title: Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials.
abstract: OBJECTIVE
  A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice.
  
  
  METHODS
  Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up.
  
  
  RESULTS
  The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied.
  
  
  CONCLUSIONS
  In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.
authors.affiliation: North Central Cancer Treatment Group, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. sargent.daniel@mayo.edu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Harry S
authors.initials: HS
authors.lastname: Wieand
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Haller
authors.forename: Richard
authors.initials: R
authors.lastname: Gray
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Benedetti
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Roberto
authors.initials: R
authors.lastname: Labianca
authors.forename: Jean Francois
authors.initials: JF
authors.lastname: Seitz
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Callaghan
authors.forename: Guido
authors.initials: G
authors.lastname: Francini
authors.forename: Axel
authors.initials: A
authors.lastname: Grothey
authors.forename: Michael
authors.initials: M
authors.lastname: O'Connell
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Catalano
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.forename: Erin
authors.initials: E
authors.lastname: Green
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
authors.forename: Thierry
authors.initials: T
authors.lastname: Andre
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Aimery
authors.initials: A
authors.lastname: De Gramont
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000601:surgery*; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000601:surgery; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D016896:Treatment Outcome