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Progression-Free Survival Is a Surrogate for Survival in Advanced Colorectal Cancer

Marc Buyse, Tomasz Burzykowski, Kevin Carroll, Stefan Michiels, Daniel J. Sargent, Langdon L. Miller, Gary L. Elfring, Jean-Pierre Pignon, Pascal Piedbois

From the International Drug Development Institute, Louvain-la-Neuve; Center for Statistics, Hasselt University, Diepenbeek, Belgium; Oncology Therapy Area, AstraZeneca Research and Development, Macclesfield, United Kingdom; Biostatistics and Epidemiology Unit, Institut Gustave Roussy, Villejuif; Oncology Therapy Area, AstraZeneca, Rueil Malmaison, France; Division of Biostatistics, Mayo Clinic, Rochester, MN; and PTC Therapeutics, South Plainfield, NJ

Address reprint requests to Marc Buyse, ScD, IDDI, 30 avenue Provinciale, 1340 Louvain-la-Neuve, Belgium; e-mail: marc.buyse{at}iddi.com

Purpose: The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer.

Patients and Methods: Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects.

Results: In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS.

Conclusion: PFS is an acceptable surrogate for OS in advanced colorectal cancer.

Supported by the IAP Research Network P6/03 of the Belgian Government (Belgian Science Policy; T.B.).

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

Related Editorial

• Toward Progression-Free Survival As a Primary End Point in Advanced Colorectal Cancer
  Greg Yothers
  JCO 2007 25: 5153-5154 [Full Text]

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