Affiliations of authors: H. M. Sandler, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI; M. L. DeSilvio, American College of Radiology, Philadelphia, PA.
Correspondence to: Howard M. Sandler, MD, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 481090010 (e-mail: hsandler{at}umich.edu).
Prostate cancer is a common malignancy. The observed incidence of prostate cancer has undergone dramatic changes because of the widespread use of prostate-specific antigen (PSA)-based screening. The debate surrounding the use of PSA as a screening method continues, whereas the use of PSA as a tool to detect recurrences of prostate cancer after initial therapy is fully enshrined in the post-therapy routine of patients with prostate cancer. Although defining the precise time of treatment failure after radiation therapy or surgery can be contested (13), there is little doubt that a sustained pattern of increasing PSA values after treatment is an indication of the presence of active prostate cancer. Furthermore, just as patients with newly diagnosed prostate cancer often choose to follow their neoplasm expectantly, patients who develop PSA-defined evidence for asymptomatic recurrent disease frequently are observed without intervention. In fact, there are reports that patients with a slowly increasing level of PSA (i.e., a doubling time of >2 years) are at very low risk of prostate cancerspecific mortality, even in the absence of salvage therapy (4,5). Conversely, those patients with a rapidly increasing level of PSA (i.e., a short doubling time of <6 months) often develop symptomatic metastatic disease and, as DAmico et al. (6) conclude, are candidates for prompt salvage treatment, usually with androgen ablation.
In addition to the invaluable role of PSA in the management of patients after primary prostate cancer therapy, there is great interest in the use of PSA-derived measures to help assess the efficacy of new treatment strategies, mostly during the development of new pharmaceuticals. As DAmico et al. note, patients with a PSA doubling time of less than 3 months have a hazard ratio for survival of 19.6 compared with patients with a longer PSA doubling time. Yet even in patients with a rapidly doubling PSA level, the median time from the detection of the surrogate end point to the traditional survival end point isfrom a clinical trial design point of viewa long 6 years away. If, indeed, an observed PSA doubling time of less than 3 months can be used as a surrogate end point for prostate cancerspecific survival, the duration of clinical trials could be dramatically shortened and new generations of therapies, which may moderate the rate of PSA increase, could be much more rapidly evaluated. There may be nothing more important in the development of novel prostate cancer treatments than shortening the time required to assess accurately the value of new treatments. However, although DAmico et al. used patients with a first PSA-defined treatment failure after primary treatment who either were never exposed to androgen ablation or were exposed only briefly before surgery, most novel antiprostate cancer agents are evaluated in patients with hormone-refractory prostate cancer, and the evaluation of PSA in such hormone-refractory patients may be challenging (7,8).
DAmico et al. provide strong methodologic groundwork in assessing PSA doubling time as a surrogate marker. The first-order kinetics observed after primary treatment has failed and the intuitive nature and the relative ease of calculation facilitate the use of PSA doubling time as a reasonable parameter to investigate as a survival surrogate. DAmico et al. used three widely accepted analytic approaches (911) to test Prentices criteria for PSA doubling time as a surrogate end point (12). Arguably, there are other methods to test Prentices criteria. For example, more preferable than the proportion explained would be the relative effect, which is the effect of treatment on the true end point relative to the effect of treatment on the surrogate (i.e., trial-level surrogacy), and the adjusted association, which is the association between the surrogate and the true end point after adjusting for treatment (i.e., individual-level surrogacy). Essentially, one would like to be able to predict the effect of treatment on the true end point by using the observed effect of treatment on the surrogate end point. Analyses of several trials or on a multicenter trial are needed to fully assess surrogate end points and to predict the effect of treatment on the true end point. The authors have access to a large cohort of patients that is both essential and necessary for establishing a surrogate end point. However, when only a single trial is used or available, the estimate of relative effect is based on the strong assumption that the relationship between the treatment effects on the surrogate and true end point is multiplicative, an assumption that may be too strong to hold and unverifiable. When multiple units are available, the adjusted association generalizes to an R2 measure of individual association, and the relative effect is supplemented by a trial-level measure of association. If the association is perfect, then knowing the effect of treatment on the surrogate allows one to predict its effect on the true end point. Again, these conditions of perfect prediction can only be verified if data are available at both the trial and individual levels (13). Thus, adopting a multi-unit approach to validate PSA doubling time as a surrogate for prostate cancerspecific mortality might be preferable.
There are other important cautions to consider before PSA doubling time can be widely implemented as an end point in clinical trial design. Given the nature of DAmicos study, one might be able to conclude that PSA doubling time would be a valuable end point in a phase II trial designed to assess the potential survival benefit of a new treatment designed to reduce mortality of newly diagnosed, hormone-naive prostate cancer patients. However, the gold standard for validating the benefit of new treatment strategies is the phase III clinical trial. Can we conclude that PSA doubling time is validated as a surrogate in this setting? Unfortunately, not yet. Recent data from a large phase III trial (RTOG 9202) that compared radiation therapy with either short-term or long-term hormone therapy seem to indicate that PSA-defined treatment failure is different between the two treatment arms, an important violation of one of Prentices criteria, presumably because some of the patients subjected to the long-term androgen deprivation were less sensitive to salvage hormonal manipulation (14). Thus, the extended use of androgen ablation may weaken the validity of PSA as a surrogate marker. Of note, data from CaPSURE demonstrate a recent trend showing a gradual increase in the use of neoadjuvant androgen ablation. Contemporary data suggest that 70% of external beamtreated, 30% of brachytherapy-treated, and 10% of surgically treated patients receive neoadjuvant androgen ablation (15). PSA surrogate definitions will need to be carefully applied to these patient populations.
Caregivers and patients with prostate cancer know intuitively that PSA levels after therapy are telling us something very important about the future course of the patients prostate cancer. Depending on the patients previous androgen exposure and the cancers subsequent androgen sensitivity, the tale being told may be somewhat different, but on a daily basis, decisions for treatment are made as a result of serum PSA testing. Thus, despite the evident clinical utility, investigators face a justifiable methodologic hurdle to convert the intuitive sense that PSA-defined failure is related to survival to a rigorous and sound statistical definition that will allow more rapid, yet rational, progression of clinical trial design, implementation, and reporting of results. Additional work in this area is urgently required.
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