title: Progression-free survival is a surrogate for survival in advanced colorectal cancer.
abstract: OBJECTIVE
  The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer.
  
  
  METHODS
  Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects.
  
  
  RESULTS
  In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS.
  
  
  CONCLUSIONS
  PFS is an acceptable surrogate for OS in advanced colorectal cancer.
authors.affiliation: International Drug Development Institute, Louvain-la-Neuve, Belgium. marc.buyse@iddi.com
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Tomasz
authors.initials: T
authors.lastname: Burzykowski
authors.forename: Kevin
authors.initials: K
authors.lastname: Carroll
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Langdon L
authors.initials: LL
authors.lastname: Miller
authors.forename: Gary L
authors.initials: GL
authors.lastname: Elfring
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pignon
authors.forename: Pascal
authors.initials: P
authors.lastname: Piedbois
mesh_terms: D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000401:mortality*; D018450:Disease Progression; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage
chemical_list: D002955:Leucovorin; D005472:Fluorouracil