Disease-free survival (DFS) vs. overall survival (OS) as a primary endpoint for adjuvant colon cancer studies: Individual patient data from 12,915 patients on 15 randomized trials

Background: The traditional endpoint for colon adjuvant clinical trials (CT) is OS, with 5 years (yrs) used to demonstrate adequacy of follow-up (f-u). A shorter-term endpoint providing both clinically and statistically convincing evidence to allow a comparison of treatments could significantly speed both the CT process and the translation of advances into clinical practice. Methods: Individual patient data were pooled from 15 large randomized phase III colon adjuvant CT. Trials included 33 arms: 9 no chemotherapy control arms, 24 5-FU based chemotherapy arms, with a pooled sample size of 12,915 patients (pts). The primary hypothesis was that DFS, with 3 yrs f-u, is an appropriate primary endpoint to replace OS with 5 yrs f-u in phase III colon adjuvant CT. Median f-u was 8 yrs; 5 yr f-u was available on 93% of patients (pts). Results: The recurrence rate for yrs 1–5 was 11%, 13%, 7%, 4%, and 3%. Median time from recurrence to death was 14 months. 95% of pts alive and disease-free at 3 yr were alive at 5 yrs; 86% of pts with recurrence by 3 yrs died before 5 yrs. Overall per-pt concordance between 2, 3, and 4 yr DFS and 5 yr OS was 88%, 92%, and 92% respectively. Across all 33 study arms, correlation between 3 yr DFS and 5 yr OS was 0.94. Correlation of the difference in 3 yr DFS and 5 yr OS comparing control vs experimental arms within each trial was 0.88. Within trial log-rank testing using DFS with 3 yrs of f-u versus OS with 5 yrs f-u resulted in the same conclusion in 15 of 18 cases (83%); all three discordant results were only marginally significant for DFS (0.03 < p < 0.05). Differences in 5 yr OS retained 92% of the difference in 3 yr DFS (95% CI 67%–117%). Conclusions: In pts treated on phase III adjuvant colon CT, 3 yr DFS and 5 yr OS are highly correlated, both within pts and across trials. Within-trial comparisons of 3 yr DFS predict 5 yr OS comparisons with high concordance. These results suggest that DFS after 3 years f-u is an appropriate endpoint for adjuvant colon CTs of 5-FU-based regimens, although marginally significant 3 yr DFS improvements may not translate into significant 5 yr OS benefits