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. 2022 Jan 11;114(1):60-67.
doi: 10.1093/jnci/djab187.

Reevaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials

Jun Yin  1 , Mohamed E Salem  2 , Jesse G Dixon  1 , Zhaohui Jin  3 , Romain Cohen  4 , Aimery DeGramont  5 , Eric Van Cutsem  6 , Julien Taieb  7 , Steven R Alberts  3 , Norman Wolmark  8 , Hans-Joachim Schmoll  9 , Leonard B Saltz  10 , Thomas J George  11 , Richard R M Goldberg  12 , Rachel Kerr  13 , Sara Lonardi  14 , Takayuki Yoshino  15 , Greg Yothers  16 , Axel Grothey  17 , Thierry Andre  4 , Qian Shi  1
Affiliations

Reevaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials

Jun Yin et al. J Natl Cancer Inst. .

Abstract

Background: Disease-free survival (DFS) with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival (OS) with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence in patients who received adjuvant FOLFOX. Hence, reevaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed.

Methods: Individual patient data from 9 randomized studies conducted between 1998 and 2009 were included; 3 trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (RWLS2) and Copula bivariate (RCopula2) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation.

Results: Data from a total of 18 396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (T1-3 and N1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high or deficient mismatch repair tumors. Trial-level correlation between 3-year DFS and 5-year OS remained strong (RWLS2 = 0.82, 95% CI = 0.67 to 0.98; RCopula2 = 0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results.

Conclusions: Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

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Figures

Figure 1.
Figure 1.
Trial-level treatment effect correlation between disease-free survival (DFS) and overall survival (OS). A) Three-year DFS vs 5-year OS. B) Three-year DFS vs 6-year OS. C) Three-year DFS vs 6.5-year OS. The circle or triangle size is proportional to the number of patients in each comparison. The solid line indicates fitted weighted least squares (WLS) regression line; gray dashed lines indicate 95% prediction limits. Triangles indicate trial comparisons with irinotecan, circles indicate comparisons with oxaliplatin, and black and gray colors indicate comparisons with and without biologics, respectively. HR = hazard ratio.
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