Looking Back at PCPT: Looking Forward to New Paradigms in Prostate Cancer Screening and Prevention

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1 european urology 51 (2007) available at journal homepage: Review Prostate Cancer Looking Back at PCPT: Looking Forward to New Paradigms in Prostate Cancer Screening and Prevention Edith Canby-Hagino a, *, Javier Hernandez b, Timothy C. Brand a, Ian Thompson a a Department of Urology, University of Texas Health Science Center at San Antonio, TX, United States b Division of Urology, Brooke Army Medical Center, San Antonio, TX, United States Article info Article history: Accepted September 3, 2006 Published online ahead of print on September 15, 2006 Keywords: Finasteride Prevention Prostate cancer Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Objectives: Provide a critical summary of the latest interpretation of findings from the Prostate Cancer Prevention Trial (PCPT). Methods: Findings from PCPT and recently published post-hoc analyses are reviewed. Results: PCPT demonstrated that finasteride can reduce the prevalence of prostate cancer, permitted the first large-scale assessment of the performance characteristics of prostate-specific antigen for prostate cancer screening, and identified new-onset erectile dysfunction as an early predictor of cardiovascular events. Conclusions: PCPT has and will continue to yield valuable information regarding future strategies for prostate cancer prevention and detection, benign prostatic hyperplasia, and other matters of public health importance. # 2006 Published by Elsevier B.V. on behalf of European Association of Urology. *Corresponding author. Department of Urology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States. Tel ; Fax: address: canbyhagino@uthscsa.edu (E. Canby-Hagino). 1. The case for prevention Prostate cancer is the most common noncutaneous malignancy in men [1]. Despite numerous advances in the early detection and treatment of the disease, approximately 27,350 men will die of the disease in 2006 [1]. Although some investigators have demonstrated a recent decrease in mortality rates from prostate cancer, the reason for this trend is not entirely clear [2]. In cases of hormone refractory disease, docetaxel-based chemotherapy improves survival. However, the improvement in survival seen with this approach is modest at best [3,4]. Furthermore, costs associated with the treatment of prostate cancer in the last year of life of patients dying from this malignancy tend to be quite substantial [5]. Therefore, strategies that focus solely on the treatment of advanced prostate cancer /$ see back matter # 2006 Published by Elsevier B.V. on behalf of European Association of Urology. doi: /j.eururo

2 28 european urology 51 (2007) are unlikely to lead to major reductions in cancer deaths. Perhaps of greater impact from a public health perspective is the cumulative cost and morbidity for the treatment of early-stage prostate cancer, a substantial portion of which could be attributed to the over-treatment of clinically insignificant disease. The treatment of patients with biochemical recurrence also contributes significantly to this cost. The aging of the US population in conjunction with the application of lower prostatic-specific antigen (PSA) cut-off levels will in all likelihood lead to increasing prostate cancer detection rates. Although screening for prostate cancer is a widespread practice in the United States, there is a lack of high-level evidence to support a public health benefit for this practice [6]. Given the limited nature of resources available for health care expenditure, the current strategies for detection and treatment of prostate cancer will most likely come under great scrutiny in the future. An important alternative approach to prostate cancer as a public health challenge is the concept of cancer prevention. The efficacy of potential preventive agents against the target disease as well as the potential side-effects are issues that must be carefully elucidated before any potential preventive agent can be widely accepted by the medical community and the public. Understandably, healthy patients may be less willing to accept the risks historically associated with chemopreventive interventions as compared to patients undergoing treatment interventions in which there may be a greater acceptance of side-effects and toxicities. Another potential challenge for prevention initiatives is the current emphasis on funding therapeutic as opposed to preventive clinical trials. This approach may not be entirely cost effective from a public health perspective, as illustrated by the recent analysis by Unger et al. [7]. The authors compared the estimated impact of eight positive phase 3 clinical trials of the Southwest Oncology Group as measured in person-years saved in the first 5 yr to the estimated impact of the Prostate Cancer Prevention Trial (PCPT). Whereas application of the new treatments from the eight therapeutic clinical trials would have saved 114,641 person-years over the first 5 yr, implementation of the findings from PCPT would have saved 99,441 person-years during a similar period of time. Moreover, the potential additional benefits of chemoprevention, such as reduction in surgery related to benign prostatic hyperplasia (BPH) and episodes of acute urinary retention in men taking finasteride, should be taken into consideration [8,9]. A final, often-forgotten aspect of chemoprevention is the effect on the individual; although most individuals will express a desire for early cancer detection and treatment, a preferred alternative is the opportunity to never have to face the diagnosis in the first place (i.e., prevention). 2. What is the status of prostate cancer chemoprevention today? To date, finasteride is the only agent that has been definitively proven in a randomised, placebocontrolled, prospective clinical trial to prevent prostate cancer [9]. However, this agent has not yet received wide use for the prevention of prostate cancer, primarily due to the increased risk of highgrade disease noted among participants in the treatment arm compared to placebo. Basic science and epidemiologic studies suggest that various agents with antioxidant, antiproliferative, anti-inflammatory, or proapoptotic actions may prevent prostate cancer [10]. Paradoxically, many of these, mostly over-the-counter dietary supplements, which have yet to be definitively proven to prevent prostate cancer in the context of a phase 3 clinical trial, are widely used by men with the goal of preventing prostate cancer. The early enthusiasm for these agents may ultimately fade away possibly from contradictory results from clinical trials, as was the case with b-carotene [11] or from adverse effects as seen in the Breast Cancer Prevention Trial or the Vioxx trial [12,13]. Closure of the Vioxx trial is certainly unfortunate given the known overexpression of cyclooxygenase-2 (COX-2) enzyme in proliferative inflammatory atrophy of the prostate, which is felt to be associated with prostatic carcinogenesis [14]. Ongoing clinical trials should better define the role of other agents in the prevention of prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) completed accrual in 2004 and trial results are anticipated in 2013 [10]. The Reduction by Dutasteride of Prostate Cancer Events (REDUCE), which is designed to determine whether or not dutasteride reduces the risk of prostate cancer in men with an elevated PSA level and a prior negative biopsy, should have results available within approximately 4 yr [15]. As the only randomised, prospective clinical trial that has demonstrated an agent to have chemopreventive properties against prostate cancer, we summarise the PCPT study design and

3 european urology 51 (2007) Fig. 1 Schema for the Prostate Cancer Prevention Trial. PSA = prostate-specific antigen. findings, as well as the impact of these findings on screening practices for prostate cancer. 3. Summary of PCPT design The PCPT is the first prospective, randomised clinical trial of prostate cancer prevention [9]. The challenges to the design of this trial were substantial and included selection of meaningful end points, recruitment and retention of a study population sufficiently large to yield statistical power, and complete ascertainment of disease status [16]. The study design is depicted in Fig. 1. PCPT, conceived in 1992 and activated in 1993 shortly after US Food and Drug Administration (FDA) approval of finasteride, was the first large-scale population-based trial to test a chemopreventive strategy against prostate cancer. This prospective, randomised, blinded, and placebo-controlled trial tested the hypothesis that finasteride, which selectively inhibits type 2 5a-reductase (5-AR), would lower intraprostatic dihydrotestosterone (DHT) levels and thereby prevent prostate cancer. At the start, 18,882 men aged 55 yr or older with a normal digital rectal examination (DRE) and serum PSA level of 3.0 ng/ml were randomly assigned to treatment with 5 mg finasteride daily or placebo for 7 yr. Prostate biopsies were performed for cause (abnormal prostate examination or PSA >4.0 ng/ml) and at the end of 7 yr. The trial was stopped 15 mo early by an independent data and safety monitoring committee, after achievement of the primary end point of a 25% risk reduction on the finasteride arm, and sensitivity analysis indicated that additional biopsies would not change the outcome. Perhaps the greatest challenge to this study was the fact that finasteride affected serum PSA measurement. At the time the study was initiated, it was generally known that finasteride reduced PSA by approximately 50%. Without controlling for this reduction and using a prostate cancer incidence end point, a reduction in prostate cancers detected would be noted but this would be merely due to the fall in PSA. To control for this detection bias, two unique steps were taken. It was acknowledged that to maintain current standard-of-care in the United States, it would be necessary to provide subjects and their physicians with PSA results on an annual basis; these PSA results would then lead to the diagnosis of prostate cancer based on elevated PSA values. At the time the study was designed, concerns existed regarding the previously reported multiply-by-two conversion factor (based on the 50% PSA fall with finasteride) because the observation period was only 24 mo, and PCPT was a 7-yr study [17]. An incorrect adjustment factor could introduce confounds and differential ascertainment. This problem was corrected by a PSA indexing procedure. On an annual basis, all men in the placebo group of the study with a PSA level >4.0 ng/ml were advised to consider a prostate biopsy. The fraction of the total placebo group >4.0 ng/ml was then calculated. Then, the PSA cut-off point in the finasteride group was adjusted so that the same highest fraction of men in the treatment group received a recommendation for biopsy. Practically, a doubling of PSA was initially used to correct for the first 3 yr, but due to a continued fall in PSA in the finasteride group, the PSA in this group was multiplied by 2.3 in subsequent years to ensure the same number of biopsies in the two study groups for the remainder of each subject s years on study. Despite this correction to the PSA value, study coordinators could not be certain that other biases in disease ascertainment and detection did not exist. For example, we know that finasteride reduces the size of the prostate gland. This may alter the gland texture, reducing or increasing the proportion of abnormal DREs. These and other potential confounds led to a second design characteristic of the study an end-of-study prostate biopsy. This biopsy was planned in all individuals not previously diagnosed with prostate cancer who reached the 7-yr mark on study. It was anticipated that 60% of men randomised

4 30 european urology 51 (2007) in the study would have an end point ascertained (interim cancer or end-of-study biopsy). 4. Summary of PCPT findings The results of the PCPT were reported in 2003 [9]. The study was closed early, based on recommendations of an independent data and safety monitoring committee because there was convincing evidence that the primary study objective had been met. There was a 24.8% reduction in period prevalence of the disease, and sensitivity analysis indicated that additional biopsies would not change the findings. The principal findings of PCPT include the following: 1. Prevalence of prostate cancer was reduced from 24.4% in the placebo group to 18.4% in the group taking finasteride (a 24.8% reduction). 2. Prevalence of Gleason grade 7 10 cancers was 6.4% in the finasteride group compared to 5.1% placebo group. 3. Risk reduction in prostate cancer was apparent both for men undergoing biopsy for cause (abnormal prostate examination or elevated PSA) and for men undergoing end-of-study biopsy. 4. Sexual side-effects were more common with finasteride. 5. Urinary symptoms (e.g., lower urinary tract symptoms and risk of urinary retention) and treatments (e.g., transurethral resection of the prostate) were more common with placebo. 6. Prostate volumes in the group taking finasteride were 24% smaller than volumes in the placebo arm. A surprising finding in this study was the high prevalence of prostate cancer among men without clinical suspicion for prostate cancer. The study design assumed a 6% prevalence based on estimates by Cooner for expected prevalence of prostate cancer in clinical urology practice [18,19]. This estimate was deliberately conservative to reduce the risk of under-powering the study. Of note, the incidence of prostate cancer detected on the basis of an abnormal prostate examination or elevated PSA at 7 yr was 6%, suggesting that a substantial fraction of prostate cancers detected by PCPT might never develop clinical manifestations that are important to patients. This over-detection of prostate cancer may be even more pronounced among men treated with finasteride, due to relative over-sampling of their smaller glands by needle biopsy. 5. High-grade prostate cancer in PCPT A concerning finding of the study was the higher prevalence of Gleason grade 7 10 cancers in the finasteride group. Further study on this subset of patients is underway to address the following issues: 1. Histologic artifact associated with finasteride use may result in incorrect grading of prostate cancers. 2. Finasteride may be more effective at preventing development of cancers with Gleason grade 2 6 than Gleason grade A reduction in gland volume may permit a greater degree of ascertainment in men receiving finasteride, resulting in a proportionally higher rate of detection of high-grade cancers in this group. 4. The performance characteristics of PSA and DRE for prostate cancer detection among men receiving finasteride may have been affected by the intervention and thereby changed the rate of detection of high-grade disease. The final hypothesis arises from observation, made at the time of the initial study publication, that the increase in the rate of high-grade disease was seen after 1 yr of subjects being on-study, but this rate did not increase during the 7 yr that the finasteride recipients received the study drug. Some investigators argue that the Gleason grading system has not been validated in men treated with androgen deprivation or finasteride, and thus, it should not be used as an end point in a trial like PCPT [20]. Others have reported that finasteride therapy does not compromise Gleason grading [21,22]. Ongoing studies by the Core Pathology Laboratory of the PCPT as well as independent pathologists not associated with PCPT should clarify whether histologic artifact was operational. It is uncertain whether it can ever be determined if finasteride induced the development of high-grade disease due to the confounds postulated above. A reduction in gland volume with finasteride was conceived at the time of trial design and was thought to potentially lead to oversampling of the glands in this study group, biasing outcomes against finasteride. (This concept can be found in the initial study design.) It is important to consider that, despite a 24% reduction in gland volume, there was still a 24.8% reduction in prostate cancer prevalence over the course of 7 yr. This observation suggests that the true reduction in prevalence is probably greater. How this volume reduction affected tumour grading at the time of biopsy is uncertain and is the subject of ongoing research.

5 european urology 51 (2007) Validation of PSA as a screening tool Even when the primary findings of PCPT have not been widely applied, secondary findings on the performance characteristics of PSA as a screening tool have reshaped the prostate cancer screening landscape. The prospective nature of the study along with the protocol recommendation for all men in the study to undergo a prostate biopsy at the end of the study have allowed for a tremendous opportunity to assess the operating characteristics of PSA as a screening test. Arguably, this may be the most significant contribution of this trial to date. Discovered in 1970 [23] and eventually purified while a search was ongoing for a marker that could be used in the investigation of rape crimes [24], PSA was introduced into clinical practice in the mid-1980s. Early experience with PSA as a tumour marker led to several important observations [25 27]. A fall in the PSA level following the institution of hormonal therapy correlated with response to treatment. Additionally, a rise in the PSA level following treatment precedes and predicts disease recurrence. Finally, it was also noted that, following radical prostatectomy, PSA levels should be undetectable. Otherwise, a detectable PSA in this setting indicates persistent or recurrent disease. Despite early recognition by some investigators of the limited specificity of PSA differentiating between cancer and other benign processes within the prostate gland, largescale screening studies were conducted in the late 1980s to early 1990s [18,28 30]. In general, these studies were characterised by major limitations in the ascertainment of disease status among the control populations as well as by the limited application of modern prostate biopsy techniques. Within the PCPT placebo arm of the study, there were 2950 men who, throughout the course of the clinical trial, did not have a PSA level >4.0 ng/ml or an abnormal DRE and underwent an end-of-study biopsy [31]. Analysis of this group found that PSA levels between 0 and 4.0 ng/ml were associated with a positive predictive value of %. Additionally, 14.9% of men diagnosed with cancer had high-grade disease, with this rate reaching 25% among men with PSA levels ranging between 3.1 and 4.0 ng/ml. There was no PSA level at which there was no risk of having cancer or high-grade disease. Moreover, analysis of 5587 men in the placebo group who had at least one PSA measurement, a DRE in the same year, and at least one biopsy has allowed careful examination of the performance characteristics of PSA [32]. Areas under the receiver operating characteristic (ROC) curve for PSA to discriminate between the presence or absence of cancer on biopsy as well as the presence of high-grade cancer versus low-grade or no cancer were established. This analysis demonstrated better performance characteristics among men with high-grade disease. Most importantly, the analysis concluded that there is no PSA cut-off level with both a high sensitivity and specificity to screen healthy men for prostate cancer, underscoring the importance of proper validation of any screening test prior to widespread clinical application of such test. 7. Other lessons learned from PCPT Designing a prostate cancer prevention trial that targets individuals felt to be at increased risk for prostate cancer (i.e., African Americans, men with a family history of prostate cancer, men with an elevated PSA) is tempting, because of the smaller sample size and possibly shorter duration required to achieve study end points. Because the etiology of prostate cancer in selected high-risk populations may be different from the general public and because the efficacy of interventions may also be different, there are problems with studying only high-risk populations. First, a preventive effect may be found that may not be seen in the general population. Second, no effect may be seen in the smaller, high-risk population, whereas a true preventive effect exists (but remains unstudied) in the general population. Third, recruitment may be more challenging. It is for these reasons that PCPT was based on the general population and the value of the study is apparent. Additionally, one cannot understate the vast potential for further evaluation of data from the population for other findings of importance to the public health. For example, the 9457 men in the placebo group comprise a prospective cohort of men who can be studied for many different health events, with conclusions that can be generalised to the public. PCPT investigators recently identified a strong association between erectile dysfunction (ED) and subsequent cardiovascular events [33]. In addition to collecting data associated with the primary end point of reduction in prostate cancer prevalence, the study investigators also monitored a host of measures regarding potential treatment toxicities, medications, hospitalisations, and, in particular, cardiovascular disease. Cardiovascular disease included angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, congestive heart failure, and cardiac arrhythmia. Because of the previously reported impact of finasteride on sexual function, this end point was also carefully measured in all men over the course of the study.

6 32 european urology 51 (2007) At study entry of 9457 men randomised to placebo, 8063 (85%) had no cardiovascular disease. Of these 8063 men, 4247 (53%) reported no ED at study entry. This group was then evaluated for incident ED and cardiovascular disease. Incident ED was associated with a hazard ratio of 1.25 (95%CI, ; p = 0.04) for subsequent diagnosis of cardiovascular disease during the course of the study. For men with either incident or prevalent ED, the hazard ratio for subsequent diagnosis of cardiovascular disease was 1.45 (95%CI, ; p < 0.001). In multivariate analysis of ED with other risk factors traditionally associated with cardiovascular disease, the authors found that incident ED carried a similar risk as did family history of myocardial infarction, current smoking, or hyperlipidaemia. In conclusion, they found ED to be a forewarning symptom for subsequent diagnosis of cardiovascular disease and suggested that ED should lead clinicians to consider further evaluation for cardiovascular disease [33]. Other studies are in progress that will characterise the impact of finasteride on sexual function and changes in sexual function over time in older men [34]. In addition, as the largest and longest clinical trial using finasteride, PCPT will illuminate the natural history of BPH and shed more light on clinical outcomes such as voiding symptoms and surgical interventions for BPH. Biopsy data will further elucidate the associations of high-grade prostatic intraepithelial neoplasia (HGPIN) and inflammation with prostate cancer [35,36]. Another precious resource collected in conjunction with prospective, longitudinal data and ascertainment of prostate cancer status is a biorepository of prediagnostic serum, and, for many patients, DNA, as well as prostatic tissues from biopsy and radical prostatectomy. As has been previously reported, PCPT has provided post-hoc validation of PSA as a biomarker for prostate cancer and has tremendous potential for both identification and validation of future biomarkers [31,32]. The biorepository will permit characterisation of the effects of type 2 5-AR inhibition on prostatic stroma and epithelium and prostate cancer, in addition to exploring the relationship between genetic polymorphisms androgen metabolic loci, BPH, and prostate cancer, among others. 8. Questions that remain unanswered Although finasteride therapy resulted in a significant reduction in prostate cancer cases during the treatment period, the long-term impact of finasteride chemoprevention remains unknown. PCPT participants who were diagnosed with prostate cancer are participating in a long-term follow-up study to assess the impact of their treatment arm on survival and other outcomes related to their diagnosis of prostate cancer. However, PCPT is unable to answer several important questions. PCPT was not designed to identify an optimal duration of 5-AR inhibition for the purpose of prostate cancer prevention. Furthermore, it cannot be determined whether or not men might experience a rebound effect after cessation of finasteride chemoprevention, at which point their risk for prostate cancer and those with higher Gleason scores would equal or even exceed that of untreated men. These unanswered questions, along with concerns regarding the higher prevalence of high-grade disease associated with finasteride therapy, and, most importantly, the reluctance to initiate costly treatment with potential side-effects in men who may never develop clinically significant prostate cancer, temper enthusiasm for widespread use of finasteride as a chemopreventive agent. 9. Conclusions Lessons learned from PCPT reach far beyond the significant finding that finasteride reduces the risk of prostate cancer by 25%. The disparity between rates of death attributed to prostate cancer and the surprisingly high prevalence of prostate cancer in PCPT participants with no clinical suspicion for prostate cancer (and, therefore, a risk of overtreatment) highlights the need for clinical parameters that can identify those who would truly benefit from prostate cancer diagnosis, treatment, or prevention. Population evidence of a net positive benefit of this preventive intervention suggests that chemoprevention of prostate cancer with finasteride will increase in attractiveness as one of only a few proven interventions for control of prostate cancer. Until biomarkers or other indicators are developed that can reliably distinguish between indolent and clinically significant prostate cancers, the true benefit of finasteride chemoprevention will be reduction in cost of diagnosis and treatment of cancers that were never likely to produce morbidity or mortality. References [1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2006;56: [2] Damber JE. Decreasing mortality rates for prostate cancer: possible role of hormonal therapy? BJU Int 2004;93:

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