Ulrich Ronellenfitsch1, Katrin Jensen2, Svenja Seide3, Meinhard Kieser4, Matthias Schwarzbach5, Tracy E Slanger6, Bryan Burmeister7, David Kelsen8, Donna Niedzwiecki9, Guillaume Piessen10, Christoph Schuhmacher11, Susan Urba12, Cornelis van de Velde13, Marc Ychou14, Ralf Hofheinz15, Sylvie Lorenzen16. 1. Medical Faculty of the Martin Luther University Halle-Wittenberg and University Hospital Halle (Saale), Department of Visceral, Vascular and Endocrine Surgery, Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany. Electronic address: ulrich.ronellenfitsch@uk-halle.de. 2. Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 130.3, 69120, Heidelberg, Germany. Electronic address: jensen@imbi.uni-heidelberg.de. 3. Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 130.3, 69120, Heidelberg, Germany. Electronic address: seide@imbi.uni-heidelberg.de. 4. Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 130.3, 69120, Heidelberg, Germany. Electronic address: meinhard.kieser@imbi.uni-heidelberg. 5. Department of General, Visceral, Vascular, and Thoracic Surgery, Klinikum Frankfurt Höchst, Gotenstraβe 6-8, 65929, Frankfurt am Main, Germany. Electronic address: matthias.schwarzbach@klinikumfrankfurt.de. 6. Institute for Quality and Efficiency in Health Care (IQWiG), Im Mediapark 8, 50670, Cologne, Germany. Electronic address: t.slanger@hotmail.com. 7. University of Queensland, Princess Alexandra Hospital, Brisbane, Australia, Princess Alexandra Hospital, Brisbane, QLD, 4102, Australia. Electronic address: bryan.burmeister@health.qld.gov.au. 8. Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Avenue, New York, NY, 10065, USA. Electronic address: kelsend@mskcc.org. 9. The Alliance for Clinical Trials in Oncology (Alliance) Statistics and Data Center, Duke University Medical Center, Hock Plaza, 2424 Erwin Rd, Room 8040, Durham, NC, 27705, USA. Electronic address: donna.niedzwiecki@duke.edu. 10. Department of Digestive and Oncological Surgery, University Hospital C. Huriez, Inserm UMR-S 1172, Jean-Pierre Aubert Research Center (JPARC) Team, 1, Rue Polonovski, 59037, Lille Cedex, France. Electronic address: guillaume.piessen@chru-lille.fr. 11. Department of Surgery, Klinikum Rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. Electronic address: christoph.schuhmacher@tum.de. 12. Division of Hematology/Oncology, University of Michigan Medical Center, 1500 E Medical Center Drive, C347, SPC 5848 Ann Arbor, MI, 48109, USA. Electronic address: surba@med.umich.edu. 13. Department of Surgery, Leiden University Medical Center, K6-R, P.O. Box 9600, 2300, RC Leiden, the Netherlands. Electronic address: c.j.h.van_de_velde@lumc.nl. 14. Centre Régional de Lutte Contre le Cancer, Val D'Aurelle, Montpellier Cedex 05, France. Electronic address: marc.ychou@icm.unicancer.fr. 15. Day Treatment Center (TTZ), Interdisciplinary Tumor Center Mannheim (ITM) & 3rd Department of Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. Electronic address: ralf.hofheinz@umm.de. 16. 3rd Department of Internal Medicine (Hematology/Medical Oncology), Klinikum Rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany. Electronic address: sylvielorenzen@gmx.de.
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.
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.
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