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

Abstract

Purpose: 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.

Conclusion: 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.

Fig 1.

Scatter plots of hazard ratios by trial (disease-free survival [DFS] v overall survival [OS]). (A) Three-year DFS versus 5-year OS (actual data). (B) Three-year DFS versus 5-year OS (hypothetical data, doubled time from recurrence to death). (C) Three-year DFS versus 6-year OS (hypothetical data, doubled time from recurrence to death). (D) Three-year DFS versus 7-year OS (hypothetical data, doubled time from recurrence to death).

Fig 2.

R² values for actual data and hypothetical survival extensions based on patient-specific characteristics.