Originally published as JCO Early Release 10.1200/JCO.2006.08.1935 on September 17 2007

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Surrogate End Points for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis From 39 Randomized Controlled Trials of First-Line Chemotherapy

Patricia A. Tang, Søren M. Bentzen, Eric X. Chen, Lillian L. Siu

From the Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Canada; and the Departments of Human Oncology and Medical Physics, University of Wisconsin Comprehensive Cancer Center, Madison, WI

Address reprint requests to Lillian L. Siu, MD, FRCPC, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Suite 5-718, Toronto, Canada M5G 2M9; e-mail: lillian.siu{at}uhn.on.ca

Purpose Our aims were to determine the correlations between progression-free survival (PFS), time to progression (TTP), and response rate (RR) with overall survival (OS) in the first-line treatment of metastatic colorectal cancer (MCRC), and to identify a potential surrogate for OS.

Methods Randomized trials of first-line chemotherapy in MCRC were identified, and statistical analyses were undertaken to evaluate the correlations between the end points.

Results Thirty-nine randomized controlled trials were identified containing a total of 87 treatment arms. Among trials, the nonparametric Spearman rank correlation coefficient (r_s) between differences () in surrogate end points (PFS, TTP, and RR) and OS were 0.74 (95% CI, 0.47 to 0.88), 0.52 (95% CI, 0.004 to 0.81), 0.39 (95% CI, 0.08 to 0.63), respectively. The r_s for PFS was not significantly different from the r_s TTP (P = .28). Linear regression analysis was performed using hazard ratios for PFS and OS. There was a strong relationship between hazard ratios for PFS and OS; the slope of the regression line was 0.54 ± 0.10, indicating that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 5.4% ± 1% risk reduction for OS.

Conclusion In first-line chemotherapy trials for MCRC, improvements in PFS are strongly associated with improvements in OS. In this patient population, PFS may be an appropriate surrogate for OS. As a clinical end point, PFS offers increased statistical power at a given time of analysis and a significant lead time advantage compared with OS.

published online ahead of print at www.jco.org on September 17, 2007.

Presented in part at the 2006 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 26-28, 2006, San Francisco, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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