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.
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.
de Gramont
Aimery
A
Hopital Saint Antoine, Group Hospitalier Pitie-Salpetriere, Paris, France.
Hubbard
Joleen
J
Shi
Qian
Q
O'Connell
Michael J
MJ
Buyse
Marc
M
Benedetti
Jacqueline
J
Bot
Brian
B
O'Callaghan
Chris
C
Yothers
Greg
G
Goldberg
Richard M
RM
Blanke
Charles D
CD
Benson
Al
A
Deng
Qiqi
Q
Alberts
Steven R
SR
Andre
Thierry
T
Wolmark
Norman
N
Grothey
Axel
A
Sargent
Daniel
D
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