This study is a secondary analysis of the randomized, cooperative group phase III trail, RTOG 92-02. The purpose of this analysis was to evaluate distant metastasis and general clinical treatment failure as surrogate endpoints for prostate cancer–specific survival by using the surrogacy criteria of Prentice (10
). 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. 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 three remaining criteria. These results suggest that distant metastasis and general clinical treatment failure at 3 and 5 years may be useful surrogate endpoints for prostate cancer–specific survival.
An increasing number of randomized clinical studies of modern local therapies for patients with clinically localized prostate cancer that found improved biochemical outcomes have been reported (14
). However, relatively few prostate cancer trials have demonstrated statistically significant differences in prostate cancer–specific survival or overall survival (1
). Because of the long natural history of prostate cancer, randomized trials designed to detect statistically significant differences in mortality often are prohibitive in terms of size, duration, and cost. In contrast, colorectal cancers have a relatively rapid natural history, and many trials of adjuvant therapy have demonstrated statistically significant survival differences (18
). By using meta-analysis of multiple randomized experiments, investigators have demonstrated that disease-free survival is a valid surrogate endpoint for overall survival in colorectal cancer (20
). The identification and rigorous validation of surrogate endpoints for overall or disease-specific survival are of great utility in clinical cancer research because the use of surrogate endpoints substantially decreases the size and duration of clinical trials, allowing more rapid prospective testing of hypotheses and potentially accelerating development of improved cancer treatment.
This study had several limitations arising from the challenges of proving Prentice's key fourth criterion and the fact that data from only one trial were available for this analysis. 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 (23
). In particular, the failure to reject the critical Prentice's fourth criterion is not necessarily definite evidence that the criterion holds. Furthermore, surrogate endpoint analyses are ideally conducted with meta-analytic approaches and include data from many randomized trials. Unfortunately, few randomized trials of treatment for localized prostate cancer have yet observed statistically significant differences in survival endpoints, limiting the opportunity for comprehensive meta-analysis.
Although this analysis included patients from only one clinical trial, the findings are strengthened because they derive from data on a large group of patients who were treated in a multi-institutional setting under the direction of a large cooperative group. The RTOG 92-02 trial was conducted with standardized data collection, treatment, and follow-up. All patients were treated between June 26, 1992, and April 15, 1995, with subsequent follow-up, all occurring within the PSA era. Although this study is a retrospective secondary analysis, data are from a prospective randomized trial, which should remove potential sources of selection or other accidental bias. The experimental treatment that was evaluated in the RTOG 92-02 trial has become a standard of care, and the experimental arm of the RTOG 92-02 trial is now the standard arm in the successor combined modality trial, RTOG 05-21, for high-risk prostate cancer. The RTOG 05-21 trial is a randomized comparison between long-term androgen deprivation therapy and external beam radiation therapy with or without adjuvant docetaxel-based chemotherapy. The continued prospective use of data from the experimental arm of the RTOG 92-02 trial indicates that the analysis is contemporary and relevant to ongoing clinical research.
Previous attempts at identification of a surrogate endpoint for prostate cancer survival have focused on the kinetics of increasing posttreatment serum PSA levels. Many studies have found that rapid PSA increases, or short posttreatment PSA doubling times, after local therapy are associated with the development of metastatic disease and prostate cancer–specific mortality (24
). D’Amico et al. (26
), by use of a large database of retrospective patient data, demonstrated that a short PSA doubling time of less than 3 months meets statistical criteria for being a surrogate endpoint for prostate cancer–specific survival. However, metrics such as PSA doubling time and PSA velocity can be confounded by the methods and frequency of PSA measurement and can be difficult to systematically assess.
Data from the RTOG 92-02 trial have been the subject of a previous secondary analysis that evaluated posttreatment PSA doubling time as a potential surrogate endpoint for prostate cancer survival (29
). Valicenti et al. (29
) confirmed that treatment was statistically significantly associated with PSA doubling times that were shorter than 6, 9, and 12 months and that these PSA doubling times were statistically significantly associated with prostate cancer–specific survival, meeting Prentice's second and third criteria. However, prostate cancer–specific survival was not independent of treatment for PSA doubling times longer than any cut point in the study (eg, P
= .89 for PSA doubling time of <6 months but P
= .014 for PSA doubling time of ≥6 months). Because PSA doubling time had been previously analyzed in this dataset and Prentice's fourth criteria for surrogacy was rejected and also because PSA kinetics have not been validated as an independent predictor of prostate cancer survival, we chose not to include PSA kinetics as a component of a surrogate endpoint definition in this study.
In patients with metastatic, androgen-independent prostate cancer, Petrylak et al. (30
) reported that several metrics, including 3-month declines in the PSA level of 20%–40%, 2-month decline in the PSA level of 30%, and PSA velocities at 2 and 3 months after chemotherapy, did meet surrogacy criteria for survival in an analysis of the Southwest Oncology Group 99-16 trial. The rate or degree of decline in the serum PSA level after initiation of androgen deprivation therapy would not likely constitute a viable endpoint for patients with hormonally naive, clinically localized prostate cancer, such as the patients in the RTOG 92-02 trial; therefore, PSA declines were also not analyzed as potential survival surrogates in this study.
The potential surrogate endpoints that were selected for this study included distant metastasis, which is a straightforward and objective finding in patients with progressive prostate cancer and has been associated with increased prostate cancer–specific death (31
). However, the detection of distant metastasis may be subject to variation in how often imaging studies (eg, bone scan or other x-ray studies) are obtained, with some clinicians using asymptomatic PSA changes to request an imaging study and others using the development of symptomatic disease progression, such as the onset of bone pain. To address this potential concern, we sought an additional candidate surrogate endpoint that could capture a wider range of indicators of clinically significant disease progression that might suggest fatal disease. We identified a composite endpoint, general clinical treatment failure, that has been applied previously (7
) and that incorporates clinical (identification of local, regional, or distant failure), biochemical (measurement of a substantial elevation in the PSA level of more than 25 ng/mL), and treatment-related (initiation of androgen deprivation therapy) indicators of treatment failure that are likely to be associated with fatal prostate cancer. Although there is considerable overlap between the two candidate surrogate endpoints evaluated in the study, the definition that we used for general clinical treatment failure broadens the failure criteria by including local and regional disease recurrence at any clinically apparent site and the stringent biochemical treatment failure criterion of a PSA level of more than 25 ng/mL. In addition, this endpoint captures other factors judged by the treating physician as clinically significant enough to warrant systemic treatment by initiating androgen deprivation therapy after the completion of curative intent local therapy. In addition to distant metastasis, we feel that the definition for the composite endpoint, general clinical treatment failure, is also a straightforward measure that can be applied to many patients with prostate cancer at various stages and may more completely capture treatment failures that are likely to be associated with increased prostate cancer–specific death.
Validation of distant metastasis and/or general clinical treatment failure, as defined in this study, as surrogate endpoints for prostate cancer–specific survival clearly requires additional study of other patient data. Although few randomized trials of treatment for localized prostate cancer have demonstrated statistically significant improvements in prostate cancer–specific survival or overall survival, certain trials conducted by the Southwest Oncology Group, the European Organization for Research and Treatment of Cancer, and other groups contain data that may be useful for validation of these factors as surrogate endpoints for prostate cancer–specific survival and that could potentially support a meta-analysis similar to the approach used for colorectal cancer (20
). This study represents an initial attempt to explore intermediate outcome criteria as possible surrogate endpoints for prostate cancer–specific survival, and its results will require validation in prospective trials, preferably involving several different treatment types, to determine whether the findings can be applied only to combination treatment with androgen deprivation therapy and external beam radiotherapy or whether they can be more broadly applied to other treatment strategies, such as those that incorporate different local and systemic therapies. The potential surrogate endpoints, distant metastasis and general clinical treatment failure, should be further and prospectively evaluated in future clinical trials along with overall and prostate cancer–specific survival endpoints.