title: Meta-analyses of randomized controlled trials show suboptimal validity of surrogate outcomes for overall survival in advanced colorectal cancer.
abstract: OBJECTIVE
  To quantify and compare the treatment effects on three surrogate end points, progression-free survival (PFS), time to progression (TTP), and tumor response rate (TR) vs. overall survival (OS) based on a meta-analysis of randomized controlled trials (RCTs) of drug interventions in advanced colorectal cancer (aCRC).
  
  
  METHODS
  We systematically searched for RCTs of pharmacologic therapies in aCRC between 2003 and 2013. Trial characteristics, risk of bias, and outcomes were recorded based on a predefined form. Univariate and multivariate random-effects meta-analyses were used to estimate pooled summary treatment effects. The ratio of hazard ratios (HRs)/odds ratios (ORs) and difference in medians were used to quantify the degree of difference in treatment effects on the surrogate end points and OS. Spearman ρ, surrogate threshold effect (STE), and R(2) were also estimated across predefined trial-level covariates.
  
  
  RESULTS
  We included 101 RCTs. In univariate and multivariate meta-analyses, we found larger treatment effects for the surrogates than for OS. Compared with OS, treatment effects were on average 13% higher when HRs were measured and 3% to 45% higher when ORs were considered; differences in median PFS/TTP were higher than on OS by an average of 0.5 month. Spearman ρ ranged from 0.39 to 0.80, mean R(2) from 0.06 to 0.65, and STE was 0.8 for HRPFS, 0.64 for HRTTP, or 0.28 for ORTR. The stratified analyses revealed high variability across all strata.
  
  
  CONCLUSIONS
  None of the end points in this study were found to achieve the level of evidence (ie, mean R(2)trial > 0.60) that has been set to select high or excellent correlation levels by common surrogate evaluation tools. Previous surrogacy relationships observed between PFS and TTP vs. OS in selected settings may not apply across other classes or lines of therapy.
authors: Institute of Health Research, University of Exeter Medical School, Veysey Building, Salmon Pool Lane, Exeter EX2 4SG, UK; Centre for Research on Health and Social Care Management, Bocconi University, via Rontgen, 1, Milan 20141, Italy. Electronic address: O.Ciani@exeter.ac.uk.
authors: Oriana
authors: O
authors: Ciani
authors: Interuniversity Institute for Biostatistics and Statistical Bioinformatics (I-BioStat), Hasselt University, Universitaire Campus, 3590 Diepenbeek, Belgium; International Drug Development Institute (IDDI), 185 Alewife Brook Parkway, Suite 410, Cambridge, MA 02138, USA.
authors: Marc
authors: M
authors: Buyse
authors: European Centre for Environment and Human Health University of Exeter Medical School Knowledge Spa, Royal Cornwall Hospital, Truro TR1 3HD, UK.
authors: Ruth
authors: R
authors: Garside
authors: Institute of Health Research, University of Exeter Medical School, Veysey Building, Salmon Pool Lane, Exeter EX2 4SG, UK.
authors: Jaime
authors: J
authors: Peters
authors: Dendrix Research, Rua Joaquim Floriano, 72/24, Sao Paulo 04534-000, Brazil.
authors: Everardo D
authors: ED
authors: Saad
authors: Institute of Health Research, University of Exeter Medical School, Veysey Building, Salmon Pool Lane, Exeter EX2 4SG, UK.
authors: Ken
authors: K
authors: Stein
authors: Institute of Health Research, University of Exeter Medical School, Veysey Building, Salmon Pool Lane, Exeter EX2 4SG, UK.
authors: Rod S
authors: RS
authors: Taylor
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D020811:Biomedical Technology / Q000379:methods / Q000706:statistics & numerical data; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000175:diagnosis / Q000401:mortality* / Q000628:therapy*; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor
keywords: Colorectal cancer; Health technology assessment; PFS; Surrogate outcome; TTP; Tumor response