Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma: Pooled analysis of individual patient data from randomised controlled trials Journal Article


Authors: Ronellenfitsch, U.; Jensen, K.; Seide, S.; Kieser, M.; Schwarzbach, M.; Slanger, T. E.; Burmeister, B.; Kelsen, D.; Niedzwiecki, D.; Piessen, G.; Schuhmacher, C.; Urba, S.; van de Velde, C.; Ychou, M.; Hofheinz, R.; Lorenzen, S.
Article Title: Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma: Pooled analysis of individual patient data from randomised controlled trials
Abstract: Introduction: Disease-free survival (DFS) is increasingly being used as surrogate end-point for overall survival (OS) in cancer trials. So far, there has been no validation of the surrogacy of DFS for OS for neoadjuvant treatment of gastroesophageal adenocarcinoma. Methods: The study uses individual patient data (IPD) from eight randomised controlled trials (RCTs) (n = 1126 patients) comparing neoadjuvant therapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. Correlation between OS time and DFS time was calculated to evaluate individual-level surrogacy. For each trial, survival curves using the Kaplan-Meier method were plotted and hazard ratios (HRs) on the treatment effects were calculated for OS and DFS separately. Those HRs were pooled in a random-effects meta-analysis. Observed HRs were compared with predicted HRs for OS using results from an error-in-variables linear regression model accounting for the uncertainty about the estimated effect. The strength of the association was quantified by the coefficient of determination to assess trial-level surrogacy. The surrogate threshold effect was calculated to determine the minimum treatment effect on DFS necessary to predict a non-zero treatment effect on OS. Results: A strong correlation between OS time and DFS time was observed, indicating a high individual-level surrogacy. For all RCTs, estimated HRs for OS and DFS were highly similar. In the meta-analysis, the overall HR for OS was virtually identical to that for DFS. The estimated coefficient of determination r2 for the association between HRs for OS and DFS was 0.912 (95% confidence interval: 0.75–1.0), indicating a very good fit of the regression model and thus a strong trial-level surrogacy between OS and DFS. The surrogate threshold effect based on the regression analysis was 0.79. Discussion: Based on strong correlations between DFS and OS, as well as a strong correlation of the treatment effects of the two end-points in the error-in-variable regression, DFS seems an appropriate surrogate marker for OS in randomised trials of neoadjuvant chemotherapy or chemoradiotherapy for gastroesophageal adenocarcinoma. © 2019 Elsevier Ltd
Keywords: disease-free survival; overall survival; neoadjuvant chemotherapy; gastroesophageal adenocarcinoma; neoadjuvant chemoradiotherapy; individual patient data meta-analysis
Journal Title: European Journal of Cancer
Volume: 123
ISSN: 0959-8049
Publisher: Elsevier Inc.  
Date Published: 2019-12-01
Start Page: 101
End Page: 111
Language: English
DOI: 10.1016/j.ejca.2019.10.001
PROVIDER: scopus
PUBMED: 31678767
PMCID: PMC8767957
DOI/URL:
Notes: Article -- Export Date: 2 December 2019 -- Source: Scopus
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  1. David P Kelsen
    537 Kelsen