COMPARATIVE STUDY
JOURNAL ARTICLE

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

Daniel J Sargent, Harry S Wieand, Daniel G Haller, Richard Gray, Jacqueline K Benedetti, Marc Buyse, Roberto Labianca, Jean Francois Seitz, Christopher J O'Callaghan, Guido Francini, Axel Grothey, Michael O'Connell, Paul J Catalano, Charles D Blanke, David Kerr, Erin Green, Norman Wolmark, Thierry Andre, Richard M Goldberg, Aimery De Gramont
Journal of Clinical Oncology 2005 December 1, 23 (34): 8664-70
16260700

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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