Journal of the National Cancer Institute Advance Access originally published online on February 10, 2009
JNCI Journal of the National Cancer Institute 2009 101(4):228-236; doi:10.1093/jnci/djn489
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© The Author 2009. Published by Oxford University Press.
ARTICLES |
Potential Surrogate Endpoints for Prostate Cancer Survival: Analysis of a Phase III Randomized Trial
Affiliations of authors: Radiology Associates of Appleton, Appleton, WI (MER); Department of Statistics, Radiation Therapy Oncology Group, Philadelphia, PA (KB); Department of Internal Medicine (MHAH) and Department of Radiation Oncology (HMS), University of Michigan, Ann Arbor, MI; Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA (GEH); Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (WUS)
Correspondence to: Michael E. Ray, MD, PhD, Radiology Associates of Appleton, 1818 North Meade St, Appleton, WI 54911 (e-mail: michael.ray{at}thedacare.org).
Background: The identification of surrogate endpoints for prostate cancer–specific survival may shorten the length of clinical trials for prostate cancer. We evaluated distant metastasis and general clinical treatment failure as potential surrogates for prostate cancer–specific survival by use of data from the Radiation Therapy and Oncology Group 92-02 randomized trial.
Methods: Patients (n = 1554 randomly assigned and 1521 evaluable for this analysis) with locally advanced prostate cancer had been treated with 4 months of neoadjuvant and concurrent androgen deprivation therapy with external beam radiation therapy and then randomly assigned to no additional therapy (control arm) or 24 additional months of androgen deprivation therapy (experimental arm). Data from landmark analyses at 3 and 5 years for general clinical treatment failure (defined as documented local disease progression, regional or distant metastasis, initiation of androgen deprivation therapy, or a prostate-specific antigen level of 25 ng/mL or higher after radiation therapy) and/or distant metastasis were tested as surrogate endpoints for prostate cancer–specific survival at 10 years by use of Prentice’s four criteria. All statistical tests were two-sided.
Results: At 3 years, 1364 patients were alive and contributed data for analysis. Both distant metastasis and general clinical treatment failure at 3 years were consistent with all four of Prentice's criteria for being surrogate endpoints for prostate cancer–specific survival at 10 years. At 5 years, 1178 patients were alive and contributed data for analysis. Although prostate cancer–specific survival was not statistically significantly different between treatment arms at 5 years (P = .08), both endpoints were consistent with Prentice's remaining criteria.
Conclusions: Distant metastasis and general clinical treatment failure at 3 years may be candidate surrogate endpoints for prostate cancer–specific survival at 10 years. These endpoints, however, must be validated in other datasets.
| CONTEXT AND CAVEATS Prior knowledge Surrogate endpoints for prostate cancer–specific survival may shorten the length of time required to conduct clinical trials for prostate cancer. Study design Prentice's four criteria were used to test 3- and 5-year results from a phase III randomized trial in patients with locally advanced prostate cancer to determine whether general treatment failure or distant metastasis at these times qualified as surrogate endpoints for prostate cancer–specific survival at 10 years. Contribution Analysis of data at 3 years from 1364 patients found that both general treatment failure or distant metastasis were consistent with all of Prentice's four criteria for being surrogate endpoints for prostate cancer–specific survival at 10 years. Implications General treatment failure or distant metastasis should be further validated as surrogate endpoints in other datasets. Limitations Data from only one trial were used in this study. Statistical methods for establishing and validating a surrogate endpoint, such as Prentice's criteria, must be applied with caution and with an appreciation of their limitations. From the Editors
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Manuscript received May 5, 2008; revised November 20, 2008; accepted December 5, 2008.
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J Natl Cancer Inst 2009 101: 215.
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