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

Ulrich Ronellenfitsch, Katrin Jensen, Svenja Seide, Meinhard Kieser, Matthias Schwarzbach, Tracy E. Slanger, Bryan Burmeister, David Kelsen, Donna Niedzwiecki, Guillaume Piessen, Christoph Schuhmacher, Susan Urba, Cornelis van de Velde, Marc Ychou, Ralf Hofheinz, Sylvie Lorenzen

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish
Pages (from-to)101-111
Number of pages11
JournalEuropean Journal of Cancer
Volume123
DOIs
StatePublished - Dec 2019
Externally publishedYes

Keywords

  • Disease-free survival
  • Gastroesophageal adenocarcinoma
  • Individual patient data meta-analysis
  • Neoadjuvant chemoradiotherapy
  • Neoadjuvant chemotherapy
  • Overall survival

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