TY - JOUR
T1 - Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma
T2 - Pooled analysis of individual patient data from randomised controlled trials
AU - Ronellenfitsch, Ulrich
AU - Jensen, Katrin
AU - Seide, Svenja
AU - Kieser, Meinhard
AU - Schwarzbach, Matthias
AU - Slanger, Tracy E.
AU - Burmeister, Bryan
AU - Kelsen, David
AU - Niedzwiecki, Donna
AU - Piessen, Guillaume
AU - Schuhmacher, Christoph
AU - Urba, Susan
AU - van de Velde, Cornelis
AU - Ychou, Marc
AU - Hofheinz, Ralf
AU - Lorenzen, Sylvie
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
KW - Disease-free survival
KW - Gastroesophageal adenocarcinoma
KW - Individual patient data meta-analysis
KW - Neoadjuvant chemoradiotherapy
KW - Neoadjuvant chemotherapy
KW - Overall survival
UR - http://www.scopus.com/inward/record.url?scp=85074158442&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2019.10.001
DO - 10.1016/j.ejca.2019.10.001
M3 - Article
C2 - 31678767
AN - SCOPUS:85074158442
SN - 0959-8049
VL - 123
SP - 101
EP - 111
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -