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NCI/PDQ^® Health professionals: Prostate Cancer Screening (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 28 de noviembre del 2012

TABLE OF CONTENTS

• 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
    • Prostate cancer gene 3 (PCA3)
    • 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

• Changes to This Summary (11/28/2012)

• Questions or Comments About This Summary

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

Summary of Evidence

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

Digital Rectal Examination and Prostate-Specific Antigen

Benefits

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 Results from two randomized trials show no effect on mortality through 7 years but are inconsistent beyond 7 to 10 years.

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

Harms

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 2 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 2012, approximately 241,740 new cases and 28,170 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 29% of all male cancers and 9% 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. Until 1989, the increased incidence 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 section of this summary for more information.)

Risk Factors

Prostate cancer is uncommonly seen in men younger than 50 years; the incidence rises rapidly with each decade thereafter. The incidence rate is higher in African American men than in white men. From 2004 to 2008, the overall age-adjusted incidence rate was 233.8 per 100,000 for African American men and 149.5 per 100,000 for white men. 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 15 16 17 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 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 16.5% 1, and the lifetime risk of dying from this disease is 2.8%. 26

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. 27

There is an association between primary tumor volume and local extent of disease, progression, and survival. 28 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. 29 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. 30

Cancer statistics from the American Cancer Society and the National Cancer Institute indicated that between 1999 and 2006, the proportion of disease diagnosed at a locoregional stage and at a distant stage was 92% and 4% for whites, compared with 90% and 6% for African Americans, respectively. 26 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 (T12, 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 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
10. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2008. Bethesda, Md: National Cancer Institute, 2011. Also available online [PUBMED Abstract]
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, Mírsky 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, Stíhelin 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. Altekruse SF, Kosary CL, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2007. Bethesda, Md: National Cancer Institute, 2010. Also available online [PUBMED Abstract]
27. 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]
28. 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]
29. McNeal JE, Bostwick DG, Kindrachuk RA, et al.: Patterns of progression in prostate cancer. Lancet 1 (8472): 60-3, 1986. [PUBMED Abstract]
30. Resnick MI: Background for screening--epidemiology and cost effectiveness. Prog Clin Biol Res 269: 111-22, 1988. [PUBMED Abstract]
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], 0.711.64; P = .72) or for PSA and/or DRE (OR, 1.13; 95% CI, 0.632.06; 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 [0.360.88]). 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 [0.560.99]). 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

A Swedish retrospective study of a nationwide cohort of patients with localized prostate cancer aged 70 years or younger reported that 10-year prostate cancer-specific mortality was 2.4% among men diagnosed with clinically local stage T1a, T1b, or T1c, with a serum PSA of less than 10 ng/mL, and with a Gleason score of 2 to 6, referred to as low-risk cases, of which there were 2,686. 6 This subgroup analysis was derived from a cohort study of 6,849 men diagnosed between January 1, 1997 and December 31, 2002, aged 70 years or younger, who had local stage T1 to T2 with no signs of lymph node metastases or bone metastases, and a PSA serum level of less than 20 ng/mL, as was abstracted from the Swedish Cancer Registry, which captured 98% of solid tumors among men aged 75 years or younger. Cohort treatment options were surveillance (n = 2,021) or curative intent by radical prostatectomy (n = 3,399) or radiation therapy (n = 1,429), which were to be determined at the discretion of treating physicians. Surveillance or expectancy treatment was either active surveillance with curative treatment if progression occurred or watchful waitinga strategy for administering hormonal treatment upon symptomatic progression. Using all-cause mortality as the benchmark, the study calculated cumulative incidence mortality for the three treatment groups of the entire cohort and the low-risk subgroup. Surveillance was more common among men with high comorbidity and among men with low-risk tumors. The 10-year cumulative risk of death from prostate cancer for the entire 6,849 person cohort was 3.6% in the surveillance group and 2.7% in the curative-intent group compared with the low-risk surveillance group (2.4%) and the low-risk curative-intent group (0.7%). Biases inherent in treatment assignment could not be accounted for adequately in the analysis, which prevented conclusions about the relative effectiveness of alternative treatments. However, a 10-year prostate cancer-specific mortality of 2.4% among patients with low-risk prostate cancer in the surveillance group suggested that surveillance may be a suitable treatment for many patients with low-risk disease compared with the 19.2% 10-year risk of death from competing causes observed in the surveillance group and 10.2% in the curative-intent group of the total 6,849 person cohort. 6

Digital Rectal Exam

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. 7 8

In 1984, one study reported on 811 unselected patients aged 50 to 80 years who underwent rectal examination and follow-up. 9 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. 10 Some investigators reported a high proportion of clinically localized disease when prostate cancer is detected by routine rectal examination, 11 while others reported that even with annual rectal examination, only 20% of cases are localized at diagnosis. 12 It has been reported that 25% of men presenting with metastatic disease had a normal prostate examination. 13 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, 0.461.1). Most men in this study were screened with DRE rather than PSA. 14 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%. 15 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%. 16 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, 0.310.84). These data suggested that screening DREs may prevent 50% to 70% of deaths from prostate cancer. 17 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. 18 One case-control study reported no statistically significant association between routine screening with DRE and occurrence of metastatic prostate cancer. 19 The Prostate Cancer Prevention Trial (PCPT) requested all men undergo prostate biopsy at study end to address ascertainment bias; the sensitivity of DRE for prostate cancer was 16.7%. The sensitivity increased to 21.3% in men receiving finasteride. 20

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 in reducing prostate cancer mortality remains to be determined.

Transrectal Ultrasound and Other Imaging Tests

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. 21 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. 22 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. 23 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. 24 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%. 25 26 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.

Prostate-Specific Antigen

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%. 27

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. 28 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. 29

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, some of which may be curable by local-modality therapies, but others of which do not require treatment. 30 31 32 33 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. 34 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. 35 Experience with repeat PSA screening suggests that tumors detected on follow-up examinations are of lower clinical stage and grade. 36 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. 37 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. 38 Furthermore, lower cutoff PSA values are associated with a high proportion of negative biopsies (false-positives). 39 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. 36 40

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). 41 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, 41 42 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. 43 44 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. 45 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 cancers on disease-specific mortality. From 1993 through 2001, 76,693 men at ten U.S. study centers were randomly assigned to receive annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and DRE for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended.

In the screening group, rates of compliance were 85% for PSA testing and 86% for DRE. Self-reported rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41% to 46% for DRE. Results from the first four rounds of screening are shown in the Summary of First Four Prostate, Lung, Colorectal, and Ovarian Screening Rounds table. 46

After 7 years of follow-up, with vital status known for 98% of men, the incidence of prostate cancer per 10,000 person-years was 116 (2,820 cancers) in the screening group and 95 (2,322 cancers) in the control group (rate ratio, 1.22; 95% CI, 1.161.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.751.70). The data at 10 years were 67% complete and consistent with these overall findings (incidence rate ratio, 1.17; 95% CI, 1.111.22 and mortality rate ratio, 1.11; 95% CI, 0.831.50). Thus, after 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups.

At 7 years, the total numbers of deaths (excluding those from prostate, lung, or colorectal cancers) were 2,544 in the screening group and 2,596 in the control group (rate ratio, 0.98; 95% CI, 0.921.03); at 10 years, the numbers of such deaths were 3,953 and 4,058, respectively (rate ratio, 0.97; 95% CI, 0.931.01). The distribution of the causes of death was similar in the two groups.

The following are several possible explanations for the lack of a reduction in mortality so far in this trial:

• Annual screening with the PSA test using the standard U.S. threshold of 4 ng per mL and DRE to trigger diagnostic evaluation may not be effective.
• The level of screening in the control group could have been substantial enough to dilute any modest effect of annual screening in the screening group.
• Approximately 44% of the men in each study group had undergone one or more PSA tests at baseline, which would have eliminated some cancers detectable on screening from the randomly assigned population; thus, the cumulative death rate from prostate cancer at 10 years in the two groups combined was 25% lower in those who had undergone two or more PSA tests at baseline than in those who had not been tested.
• Potentially, the most important explanation is that improvement in therapy for prostate cancer during the course of the trial probably resulted in fewer prostate-cancer deaths in the two study groups, which blunted any potential benefits of screening.
• The follow-up may not be long enough for benefit from the earlier detection of an increased number of prostate cancers in the screening group to emerge. 47
• After a PSA finding greater than 4.0 ng/mL, within 1 year only 41% of men underwent prostate biopsy; within 3 years of this finding, only 64% of men underwent prostate biopsy. Such lower biopsy rates, associated with lower prostate cancer detection rates, may have blunted the impact of screening on mortality. 48

Prostate cancer mortality data from the PLCO cancer screening trial after 13 years of follow-up show no reduction in mortality due to prostate cancer screening with PSA and DRE. 49 Organized screening in the intervention arm of the trial did not produce a mortality reduction compared with opportunistic screening in the control arm. There were no apparent interactions with age, baseline comorbidity, or pre-trial PSA testing as hypothesized in an intervening analysis by a subgroup analysis. These results are consistent with the prior report at 7 to 10 years of follow-up described above. 47 The update accounts for 76,685 men, aged 55 to 74 years, enrolled at 10 screening centers between November 1993 and July 2001 who were randomly assigned to annual PSA screening for 6 years and DRE for 4 years (38,340 men) or usual care (38,345 men), which sometimes included opportunistic screening in the local communities. All prostate cancer incidents and deaths through 13 years of follow-up or through December 31, 2009 were ascertained.

The 13-year follow-up analysis reports 45% of men in the PLCO trial had at least one PSA test in the 3 years prior to randomization. PSA screening in the usual care arm was estimated to be as high as 52% by the end of the screening period. The intensity of PSA screening in the usual care arm was estimated to be half that in the intervention arm. Stage-specific treatment between the two arms was similar. 49

The European Randomized Study of Screening for Prostate Cancer (ERSPC) was initiated in the early 1990s to evaluate the effect of screening with PSA testing on death rates from prostate cancer. Through registries in seven European countries, investigators identified 182,000 men between the ages of 50 and 74 years for inclusion in the study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006.

Recruitment and randomization procedures differed among countries and were developed in accordance with national regulations. In Finland, Sweden, and Italy, the trial subjects were identified from population registries and were randomly assigned to the trials before written informed consent was provided. In the Netherlands, Belgium, Switzerland, and Spain, the target population was also identified from population lists, but when the men were invited to participate in the trial, only those who provided consent were randomly assigned.

In the screening group, 82% of men accepted at least one offer of screening. With 14 years of data, and a median follow-up of 9 years, there were 5,990 prostate cancers diagnosed in the screening group and 4,307 in the control group, corresponding to a cumulative incidence of 8.2% and 4.8%, respectively. There were 214 prostate-cancer deaths in the screening group and 326 prostate cancer deaths in the control group in the core age group. The unadjusted rate ratio for death from prostate cancer in the screening group was 0.80 (95% CI, 0.670.95); after adjustment for sequential testing with alpha spending due to two previous interim analyses (based on Poisson regression analysis), the rate ratio was 0.80 (95% CI, 0.650.98). The rates of death in the two study groups began to diverge after 7 to 8 years and continued to diverge further over time.

The absolute difference between the screening and control groups was 0.71 prostate-cancer deaths per 1,000 men. Thus, in order to prevent one prostate-cancer death, the number of men who would need to be screened would be 1,410. The additional prostate cancers diagnosed by screening resulted in an increase in cumulative incidence of 34 per 1,000 men, so that 48 additional subjects would need to be treated to prevent one death from prostate cancer. Thus, PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. 50

Important information that was not reported includes the contamination rate in the control group, and the treatment administered to the prostate cancer cases by stage and by randomly assigned group. Incompleteness of data is also a concern because it appears that several of the participating countries have not yet provided data beyond the 10-year point at which the major effect appears to occur. Longer follow-up will be needed to determine the final results of this trial.

The Goteborg (Sweden) trial is a prospective randomized trial of 20,000 men born between 1930 and 1944. Data from participants born between 1930 and 1939 is used in the pooled ERSPC data. Recently, data with up to 14 years of follow-up was reported. Of the screened group, 12.7% was diagnosed with prostate cancer versus 8.2% of the control group. The absolute risk of prostate death was 0.9% in the control group and 0.5% in the screening group (95% CI, 0.170.64). This is a 44% RR reduction in prostate-cancer mortality (95% CI, 0.280.68; P = .0002). Of note, the number of deaths from all causes was equal in the intervention group and the control group. The authors estimated that 12 men needed to be diagnosed and treated to prevent one death. 51

The Norrkoping study (Sweden) is a population-based nonrandomized trial of prostate cancer screening. All men aged 50 to 69 years living in Norrkoping, Sweden in 1987 were allocated to either invited (every sixth man allocated to invited group) or not-invited groups. The 1,494 men in the invited group were offered screening every 3 years from 1