Download Disease-Free Survival Versus Overall Survival As a Primary End

VOLUME
23
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NUMBER
34
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DECEMBER
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2005
JOURNAL OF CLINICAL ONCOLOGY
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Disease-Free Survival Versus Overall Survival As a
Primary End Point for Adjuvant Colon Cancer
Studies: A Commentary
Judith Abrams, Karmanos Cancer Institute, Wayne State University, Detroit, MI
In this issue of the Journal of Clinical Oncology, Sargent
et al1 evaluated disease-free survival with 3 years of followup (DFS3 years) as a surrogate for overall survival with 5 years of
follow-up (OS5 years) and conclude that it is an appropriate
primary end point to replace OS in phase III clinical trials of
adjuvant fluorouracil (FU) -based therapies for colon cancer.
In most definitive studies of the benefits of potential cancer therapies, OS is the primary end point because (1) it has
obvious clinical importance, (2) survival of an individual patient can be unambiguously assessed, and (3) even if a patient
does not return for follow-up evaluation, survival information
can be obtained from death registries such as that provided by
the United States Social Security Administration. These advantages are balanced by several disadvantages: (1) use of OS as the
primary end point may prolong evaluation of new therapies
because of the long follow-up time required to obtain adequate
information for assessment; (2) studies of long duration may
be weakened by decreasing patient compliance over time and
increasing losses to follow-up; (3) because of this, long-term
studies are more expensive to conduct; (4) studies of long
duration may delay approval and dissemination of effective
therapies and postpone pursuit of alternative research strategies when a therapy proves to be ineffective.
For these reasons, investigators have considered the use
of clinical end points that are surrogates for the true end
point and that require less time to evaluate and may be less
costly to assess. There are, however, significant statistical
challenges to be addressed when considering use of a surrogate end point. Although the true end point is assumed to be
causally related to the effectiveness of treatment, that relationship must be verified for a surrogate. Additionally, there
are critical assumptions about the relationship between the
surrogate and the true end point that require verification.2-6
In the current study, the authors analyzed data from 18
different trials in which there were 43 different treatment
8564
arms with a total of nearly 21,000 patients. Their evaluation
of DFS as a surrogate is strengthened by their consideration
of the relationship between DFS3 years and OS5 years at 3
levels: the patient, the treatment arm, and the trial. An end
point that is a good surrogate at the level of the patient but not
at the level of the trial is not useful for hastening evaluation of
new therapies. One that meets the criteria of a good surrogate
at the level of the trial but not at the level of the patient has no
clinical value. One that is valid only for some treatment arms
may distort the effects of therapy and is, obviously, not a useful
surrogate. In this study, DFS3 years is shown to be an appropriate surrogate for OS5 years at each level of analysis.
Although future studies of FU-based adjuvant therapy
for patients with stages II and III colon cancer may comfortably use DFS3 years as a primary end point replacing OS5 years,
casual readers are cautioned against generalizing these results to all colon cancer trials or to cancer clinical trials in
general. These results depend on specific features of the
disease and the current state of diagnosis and therapy. For
example, colon cancer diagnosed at stages II and III has
poor prognosis and, if the disease recurs, it is likely to result
in imminent death, median survival time being approximately 1 year. DFS may not be an appropriate surrogate
clinical end point for diseases in which treatment for recurrence is more often successful in prolonging survival. If
there are significant advances in treatment for recurrence,
then the statistical association between DFS and OS will be
weakened, and one of the critical assumptions needed for
determination of a surrogate end point will be violated.
As the authors point out, if new diagnostic methods
detect recurrent disease sooner than current methods, then
there will be an apparent decrease in time to recurrence and
an apparent increase in time from recurrence to death.
Without advances in treatment for recurrence, advances in
diagnosis may require consideration of other time points
Journal of Clinical Oncology, Vol 23, No 34 (December 1), 2005: pp 8564-8565
DOI: 10.1200/JCO.2005.03.6186
Downloaded from jco.ascopubs.org on January 4, 2010 . For personal use only. No other uses without permission.
Copyright © 2005 by the American Society of Clinical Oncology. All rights reserved.
Editorial
for DFS and OS, although the underlying relationship between DFS and OS is unlikely to be altered.
Sargent et al1 not only provide important results on the
choice of clinical end points for clinical researchers, but
they also provide a model for the careful evaluation of
possible clinical surrogates for true clinical end points.
■ ■ ■
Author’s Disclosures of Potential
Conflicts of Interest
The author indicated no potential conflicts of interest.
© 2005 by American Society of Clinical Oncology
REFERENCES
1. Sargent DF, Wieand S, Haller DG, et al: 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. J Clin
Oncol 23:8664-8670, 2005
2. Prentice RL: Surrogate endpoints in clinical trials: Definition and
operational criteria. Stat Med 8:411-440, 1989
3. Freedman LS, Graubard BL, Schatzkin A: Statistical validation of
intermediate endpoints for chronic diseases. Stat Med 11:167-178, 1992
4. Buyse M, Molenberghs G: Criteria for the validation of surrogate
endpoints in randomized experiments. Biometrics 54:1014-1029, 1998
5. Biomarkers Definitions Working Group: Commentary: Biomarkers and
surrogate endpoints—Preferred definitions and conceptual framework. Clin
Pharmacol Ther 69:89-95, 2001
6. Molenberghs G, Buyse M, Geys H, et al: Statistical challenges in the
evaluation of surrogate endpoints in randomized trials. Control Clin Trials
23:607-625, 2002
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