TY - JOUR
T1 - Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies
T2 - Individual patient data from 20,898 patients on 18 randomized trials
AU - Sargent, Daniel J.
AU - Wieand, Harry S.
AU - Haller, Daniel G.
AU - Gray, Richard
AU - Benedetti, Jacqueline K.
AU - Buyse, Marc
AU - Labianca, Roberto
AU - Seitz, Jean Francois
AU - O'Callaghan, Christopher J.
AU - Francini, Guido
AU - Grothey, Axel
AU - O'Connell, Michael
AU - Catalano, Paul J.
AU - Blanke, Charles D.
AU - Kerr, David
AU - Green, Erin
AU - Wolmark, Norman
AU - Andre, Thierry
AU - Goldberg, Richard M.
AU - De Gramont, Aimery
PY - 2005
Y1 - 2005
N2 - Purpose: 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. Conclusion: 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.
AB - Purpose: 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. Conclusion: 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.
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U2 - 10.1200/JCO.2005.01.6071
DO - 10.1200/JCO.2005.01.6071
M3 - Article
C2 - 16260700
AN - SCOPUS:33644834827
SN - 0732-183X
VL - 23
SP - 8664
EP - 8670
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 34
ER -