title: Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data.
abstract: BACKGROUND
  The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels.
  
  
  METHODS
  We analysed individual patients' data from 15,071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints.
  
  
  RESULTS
  In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ(2)=0.83, 95% CI 0.83-0.83 in trials without radiotherapy, and 0.87, 0.87-0.87 in trials with radiotherapy) and excellent at trial level (R(2)=0.92, 95% CI 0.88-0.95 in trials without radiotherapy and 0.99, 0.98-1.00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ(2) range 0.77-0.85, dependent on the regimen being assessed) and trial level (R(2) range 0.89-0.97). In studies with data on locoregional control, individual-level correlations were good (ρ(2)=0.71, 95% CI 0.71-0.71 for concurrent chemotherapy and ρ(2)=0.61, 0.61-0.61 for modified vs standard radiotherapy) and trial-level correlations very good (R(2)=0.85, 95% CI 0.77-0.92 for concurrent chemotherapy and R(2)=0.95, 0.91-0.98 for modified vs standard radiotherapy).
  
  
  CONCLUSIONS
  We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted.
  
  
  BACKGROUND
  Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.
authors.affiliation: Meta-analysis Unit, Department of Biostatistics and Epidemiology, Gustave Roussy Institute, Villejuif, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Mauguen
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pignon
authors.forename: Sarah
authors.initials: S
authors.lastname: Burdett
authors.forename: Caroline
authors.initials: C
authors.lastname: Domerg
authors.forename: David
authors.initials: D
authors.lastname: Fisher
authors.forename: Rebecca
authors.initials: R
authors.lastname: Paulus
authors.forename: Samithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: Tim
authors.initials: T
authors.lastname: Eisen
authors.forename: Herbert
authors.initials: H
authors.lastname: Pang
authors.forename: Laurence
authors.initials: L
authors.lastname: Collette
authors.forename: William T
authors.initials: WT
authors.lastname: Sause
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dahlberg
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Crawford
authors.forename: Mary
authors.initials: M
authors.lastname: O'Brien
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schild
authors.forename: Mahesh
authors.initials: M
authors.lastname: Parmar
authors.forename: Jayne F
authors.initials: JF
authors.lastname: Tierney
authors.forename: Cécile
authors.initials: C
authors.lastname: Le Pechoux
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
mesh_terms: D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality* / Q000628:therapy; D059248:Chemoradiotherapy / Q000401:mortality*; D017024:Chemotherapy, Adjuvant; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality* / Q000628:therapy; D011379:Prognosis; D018714:Radiotherapy, Adjuvant; D016032:Randomized Controlled Trials as Topic; D015996:Survival Rate
chemical_list: D015415:Biomarkers