Purpose of This PDQ Summary
Summary of Evidence

Digital Rectal Examination and Prostate-Specific Antigen         Benefits         Harms

Significance

Incidence and Mortality Risk Factors

Evidence of Benefit

Digital Rectal Exam Transrectal Ultrasound and Other Imaging Tests Prostate-Specific Antigen Methods to Improve the Performance of Serum PSA Measurement for the Early Detection of Prostate Cancer         Complexed PSA and percent-free PSA         Third-generation PSA         PSA density         PSA density of the transition zone         Age-adjusted PSA         PSA velocity         Alteration of PSA cutoff level         Frequency of screening Types of Tumors Detected by Prostate Cancer Screening Physician Behaviors Related to Screening Randomized Prospective Clinical Trials of Screening for Prostate Cancer Population Observations on Early Detection, Incidence, and Prostate Cancer Mortality Simulation Models Providing Information to the Public, to Patients, and to Their Families

Evidence of Harms
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about prostate cancer screening. This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board ¹.

Information about the following is included in this summary:

• Prostate cancer incidence and mortality statistics and information about prostate cancer risk factors.
• Prostate cancer screening modalities.
• Benefits and harms of prostate cancer screening.

This summary is intended as a resource to inform clinicians and other health professionals about currently available prostate cancer screening modalities. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system ² in reporting the evidence of benefit and potential harms associated with each screening modality. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version ³, which is written in less technical language.

Summary of Evidence

Note: Separate PDQ summaries on Prostate Cancer Prevention ⁴, Prostate Cancer Treatment ⁵, and Levels of Evidence for Cancer Screening and Prevention Studies ² are also available.

The evidence is insufficient to determine whether screening for prostate cancer with prostate-specific antigen (PSA) or digital rectal exam (DRE) reduces mortality from prostate cancer. Screening tests are able to detect prostate cancer at an early stage, but it is not clear whether this earlier detection and consequent earlier treatment leads to any change in the natural history and outcome of the disease. Observational evidence shows a trend toward lower mortality for prostate cancer in some countries, but the relationship between these trends and intensity of screening is not clear, and associations with screening patterns are inconsistent. The observed trends may be due to screening, or to other factors such as improved treatment.[1]

Description of the Evidence

• Study Design: Evidence obtained from observational and descriptive studies (e.g., international patterns studies, time series).
• Internal Validity: Poor.
• Consistency: Poor.
• Magnitude of Effects on Health Outcomes: Uncertain.
• External Validity: Poor.

Based on solid evidence, screening with PSA and/or DRE detects some prostate cancers that would never have caused important clinical problems. Thus, screening leads to some degree of overtreatment. Based on solid evidence, current prostate cancer treatments, including radical prostatectomy and radiation therapy, result in permanent side effects in many men. The most common of these side effects are erectile dysfunction and urinary incontinence.[1-3] Whatever the screening modality, the screening process itself can lead to adverse psychological effects in men who have a prostate biopsy but do not have identified prostate cancer.[4] Prostatic biopsies are associated with complications, including fever, pain, hematospermia/hematuria, positive urine cultures, and rarely sepsis.[5]

Description of the Evidence

• Study Design: Evidence obtained from cohort or case-control studies.
• Internal Validity: Good.
• Consistency: Good.
• Magnitude of Effects on Health Outcomes: 20% to 70% of men who had no problems before radical prostatectomy or external-beam radiation therapy will have reduced sexual function and/or urinary problems.[1]
• External Validity: Good.

References

1. Harris R, Lohr KN: Screening for prostate cancer: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 137 (11): 917-29, 2002.  [PUBMED Abstract]
   
   
2. Litwin MS, Pasta DJ, Yu J, et al.: Urinary function and bother after radical prostatectomy or radiation for prostate cancer: a longitudinal, multivariate quality of life analysis from the Cancer of the Prostate Strategic Urologic Research Endeavor. J Urol 164 (6): 1973-7, 2000.  [PUBMED Abstract]
   
   
3. Steineck G, Helgesen F, Adolfsson J, et al.: Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 347 (11): 790-6, 2002.  [PUBMED Abstract]
   
   
4. Fowler FJ Jr, Barry MJ, Walker-Corkery B, et al.: The impact of a suspicious prostate biopsy on patients' psychological, socio-behavioral, and medical care outcomes. J Gen Intern Med 21 (7): 715-21, 2006.  [PUBMED Abstract]
   
   
5. Rietbergen JB, Kruger AE, Kranse R, et al.: Complications of transrectal ultrasound-guided systematic sextant biopsies of the prostate: evaluation of complication rates and risk factors within a population-based screening program. Urology 49 (6): 875-80, 1997.  [PUBMED Abstract]
   
   

Significance

Incidence and Mortality

Prostate cancer is the most common cancer diagnosed in North American men, excluding skin cancers. It is estimated that in 2008, approximately 186,320 new cases and 28,660 prostate cancer-related deaths will occur in the United States.[1]. Prostate cancer is now the second leading cause of cancer death in men, exceeded only by lung cancer. It accounts for 25% of all male cancers and 10% of male cancer-related deaths.[1] Age-adjusted incidence rates increased steadily over the past several decades, with particularly dramatic increases associated with the inception of widespread use of prostate-specific antigen (PSA) screening in the late 1980s and early 1990s, followed by a more recent fall in incidence. Age-adjusted mortality rates have recently paralleled incidence rates, with an increase followed by a decrease in the early 1990s.[2] It has been suggested that declines in mortality rates in certain jurisdictions reflect the benefit of PSA screening,[3] but others have noted that these observations may be explained by independent phenomena such as improved treatment effects.

Regional differences have been observed in prostate cancer incidence and mortality rates and in rates of radical prostatectomy. The increased incidence until 1989 was most likely the result of increased tumor detection due to increasing rates of transurethral prostatectomy.[4,5] Subsequent increases were most likely the result of widespread use of PSA testing for early detection and screening.[6,7] Variable incidence rates may reflect variability in the intensity of early detection practices across the United States and other jurisdictions. While differences in aggregate mortality by regions of the United States have not been observed, considerable variation in mortality rates between African American and white men are seen.[8,9] (Refer to the Population Observations on Early Detection, Incidence, and Prostate Cancer Mortality ⁶ section of this summary for more information.)

Prostate cancer is uncommonly seen in men younger than 50 years; the incidence rises rapidly with each decade thereafter. The age-adjusted incidence is higher in African American males (258.3 per 100,000) than in white males (163.4 per 100,000).[10] African American males have a higher mortality from prostate cancer, even after attempts to adjust for access-to-care factors.[11] Men with a family history of prostate cancer are at an increased risk of the disease compared with men without this history.[12,13] Other potential risk factors besides age, race, and family history of prostate cancer include alcohol consumption, vitamin or mineral interactions, and other dietary habits.[14-18] A significant body of evidence suggests that a diet high in fat, especially saturated fats and fats of animal origin, is associated with a higher risk of prostate cancer.[19,20] Other possible dietary influences include selenium, vitamin E, vitamin D, lycopene, and isoflavones. (Refer to the PDQ summary on Prostate Cancer Prevention ⁴ for more information.) Evidence from a nested case-control study within the Physicians’ Health Study,[21] in addition to a case-control study [22] and a retrospective review of screened prostate cancer patients,[23] suggests that higher plasma insulin-like growth factor-I levels may be associated with a higher prostate cancer risk.[24] Not all studies, however, have confirmed this association.[25] The estimated lifetime risk of diagnosis of prostate cancer is about 17.1%, and the lifetime risk of dying from this disease is 2.9%.[10]

The biology and natural history of prostate cancer is not completely understood. Rigorous evaluation of any prostate cancer screening modality is desirable because the natural history of the disease is variable, and appropriate treatment is not clearly defined. Although the prevalence of prostate cancer and preneoplastic lesions found at autopsy steadily increases for each decade of age, most of these lesions remain clinically undetected.[26]

There is an association between primary tumor volume and local extent of disease, progression, and survival.[27] A review of a large number of prostate cancers in radical prostatectomy, cystectomy, and autopsy specimens showed that capsular penetration, seminal vesicle invasion, and lymph node metastases were usually found only with tumors larger than 1.4 cc.[28] Furthermore, the semiquantitative histopathologic grading scheme proposed by Gleason is reasonably reproducible among pathologists and correlates with the incidence of nodal metastases and with patient survival in a number of reported studies.[29]

Cancer statistics from the American Cancer Society and the National Cancer Institute indicated in 2004 that the proportion of disease diagnosed at a locoregional stage and at a distant stage is 91% and 5% for whites, compared with 89% and 7% for African Americans, respectively.[30] Stage distribution of prostate cancer is affected substantially by the intensity of early detection efforts.

Pathologic stage does not always reflect clinical stage and upstaging (owing either to extracapsular extension, positive margins, seminal vesicle invasion, or lymph node involvement) occurs frequently. Of the prostate cancers detected by digital rectal exam (DRE) in the pre-PSA era, 67% to 88% were at a clinically localized stage (T1–2 Nx M0 [T = tumor size, N = lymph node involvement, and M = metastasis]).[31,32] However, in one of those series of 2,002 patients undergoing annual screening DRE, only one-third of men proved to have pathologically organ-confined disease.[32]

With the proliferation of PSA for early detection, reviews of large numbers of asymptomatic men with prostate cancer found that most have organ-confined disease. One study found that 63% of cancers detected in men undergoing their first screening PSA were pathologically organ-confined cancers; the percentage increased to 71% if cancer was detected on a subsequent examination.[33] In a series of 2,999 men undergoing screening with PSA, DRE, and transrectal ultrasound, 62% of the tumors detected were reported to be pathologically organ-confined.[34] While the proportion of node-positive cancers in the pre-PSA era were in the range of 25% for patients with ostensibly localized disease, current series report proportions as low as 3%.[35] Stage T1c tumors detected by serial PSA and removed by radical prostatectomy are organ-confined in 79% of cases.[36]

Survival rates for prostate cancer have improved from 1974 to the present. Lead-time and length-bias effects of early detection and the possible influence of stage migration must also be considered when trends in survival data are interpreted.[37] Reported survival rates may also vary, depending on whether the analytical methods reflect crude disease-specific rates (absolute disease-specific survival) or take into account competing risks for the given age group (relative disease-specific survival).

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. ⁷ Last accessed October 1, 2008. 
   
   
2. Trends in SEER incidence and U.S. mortality using the joinpoint regression program, 1973-1998 with up to three joinpoints by race and age. In: Ries LA, Eisner MP, Kosary CL, et al., eds.: SEER Cancer Statistics Review 1973-1998. Bethesda, Md: National Cancer Institute, 2001., Section 22: Prostate Cancer, Table XXII-1. Also available online. ⁸ Last accessed October 07, 2008. 
   
   
3. Bartsch G, Horninger W, Klocker H, et al.: Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 58 (3): 417-24, 2001.  [PUBMED Abstract]
   
   
4. Potosky AL, Kessler L, Gridley G, et al.: Rise in prostatic cancer incidence associated with increased use of transurethral resection. J Natl Cancer Inst 82 (20): 1624-8, 1990.  [PUBMED Abstract]
   
   
5. Levy IG, Gibbons L, Collins JP, et al.: Prostate cancer trends in Canada: rising incidence or increased detection? CMAJ 149 (5): 617-24, 1993.  [PUBMED Abstract]
   
   
6. Potosky AL, Miller BA, Albertsen PC, et al.: The role of increasing detection in the rising incidence of prostate cancer. JAMA 273 (7): 548-52, 1995.  [PUBMED Abstract]
   
   
7. Jacobsen SJ, Katusic SK, Bergstralh EJ, et al.: Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA 274 (18): 1445-9, 1995.  [PUBMED Abstract]
   
   
8. Lu-Yao GL, Greenberg ER: Changes in prostate cancer incidence and treatment in USA. Lancet 343 (8892): 251-4, 1994.  [PUBMED Abstract]
   
   
9. Devesa SS, Grauman DG, Blot WJ, et al.: Atlas of Cancer Mortality in the United States, 1950-94. Washington DC: US Govt Print Off., 1999. NIH Publ No. (NIH) 99-4564. Also available online. ⁹ Last accessed September 5, 2008. 
   
   
10. Ries LAG, Harkins D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2003. Bethesda, Md: National Cancer Institute, 2006. Also available online ¹⁰. Last accessed October 07, 2008. 
    
    
11. Robbins AS, Whittemore AS, Van Den Eeden SK: Race, prostate cancer survival, and membership in a large health maintenance organization. J Natl Cancer Inst 90 (13): 986-90, 1998.  [PUBMED Abstract]
    
    
12. Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. Prostate 17 (4): 337-47, 1990.  [PUBMED Abstract]
    
    
13. Matikainen MP, Schleutker J, Mörsky P, et al.: Detection of subclinical cancers by prostate-specific antigen screening in asymptomatic men from high-risk prostate cancer families. Clin Cancer Res 5 (6): 1275-9, 1999.  [PUBMED Abstract]
    
    
14. Hayes RB, Brown LM, Schoenberg JB, et al.: Alcohol use and prostate cancer risk in US blacks and whites. Am J Epidemiol 143 (7): 692-7, 1996.  [PUBMED Abstract]
    
    
15. Platz EA, Leitzmann MF, Rimm EB, et al.: Alcohol intake, drinking patterns, and risk of prostate cancer in a large prospective cohort study. Am J Epidemiol 159 (5): 444-53, 2004.  [PUBMED Abstract]
    
    
16. Eichholzer M, Stähelin HB, Gey KF, et al.: Prediction of male cancer mortality by plasma levels of interacting vitamins: 17-year follow-up of the prospective Basel study. Int J Cancer 66 (2): 145-50, 1996.  [PUBMED Abstract]
    
    
17. Gann PH, Hennekens CH, Sacks FM, et al.: Prospective study of plasma fatty acids and risk of prostate cancer. J Natl Cancer Inst 86 (4): 281-6, 1994.  [PUBMED Abstract]
    
    
18. Morton MS, Griffiths K, Blacklock N: The preventive role of diet in prostatic disease. Br J Urol 77 (4): 481-93, 1996.  [PUBMED Abstract]
    
    
19. Fleshner NE, Klotz LH: Diet, androgens, oxidative stress and prostate cancer susceptibility. Cancer Metastasis Rev 17 (4): 325-30, 1998-99.  [PUBMED Abstract]
    
    
20. Clinton SK, Giovannucci E: Diet, nutrition, and prostate cancer. Annu Rev Nutr 18: 413-40, 1998.  [PUBMED Abstract]
    
    
21. Chan JM, Stampfer MJ, Giovannucci E, et al.: Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279 (5350): 563-6, 1998.  [PUBMED Abstract]
    
    
22. Oliver SE, Barrass B, Gunnell DJ, et al.: Serum insulin-like growth factor-I is positively associated with serum prostate-specific antigen in middle-aged men without evidence of prostate cancer. Cancer Epidemiol Biomarkers Prev 13 (1): 163-5, 2004.  [PUBMED Abstract]
    
    
23. Turkes A, Peeling WB, Griffiths K: Serum IGF-1 determination in relation to prostate cancer screening: possible differential diagnosis in relation to PSA assays. Prostate Cancer Prostatic Dis 3 (3): 173-175, 2000.  [PUBMED Abstract]
    
    
24. Stattin P, Rinaldi S, Biessy C, et al.: High levels of circulating insulin-like growth factor-I increase prostate cancer risk: a prospective study in a population-based nonscreened cohort. J Clin Oncol 22 (15): 3104-12, 2004.  [PUBMED Abstract]
    
    
25. Chen C, Lewis SK, Voigt L, et al.: Prostate carcinoma incidence in relation to prediagnostic circulating levels of insulin-like growth factor I, insulin-like growth factor binding protein 3, and insulin. Cancer 103 (1): 76-84, 2005.  [PUBMED Abstract]
    
    
26. Sakr WA, Haas GP, Cassin BF, et al.: The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 150 (2 Pt 1): 379-85, 1993.  [PUBMED Abstract]
    
    
27. Freedland SJ, Humphreys EB, Mangold LA, et al.: Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 294 (4): 433-9, 2005.  [PUBMED Abstract]
    
    
28. McNeal JE, Bostwick DG, Kindrachuk RA, et al.: Patterns of progression in prostate cancer. Lancet 1 (8472): 60-3, 1986.  [PUBMED Abstract]
    
    
29. Resnick MI: Background for screening--epidemiology and cost effectiveness. Prog Clin Biol Res 269: 111-22, 1988.  [PUBMED Abstract]
    
    
30. Ries LAG, Eisner MP, Kosary CL, et al., eds.: SEER Cancer Statistics Review, 1975-2002. Bethesda, Md: National Cancer Institute, 2005. Also available online ¹¹. Last accessed May 30, 2008. 
    
    
31. Chodak GW, Keller P, Schoenberg HW: Assessment of screening for prostate cancer using the digital rectal examination. J Urol 141 (5): 1136-8, 1989.  [PUBMED Abstract]
    
    
32. Thompson IM, Ernst JJ, Gangai MP, et al.: Adenocarcinoma of the prostate: results of routine urological screening. J Urol 132 (4): 690-2, 1984.  [PUBMED Abstract]
    
    
33. Catalona WJ, Smith DS, Ratliff TL, et al.: Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 270 (8): 948-54, 1993.  [PUBMED Abstract]
    
    
34. Mettlin C, Murphy GP, Lee F, et al.: Characteristics of prostate cancer detected in the American Cancer Society-National Prostate Cancer Detection Project. J Urol 152 (5 Pt 2): 1737-40, 1994.  [PUBMED Abstract]
    
    
35. Rees MA, Resnick MI, Oesterling JE: Use of prostate-specific antigen, Gleason score, and digital rectal examination in staging patients with newly diagnosed prostate cancer. Urol Clin North Am 24 (2): 379-88, 1997.  [PUBMED Abstract]
    
    
36. Epstein JI, Walsh PC, Carmichael M, et al.: Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 271 (5): 368-74, 1994.  [PUBMED Abstract]
    
    
37. Pfister DG, Wells CK, Chan CK, et al.: Classifying clinical severity to help solve problems of stage migration in nonconcurrent comparisons of lung cancer therapy. Cancer Res 50 (15): 4664-9, 1990.  [PUBMED Abstract]
    
    

Evidence of Benefit

Before the 1990s, the digital rectal examination (DRE) was the test traditionally used for prostate cancer screening. Two other procedures are also available: transrectal ultrasound (TRUS) imaging and serum prostate-specific antigen (PSA) concentrations.[1] Prostate cancer screening is controversial because of the lack of definitive evidence of benefit. A small randomized trial in Sweden evaluated the effects of screening men aged 50 to 69 years every 3 years; the first two screenings included DRE only, followed by two screenings with DRE combined with a test for PSA. The trial was not powered to detect even moderate differences in prostate cancer mortality, which was the same in the two groups: 1.3% (20 of 1,494 patients) for men assigned to screening and 1.3% (97 of 7,532 patients) for controls.[2] The controversy persists. A nested case-control study was conducted at ten U.S. Department of Veterans Affairs (VA) medical centers in New England (71,661 patients receiving ambulatory care between 1989 and 1990), identifying 501 patients who were diagnosed with adenocarcinoma of the prostate from 1991 to 1995 and who died between 1991 and 1999. Controls were selected from among patients living at the time case patients died (matched 1:1 for age and VA facility). A benefit from screening by PSA or PSA and/or DRE was not found for PSA (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.71–1.64; P = .72) or for PSA and/or DRE (OR, 1.13; 95% CI, 0.63–2.06; P = .68). Because prostate cancer has a relatively slow course, it is possible that the relatively short follow-up period in this study precluded the observation of a benefit, which might accrue only after 10 or more years from the time of screening.[3]

Adding to the controversy is the lack of consensus regarding optimal treatment of localized disease and the clear evidence that active treatment options are associated with significant morbidity. Treatment options for early-stage disease include radical prostatectomy, definitive radiation therapy, and watchful waiting (no immediate treatment; treatment if indications of progression are present, but treatment not designed with curative intent). Multiple series from various years and institutions have been reported on the outcomes of patients with localized prostate cancer who received no treatment but were followed with surveillance alone. Outcomes have also been reported for active treatments, but valid comparisons of efficacy between surgery, radiation, and watchful waiting are seldom possible because of differences in reporting and selection factors in the various reported series. A randomized trial in Scandinavian men published in 2002 explored the benefit of radical prostatectomy over watchful waiting in men with newly diagnosed, well-differentiated, or moderately well-differentiated prostate cancers of clinical stages T1b, T1c, or T2.[4] Six hundred ninety-eight men younger than 75 years, most with clinically detected rather than screen-detected cancers (unlike most newly diagnosed patients in North America) were randomly assigned to the two-arm trial. After 5 years of follow-up, the difference in prostate cancer-specific mortality between radical prostatectomy and watchful waiting groups was 2%; after 10 years of follow-up, the difference was 5.3% (relative risk [RR], 0.56 [0.36–0.88]). There was also a difference of about 5% in all-cause mortality that was apparent only after 10 years of follow-up (RR, 0.74 [0.56–0.99]). Thus 20 men with palpable, clinically localized prostate cancer would require radical prostatectomy rather than watchful waiting to extend the life of one man. Because most prostate cancers that are detected today with PSA screening are not palpable, this study may not be directly generalizable to the average newly diagnosed patient in the United States.[5]

Although DRE has been used for many years, careful evaluation of this modality has yet to take place. Several observational studies have examined process measures such as sensitivity and case-survival data, but without appropriate controls and with no adjustment for lead-time and length biases.[6,7]

In 1984, one study reported on 811 unselected patients aged 50 to 80 years who underwent rectal examination and follow-up.[8] Thirty-eight of 43 patients with a palpable abnormality in the prostate agreed to undergo biopsy. The positive predictive value (PPV) of a palpable nodule, i.e., prostate cancer on biopsy, was 29% (11 of 38). Further evaluation revealed that 45% of the cases were stage B, 36% were stage C, and 18% were stage D. More results from the same investigators revealed a 25% positive predictive value, with 68% of the detected tumors clinically localized but only approximately 30% pathologically localized after radical prostatectomy.[9] Some investigators reported a high proportion of clinically localized disease when prostate cancer is detected by routine rectal examination,[10] while others reported that even with annual rectal examination, only 20% of cases are localized at diagnosis.[11] It has been reported that 25% of men presenting with metastatic disease had a normal prostate examination.[12] Another case-control study examining screening with both DRE and PSA found a reduction in prostate cancer mortality that was not statistically significant (OR, 0.7; 95% CI, 0.46–1.1). Most men in this study were screened with DRE rather than PSA.[13] All four of these case-control studies are consistent with a reduction of 20% to 30% in prostate cancer mortality. Potential biases inherent in this study design, however, limit the ability to draw conclusions on the basis of this evidence alone.

Since PSA assays became widely available in the late 1980s, DRE alone is rarely discussed as a screening modality. A number of studies have found that DRE has a poor predictive value for prostate cancer if PSA is at very low levels. In the European Study on Screening for Prostate Cancer, it was found that if DRE is used only for a PSA higher than 1.5 ng/mL (thus, no DRE is performed with PSA < 1.5 ng/mL), 29% of all biopsies would be eliminated while maintaining a 95% prostate cancer detection sensitivity. By applying DRE only for patients with a PSA higher than 2.0 ng/mL, the biopsy rate would decrease by 36% while sensitivity would drop to only 92%.[14] A previous report from this same institution found DRE to have poor performance characteristics. Among 10,523 men randomly assigned to screening, it was reported that the overall prostate cancer detection rate using PSA, DRE, and TRUS was 4.5% compared with only 2.5% if DRE alone had been used. Among men with a PSA lower than 3.0 ng/mL, the PPV of DRE was only 4% to 11%.[15] Despite the poor performance of DRE, a retrospective case-control study of men in Olmsted County, Minnesota, who died of prostate cancer found that case patients were less likely to have undergone DRE during the 10 years before diagnosis of prostate cancer (OR, 0.51; 95% CI, 0.31–0.84). These data suggested that screening DREs may prevent 50% to 70% of deaths from prostate cancer.[16] Contrary to these findings, results from a case-control study of 150 men who ultimately died of prostate cancer were compared with 299 controls without disease. In this different population, a similar number of cases and controls had undergone DRE during the 10-year interval before prostate cancer diagnosis.[17] One case-control study reported no statistically significant association between routine screening with DRE and occurrence of metastatic prostate cancer.[18]

Rectal examination is inexpensive, relatively noninvasive, and nonmorbid and can be taught to nonprofessional health workers; however, its effectiveness depends on the skill and experience of the examiner. The possible contribution of routine annual screening by rectal examination to reducing prostate cancer mortality remains to be determined.

Imaging procedures have been suggested as possible screening modalities for prostate cancer. Prostatic imaging is possible by ultrasound, computed tomography, and magnetic resonance imaging. Each modality has relative merits and disadvantages for distinguishing different features of prostate cancer. Ultrasound has received the most attention, having been examined by several investigators in observational settings.[19] Sensitivity ranged from 71% to 92% for prostatic carcinoma and 60% to 85% for subclinical disease. Specificity values ranged from 49% to 79%, and positive predictive values in the 30% range have been reported. The sensitivity and positive predictive value for ultrasound as a single test may be better than for rectal examination. The rate of cancer is extremely low among ultrasound-positive patients in whom rectal and PSA examinations are normal.[20] TRUS is generally relegated to a role in the diagnostic work-up of an abnormal screening test rather than in the screening algorithm. The cost and poor performance of other imaging modalities have led to their elimination from all early detection algorithms.

Contemporary prostate biopsy relies on spring-loaded biopsy devices that are either digitally guided or guided via ultrasound. TRUS guidance is the most frequently used method of directing prostate needle biopsy because there is some suggestion that the yield of biopsy is improved with such guidance.[21] With the virtually simultaneous clinical acceptance of TRUS, spring-loaded biopsy devices, and the proliferation of PSA screening in the late 1980s, the number of prostate cores obtained from patients with either an abnormal DRE or PSA was most commonly six, using a sextant method of sampling the prostate.[22] There is evidence that the predictable increase in cancer detection rates that would be expected by increasing the number of biopsy cores beyond six does occur; e.g., biopsies with 12 or 15 cores would increase the proportion of biopsied men having cancer detected by 30% to 35%.[23,24] The extent to which such increased detection will reduce morbidity and mortality from the disease or increase the fraction of men treated unnecessarily is unknown.

The PSA test has been examined in several observational settings for initial diagnosis of disease, as a tool to monitor for recurrence after initial therapy, and for prognosis of outcomes after therapy. There is no PSA value below which a man can be assured that he has no risk of prostate cancer. Parameter estimates for this test include sensitivity in the range of 70%.[25]

In a review of the Prostate Cancer Prevention Trial, 2,950 men who never had a PSA level higher than 4.0 ng/mL or an abnormal DRE had a final PSA determination and underwent a prostate biopsy after being in the study for 7 years.[26] There was a 15.2% (n = 449) biopsy-proven prevalence of prostate cancer in men with PSA levels no higher than 4.0 ng/mL. High-grade prostate cancer (defined as Gleason score ≥7) was seen in 15.8% (n = 71) of these men. Size of the tumor was not reported.

In the placebo arm of the Prostate Cancer Prevention Trial, there was no cutpoint of PSA with simultaneous high sensitivity and high specificity for detection of prostate cancer in healthy men, but rather a continuum of prostate cancer risk at all values of PSA.[27]

The potential value of the test appears to be in its simplicity, objectivity, reproducibility, relative lack of invasiveness, and relatively low cost. PSA has increased the detection rate of early-stage cancers, many of which may be curable by local-modality therapies.[28-31] Circumstantial evidence favoring screening for prostate cancer is analogous to that for lung cancer screening in the 1950s and 1960s; screening results in a shift to a higher proportion of cases with earlier-stage cancers at diagnosis. This shift may result in mortality reduction. For lung cancer, no mortality benefit resulted.[32] However, the possibility of identifying an excessive number of false-positives in the form of benign prostatic lesions requires that the test be evaluated carefully. Furthermore, there is a risk of overdiagnosis and overtreatment, i.e., the detection of a histological malignancy that if left untreated would have had a benign or indolent natural history and would have been of no clinical significance.

A nested case-control prospective study with 10 years of follow-up reported that a single elevated PSA higher than 4.0 ng/mL predicted subsequent cancer with a sensitivity of 71% for the first 5 years and a specificity of 91% for the first 10 years of follow-up. The cancers diagnosed were characterized by stage and grade to be clinically important. Forty-two percent were extracapsular at diagnosis.[33] Experience with repeat PSA screening suggests that tumors detected on follow-up examinations are of lower clinical stage and grade.[34] Although a cutoff value of 4.0 ng/mL is frequently used to prompt prostate biopsy, screening studies have demonstrated that lowering the PSA cutoff will substantially increase the number of cancers detected, particularly in African Americans.[35] In one study of the impact of race on PSA and tumor volume, these two variables were higher among African American men after adjustment for age, stage, pathologic stage, Gleason score, and volume of benign disease.[36] Furthermore, lower cutoff PSA values are associated with a high proportion of negative biopsies (false-positives).[37] An initial PSA lower than 2.5 ng/mL is associated with a very low risk of cancer detection within a 4-year follow-up.[34,38]

Probably the largest PSA/DRE early diagnosis experience comes from the Prostate Cancer Awareness Week program conducted at numerous sites around the United States. A report from that program indicates that of 116,073 participating men, if a 4.0 ng/mL PSA cutoff value was used, 22,014 men had an abnormal PSA, DRE, or both.

Various methods to improve the performance of PSA in early cancer detection have been developed (see below). The proportion of men who have abnormal PSA test results that revert to normal after 1 year is high (65%–83%, depending on the method).[39] This is likely because of a substantial biological or other variability in PSA levels in individual men. Several variables can affect PSA levels in men. Besides normal biological fluctuations that appear to occur,[39,40] pharmaceuticals such as finasteride (which reduces PSA by approximately 50%) and over-the-counter agents such as PC-SPES (an herbal agent that appears to have estrogenic effects) can affect PSA levels.[41,42] Some authors have suggested that ejaculation and DRE can also affect PSA levels, but subsequent examination of these variables have found that they do not have a clinically important effect on PSA.[43] In any case, given this high variability, an elevated PSA should be confirmed by repeat testing before more invasive diagnostic tests are performed.

The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) is a multicenter, randomized, two-armed trial designed to evaluate the effect of screening for prostate, lung, colorectal, and ovarian cancer on disease-specific mortality. Enrollment began in November 1993 and concluded in June 2001. Participants were randomly assigned to the screening or control arm. A total of 76,705 men were enrolled, 38,250 of whom were assigned to the screening arm. Of these, 34,244 men underwent an initial PSA and/or DRE screening examination. Compliance rates for PSA and DRE were roughly equivalent at 89%. More than 99% of men who underwent screening with either PSA or DRE received both screening tests.[44]

The trial has not yet reached mortality endpoints.

As noted above, various approaches aimed at improving the performance of PSA in early cancer detection have been tested. None are clearly more accurate than total serum PSA levels, but these approaches are discussed below.

Serum PSA exists in both free form and complexed to a number of protease inhibitors, especially alpha-1-antichymotrypsin. Assays for total PSA measure both free and complexed forms. Assays for free PSA are available. Complexed PSA can be found by subtracting free PSA from the total PSA. Several studies have addressed whether complexed PSA or percent-free PSA (ratio of free to total) are more sensitive and specific than total PSA. One retrospective study evaluated total PSA, free/total, and complexed PSA in a group of 300 men, 75 of whom had prostate cancer. Large values of total, small values of free/total, and large values of complexed PSA were associated with the presence of cancer; the authors chose the cutoff of each measure to yield 95% sensitivity and found estimated specificities of 21.8%, 15.6%, and 26.7%.[45] The preponderance of evidence concerning the utility of complexed and percent-free PSA is not clear, however, total PSA remains the standard.

A number of authors have considered whether complexed PSA or percent-free PSA in conjunction with total PSA can improve the latter’s sensitivity. Of special interest is the gray zone of total PSA, the range from 2.5 ng/mL to 4.0 ng/mL. A meta-analysis of 18 studies addressed the added diagnostic benefit of percent-free PSA. There was no uniformity of cutoff among these studies. For cutoffs ranging from 8% to 25% (free/total), sensitivity/specificity ranged from about 45%/95% to 95%/15%.[46]

Percent-free PSA may be related to biologic activity of the tumor. One study compared the percent-free PSA with the pathologic features of prostate cancer among 108 men with clinically localized disease who ultimately underwent radical prostatectomy. Lower percent-free PSA values were associated with higher risk of extracapsular disease and greater capsular volume.[47] Similar findings were reported in another large series.[48]

The third-generation (ultrasensitive) PSA test is an enzyme immunometric assay intended strictly (or solely) as an aid in the management of prostate cancer patients. The clinical usefulness of this assay as a diagnostic or screening test is unproven.[49,50]

Because larger prostates caused by increased amounts of transition-zone hyperplasia are known to be associated with higher serum PSA levels, reports have suggested indexing PSA to gland volume, using a measure known as PSA density. PSA density is defined as serum PSA divided by gland volume. Generally, ultrasound is used to measure gland volume. While early studies suggested that this measure may discriminate between patients with cancer and those with benign disease,[51] subsequent evaluations have failed to confirm any clinically useful association.[52,53]

PSA density of the transition zone (serum PSA divided by the volume of the transition zone) has been suggested to better adjust for benign sources of PSA. One study prospectively evaluated 559 men with PSA levels between 4.0 ng/mL and 10.0 ng/mL. A total of 217 of these men were ultimately found to have prostate cancer; of all PSA variants analyzed, percent-free PSA and PSA density of the transition zone were found to have the best predictive value (area under the receiver operator curve values of 0.78 and 0.83).[54] Another study also found that PSA density of the transition zone had superior performance characteristics. In this study of 308 volunteers undergoing first-time screening, it was reported that the combination of percent-free PSA (<20%) and PSA density of the transition zone resulted in elimination of 54.2% of biopsies that ultimately proved to be benign.[55]

Many series have noted that PSA levels increase with age, such that men without prostate cancer will have higher PSA values as they grow older. One study examined the impact of the use of age-adjusted PSA values during screening and estimated that it would reduce the false-positive screenings by 27% and overdiagnosis by more than 33% while retaining 95% of any survival advantage gained by early diagnosis.[56] While age adjustment tends to improve sensitivity for younger men and specificity for older men, the trade-off in terms of more biopsies in younger men and potentially missed cancers in older men has prevented uniform acceptance of this approach.

A study using frozen serum from 18 patients concluded that an annual rise of PSA level of 0.8% ng/mL warranted a prostate biopsy.[57] In a follow-up study that used serum collected serially from men without known prostate cancer (two groups with benign prostatic hyperplasia, one diagnosed by histology and the other clinically, both with PSA levels no higher than 10 ng/mL, and a third group with no more than one PSA exceeding 10 ng/mL), it was reported that averaging three PSA changes measured at 2-year intervals could be useful for cancer discrimination, while changes measured at 3-month or 6-month intervals were volatile and nonspecific, perhaps because of a biologic fluctuation of PSA that may be as high as 30%.[40,58] One study followed 1,249 men screened by PSA and concluded that patients with a 20% annual increase in their PSA level should undergo further evaluation.[59]

A study specifically tested whether total PSA velocity (tPSAv) improves the accuracy of total PSA level (tPSA) to predict long-term risk of prostate cancer. In the 1974 to 1986 Swedish Malmo Preventive Medicine cardiovascular risk study, 5,722 men younger than 51 years gave two blood samples about 6 years apart. Four thousand nine hundred-seven of the archived plasma samples were analyzed for tPSA. Prostate cancer was subsequently diagnosed in 443 (9%) of the men via the Swedish National Cancer Registry through December 31, 2003. Cox proportional hazards regression was used to evaluate tPSA and tPSAv as predictors of prostate cancer. Predictive accuracy was assessed by the concordance index (similar to the area under the receiver operating characteristic).[60]

The median time from the second blood draw to cancer diagnosis was 16 years. Median follow-up for men not diagnosed with prostate cancer was 21 years. PSA assays were done in plasma stored under conditions that preserved the integrity of PSA. TPSA and tPSAv were highly correlated. Both tPSA and tPSAv were associated with prostate cancer in univariate models (P < .001). Men subsequently diagnosed with prostate cancer have increased tPSA and increased tPSAv up to 20 years before diagnosis. Overall predictive accuracy of tPSA plus tPSAv was equivalent to tPSA alone (concordance index: 0.771 tPSA alone; 0.712 tPSAv alone; 0.771 tPSAv added to tPSA). TPSAv did not aid long-term prediction of cancer in early middle-aged men.[60]

A number of authors have explored the possibility of using PSA levels lower than 4.0 ng/mL as the upper limit of normal for screening examinations. One study screened 14,209 white and 1,004 African American men for prostate cancer using an upper limit of normal of 2.5 ng/mL for PSA. A major confounding factor of this study was that only 40% of those men in whom a prostate biopsy was recommended actually underwent biopsy. Nevertheless, 27% of all men undergoing biopsy were found to have prostate cancer.[35] Several collaborating European jurisdictions are conducting prostate cancer screening trials, Rotterdam (the Netherlands) and Finland among them. In Rotterdam, data for 7,943 screened men between the ages of 55 and 74 years have been reported. Of the 534 men who had PSA levels between 3.0 ng/mL and 3.9 ng/mL, 446 (83.5%) had biopsies and 96 (18%) of these had prostate cancer. In all, 4.7% of the screened population had prostate cancer.[61] In Finland, 15,685 men were screened and 14% of screened men had PSA levels of at least 3.0 ng/mL. All men with PSAs higher than 4.0 ng/mL were recommended to diagnostic follow-up by DRE, ultrasound, and biopsy; 92% complied, and 2.6% of the 15,685 men screened were diagnosed with prostate cancer. Of the 801 men with screening PSAs between 3.0 ng/mL and 3.9 ng/mL (all biopsied), 22 (3%) had cancer. Of the 1,116 men with screening PSAs between 4.0 ng/mL and 9.9 ng/mL, 247 (22%) had cancer; of the 226 men with screening PSAs of at least 10 ng/mL, 139 (62%) had cancer.[62] Several factors could have contributed to these differences, including background prostate cancer prevalence, background screening levels, and details regarding diagnostic follow-up practices; the necessary comparative data are not available.

Another study adopted a change in the PSA cutoff to a level of 3.0 ng/mL to study the impact of this change in 243 men with PSA levels between 3.0 ng/mL and 4.0 ng/mL. Thirty-two of the men (13.2%) were ultimately found to have prostate cancer. An analysis of radical prostatectomy specimens from this series found a mean tumor volume of 1.8 cc (range, 0.6–4.4). The extent of disease was significant in a number of cases, with positive margins in five cases and pathologic pT3 disease in six cases.[37]

The optimal frequency and age range for PSA (and DRE) testing are unknown.[56,63,64] Cancer detection rates have been reported to be similar for intervals of 1 to 4 years.[65] With serial annual screening in the PLCO trial, 8% of men with baseline PSA lower than 1 ng/mL had a prostate cancer diagnosis within 2 years.[66] In the same trial, 2-year intervals in screening produced average delays of 5.4 to 6.5 months, while 4-year screening intervals produced average delays of 15.6 months (baseline PSA < 1 ng/mL) to 20.9 months (baseline PSA 3–4 ng/mL).[66] While the authors caution that an optimal prostate screening frequency cannot be determined from these data, they conclude that among men who choose to be screened, these data may provide a context for determining a PSA screening schedule.

A report from the European Randomized Study of Screening for Prostate Cancer (ERSPC) trials demonstrated that while more frequent screenings lead to more diagnosed cancers, the detection rates for aggressive interval cancers was very similar with the different screening intervals in place in the two countries reporting (0.11 with a 4-year interval in Rotterdam and 0.12 with a 2-year interval in Gothenburg). The report suggests that mortality outcomes from the ERSPC (2- and 4-year intervals) and PLCO (1-year interval) trials should facilitate a more reliable assessment of the benefits and costs of different screening intervals.[67]

Of serious concern with regard to prostate cancer screening is the high background histologic prevalence of the disease. It has been demonstrated that a considerable fraction (approximately one-third) of men in their fourth and fifth decades have histologically evident prostate cancer.[68] Most of these tumors are well-differentiated and microscopic in size. Conversely, evidence suggests that tumors of potential clinical importance are larger and of higher grade.[69] Since the inception of PSA screening, several events have occurred: (1) a contemporaneous but unrelated decrease in detections of transition-zone tumors caused by a fall in the number of transurethral resections of the prostate due to the advent of effective treatment for benign prostatic hyperplasia (including alpha blockers and finasteride); and (2) an increase in detection of peripheral-zone tumors due to the incorporation of TRUS-guided prostate biopsies. Because transition-zone tumors are predominantly low volume and low grade and because peripheral-zone tumors have a preponderance of moderate-grade and high-grade disease, the proportion of higher grade tumors detected by current screening practices has increased substantially. A Detroit study found that between 1989 and 1996, poorly differentiated tumors remained stable and well-differentiated tumors fell in frequency while moderately differentiated disease increased in frequency. The largest rise in incidence was in clinically localized disease.[70] It is now known that systematic changes to the histological interpretation of biopsy specimens by anatomical pathologists has occurred during the PSA screening era (i.e., since about 1985) in the United States.[71] This phenomenon, sometimes called “grade inflation,” is the apparent increase in the distribution of high-grade tumors in the population over time but in the absence of a true biological or clinical change. It is possibly the result of an increasing tendency for pathologists to read tumor grade as more aggressive.[72]

Prostate biopsies in a small percentage of men will demonstrate prostatic intraepithelial neoplasia (PIN). High-grade PIN is not cancer but may predict an increased risk for prostate cancer. PSA does not appear to be elevated with PIN.[73,74]

A variety of variables affect the likelihood of a recommendation for prostate cancer screening from a physician. In Washington state, 1,369 primary care physicians were surveyed to determine patterns of PSA screening recommendations. Of the 714 respondents, 68% routinely recommended PSA screening. The survey results suggest that gender (male), age (medical school graduation before 1974), and mode of reimbursement (fee for service) all increase the likelihood of PSA screening recommendations among this population.[75]

While two large randomized clinical trials are under way to assess whether early detection of prostate cancer can reduce mortality from the disease,[76,77] a Canadian trial has been reported to have been performed in a randomized prospective manner. In this study, 46,486 men identified from the electoral rolls of Quebec City and its metropolitan area were randomly assigned to be either approached or not approached for PSA and DRE screening. A total of 31,133 men were randomly assigned to screening, while a total of 15,353 were randomly assigned to observation. (It appears that these men were unaware that they had been enrolled in a randomized clinical trial.) A notable difference from other screening studies was that a PSA of 3.0 ng/mL was used to determine whether further evaluation was warranted. In this study (in which the patient numbers have been variously reported by the authors) of the 31,133 men who were randomly assigned to screening, 7,348 actually underwent screening while 23,785 did not. Of the 15,353 who were randomly assigned to observation, 1,122 actually underwent screening while 14,231 did not. Two hundred-seventeen deaths were noted among the 38,016 men who did not undergo screening, compared with only 11 deaths among the 8,470 men who underwent screening. Using an intention-to-treat analysis based on the study arm to which an individual was originally assigned, however, no difference in mortality was seen (there were 75 deaths among the 15,353 men who were randomly assigned to observation compared with 153 deaths among the 31,133 men randomly assigned to screening [RR, 1.085]). Because of noncompliance, this study does not answer the question of whether early detection with PSA will reduce prostate cancer mortality.[78]

While DRE has been a staple of medical practice for many decades, PSA did not come into common use until the late 1980s for the early diagnosis of prostate cancer. Following widespread dissemination of PSA testing, incidence rates rose abruptly. In a study of Medicare beneficiaries, a first-time PSA test was associated with a 4.7% likelihood of a prostate cancer diagnosis within 3 months. Subsequent tests were associated with statistically significant lower rates of prostate cancer diagnosis.[79]

In an examination of trends of prostate cancer detection and diagnosis among 140,936 white and 15,662 African American men diagnosed with prostate cancer between 1973 and 1994 in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, substantial changes were found beginning in the late 1980s as use of PSA diffused through the United States; age at diagnosis fell, stage of disease at diagnosis decreased, and most tumors were noted to be moderately differentiated. For African American men, however, a larger proportion of tumors were poorly differentiated.[80]

Since the outset of PSA screening beginning around 1988, incidence rates initially rose dramatically and then fell, presumably as the fraction of the population undergoing their first PSA screening initially rose and subsequently fell. There has also been an observed decrease in mortality rates. In Olmsted County, Minnesota, age-adjusted prostate cancer mortality rates increased from 25.8 per 100,000 men from 1980 to 1984 to a peak of 34 per 100,000 from 1989 to 1992; rates subsequently decreased to 19.4 per 100,000 from 1993 to 1997.[81] Similar observations have been made elsewhere in the world,[82,83] leading some to hypothesize that the mortality decline is related to PSA testing. In Quebec, Canada, however, examinations of the association between the size of the rise in incidence rates (1989–1993) and the size of the decrease in mortality rates (1995–1999), by birth cohort and residential grouping, showed no correlation between these two variables.[83] This study suggests that, at least during this time frame, the decline in mortality is not related to widespread PSA testing.

Cause-of-death misclassification has also been studied as a possible explanation for changes in prostate cancer mortality. A relatively fixed rate was found at which individuals who have been diagnosed with prostate cancer are mislabeled as dying from prostate cancer. As such, the substantial increase in prostate cancer diagnoses in the late 1980s and early 1990s would then explain the increased rate of prostate cancer death during those years. As the rate of prostate cancer diagnosis fell in the early 1990s, this reduced rate of mislabeling death due to prostate cancer would fall, as would the overall rate of prostate cancer death.[84] Since the evidence in this respect is inconsistent, it remains unclear whether the causes of these mortality trends are chance, misclassification, early detection, improved treatments, or a combination of effects.

The incidence of distant-stage prostate carcinoma was relatively flat until 1991 and then started declining rapidly. This decline probably was caused by the shift to earlier stage disease associated with the rapid dissemination of PSA screening. This stage shift can have a fairly sizable and rapid impact on population mortality, but it is possible that other factors such as hormonal therapy are responsible for much of the decline in mortality. Ongoing randomized clinical trials in the United States and Europe are designed to determine whether a mortality benefit is associated with PSA screening.[85]

The Gleason score is an important prognostic measure relying on the pathologic assessment of the architectural growth patterns of prostate biopsy. The Gleason grading system assigns a grade to each of the two largest areas of prostate cancer in the tissue samples. A sampling of eight or more biopsy cores improves the pathological grading accuracy.[86] Grades range from 1 to 5, with 1 being the most differentiated and 5 the least differentiated. Grade 3 tumors seldom have associated metastases, but metastases are common with grade 4 or grade 5 tumors. The two grades are added together to produce a Gleason score. A score of 2 to 4 is considered low grade, 5 to 7 is intermediate grade, and 8 to 10 is high grade. The overall rate of concordance between original interpretations and review of the needle biopsy specimens has been reported to be 60%, with accuracy improving with increased tumor grade and percentage of tumor involvement in the biopsy specimen.[87]

As of 2005, approximately 90% of prostate cancers detected are clinically localized and have more favorable tumor characteristics or grades than the pre-PSA screening era.[88] A retrospective population-cohort study using the Connecticut Tumor registry reviewed the mortality probability from prostate cancer given the patient’s age at diagnosis and tumor grade.[89] Patients were treated with either observation or immediate or delayed androgen withdrawal therapy, with a median observation of 24 years. This study was initiated before the PSA screening era. Transurethral resection or open surgery for benign prostatic hyperplasia identified 71% of the tumors incidentally. The prostate cancer mortality rate was 33 per 1,000 person-years during the first 15 years of follow-up (95% CI, 28–38) and 18 per 1,000 person-years after 15 years of follow-up (95% CI, 10–29). Men with low-grade prostate cancers had a minimal risk of dying from prostate cancer during 20 years of follow-up (Gleason score of 2 to 4; six deaths per 1,000 person-years; 95% CI, 2–11). Men with high-grade prostate cancers had an increased probability of dying from prostate cancer within 10 years of diagnosis (Gleason score of 8 to 10, 121 deaths per 1,000 person-years; 95% CI, 90–156). Men with tumors that had a Gleason score of 5 or 6 had an intermediate risk of prostate cancer death. The annual mortality rate from prostate cancer appears to remain stable after 15 years from diagnosis.[89]

A computer simulation model has been developed to analyze the trends in prostate cancer detection (PSA screening beginning in approximately 1988) to compare these trends with the reported fall in prostate cancer deaths observed between 1992 and 1994. The level of screening efficacy was hypothesized to be similar to those postulated in the PLCO. The changes in prostate cancer mortality could not be explained entirely by PSA screening alone.[90]

Decision analyses using the Markov model yield variable treatment outcomes because of the uncertainty regarding metastatic rates expected for prostate cancer and uncertainty about treatment efficacy.[91-93] A review of 59,876 men with prostate cancer diagnosed between 1983 and 1992 and registered by the SEER registries, however, shows that treatment of men with poorly differentiated and moderately differentiated disease is associated with an improved survival rate, compared with observation.[94] It is not known to what degree this can be attributed to treatment effect as opposed to other factors such as a preponderance of relatively healthy patients in the treated group. The information from Swedish studies of expectant therapy lead to different conclusions depending on methodology and populations used in analysis.[95]

A simulation model based on available evidence suggests that if there is a benefit to screening, this benefit decreases with age.[96] No trial of prostate cancer screening in which the intervention arms were analyzed as randomized (analogous to an intention-to-treat analysis in a treatment trial) has been reported. There is insufficient evidence on which to decide the efficacy of TRUS and serum tumor markers (including PSA) for routine screening in asymptomatic men.[91,97]

While awaiting results of current studies, physicians and men (and their partners) are faced with the dilemma of whether to recommend or request a screening test. A qualitative study undertaken on focus groups of men, physician experts, and couples with screened and unscreened men has explored what information may help to inform a man undertaking a decision regarding PSA screening.[98] At a minimum, men should be informed about the possibility that false-positive or false-negative test results can occur, that it is not known whether regular screening will reduce the number of deaths from prostate cancer, and that among experts, the recommendation to screen is controversial. The PLCO-1 ¹³, which is now closed to accrual, is following participants to test the effect of early detection by DRE and PSA on reducing mortality. A trial of screening is also being performed in Europe.[76,99]

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45. Brawer MK, Meyer GE, Letran JL, et al.: Measurement of complexed PSA improves specificity for early detection of prostate cancer. Urology 52 (3): 372-8, 1998.  [PUBMED Abstract]
    
    
46. Hoffman RM, Clanon DL, Littenberg B, et al.: Using the free-to-total prostate-specific antigen ratio to detect prostate cancer in men with nonspecific elevations of prostate-specific antigen levels. J Gen Intern Med 15 (10): 739-48, 2000.  [PUBMED Abstract]
    
    
47. Arcangeli CG, Humphrey PA, Smith DS, et al.: Percentage of free serum prostate-specific antigen as a predictor of pathologic features of prostate cancer in a screening population. Urology 51 (4): 558-64; discussion 564-5, 1998.  [PUBMED Abstract]
    
    
48. Pannek J, Rittenhouse HG, Chan DW, et al.: The use of percent free prostate specific antigen for staging clinically localized prostate cancer. J Urol 159 (4): 1238-42, 1998.  [PUBMED Abstract]
    
    
49. Taylor JA 3rd, Koff SG, Dauser DA, et al.: The relationship of ultrasensitive measurements of prostate-specific antigen levels to prostate cancer recurrence after radical prostatectomy. BJU Int 98 (3): 540-3, 2006.  [PUBMED Abstract]
    
    
50. Sakai I, Harada K, Kurahashi T, et al.: Usefulness of the nadir value of serum prostate-specific antigen measured by an ultrasensitive assay as a predictor of biochemical recurrence after radical prostatectomy for clinically localized prostate cancer. Urol Int 76 (3): 227-31, 2006.  [PUBMED Abstract]
    
    
51. Benson MC, Whang IS, Pantuck A, et al.: Prostate specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. J Urol 147 (3 Pt 2): 815-6, 1992.  [PUBMED Abstract]
    
    
52. Bangma CH, Grobbee DE, Schröder FH: Volume adjustment for intermediate prostate-specific antigen values in a screening population. Eur J Cancer 31A (1): 12-4, 1995.  [PUBMED Abstract]
    
    
53. Babaian RJ, Kojima M, Ramirez EI, et al.: Comparative analysis of prostate specific antigen and its indexes in the detection of prostate cancer. J Urol 156 (2 Pt 1): 432-7, 1996.  [PUBMED Abstract]
    
    
54. Djavan B, Remzi M, Zlotta AR, et al.: Combination and multivariate analysis of PSA-based parameters for prostate cancer prediction. Tech Urol 5 (2): 71-6, 1999.  [PUBMED Abstract]
    
    
55. Horninger W, Reissigl A, Klocker H, et al.: Improvement of specificity in PSA-based screening by using PSA-transition zone density and percent free PSA in addition to total PSA levels. Prostate 37 (3): 133-7; discussion 138-9, 1998.  [PUBMED Abstract]
    
    
56. Etzioni R, Cha R, Cowen ME: Serial prostate specific antigen screening for prostate cancer: a computer model evaluates competing strategies. J Urol 162 (3 Pt 1): 741-8, 1999.  [PUBMED Abstract]
    
    
57. Carter HB, Pearson JD, Metter EJ, et al.: Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 267 (16): 2215-20, 1992 Apr 22-29.  [PUBMED Abstract]
    
    
58. Woolf SH: Screening for prostate cancer with prostate-specific antigen. An examination of the evidence. N Engl J Med 333 (21): 1401-5, 1995.  [PUBMED Abstract]
    
    
59. Brawer MK, Beatie J, Wener MH, et al.: Screening for prostatic carcinoma with prostate specific antigen: results of the second year. J Urol 150 (1): 106-9, 1993.  [PUBMED Abstract]
    
    
60. Ulmert D, Serio AM, O'Brien MF, et al.: Long-term prediction of prostate cancer: prostate-specific antigen (PSA) velocity is predictive but does not improve the predictive accuracy of a single PSA measurement 15 years or more before cancer diagnosis in a large, representative, unscreened population. J Clin Oncol 26 (6): 835-41, 2008.  [PUBMED Abstract]
    
    
61. Schröder FH, Roobol-Bouts M, Vis AN, et al.: Prostate-specific antigen-based early detection of prostate cancer--validation of screening without rectal examination. Urology 57 (1): 83-90, 2001.  [PUBMED Abstract]
    
    
62. Määttänen L, Auvinen A, Stenman UH, et al.: Three-year results of the Finnish prostate cancer screening trial. J Natl Cancer Inst 93 (7): 552-3, 2001.  [PUBMED Abstract]
    
    
63. Ross KS, Carter HB, Pearson JD, et al.: Comparative efficiency of prostate-specific antigen screening strategies for prostate cancer detection. JAMA 284 (11): 1399-405, 2000.  [PUBMED Abstract]
    
    
64. Carter HB, Landis PK, Metter EJ, et al.: Prostate-specific antigen testing of older men. J Natl Cancer Inst 91 (20): 1733-7, 1999.  [PUBMED Abstract]
    
    
65. van der Cruijsen-Koeter IW, Roobol MJ, Wildhagen MF, et al.: Tumor characteristics and prognostic factors in two subsequent screening rounds with four-year interval within prostate cancer screening trial, ERSPC Rotterdam. Urology 68 (3): 615-20, 2006.  [PUBMED Abstract]
    
    
66. Crawford ED, Pinsky PF, Chia D, et al.: Prostate specific antigen changes as related to the initial prostate specific antigen: data from the prostate, lung, colorectal and ovarian cancer screening trial. J Urol 175 (4): 1286-90; discussion 1290, 2006.  [PUBMED Abstract]
    
    
67. Roobol MJ, Grenabo A, Schröder FH, et al.: Interval cancers in prostate cancer screening: comparing 2- and 4-year screening intervals in the European Randomized Study of Screening for Prostate Cancer, Gothenburg and Rotterdam. J Natl Cancer Inst 99 (17): 1296-303, 2007.  [PUBMED Abstract]
    
    
68. Sakr WA, Haas GP, Cassin BF, et al.: The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 150 (2 Pt 1): 379-85, 1993.  [PUBMED Abstract]
    
    
69. Stamey TA, McNeal JE, Yemoto CM, et al.: Biological determinants of cancer progression in men with prostate cancer. JAMA 281 (15): 1395-400, 1999.  [PUBMED Abstract]
    
    
70. Schwartz KL, Grignon DJ, Sakr WA, et al.: Prostate cancer histologic trends in the metropolitan Detroit area, 1982 to 1996. Urology 53 (4): 769-74, 1999.  [PUBMED Abstract]
    
    
71. Albertsen PC, Hanley JA, Barrows GH, et al.: Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 97 (17): 1248-53, 2005.  [PUBMED Abstract]
    
    
72. Thompson IM, Canby-Hagino E, Lucia MS: Stage migration and grade inflation in prostate cancer: Will Rogers meets Garrison Keillor. J Natl Cancer Inst 97 (17): 1236-7, 2005.  [PUBMED Abstract]
    
    
73. Lefkowitz GK, Sidhu GS, Torre P, et al.: Is repeat prostate biopsy for high-grade prostatic intraepithelial neoplasia necessary after routine 12-core sampling? Urology 58 (6): 999-1003, 2001.  [PUBMED Abstract]
    
    
74. O'Shaughnessy JA, Kelloff GJ, Gordon GB, et al.: Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 8 (2): 314-46, 2002.  [PUBMED Abstract]
    
    
75. Edlefsen KL, Mandelson MT, McIntosh MW, et al.: Prostate-specific antigen for prostate cancer screening. Do physician characteristics affect its use? Am J Prev Med 17 (1): 87-90, 1999.  [PUBMED Abstract]
    
    
76. Denis LJ: Prostate cancer screening and prevention: "realities and hope". Urology 46 (3 Suppl A): 56-61, 1995.  [PUBMED Abstract]
    
    
77. Gohagan JK, Levin DL, Prorok JC, et al., eds.: The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Control Clin Trials 21(6 suppl): 249S-406S, 2000. 
    
    
78. Labrie F, Candas B, Cusan L, et al.: Screening decreases prostate cancer mortality: 11-year follow-up of the 1988 Quebec prospective randomized controlled trial. Prostate 59 (3): 311-8, 2004.  [PUBMED Abstract]
    
    
79. Legler JM, Feuer EJ, Potosky AL, et al.: The role of prostate-specific antigen (PSA) testing patterns in the recent prostate cancer incidence decline in the United States. Cancer Causes Control 9 (5): 519-27, 1998.  [PUBMED Abstract]
    
    
80. Farkas A, Schneider D, Perrotti M, et al.: National trends in the epidemiology of prostate cancer, 1973 to 1994: evidence for the effectiveness of prostate-specific antigen screening. Urology 52 (3): 444-8; discussion 448-9, 1998.  [PUBMED Abstract]
    
    
81. Roberts RO, Bergstralh EJ, Katusic SK, et al.: Decline in prostate cancer mortality from 1980 to 1997, and an update on incidence trends in Olmsted County, Minnesota. J Urol 161 (2): 529-33, 1999.  [PUBMED Abstract]
    
    
82. Bartsch G, Horninger W, Klocker H, et al.: Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 58 (3): 417-24, 2001.  [PUBMED Abstract]
    
    
83. Perron L, Moore L, Bairati I, et al.: PSA screening and prostate cancer mortality. CMAJ 166 (5): 586-91, 2002.  [PUBMED Abstract]
    
    
84. Feuer EJ, Merrill RM, Hankey BF: Cancer surveillance series: interpreting trends in prostate cancer--part II: Cause of death misclassification and the recent rise and fall in prostate cancer mortality. J Natl Cancer Inst 91 (12): 1025-32, 1999.  [PUBMED Abstract]
    
    
85. Feuer EJ, Mariotto A, Merrill R: Modeling the impact of the decline in distant stage disease on prostate carcinoma mortality rates. Cancer 95 (4): 870-80, 2002.  [PUBMED Abstract]
    
    
86. Makhlouf AA, Krupski TL, Kunkle D, et al.: The effect of sampling more cores on the predictive accuracy of pathological grade and tumour distribution in the prostate biopsy. BJU Int 93 (3): 271-4, 2004.  [PUBMED Abstract]
    
    
87. Coard KC, Freeman VL: Gleason grading of prostate cancer: level of concordance between pathologists at the University Hospital of the West Indies. Am J Clin Pathol 122 (3): 373-6, 2004.  [PUBMED Abstract]
    
    
88. Carroll PR: Early stage prostate cancer--do we have a problem with over-detection, overtreatment or both? J Urol 173 (4): 1061-2, 2005.  [PUBMED Abstract]
    
    
89. Albertsen PC, Hanley JA, Fine J: 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 293 (17): 2095-101, 2005.  [PUBMED Abstract]
    
    
90. Etzioni R, Legler JM, Feuer EJ, et al.: Cancer surveillance series: interpreting trends in prostate cancer--part III: Quantifying the link between population prostate-specific antigen testing and recent declines in prostate cancer mortality. J Natl Cancer Inst 91 (12): 1033-9, 1999.  [PUBMED Abstract]
    
    
91. Fleming C, Wasson JH, Albertsen PC, et al.: A decision analysis of alternative treatment strategies for clinically localized prostate cancer. Prostate Patient Outcomes Research Team. JAMA 269 (20): 2650-8, 1993.  [PUBMED Abstract]
    
    
92. Barry MJ, Fleming C, Coley CM, et al.: Should Medicare provide reimbursement for prostate-specific antigen testing for early detection of prostate cancer? Part IV: Estimating the risks and benefits of an early detection program. Urology 46 (4): 445-61, 1995.  [PUBMED Abstract]
    
    
93. Beck JR, Kattan MW, Miles BJ: A critique of the decision analysis for clinically localized prostate cancer. J Urol 152 (5 Pt 2): 1894-9, 1994.  [PUBMED Abstract]
    
    
94. Lu-Yao GL, Yao SL: Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 349 (9056): 906-10, 1997.  [PUBMED Abstract]
    
    
95. Grönberg H, Damber L, Jonson H, et al.: Prostate cancer mortality in northern Sweden, with special reference to tumor grade and patient age. Urology 49 (3): 374-8, 1997.  [PUBMED Abstract]
    
    
96. Coley CM, Barry MJ, Fleming C, et al.: Early detection of prostate cancer. Part II: Estimating the risks, benefits, and costs. American College of Physicians. Ann Intern Med 126 (6): 468-79, 1997.  [PUBMED Abstract]
    
    
97. Kramer BS, Brown ML, Prorok PC, et al.: Prostate cancer screening: what we know and what we need to know. Ann Intern Med 119 (9): 914-23, 1993.  [PUBMED Abstract]
    
    
98. Chan EC, Sulmasy DP: What should men know about prostate-specific antigen screening before giving informed consent? Am J Med 105 (4): 266-74, 1998.  [PUBMED Abstract]
    
    
99. Schröder FH, Bangma CH: The European Randomized Study of Screening for Prostate Cancer (ERSPC). Br J Urol 79 (Suppl 1): 68-71, 1997.  [PUBMED Abstract]
    
    

Evidence of Harms

Any potential benefits derived from screening asymptomatic men need to be weighed against the harms of screening and diagnostic procedures and treatments for prostate cancer.

Whatever the screening modality, the screening process itself can lead to psychological effects in men who have a prostate biopsy but do not have prostate cancer. One study of these men at 12 months after their negative biopsy who reported worrying that they may develop cancer (P < .001), showed large increases in prostate-cancer worry compared with men with a normal prostate-specific antigen (PSA) (26% vs. 6%).[1] In the same study, biopsied men were more likely than those in the normal PSA group to have had at least one follow-up PSA test in the first year (73% vs. 42%; P < .001), more likely to have had another biopsy (15% vs. 1%; P < .001), and more likely to have visited a urologist (71% vs. 13%; P < .001).

While there is no literature suggesting serious complications of digital rectal examination or transrectal sonography, and the harms associated with venipuncture for PSA testing can be regarded as trivial, prostatic biopsies are associated with important complications. Transient fever, pain, hematospermia, and hematuria are all common, as are positive urine cultures.[2-4] Sepsis occurs in approximately 0.4% of cases.[3]

Long-term complications of radical prostatectomy include urinary incontinence, urethral stricture, erectile dysfunction, and the morbidity associated with general anesthesia and a major surgical procedure. Fecal incontinence can also occur. The associated mortality rate is reported to be 0.1% to 1%, depending on age. In the population-based Prostate Cancer Outcomes Study, 8.4% of 1,291 men were incontinent and 59.9% were impotent at 18 or 24 months following radical prostatectomy. More than 40% of men reported that their sexual performance was a moderate-to-large problem. Both sexual and urinary function varied by age, with younger men relatively less affected.[5]

Definitive external-beam radiation therapy can result in acute cystitis, proctitis, and sometimes enteritis. These are generally reversible but may be chronic. In the short-term, potency is preserved with irradiation in most cases but may diminish over time. A systematic review of evidence of complications of radiation therapy shows that 20% to 40% of men who had no erectile dysfunction before treatment developed dysfunction 12 to 24 months afterwards. Furthermore, 2% to 16% of men who had no urinary incontinence before treatment developed dysfunction 12 to 24 months afterward, and about 18% of men have some bowel dysfunction 1 year after treatment. The magnitude of effects of brachytherapy has not been determined, but the spectrum of complications are similar.[6] The same review of evidence found hormone therapy with luteinizing hormone-releasing hormone (LHRH) agonists reduces sexual function by 40% to 70%, and is associated with breast swelling in 5% to 25% of men. Hot flashes occur in 50% to 60% of men taking LHRH agonists. (Refer to the PDQ summary on Prostate Cancer Treatment ⁵ for more information.)

References

1. Fowler FJ Jr, Barry MJ, Walker-Corkery B, et al.: The impact of a suspicious prostate biopsy on patients' psychological, socio-behavioral, and medical care outcomes. J Gen Intern Med 21 (7): 715-21, 2006.  [PUBMED Abstract]
   
   
2. Aus G, Ahlgren G, Bergdahl S, et al.: Infection after transrectal core biopsies of the prostate--risk factors and antibiotic prophylaxis. Br J Urol 77 (6): 851-5, 1996.  [PUBMED Abstract]
   
   
3. Rietbergen JB, Kruger AE, Kranse R, et al.: Complications of transrectal ultrasound-guided systematic sextant biopsies of the prostate: evaluation of complication rates and risk factors within a population-based screening program. Urology 49 (6): 875-80, 1997.  [PUBMED Abstract]
   
   
4. Sharpe JR, Sadlowski RW, Finney RP, et al.: Urinary tract infection after transrectal needle biopsy of the prostate. J Urol 127 (2): 255-6, 1982.  [PUBMED Abstract]
   
   
5. Stanford JL, Feng Z, Hamilton AS, et al.: Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 283 (3): 354-60, 2000.  [PUBMED Abstract]
   
   
6. Harris R, Lohr KN, Beck R, et al.: Screening for Prostate Cancer . Rockville, Md: Agency for Healthcare Research and Quality, 2002, Systematic Evidence Review Number 16. Available online. ¹⁴ Last accessed October 07, 2008. 
   
   

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Evidence of Benefit ¹⁸

Added text ¹⁹ to state that in a study testing total PSA velocity, PSA assays were done in plasma stored under conditions that preserved the integrity of PSA.

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