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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/8746

Title: Individual- and trial-level surrogacy in colorectal cancer
Authors: BUYSE, Marc
BURZYKOWSKI, Tomasz
Michiels, Stefan
Carroll, Kevin
Issue Date: 2008
Publisher: SAGE PUBLICATIONS LTD
Citation: STATISTICAL METHODS IN MEDICAL RESEARCH, 17(5). p. 467-475
Abstract: Two conditions must be fulfilled for an intermediate endpoint to be an acceptable surrogate for a true clinical endpoint: (1) there must be a strong association between the surrogate and the true endpoint, and (2) there must be a strong association between the effects of treatment on the surrogate and the true endpoint. We rest whether these conditions are fulfilled for disease-free survival (DFS) and progression-free Survival (PFS) on data from 20 clinical trials comparing experimental treatments with standard treatments for early and advanced colorectal cancer. The effects of treatment on DFS jot ITS in advanced disease) and OS were quantified through log hazard ratios (log HR), estimated through a Weibull model stratified for trial. The rank correlation coefficients between DFS and OS, and trial-specific treatment effects, were estimated using a bivariate copula distribution for these endpoints. A linear regression model between the estimated log hazard ratios was used to compute the "surrogate threshold effect", which is the minimum treatment effect on IFS required to predict a non-zero treatment effect on OS in a future trial. In early disease, the rank correlation coefficient between DFS and OS was equal to 0.96, (CI 0.95-0.97). The correlation coefficient between the log hazard ratios was equal to 0.94 (CI 0.87-1.01). The risk reductions were approximately 3% smaller on OS than on DFS, and the surrogate threshold effect corresponded to a DFS hazard ratio of 0.93. In advanced disease, the rank correlation coefficient between PFS and OS was equal to 0.82 (CI 0.82-0.83). The correlation coefficient between the log hazard ratios was equal to 0.99 (CI 0.94-1.04). The risk reductions were approximately, 19%, smaller on OS than on ITS, and the surrogate threshold effect corresponded to a PFS hazard ratio of 0.86. One trial with a large treatment effect on PFS and OS had a strong influence on the results in advanced disease. DFS (and PFS in advanced disease) are acceptable surrogates for OS in colorectal cancer.
Notes: [Buyse, Marc] IDDI, Louvain, Belgium. [Buyse, Marc; Burzykowski, Tomasz] Hasselt Univ, Ctr Stat, Diepenbeek, Belgium. [Michiels, Stefan] Inst Gustave Roussy, Biostat & Epidemiol Unit, Villejuif, France. [Carroll, Kevin] Astra Zeneca Res & Dev, Oncol Therapy Area, Macclesfield, Cheshire, England.
URI: http://hdl.handle.net/1942/8746
DOI: 10.1177/0962280207081864
ISI #: 000260216700002
ISSN: 0962-2802
Category: A1
Type: Journal Contribution
Validation: ecoom, 2009
Appears in Collections: Research publications

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