Prostate Cancer 2004: Insights From National Disease Registries

I am honored and delighted to be able to comment on the outstanding contribution from Drs. Cooperberg, Park, and Carroll relating recent prostate cancer research from the various national efforts in prostate disease research database efforts. As a former director of the Department of Defense Center for Prostate Disease Research (DoD-CPDR), I was blessed to be able to lead one of these database efforts as well as collaborate with Dr. Carroll and his colleagues from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). Dr. Anthony D'Amico and his colleagues headed several of our joint collaborations from Harvard. In this light, I would like to focus my editorial comments on providing a more in-depth review of work[1] that was briefly mentioned in the article by Cooperberg et al. We recently reported that a prostate- specific antigen (PSA) doubling time of less than 3 months is a surrogate for prostate cancer-specific death. The paper is important because it is the first published report in which any PSA-related biomarker is strongly related to the prostate-specific survival end point. The clinical relevance is that this PSA intermediate end point may be useful in clinical trials to speed up the approval of new drugs and other treatments. Specifically, if PSA doubling time is accepted by the US Food and Drug Administration (FDA) as a valid surrogate for death from prostate cancer, then treatment trial end points would be achieved more quickly, and therapeutic agents could receive approval more rapidly, moving novel agents from bench to bedside. Concept and Methods
The idea for the study started in a series of workshops on the topic of PSA in clinical trials led by Howard Scher, MD, from Memorial Sloan-Kettering Cancer Center and funded by a grant and support from the CaPCURE Foundation.[2] Attendees at those meetings were frustrated that the FDA did not recognize any PSA-based end points for drug approval. As a specific example, the FDA officials did not think that PSA alone (ie, biochemical recurrence) could be used to assess therapeutic efficacy.[3] The project involved the examination of 8,669 men from the DoDCPDR, CaPSURE, and the Harvard prostate database who had undergone previous radical prostatectomy (n = 5,918) or external-beam radiotherapy (n = 2,751). The basic goal was to look at men who had experienced PSA-only recurrence and examine PSA doubling time during recurrence to see if this measurement was associated with the outcome of both overall and cancer-specific mortality. For radical prostatectomy patients, we started "counting" PSA elevations only after the recurrence definition of a PSA value of 0.2 ng/mL had been achieved. Patients undergoing external- beam radiotherapy had to meet the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of recurrence of three consecutive PSA elevations after the posttreatment nadir.[4] We subtracted the nadir value from the PSA values used in the PSA doubling time calculation. The PSA doubling time was calculated using first-order kinetics, with a minimum of three PSA values required. A total of 611 radical prostatectomy patients and 840 external-beam radiotherapy patients experienced a recurrence and had PSA values sufficient to be used. The overall follow-up of the entire study cohort was 7.0 years. For the group of men who underwent radical prostatectomy and had a subsequent recurrence, follow-up was 4.1 years, and for those undergoing externalbeam radiotherapy, it was 3.8 years after the PSA recurrence was defined. Overall, 154 subjects died; 110 of those deaths were caused by prostate cancer. Various PSA doubling time values (< 12, < 6, < 4, < 3, or < 2 months) were used to test for a relationship to death. We used Prentice's criteria[5] to determine if PSA time was a surrogate for death due to prostate cancer. Results
Our key finding was that a PSA doubling time < 3 months was a direct surrogate for death from prostate cancer. In other words, none of the known prognostic factors, such as stage at diagnosis, tumor grade, pretreatment PSA level, and type of treatment (radical prostatectomy or external-beam radiotherapy) influenced cancer-specific mortality in men who achieved a PSA doubling time < 3 months during the course of biochemical recurrence. Prostate cancer-specific survival after PSA-defined recurrence was stratified by treatment received and the value of the PSA doubling time after treatment (Figure 1).[6] A pairwise two-sided log-rank test was used, and the P values are as follows: For a PSA doubling time < 3 months (surgery vs radiation), P = .38; for PSA doubling time ≥ 3 months (surgery vs radiation), P < .001; for PSA doubling time < 3 months vs PSA doubling time 3 months (surgery), P < .001; for PSA doubling time < 3 months vs PSA doubling time ≥ 3 months (radiation), P < .001. For a PSA doubling time ≥ 3 months among surgery patients, prostate cancer-specific survival at 3 years was 99.8% (95% confidence interval [CI] = 99.4%-100%); at 5 years, 99.4% (95% CI = 98.6%-100%); and at 8 years, 98.9% (95% CI = 97.6%- 100%). For PSA doubling time ≥ 3 months among radiation patients, survival at 3 years was 99.6% (95% CI = 99.1%-100%); at 5 years, 96.1% (95% CI = 94%-98.2%); and at 8 years, 87.6% (95% CI = 81.2%-94%). For PSA doubling time < 3 months (surgery), at 3 years, survival was 84.1% (95% CI = 74.4%-93.8%); at 5 years, 68.8% (95% CI = 55.0%- 82.6%); and at 8 years, 51.5% (95% CI = 34.8%-68.3%). For PSA doubling time < 3 months (radiation), the rate at 3 years was 79.1% (95% CI = 72.5%-85.8%); at 5 years, 61.6% (95% CI = 53.0%-70.4%); and at 8 years, 41.6% (95% CI = 29.8%- 53.4%). These data illustrate the pro- found impact of this biomarker-derived parameter on cancer-specific death. Table 1 illustrates the 5-, 8-, and 10-year all-cause and cancer-specific mortality rates after radical prostatectomy or external-beam radiotherapy for various levels of PSA doubling time from 2 to 12 months. This table is useful for clinicians counseling men with biochemical recurrence regarding their prognosis and may be used to design clinical trials in the setting of biochemical recurrence. The median time to death for men who reach a PSA doubling time < 3 months was approximately 6 years. If the end point of PSA doubling time < 3 months were an accepted trial end point, then approximately 6 years could be shaved from the time to get valid outcome data from clinical trials. The 6-year period after the determination of PSA doubling time < 3 months is not part of the natural history of the disease, because these men were generally treated with hormone therapy or other treatments during this interval at the discretion of the treating physicians. Conclusions
Our study is the first to demonstrate that a PSA-based biomarker (PSA doubling time < 3 months) is a surrogate for prostate cancer-specific mortality. The data for various PSA doubling time values will be very useful for clinicians. Since the publication of our work in September 2003, there has been much interest in the concept of surrogate end points for prostate cancer outcomes. In mid-June 2004, the FDA held a public forum in Bethesda, Md, to discuss this work and other recent contributions. By the tone of the meeting, it appeared that FDA officials were willing to consider a PSA-based surrogate end point for future drug approval considerations. It was gratifying to see that these national prostate cancer research database efforts are providing useful information that may help to advance the field. It is hoped that the value of these efforts will continue to be recognized by funding agencies, as well as by academic and private institutions. Again, I thank Drs. Cooperberg, Park, and Carroll for their marvelous contribution.