Prostate Cancer: Epidemiology and Screening

13TH INTERNATIONAL PROSTATE CANCER UPDATE Prostate Cancer: Epidemiology and Screening Timothy J. Wilt, MD, MPH Minneapolis VA Center for Chronic Disease Outcomes Research, Minneapolis, MN Additional Contributors Per-Anders Abrahamsson, MD, PhD, E. David Crawford, MD, M. Scott Lucia, MD, Wael A. Sakr, MD, Jack Schalken, PhD The 13th International Prostate Cancer Update provided an overview of diagnosis, treatment, and management strategies in prostate cancer. This article provides a summary of the reports presented during the epidemiology and screening session. Methods to improve early detection and treatment are being developed. Proposed refinements to prostate-specific antigen (PSA) testing include the use of age-specific PSA levels, PSA velocity, prostate volume–adjusted PSA densities, free-to-total PSA ratios, and complexed PSA. Optimal follow-up screening intervals for persons who elect PSA testing and are found to have initially normal levels have been proposed. Molecular oncology is becoming increasingly important in understanding the development and progression of prostate cancer as well as identifying new therapeutic targets for hormone-refractory disease. Nomograms that include PSA levels, histologic grade, and the extent of the tumor have been developed to optimize management decisions. Despite advances in early detection and treatment, controversy persists because of the lack of evidence demonstrating that they improve length and quality of life. Until results from randomized trials are completed, clinicians should provide patients with balanced information that incorporates the potential risks and benefits of screening and treatment and individual preferences for various outcomes. [Rev Urol. 2003;5(suppl 6):S3-S9] © 2003 MedReviews, LLC Key words: Prostate cancer • Early detection • Treatment • Expectant management • Randomized controlled trials • Shared decision making rostate cancer is one of the leading causes of morbidity and mortality in the world. According to World Health Organization reports, an estimated 513,000 cases and 255,000 deaths were attributed to prostate cancer in 1999.1 Each year in the United States, approximately 220,000 new cases of P VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S3 Prostate Cancer: Epidemiology and Screening continued prostate cancer will be diagnosed, and 30,000 men will die of prostate cancer. Refinements in early detection and treatment of prostate cancer can lead to theoretic cure of a potentially disabling and deadly disease. However, controversy exists because no conclusive direct evidence demonstrates that early detection and treatment improve length and quality of life. Epidemiology The unusual epidemiology and natural history of prostate cancer adds to uncertainty regarding screening and treatment. Prostate cancer is diag- The relatively high ratio of prostate cancer incidence to mortality was evident even before widespread PSA testing and aggressive treatment. This is probably due to the slow doubling time of early prostate cancer and the fact that prostate cancer is frequently diagnosed in elderly men with comorbid conditions who will likely die of other causes. The papers presented in the epidemiology and screening session of the 13th International Prostate Cancer Update provide insights into detection strategies and screening intervals, molecular diagnostic and treatment Each year in the United States, approximately 220,000 new cases of prostate cancer will be diagnosed, and 30,000 men will die of prostate cancer. nosed in very few men who are younger than 50 years (< 0.1% of all patients). The median age at diagnosis is 71 years, and the median age at death is 78.2 Approximately 85% of all cases of prostate cancer are diagnosed in men older than 65 years, and 90% of deaths due to prostate cancer are in men older than 65. With the advent of prostate-specific antigen (PSA) screening, the lifetime risk of a diagnosis is approximately 16%, making prostate cancer the most common malignancy among men. However, the lifetime risk of death from prostate cancer is approximately 3.4%. Therefore, most prostate cancers diagnosed in the United States do not result in death, even without treatment.2 Decisions regarding prostate cancer detection and treatment must balance the potential benefits and known adverse effects of early intervention with the likelihood that elderly men or those with comorbid conditions will have life-threatening or disabling progression of prostate cancer. S4 VOL. 5 SUPPL. 6 2003 techniques, pathology, and shareddecision making. Those presentations will be reviewed here. The etiology of prostate cancer is unknown. The risk of prostate cancer is associated with race, age, ethnicity, geographic region, and a family history of prostate cancer. Some studies have shown an association between prostate cancer and high dietary intake of fat, meat, and dairy products. Inverse associations have been uted to many factors, including improvements in detection and treatment of early-stage prostate cancer. Ongoing randomized clinical trials may one day demonstrate this to be true. However, even in the United States, it is difficult to attribute this effect to detection and treatment without making extremely optimistic assumptions.2 In addition, two studies in the United States and Canada showed that regions of these countries with higher rates of PSA testing, prostate cancer diagnosis, and early intervention had prostate cancer mortality rates that were not significantly lower than those in areas with less intense testing and treatment.2 Therefore, declines in mortality in these countries are more plausibly explained by better therapy for advanced disease and misattribution of cause of death. Screening: PSA Testing Despite uncertainty regarding the value of routine PSA testing, it has been widely used. Furthermore, there are problems with sensitivity and specificity using standard PSA testing strategies. This results in missing clinically significant prostate cancers and/or performing unnecessary biopsies.3 The sensitivity of a PSA with a cutpoint of 4.0 ng/mL for detecting The risk of prostate cancer is associated with race, age, ethnicity, geographic region, and a family history of prostate cancer. observed in men eating diets high in soy, tomato-based products (lycopenes), selenium, and vitamin E. Associations with serum testosterone levels or androgen concentrations have been inconclusive. The age-adjusted mortality rate in the United States has declined by approximately 15% in the past decade. This decline has been attrib- REVIEWS IN UROLOGY prostate cancer ranges from 63% to 83%.2 Among men who were not diagnosed with prostate cancer over 10 years, 9% had an initial PSA greater than 4.0 ng/mL (specificity of 91%). The specificity is lower in men with larger prostate glands or those with lower urinary tract symptoms. For example, among 1000 asymptomatic men aged 60 to 69 years with Prostate Cancer: Epidemiology and Screening no previous screening, approximately 150 would have a PSA greater than 4.0 ng/mL; for men in their 70s, approximately 270 would have a PSA greater than 4.0 ng/mL. These men often require further evaluation with a prostate biopsy. Of these men, approximately 40 would have prostate cancer, and 110 would have no prostate cancer. Approximately 80% to 90% of men would have clinically localized prostate cancer and be candidates for early intervention. Whether early intervention in these men extends or improves their lives is not yet known. However, early treatment results in long-term effects, including reduced sexual function in 20% to 70% of men, severe urinary problems in 2% to 5%, and bowel problems in 6% to 25%.2 In attempts to overcome problems of sensitivity and specificity, a variety of diagnostic parameters and tests have been proposed. None have been proved to be beneficial or superior to current PSA reference ranges. Refinements include lowering the cutpoint for defining an abnormal PSA level to below 4.0 ng/mL (eg, below 3.0 ng/mL), age-specific PSA, PSA velocity (PSA-V), volume-adjusted PSA densities, the free-to-total PSA ratio (%fPSA), and bound/ complexed PSA. Dr. Per-Anders Abrahamsson, from Lund University in Sweden, provided information about the potential strengths and weaknesses of these strategies. Decreasing the PSA cutpoint for further evaluation from 4.0 ng/mL to 3.0 ng/mL would increase the percentage of men undergoing biopsies by an absolute 6% to 11%.4 Studies evaluating the ability to use PSA levels as a function of time (PSA-V and PSAchange) are inconclusive. Because of intraindividual variation, the PSA-V is most useful if three or more measurements are obtained over an interval of 1 to 3 years.5 An abnormal PSA-V has been defined as a PSA increase of 0.75 ng/mL or more per year. Because prostate inflammation contributes to PSA elevations, the use of PSA-V change after antibacterial therapy for infectious/inflammatory symptoms might help differentiate benign and malignant conditions in men with elevated PSA. PSA circulates in two forms: free and complexed with molecules as 1antichymotrypsin. Men with prostate cancer tend to have a lower percentage of their PSA in the free form compared with men without prostate the frequency of PSA testing, that is, whether annual screening confers any gain compared with intervals of at least 2 years and whether certain groups of men are at sufficiently low risk for prostate cancer that annual PSA testing is of little use. Information from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial that addresses these issues was presented by E. David Crawford, MD, of the University of Colorado Health Sciences Center. PLCO is a randomized, controlled trial of more than 154,000 men and Controversy exists regarding the frequency of PSA testing, that is, whether annual screening confers any gain compared with intervals of at least 2 years. cancer.6 The free/total PSA measurements might help differentiate between prostate cancer and benign prostate conditions among men with PSA concentrations between 4.0 ng/mL and 10 ng/mL. To be useful, a negative value for %fPSA would need to reduce the probability of prostate cancer to a low enough level that men would be willing to forego biopsy. Results from a systematic review examining %fPSA found that a policy of not performing biopsies on men with a total PSA between 4.0 ng/mL and 9.9 ng/mL and a %fPSA above 25% would avoid about 20% of biopsies. However, these men would still have a probability of prostate cancer of 8%.7 Whether this is a low enough level for patients and physicians to withhold biopsy is not clear. PSA complexed with 1-antichymotrypsin, 2-macroglobulin or 1-protease inhibitor as well as human glandular kallekrein-2 might hold promise when evaluating the need for repeat biopsies in men with a mildly elevated PSA and negative initial biopsy. Controversy also exists regarding women, aged 55 to 74 years. This study is designed to determine, in part, whether early detection with annual PSA tests and digital rectal examinations (DREs) will reduce prostate cancer-specific mortality. Dr. Crawford and colleagues determined the pattern of changes in PSA levels over 5 years among 27,863 men in the screening arm who had baseline PSA levels of less than 4 ng/mL and at least one subsequent PSA measurement. They used a statistical model to estimate the cumulative probability of converting to PSA levels of 4 ng/mL or higher at years 1 through 5 post-baseline independent of baseline DRE status. Preliminary evidence indicates that a baseline PSA level less than 1 ng/mL would remain negative (ie, PSA < 4 ng/mL) after 4 subsequent years of annual PSA testing in almost 99% of men. In addition, 99% of men with PSA levels of 1 ng/mL to 2 ng/mL would have negative PSA test results the following year. A strategy of PSA screening every 5 years for men with PSA levels below 1 ng/mL and every VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S5 Prostate Cancer: Epidemiology and Screening continued 2 years for men with PSA in the 1 to 2 ng/mL range would produce a 55% reduction in the number of PSA tests, but it would result in only a small percentage of men missing an earlier positive test. The estimated cost savings of this strategy is $1 billion per year. of cellular signal transduction might also be important. The prostate is a highly structured gland with hormone-modulated signaling between the compartments. CEP-751, an inhibitor of growth-factor receptor phosphorylation, has been found to have a growth inhibitory effect in human prostate cancer xenografts.9 Molecular Oncology Molecular oncology is becoming increasingly important in elucidating many of the basic mechanisms underlying the initiation and progression of prostate cancer. Molecular oncology might lead to development of individualized therapeutic strategies. Some of the most fruitful Diagnosis and the “Shared Decision-Making" Process Despite recent advances in PSA testing, molecular diagnostics, and imaging modalities, the pathologic evaluation of tissue is still the gold standard for the diagnosis and assessment of prostate cancer. M. Molecular oncology is becoming increasingly important in elucidating many of the basic mechanisms underlying the initiation and progression of prostate cancer. areas for research are those identifying new therapeutic targets responsible for hormone-refractory disease. According to Jack Schalken, PhD, of the University Medical Center in Nijmegen, 2 pathways furthest along in clinical trials involve targeting the activation of programmed cell death and inhibition of cell signal transduction. Because therapies designed to reduce or inhibit prostate cancer cell proliferation have not been successful, attention has turned to the induction of apoptosis. Androgen ablation leads to activation of apoptosis in prostate cells; in androgenindependent prostate cancer, this no longer occurs. However, the program for cell death can be activated pharmacologically. One bound prodrug, thapsigargin, becomes activated by high concentrations of PSA. In turn, this activates apoptosis by increasing intracellular calcium ion concentration.8 The results of phase 1 and 2 studies are expected soon. Inhibitors S6 VOL. 5 SUPPL. 6 2003 Scott Lucia, MD, also from the University of Colorado, provided an overview of the nature of prostate cancer, the utility and limitations of prostatic needle biopsies, and tissue prognostic factors. There are dramatic differences among the zones in susceptibility to disease. Most carcinomas are found in the peripheral zone, whereas the nodules of benign prostatic hyperplasia are found almost exclusively in the transition zone. The central zone is relatively resistant to these diseases. The majority of tumors arise in, or extend close to, the prostatic capsule,10 allowing for detection by transrectal needle biopsy. Prostatic tumors detected because of PSA testing are often small, organ-confined, and associated with extensive prostatic intraepithelial neoplasia (PIN).11 Prostate cancer is a multifocal disease, and large tumors often result from the assimilation of multiple smaller tumors as they grow to con- REVIEWS IN UROLOGY fluence.11 Unfortunately, the ability of a particular needle biopsy sample to represent the range of heterogeneity of the entire tumor (and thus provide accurate prognostic information) is relatively low. A diagnostic dilemma also exists when a biopsy reveals the finding of distinctly atypical acini without definitive presence of prostate cancer. Although controversy exists regarding the nature of these lesions and the best terminology to use (eg, “suspicious for cancer" vs "atypical small acinar proliferation"), the importance lies in the uncertainty regarding the potentially malignant behavior.12 However, the presence of such lesions (as well as high-grade PIN) carries a high probability (40%–60%) that cancer will be detected on subsequent biopsy. Features that predict the biologic aggressiveness, extent of tumor, and eventual outcome of prostate cancer are important in trying to assist the patient and clinician to choose among the wide range of treatment options. The most important and established prognostic factors are the Gleason histologic grade, the extent of the tumor (tumor volume), and the presence of extracapsular extension and/or margin involvement of the prostatectomy specimen. In needle specimens, typically only the Gleason grade can be reliably determined. The most important prognostic parameter seems to be the relative amount of tumor that is of high grade (pattern 4 or 5).13 Unfortunately, data from individuals treated with radical prostatectomy indicate that the Gleason sum, as determined on needle biopsy, might not be the same as, and is often lower than, that present in the whole gland.14 Some studies suggest that the amount of tumor present on individual biopsy needle cores and the number of cores involved correlates with pathologic stage, tumor volume, Prostate Cancer: Epidemiology and Screening and subsequent biochemical failure.15,16 However, these correlations have been only shown with random, and not directed, biopsy strategies. The College of American Pathologists recommends that pathologists should estimate the percent of submitted tissue involved with tumor.17 The presence of capsular penetration and/or seminal vesicle involvement portends a much worse prognosis than if cancer is confined to an organ. Methods to identify this information prior to treatment include the use of staging biopsies (eg, of seminal vesicles as well as extraprostatic and neurovascular bundles).18 However, their utility (especially if negative) is unknown. In the absence of definitive information from randomized clinical trials about the relative benefits of detection and treatment strategies, patients seek information and recommendations from many sources. Evidence suggests that physicians could improve information delivery regarding the uncertainty of the risks and benefits of screening for prostate cancer, as well as detection and treatment.19 Rather than recommending for or against routine PSA testing, physicians should provide balanced information as to the potential benefits and established risks of screening, diagnosis, and treatment. This “shared decision-making" approach should focus on men who are interested in prostate cancer testing, are aged 50 years or older, and who have a life expectancy of at least 10 to 15 years. In addition, physicians should advise against prostate cancer testing in men who are more likely to be harmed than helped by screening (eg, due to advanced age, comorbid conditions, or desire not to receive early intervention). Validated informational materials can effectively and efficiently promote shared decision making. The minimum information should Table 1 Elements of Informed Consent for Prostate Cancer Screening 1. Prostate cancer is an important health problem. 2. The benefits of one-time or repeated screening and aggressive treatment of prostate cancer have not yet been proved. 3. Digital rectal examination and prostate-specific antigen measurement can both have false-positive and false-negative results. 4. The probability that further invasive evaluation will be required as a result of testing is relatively high. 5. Aggressive therapy is necessary to realize any benefit from the discovery of a tumor. 6. A small but finite risk for early death and a significant risk for chronic illness, particularly with regard to sexual and urinary function, are associated with these treatments. 7. Early detection might save lives. 8. Early detection and treatment might avert future cancer-related illness. Adapted with permission from American College of Physicians. Ann Intern Med. 1997; 126:480–484.26 include the potential magnitude and seriousness of prostate cancer, the likelihood that prostate cancer will be diagnosed, possibilities of falsepositive and false-negative results, anxiety associated with a positive test, and uncertainty regarding whether screening reduces the risk of death from prostate cancer (Table 1). The basic message to convey when promoting informed decision making for prostate cancer screening is that there is currently no right or wrong answer; that is, there is insufficient evidence to determine whether early detection and treatment of prostate cancer helps men live longer. Therefore, screening is a personal decision. Patients should participate in the decision after considering the potential, but unproven, pros and cons and incorporating their own preferences for various outcomes. With few exceptions,20 most prostate cancer screening materials do not reinforce the message of uncertainty but instead recommend offering or actively promoting annual prostate cancer screening for eligible men. However, the U.S. Preventive Services Task Force (USPSTF) recently published the most evidence-based assessment of the information related to screening and treatment for earlystage prostate cancer.2 The USPSTF concluded that “there was good evidence that PSA screening can detect early-stage prostate cancer but mixed and inconclusive evidence that early detection improves health outcomes. Screening is associated with important harms, including frequent falsepositive results and unnecessary anxiety, biopsies, and potential complications of treatment of some cancers that might never have affected a patient’s health. The evidence was insufficient to determine whether the benefits outweigh the harms for a screened population."2 Practitioners have a difficult and time-consuming task in trying to make this information comprehensible to the average patient. The issues that must be conveyed are complex, difficult to deliver concisely, and challenging for the general population to comprehend. Thus, it is recommended that health education materials be written at a sixth-grade VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S7 Prostate Cancer: Epidemiology and Screening continued reading or comprehension level.20 The final challenge is convincing patients that decisions regarding prostate cancer screening are important to ponder. Patients (and some physicians) have difficulty understanding why it is important to deliberate over a simple, low-cost blood test that seemingly poses no immediate or significant health risks in and of itself—particularly given the widespread belief that early prostate cancer testing and treatment However, there is strong evidence to suggest that men with lower urinary tract symptoms are not at greater risk for prostate cancer, aside from the risk conferred by their age. Routinely testing these men will result in more false-positive test results and serendipitous identification of clinically insignificant prostate cancer.22 Impressing upon patients the importance of pondering the PSA test is complicated by the fact that The most significant “risks" of prostate cancer screening are not associated with the initial PSA test or DRE but rather the diagnostic and treatment procedures that might be used if these screening tests are abnormal. are necessary and effective. Indeed, the majority of primary care physicians in the United States report that they performed PSA testing in men older than 80 years, even though these men are more likely to be harmed than helped by testing and treatment.21 Furthermore, because approximately one third of men older than 50 years have bothersome lower urinary tract symptoms, PSA testing is often ordered for diagnostic rather then screening purposes. the prevailing medical and social culture in the United States tends to underemphasize the downsides and overemphasize the benefits of screening.23 In addition, the most significant “risks" of prostate cancer screening are not associated with the initial PSA test or DRE but rather the diagnostic and treatment procedures that might be used if these screening tests are abnormal. In effect, the perceived seriousness of prostate cancer, innocuousness of the PSA test, the fact that the significant risks associated with screening apply only if a diagnosis occurs, all work to discourage careful deliberation of the screening decision. Hence, clinicians attempting to promote informed decision making for prostate cancer screening, rather than merely ordering a PSA test as a matter of routine, face an uphill effort in getting their point across. However, the importance of this effort is emphasized by the initial results of the Scandinavian Prostate Cancer Group-4 (SPCG-4) randomized trial comparing radical prostatectomy with watchful waiting for men with clinically detected (opposed to screen detected) prostate cancer.24 In the SPCG-4 study, surgery compared with watchful waiting reduced the number of men whose death was attributed to prostate cancer by about 4 in 100, and reduced the number of men in whom metastatic disease developed by about 5 in 100, but overall survival and quality of life25 were similar in the two groups. Men receiving radical prostatectomy had higher rates of erectile dysfunction and urinary leakage but lower rates of weak urinary stream. These results indicate that, on average, 25 Main Points • Prostate cancer is the most common malignancy among men. The lifetime risk of a diagnosis is approximately 16%; the lifetime risk of death from prostate cancer is about 3.4%. Therefore, most patients in the United States in whom prostate cancer is diagnosed do not die of prostate cancer even without treatment. • Prostate-specific antigen (PSA) circulates in 2 forms: free and complexed. Men with prostate cancer tend to have a lower percentage of free form PSA than do men without prostate cancer. The free/total PSA measurements might help differentiate between prostate cancer and benign prostate conditions among men with PSA concentrations between 4.0 ng/mL and 10 ng/mL. • Because therapies designed to reduce or inhibit prostate cancer cell proliferation have not been successful, attention has turned to the induction of apoptosis. Androgen ablation leads to activation of apoptosis in prostate cells; in androgen-independent prostate cancer this no longer occurs. Cell death can be activated pharmacologically; thapsigargin becomes activated by high concentrations of PSA. In turn, this activates apoptosis by increasing intracellular calcium ion concentration. • Despite recent advances in PSA testing, molecular diagnostics, and imaging modalities, the pathologic evaluation of tissue is still the gold standard for the diagnosis and assessment of prostate cancer. • Rather than recommending for or against routine PSA testing, physicians should provide balanced information as to the potential benefits and established risks of screening, diagnosis, and treatment. This “shared decision-making" approach should focus on men who are interested in prostate cancer testing, are aged 50 years or older, and have a life expectancy of at least 10 to 15 years. S8 VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY Prostate Cancer: Epidemiology and Screening men with clinically detected prostate cancer would need to be treated with surgery to prevent one death attributed to prostate cancer over a 6-year time period, without evidence that this would improve length or quality of life. The SPCG-4 results reinforce the importance of counseling men about the relative risks and benefits of prostate cancer screening and early treatment. In the United States, the vast majority of newly diagnosed prostate cancer cases are detected by PSA Conclusion The opportunity exists to resolve the confusion, close the gaps in knowledge, and enhance prostate cancer care by conducting randomized clinical trials evaluating prevention, detection, and treatment of prostate cancer. Until these randomized clinical trials are completed, physicians can serve as their patients’ advocate by providing a balanced presentation of the known risks and potential benefits of prevention, detection, and treatment options and incorporating 8. 9. 10. 11. 12. In the United States, the vast majority of newly diagnosed prostate cancer cases are detected by PSA screening rather than clinical examination. 13. 14. screening rather than clinical examination. The baseline risk of death from screen detected prostate cancer and the absolute reduction in deaths attributed to prostate cancer from radical treatment might be even less pronounced than observed in SPCG-4. In addition, the lead-time due to PSA screening—which is likely to be many years—would add to the time before a benefit (if any) emerges. The VA/NCI/AHRQ Prostate Cancer Intervention Versus Observation Trial (PIVOT) recently completed enrollment of 731 men. PIVOT is a randomized clinical trial comparing radical prostatectomy with expectant management in men with clinically localized prostate cancer. Baseline results indicate that PIVOT enrollees are representative of men in whom early-stage prostate cancer is being diagnosed in the United States; these men are considered to be candidates for radical prostatectomy. A balanced presentation of the evidence will permit patients to incorporate their personal preferences relative to the importance they place on various outcomes. This will result in varying choices related to early detection and treatment. patient preferences into health care decisions. Providers might increase their success in shared decision making if they use educational materials to convey most of the time-consuming and challenging information. Two of the many developed can be easily and efficiently administered with very few resources and independent of primary care encounters.20 15. 16. 17. 18. 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Srigley JR, Amin MB, Bostwick DG. Updated protocol for the examination of specimens from patients with carcinoma of the prostate gland: a basis for checklists. Cancer Committee. Arch Pathol Lab Med. 2000;124:1034–1039. Okihara K, Kamoi K, Lane RB. Role of systematic ultrasound-guided staging biopsies in predicting extraprostatic extension and seminal vesicle invasion in men with prostate cancer. J Clin Ultrasound. 2002;30:123–131. Aspen Reference Group. Community Health Education and Promotion Manual. Gaithersburg, MD: Aspen Publishers; 1998. Partin MR, Wilt TJ. Informing patients about prostate cancer screening: identifying and meeting the challenges while the evidence remains uncertain. Am J Med. 2002;113:691–693. Fowler FJ Jr, Bin L, Collins MM, et al. Prostate cancer screening and beliefs about treatment efficacy: a national survey of primary care physicians and urologists. Am J Med. 1998; 104:526–532. McNaughton Collins M, Ransohoff DF, Barry MJ. Early detection of prostate cancer. Serendipity strikes again. JAMA. 1997; 278:1516–1519. Welch HG. Informed choice in cancer screening. JAMA. 2001;285:2776–2778. Holmberg L, Bill-Axelson A, Helgesen F, et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med. 2002;347:781–789. Steineck G, Helgesen F, Adolfsson J, et al. Quality of life after radical prostatectomy or watchful waiting. N Engl J Med. 2002; 347:790–796. American College of Physicians. Screening for prostate cancer. Ann Intern Med. 1997; 126:480-484. VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S9