 44, and 35 RCTs, respectively. HR for OS (HRos), median PFS in the experimental arm minus median PFS in the control arm, ORrr, and OR for DCR had weighted Spearman's rank correlation coefficients with an HRos of 0.496, 0.477, 0.570, and 0.470, respectively; the standardized weighted regression coefficients were 0.439, -0.376, -0.605, and -0.381, respectively; and the adjusted weighted coefficients of determination were 0.224, 0.161, 0.350, and 0.176, respectively.
  
  
  
  ORrr, followed by HRpfs, had the strongest association with HRos at the trial level. However, these measures were not strong enough to replace OS.
authors.affiliation: Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: nobuyuki_horita@yahoo.co.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Horita
authors.affiliation: Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Department of Thoracic Oncology, Kanagawa Cancer Center, Kanagawa, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Manabe
authors.affiliation: Department of Thoracic Oncology, Kanagawa Cancer Center, Kanagawa, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Department of Health Policy, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Ota
authors.affiliation: Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000401:mortality*; D018572:Disease-Free Survival; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality*; D011788:Quality of Life
keywords: Cytotoxic agent; Molecular targeted therapy; Postprogression survival; Surrogate marker