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Meta-Analysis
. 2011 May;47(7):990-6.
doi: 10.1016/j.ejca.2010.12.015. Epub 2011 Jan 21.

Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803

D Sargent  1 , Q Shi, G Yothers, E Van Cutsem, J Cassidy, L Saltz, N Wolmark, B Bot, A Grothey, M Buyse, A de Gramont; Adjuvant Colon Cancer End-points (ACCENT) Group
Collaborators, Affiliations
Meta-Analysis

Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803

D Sargent et al. Eur J Cancer. 2011 May.

Abstract

Background: The ACCENT group previously established disease-free survival (DFS) with 2 or 3 years median follow-up to predict 5 year overall survival (5 year OS) in stage II and III colon cancer. ACCENT further proposed (1) a stronger association between DFS and OS in stage III than II, and (2) 6 or 7 years necessary to demonstrate DFS/OS surrogacy in recent trials. The relationship between end-points in trials with oral fluoropyrimidines, oxaliplatin and irinotecan is unknown.

Methods: Associations between the treatment effect hazard ratios (HRs) on 2 and 3 years DFS, and 5 and 6 years OS were examined in 6 phase III trials not included in prior analyses from 1997 to 2002. Individual data for 12,676 patients were analysed; two trials each tested oxaliplatin, irinotecan and oral treatment versus 5-FU/LV.

Findings: Overall association between 2/3 year DFS and 5/6 year OS HRs was modest to poor (simple R² measures: 0.58-0.76, model-based R²: 0.17-0.49). In stage III patients, the association increased (model-based R² ≥ 0.79). Observed treatment effects on 2 year DFS accurately 5/6 year OS effects overall and in stage III patients.

Interpretation: In recent trials of cytotoxic chemotherapy, 2 or 3 years DFS HRs are highly predictive of 5 and 6 years OS HRs in stage III but not stage II patients. In all patients the DFS/OS association is stronger for 6 year OS, thus at least 6 year follow-up is recommended to assess OS benefit. These data support DFS as the primary end-point for stage III colon cancer trials testing cytotoxic agents.

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Figures

Figure 1
Figure 1
Rate of recurrence and death by time from randomization (online only) Legend: Risk of recurrence in each 6 month interval following randomization among those remaining recurrence free at the start of each interval, by time.
Figure 2
Figure 2
Hazard ratios for 2 and 3yr DFS vs 5 and 6yr OS, stage III patients Figure 2A: 2yr DFS vs 5yr OS Figure 2B: 3yr DFS vs 5yr OS Figure 2C: 2yr DFS vs 6yr OS Figure 2D: 3yr DFS vs 6yr OS
Figure 2
Figure 2
Hazard ratios for 2 and 3yr DFS vs 5 and 6yr OS, stage III patients Figure 2A: 2yr DFS vs 5yr OS Figure 2B: 3yr DFS vs 5yr OS Figure 2C: 2yr DFS vs 6yr OS Figure 2D: 3yr DFS vs 6yr OS
Figure 2
Figure 2
Hazard ratios for 2 and 3yr DFS vs 5 and 6yr OS, stage III patients Figure 2A: 2yr DFS vs 5yr OS Figure 2B: 3yr DFS vs 5yr OS Figure 2C: 2yr DFS vs 6yr OS Figure 2D: 3yr DFS vs 6yr OS
Figure 2
Figure 2
Hazard ratios for 2 and 3yr DFS vs 5 and 6yr OS, stage III patients Figure 2A: 2yr DFS vs 5yr OS Figure 2B: 3yr DFS vs 5yr OS Figure 2C: 2yr DFS vs 6yr OS Figure 2D: 3yr DFS vs 6yr OS
Figure 3
Figure 3
Model-based predictions and actual hazard ratios, 2yr DFS as a predictor for 6yr OS, stage III only
See this image and copyright information in PMC

References

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