title: Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: simulations based on the 20,800 patient ACCENT data set.
abstract: OBJECTIVE
  We previously validated disease-free survival (DFS) as a surrogate for overall survival (OS) in fluorouracil-based adjuvant colon cancer clinical trials. New therapies have extended survival after recurrence from 1 to approximately 2 years. We examined the possible impact of this improvement on the DFS/OS association.
  
  
  METHODS
  The Adjuvant Colon Cancer Endpoints (ACCENT) data set of 20,898 patients was analyzed. In an exploratory fashion, time from recurrence to death in patients experiencing recurrence was extended using several algorithms, and the association of DFS after 3 years of median follow-up and OS after varying lengths of follow-up (median of 5, 6, and 7 years) was assessed.
  
  
  RESULTS
  Seven thousand four hundred two patients (35%) experienced recurrence. Median time from recurrence to death was 24 months in the hypothetical data sets. When times from recurrence to death were doubled, the association between treatment effects on DFS and 5-year OS was modest (R(2) = 0.51 for both 2- and 3-year DFS) but remained strong for DFS and 6-year OS (R(2) = 0.67 for both 2- and 3-year DFS) and 7-year OS (R(2) = 0.70 for both 2- and 3-year DFS). The reduced DFS/OS association with extended survival after recurrence was greater in stage II than stage III patients. Multiple simulations provided consistent findings.
  
  
  CONCLUSIONS
  Extended survival after recurrence reduces the association between treatment effects on 3-year DFS and 5-year OS, particularly in stage II patients; longer follow-up strengthens the association. In modern adjuvant trials, 6 or 7 years may be required to demonstrate OS improvements, further supporting DFS as the preferred primary end point for future adjuvant colon cancer clinical trials.
authors.affiliation: Hopital Saint Antoine, Group Hospitalier Pitie-Salpetriere, Paris, France.
authors.forename: Aimery
authors.initials: A
authors.lastname: de Gramont
authors.forename: Joleen
authors.initials: J
authors.lastname: Hubbard
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Connell
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Benedetti
authors.forename: Brian
authors.initials: B
authors.lastname: Bot
authors.forename: Chris
authors.initials: C
authors.lastname: O'Callaghan
authors.forename: Greg
authors.initials: G
authors.lastname: Yothers
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
authors.forename: Al
authors.initials: A
authors.lastname: Benson
authors.forename: Qiqi
authors.initials: Q
authors.lastname: Deng
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
authors.forename: Thierry
authors.initials: T
authors.lastname: Andre
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
authors.forename: Axel
authors.initials: A
authors.lastname: Grothey
authors.forename: Daniel
authors.initials: D
authors.lastname: Sargent
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D018572:Disease-Free Survival; D005500:Follow-Up Studies; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000401:mortality*; D016019:Survival Analysis; D013997:Time Factors