Originally published as JCO Early Release 10.1200/JCO.2005.01.6071 on October 31 2005

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Disease-Free Survival Versus Overall Survival As a Primary End Point for Adjuvant Colon Cancer Studies: Individual Patient Data From 20,898 Patients on 18 Randomized Trials

From the North Central Cancer Treatment Group, Mayo Clinic, Rochester, MN; National Surgical Adjuvant Breast and Bowel Project Statistical Center and Operations Office, Pittsburgh; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; QUASAR Collaborative Group, Birmingham and Oxford, United Kingdom; Southwest Oncology Group Statistical Center, Seattle, WA; International Drug Development Institute, Brussels, Belgium; Ospedali Riuniti, Bergamo; University of Siena, Siena, Italy; University of the Mediterranean, Marseilles; Groupe d'Etude et de Recherche Clinique en Oncologie et Radiothérapie, Paris; Hospital Saint Antoine, Paris, France; National Cancer Institute of Canada Clinical Trials Group, Queens University, Kingston, Ontario, Canada; Eastern Cooperative Oncology Group Statistical Center, Boston, MA; Oregon Health and Science University Cancer Institute, Portland, OR; and University of North Carolina, Chapel Hill, NC

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

PURPOSE: A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice.

METHODS: Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up.

RESULTS: The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied.

CONCLUSION: In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

Supported in part by National Cancer Institute Grant No. CA25224.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.

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

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• Disease-Free Survival Versus Overall Survival As a Primary End Point for Adjuvant Colon Cancer Studies: A Commentary
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  JCO 2005 23: 8564-8565 [Full Text]

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