Originally published as JCO Early Release 10.1200/JCO.2006.10.4323 on September 17 2007

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End Points for Colon Cancer Adjuvant Trials: Observations and Recommendations Based on Individual Patient Data From 20,898 Patients Enrolled Onto 18 Randomized Trials From the ACCENT Group

Daniel J. Sargent, Smitha Patiyil, Greg Yothers, Daniel G. Haller, Richard Gray, Jacqueline Benedetti, Marc Buyse, Roberto Labianca, Jean Francois Seitz, Christopher J. O'Callaghan, Guido Francini, Axel Grothey, Michael O'Connell, Paul J. Catalano, David Kerr, Erin Green, Harry S. Wieand, Richard M. Goldberg, Aimery de Gramont

From the Departments of Health Sciences Research and Medical Oncology, North Central Cancer Treatment Group, Mayo Clinic, Rochester, MN; Biostatistics Center, National Surgical Adjuvant Breast and Bowel Project Statistical Center and Operations Office, Pittsburgh; Abramson Cancer Center, University of Pennsylvania; the Department of Human Oncology, Allegheny General Hospital Philadelphia, PA; Southwest Oncology Group Statistical Center; Fred Hutchinson Cancer Research Center, Seattle, WA; Eastern Cooperative Oncology Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard University, Boston, MA; Department of Hematology/Oncology, University of North Carolina, Chapel Hill, NC; Quick and Simple and Reliable Collaborative Group, Clinical Trials Unit, University of Birmingham, Birmingham and the Department of Clinical Pharmacology, University of Oxford, Oxford, United Kingdom; International Drug Development Institute, Brussels Belgium; Unit Medical Oncology, Ospedali Riuniti, Bergamo; Medical Oncology Division, Institute of Internal Medicine, University of Siena, Siena, Italy; Gastroenterology Unit, C.H.U. la Timone; University of the Mediterranean, Marseilles; Hospital Saint Antoine, Paris, France; and the National Cancer Institute of Canada Clinical Trials Group, Queens University, Kingston, Ontario, Canada

Address reprint requests to Daniel J. Sargent, PhD, Mayo Clinic, 200 First St SW, Harwick 8-27, Rochester, MN 55905; e-mail: sargent.daniel{at}mayo.edu

Purpose: The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency.

Methods: Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model.

Results: DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients.

Conclusion: DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.

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

Supported by National Cancer Institute Grant No. CA25224.

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