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.
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.
Sargent
Daniel J
DJ
North Central Cancer Treatment Group, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. sargent.daniel@mayo.edu
Wieand
Harry S
HS
Haller
Daniel G
DG
Gray
Richard
R
Benedetti
Jacqueline K
JK
Buyse
Marc
M
Labianca
Roberto
R
Seitz
Jean Francois
JF
O'Callaghan
Christopher J
CJ
Francini
Guido
G
Grothey
Axel
A
O'Connell
Michael
M
Catalano
Paul J
PJ
Blanke
Charles D
CD
Kerr
David
D
Green
Erin
E
Wolmark
Norman
N
Andre
Thierry
T
Goldberg
Richard M
RM
De Gramont
Aimery
A
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