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Title: Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer.
Austin Authors: Burzykowski, Tomasz;Coart, Elisabeth;Saad, Everardo D;Shi, Qian;Sommeijer, Dirkje W;Bokemeyer, Carsten;Díaz-Rubio, Eduardo;Douillard, Jean-Yves;Falcone, Alfredo;Fuchs, Charles S;Goldberg, Richard M;Hecht, J Randolph;Hoff, Paulo M;Hurwitz, Herbert;Kabbinavar, Fairooz F;Koopman, Miriam;Maughan, Timothy S;Punt, Cornelis J A;Saltz, Leonard;Schmoll, Hans-Joachim;Seymour, Matthew T;Tebbutt, Niall C ;Tournigand, Christophe;Van Cutsem, Eric;de Gramont, Aimery;Zalcberg, John R;Buyse, Marc
Affiliation: University Hospital S Chiara, Pisa, Italy
International Drug Development Institute, Louvain-la-Neuve, Belgium
Academic Medical Centre, Amsterdam, the Netherlands
Flevohospital, Almere, the Netherlands
Katholieke Universiteit, Leuven, Belgium
Hasselt University, Diepenbeek, Belgium
International Drug Development Institute Inc, San Francisco, California
Centre René Gauducheau, St Herblain, France
Hôpital Henri Mondor, Creteil, France
Franco-British Institute, Levallois-Perret, France
Division of Digestive Oncology, University Hospitals Gasthuisberg Leuven, Leuven, Belgium
The University of Sydney, Camperdown, New South Wales, Australia
Austin Health, Heidelberg, Victoria, Australia
School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
Department of Internal Medicine II and Clinic, University of Hamburg, Hamburg, Germany
Hospital Clinico San Carlos and Centro de Investigación Biomédica en Red Cáncer, CIBERONC, Madrid, Spain
Dana-Farber Cancer Institute, Boston, Massachusetts
West Virginia University Cancer Institute, Morgantown
David Geffen School of Medicine, University of California, Los Angeles
Instituto de Câncer do Estado de São Paulo, São Paulo, Brazil
Genentech, South San Francisco, California
David Geffen School of Medicine, University of California, Los Angeles
Department of Medical Oncology, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands
Cancer Research UK and the Medical Research Council Oxford Institute for Radiation Oncology, Oxford, United Kingdom
Amsterdam University Medical Centrum, Department of Medical Oncology, University of Amsterdam, Amsterdam, the Netherlands
Memorial Sloan-Kettering Cancer Center, New York, New York
Martin-Luther University, Halle, Germany
St James's Hospital, University of Leeds, Leeds, United Kingdom
Issue Date: 4-Sep-2019
Date: 2019-09-04
Publication information: JAMA network open 2019; 2(9): e1911750
Abstract: Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti-epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size-weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti-epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78). In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.
DOI: 10.1001/jamanetworkopen.2019.11750
Journal: JAMA network open
PubMed URL: 31539075
Type: Journal Article
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