This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buyse, M. Articles by Piedbois, P. Search for Related Content PubMed PubMed Citation Articles by Buyse, M. Articles by Piedbois, P. Related Articles Related Editorial Social Bookmarking                            What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

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

This article has been cited by other articles:

				K. R. Broglio and D. A. Berry Detecting an Overall Survival Benefit that Is Derived From Progression-Free Survival J Natl Cancer Inst, November 9, 2009; (2009) djp369v1. [Abstract] [Full Text] [PDF]

				E. D. Saad, A. Katz, P. M. Hoff, and M. Buyse Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature Ann. Onc., November 9, 2009; (2009) mdp523v1. [Abstract] [Full Text] [PDF]

				P. A. Tang, G. R. Pond, and E. X. Chen Influence of an independent review committee on assessment of response rate and progression-free survival in phase III clinical trials Ann. Onc., October 29, 2009; (2009) mdp478v1. [Abstract] [Full Text] [PDF]

				A. Grothey and D. J. Sargent Reply to F. Montagnani et al J. Clin. Oncol., October 1, 2009; 27(28): e134 - e135. [Full Text] [PDF]

				N. Methy, L. Bedenne, T. Conroy, O. Bouche, O. Chapet, M. Ducreux, J.-P. Gerard, and F. Bonnetain Surrogate end points for overall survival and local control in neoadjuvant rectal cancer trials: statistical evaluation based on the FFCD 9203 trial Ann. Onc., September 16, 2009; (2009) mdp340v1. [Abstract] [Full Text] [PDF]

				R. M. Giusti, M. H. Cohen, P. Keegan, and R. Pazdur FDA Review of a Panitumumab (VectibixTM) Clinical Trial for First-Line Treatment of Metastatic Colorectal Cancer Oncologist, March 1, 2009; 14(3): 284 - 290. [Abstract] [Full Text] [PDF]

				M. E. Ray, K. Bae, M. H. A. Hussain, G. E. Hanks, W. U. Shipley, and H. M. Sandler Potential Surrogate Endpoints for Prostate Cancer Survival: Analysis of a Phase III Randomized Trial J Natl Cancer Inst, February 18, 2009; 101(4): 228 - 236. [Abstract] [Full Text] [PDF]

				F. G Miller and S. Joffe Benefit in phase 1 oncology trials: therapeutic misconception or reasonable treatment option? Clinical Trials, December 1, 2008; 5(6): 617 - 623. [Abstract] [PDF]

				M. Buyse, T. Burzykowski, S. Michiels, and K. Carroll Individual- and trial-level surrogacy in colorectal cancer Statistical Methods in Medical Research, October 1, 2008; 17(5): 467 - 475. [Abstract] [PDF]

				I. Iwanicki-Caron, F. Di Fiore, I. Roque, E. Astruc, M. Stetiu, A. Duclos, D. Tougeron, S. Saillard, S. Thureau, J. Benichou, et al. Usefulness of the Serum Carcinoembryonic Antigen Kinetic for Chemotherapy Monitoring in Patients With Unresectable Metastasis of Colorectal Cancer J. Clin. Oncol., August 1, 2008; 26(22): 3681 - 3686. [Abstract] [Full Text] [PDF]

				D. J. Sargent and D. F. Hayes Assessing the Measure of a New Drug: Is Survival the Only Thing That Matters? J. Clin. Oncol., April 20, 2008; 26(12): 1922 - 1923. [Full Text] [PDF]

				T. Burzykowski, M. Buyse, M. J. Piccart-Gebhart, G. Sledge, J. Carmichael, H.-J. Luck, J. R. Mackey, J.-M. Nabholtz, R. Paridaens, L. Biganzoli, et al. Evaluation of Tumor Response, Disease Control, Progression-Free Survival, and Time to Progression As Potential Surrogate End Points in Metastatic Breast Cancer J. Clin. Oncol., April 20, 2008; 26(12): 1987 - 1992. [Abstract] [Full Text] [PDF]

				M. E Buyse Surrogate Endpoints for Efficacy in Clinical Research: Working Definitions and Validation Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 659 - 663. [Abstract] [Full Text] [PDF]

				G. Yothers Toward Progression-Free Survival As a Primary End Point in Advanced Colorectal Cancer J. Clin. Oncol., November 20, 2007; 25(33): 5153 - 5154. [Full Text] [PDF]