Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: Findings from the analysis and research in cancers of the digestive system database

Qian Shi, Aimery De Gramont, Axel Grothey, John Zalcberg, Benoist Chibaudel, Hans Joachim Schmoll, Matthew T. Seymour, Richard Adams, Leonard Saltz, Richard M. Goldberg, Cornelis J.A. Punt, Jean Yves Douillard, Paulo M. Hoff, Joel Randolph Hecht, Herbert Hurwitz, Eduardo Díaz-Rubio, Rainer Porschen, Niall C. Tebbutt, Charles Fuchs, John SouglakosAlfredo Falcone, Christophe Tournigand, Fairooz F. Kabbinavar, Volker Heinemann, Eric Van Cutsem, Carsten Bokemeyer, Marc Buyse, Daniel J. Sargent

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Purpose: Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination. Methods: Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti-epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2 statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models. Results: Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy. Conclusion: In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

Original languageEnglish (US)
Pages (from-to)22-28
Number of pages7
JournalJournal of Clinical Oncology
Volume33
Issue number1
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Shi, Q., De Gramont, A., Grothey, A., Zalcberg, J., Chibaudel, B., Schmoll, H. J., Seymour, M. T., Adams, R., Saltz, L., Goldberg, R. M., Punt, C. J. A., Douillard, J. Y., Hoff, P. M., Hecht, J. R., Hurwitz, H., Díaz-Rubio, E., Porschen, R., Tebbutt, N. C., Fuchs, C., ... Sargent, D. J. (2015). Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: Findings from the analysis and research in cancers of the digestive system database. Journal of Clinical Oncology, 33(1), 22-28. https://doi.org/10.1200/JCO.2014.56.5887