title: End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group.
abstract: OBJECTIVE
  The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency.
  
  
  METHODS
  Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model.
  
  
  RESULTS
  DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients.
  
  
  CONCLUSIONS
  DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.
authors: Department of Health Sciences Research, North Central Cancer Treatment Group, Mayo Clinic, Rochester, MN 55905, USA. sargent.daniel@mayo.edu
authors: Daniel J
authors: DJ
authors: Sargent
authors: Smitha
authors: S
authors: Patiyil
authors: Greg
authors: G
authors: Yothers
authors: Daniel G
authors: DG
authors: Haller
authors: Richard
authors: R
authors: Gray
authors: Jacqueline
authors: J
authors: Benedetti
authors: Marc
authors: M
authors: Buyse
authors: Roberto
authors: R
authors: Labianca
authors: Jean Francois
authors: JF
authors: Seitz
authors: Christopher J
authors: CJ
authors: O'Callaghan
authors: Guido
authors: G
authors: Francini
authors: Axel
authors: A
authors: Grothey
authors: Michael
authors: M
authors: O'Connell
authors: Paul J
authors: PJ
authors: Catalano
authors: David
authors: D
authors: Kerr
authors: Erin
authors: E
authors: Green
authors: Harry S
authors: HS
authors: Wieand
authors: Richard M
authors: RM
authors: Goldberg
authors: Aimery
authors: A
authors: de Gramont
mesh_terms: D000368:Aged; D017024:Chemotherapy, Adjuvant / Q000379:methods*; D017326:Clinical Trials, Phase III as Topic; D003110:Colonic Neoplasms / Q000401:mortality* / Q000628:therapy*; D015179:Colorectal Neoplasms / Q000401:mortality / Q000628:therapy*; D003627:Data Interpretation, Statistical; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D012008:Recurrence; D013997:Time Factors; D016896:Treatment Outcome