Clínica de Urologia Dr. Charles Rosenblatt

Incidence and Mortality
Prostate cancer is the most common malignant cancer in North American men (excluding skin cancers). It is estimated that in 2002, approximately 189,000 new cases and 30,200 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 11% of male cancer-related deaths. Age-adjusted incidence rates increased steadily over the past several decades, with dramatic increases associated with the 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.2,3 It has been suggested by some that declines in mortality rates in certain jurisdictions reflect the benefit of PSA screening,4 but other authors have noted that these observations may be explained by independent phenomena such as improved treatment effects. Regional differences have been observed in incidence and mortality rates of prostate cancer as well as rates of radical prostatectomy. The increased incidence until 1989 was most likely the result of increased tumor detection as a result of increasing rates of transurethral prostatectomy.5,6 Subsequent increases were most likely due to widespread use of PSA for early detection and screening.7,8 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.9,10

Risk Factors
Prostate cancer is rarely seen in men younger than 50 years of age; the incidence rises rapidly with each decade thereafter. The age-adjusted incidence is higher in African American males (234.2 per 100,000) compared with white males (144.6 per 100,000).1 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 Other potential risk factors besides age, race, and family history of prostate cancer include alcohol consumption, vitamin or mineral interactions, and other dietary habits.13-16 (Refer to the PDQ summary on Prevention of Prostate Cancer for more information.) Evidence from a case-control study within the Physicians' Health Study suggests that higher plasma insulin-like growth factor-I levels may be associated with a higher prostate cancer risk.17 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.18 The estimated lifetime risk of the diagnosis of prostate cancer is about 16% and 3% to 4% die of this disease.19 The biology and natural history of prostate cancer is not completely understood. However, there is an association between primary tumor volume and local extent of disease, progression, and survival.20 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.21 Further, 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.22 Cancer statistics from the American Cancer Society and the National Cancer Institute indicated in 2002 that the proportion of disease diagnosed at a locoregional stage or distant stage is 83% and 6% for whites compared to 78% and 9% for African Americans, respectively.23 Stage distribution is affected substantially by early detection programs for prostate cancer. Pathologic stage does not always reflect clinical stage and upstaging (due to either extracapsular extension, positive margins, seminal vesicle invasion, or lymph node involvement) occurs frequently. Of the prostate cancers detected by digital rectal exam in the pre-PSA era, 67% to 88% were at a clinically-localized stage (T1-2NxM0).24,25 In one of those series, however, of 2,002 patients undergoing annual screening digital rectal exam (DRE), only one third of men proved to have pathologically organ-confined disease.25 With the proliferation of PSA for early detection, reviews of large numbers of asymptomatic men found that the majority are organ-confined. 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.26 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.27 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%.28 Stage T1c tumors detected by serial PSA and removed by radical prostatectomy are organ-confined in 79% of cases.29 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 interpreting trends in survival data.30 Reported survival rates may also vary, depending upon whether or not the analytical methods used reflect crude disease specific rates (absolute disease specific survival) or take into account competing risks for the given age group (relative disease-specific survival). Five year survival rates remain lower for all stages combined for African American patients than for white patients (92% versus 97% overall). Survival rates for all races are 100% at 5 years for men with locoregional disease, but African American men with metastatic disease have a somewhat lower 5-year survival rate than white men with metastatic disease (30.5% versus 33.4%).23 The reasons for these differences are unclear and studies in populations with equal access to medical care systems, such as the U.S. military medical system, have shown an absence of differences in stage-specific survival between African Americans and whites.31,32

References:

1. American Cancer Society: Cancer Facts and Figures-2002. Atlanta, Ga: American Cancer Society, 2002.

2. Annual report shows overall decline in U.S. cancer incidence and death rates; feature focuses on cancers with recent increasing trends Bethesda, Md: National Cancer Institute, 1996. http://newscenter.cancer.gov/pressreleases/reportnation.html. Accessed 7/17/01.

3. 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 XII-1 Available at http://seer.cancer.gov/Publications/CSR1973_1998/prostate.pdf. Accessed 7/17/01.

4. 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): 417-424, 2001.

5. Potosky AL, Kessler L, Gridley G, et al.: Rise in prostatic cancer incidence associated with increased use of transurethral resection. Journal of the National Cancer Institute 82(20): 1624-1628, 1990.

6. Levy IG, Gibbons L, Collins JP, et al.: Prostate cancer trends in Canada: rising incidence or increased detection? Canadian Medical Association Journal 149(5): 617-624, 1993.

7. Potosky AL, Miller BA, Albertsen PC, et al.: The role of increasing detection in the rising incidence of prostate cancer. JAMA: Journal of the American Medical Association 273(7): 548-552, 1995.

8. 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: Journal of the American Medical Association 274(18): 1445-1449, 1995.

9. Lu-Yao GL, Greenberg ER: Changes in prostate cancer incidence and treatment in USA. Lancet 343(8892): 251-254, 1994.

10. Devesa SS, Grauman DG, Blot WJ, et al.: Atlas of Cancer Mortality in the United States, 1950-94. Washington DC: US Govt Print Off., NIH Publ No. (NIH) 99-4564, 1999. Also available at: http://www.cancer.gov/atlas/mortality.html. Accessed April 25, 2002.

11. Robbins AS, Whittemore AS, Van Den Eeden SK: Race, prostate cancer survival, and membership in a large health maintenance organization. Journal of the National Cancer Institute 90(13): 986-990, 1998.

12. Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. The Prostate 17(1): 337-347, 1990.

13. Hayes RB, Brown LM, Schoenberg JB, et al.: Alcohol use and prostate cancer risk in US blacks and whites. American Journal of Epidemiology 143(7): 692-697, 1996.

14. Eichholzer M, Stahelin 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. International Journal of Cancer 66(2): 145-150, 1996.

15. Gann PH, Hennekens CH, Sacks FM, et al.: Prospective study of plasma fatty acids and risk of prostate cancer. Journal of the National Cancer Institute 86(4): 281-286, 1994.

16. Morton MS, Griffiths K, Blacklock N: The preventive role of diet in prostatic disease. British Journal of Urology 77(4): 481-493, 1996.

17. Chan JM, Stampfer MJ, Giovannucci E, et al.: Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279(5350): 563-566, 1998.

18. Sakr WA, Haas GP, Cassin BF, et al.: The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. Journal of Urology 150(2 pt 1): 379-385, 1993.

19. Surveillance, Epidemiology, and End Results. Bethesda Md:, National Cancer Institute. Available at: http://seer.cancer.gov. Accessed April 25, 2002.

20. Pound CR, Partin AW, Eisenberger MA, et al.: Natural history of progression after PSA elevation following radical prostatectomy. JAMA: Journal of the American Medical Association 281(17): 1591-1597, 1999.

21. McNeal JE, Bostwick DG, Kindrachuk RA, et al.: Patterns of progression in prostate cancer. Lancet 1(8472): 60-63, 1986.

22. Resnick MI: Background for screening - epidemiology and cost effectiveness. Progress in Clinical and Biological Research 269: 111-120, 1988.

23. Ries LA, Eisner MP, Kosary CL, et al., eds.: SEER Cancer Statistics Review 1973-1998. Bethesda, Md: National Cancer Institute, 2001. Available at: http://seer.cancer.gov/CSR/1973_1998/. Accessed 4/22/02.

24. Chodak GW, Keller P, Schoenberg HW: Assessment of screening for prostate cancer using the digital rectal examination. Journal of Urology 141(5): 1136-1138, 1989.

25. Thompson IM, Ernst JJ, Gangai MP, et al.: Adenocarcinoma of the prostate: results of routine urological screening. Journal of Urology 132(4): 690-692, 1984.

26. Catalona WJ, Smith DS, Ratliff TL, et al.: Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA: Journal of the American Medical Association 270(8): 948-954, 1993.

27. Mettlin C, Murphy GP, Lee F, et al.: Characteristics of prostate cancer detected in the American Cancer Society-National Prostate Cancer Detection Project. Journal of Urology 152(5 pt 2): 1737-1740, 1994.

28. 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. Urologic Clinics of North America 24(2): 379-388, 1997.

29. Epstein JI, Walsh PC, Carmichael M, et al.: Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA: Journal of the American Medical Association 271(5): 368-374, 1994.

30. Pfister DG, Wells CK, Chan CK: Classifying clinical severity to help solve problems of stage migration in nonconcurrent comparisons of lung cancer therapy. Cancer Research 50(15): 4664-4669, 1990.

31. Optenberg SA, Thompson IM, Friedrichs P, et al.: Race, treatment, and long-term survival from prostate cancer in an equal-access medical care delivery system. JAMA: Journal of the American Medical Association 274(20): 1599-1605, 1995.

32. Fowler JE, Terrell F: Survival in blacks and whites after treatment for localized prostate cancer. Journal of Urology 156(1): 133-136, 1996.

Evidence of Benefit
Prior to the 1990s, the digital rectal examination (DRE) was the test traditionally mentioned for prostate cancer screening. Two other test procedures are also available: transrectal ultrasound (TRUS) and prostate-specific antigen (PSA).1 Prostate cancer screening is controversial due to the lack of definitive evidence of benefit. 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 active treatment unless indications of progression are present on active surveillance). 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, unfortunately, not possible because of differences in reporting and selection factors in the various reported series. Complications of radical prostatectomy can include urinary incontinence, urethral stricture, erectile dysfunction, and the morbidity associated with general anesthesia and a major surgical procedure. Fecal incontinence can also occur. Definitive external-beam radiation therapy can result in acute cystitis, proctitis, and some times enteritis. These are generally reversible but may be chronic. Potency, in the short term, is preserved with irradiation in the majority of cases, but may diminish over time. (Refer to the PDQ summary on Prostate Cancer Treatment for more information.)

Digital Rectal Exam (DRE)
Although DRE has been used for many years, careful evaluation of this modality has yet to take place. Several observational studies have been reported that examined process measures such as sensitivity as well as case survival data, but without appropriate controls and with no adjustment for lead time and length biases.2,3 In 1984, one study reported on 811 unselected patients from 50 to 80 years of age who underwent rectal examination and follow-up.4 Thirty-eight of 43 patients with a palpable abnormality in the prostate agreed to undergo biopsy. The positive predictive value 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.5 Some additional investigators also reported a high proportion of clinically localized disease when prostate cancer is detected by routine rectal examination,6 while others reported that even with annual rectal examination, only 20% of cases are localized at diagnosis.7 On the other hand, it has been reported that 25% of men presenting with metastatic disease had a normal prostate examination.8 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, one report found that if DRE is only used for a PSA > 1.5 ng/ml (thus, if PSA < 1.5 ng/ml, no DRE is performed), 29% of all biopsies would be eliminated while maintaining a 95% prostate cancer detection sensitivity. By applying DRE only for patients with a PSA > 2.0 ng/ml, the biopsy rate would decrease by 36% while sensitivity would drop to only 92%.9 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 to only 2.5% if DRE alone had been used. Among men with a PSA less than 3.0 ng/ml, the positive predictive value of DRE was only 4% to 11%.10 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 subjects were less likely to have undergone DRE during the 10 years before diagnosis of prostate cancer (odds ratio = 0.51, 95% confidence interval of 0.31-0.84). These data suggested that screening DREs may prevent from 50% to 70% of deaths from prostate cancer.11 Contrary to these findings, results from a case-control study of 150 men who ultimately died of prostate cancer were compared to 299 controls without disease. In this different population, a similar number of cases and controls had undergone DRE during the 10-year interval prior to prostate cancer diagnosis.12 One case-control study reported no statistically significant association between routine screening with digital rectal examination and occurrence of metastatic prostate cancer.13 Rectal examination is inexpensive, relatively noninvasive, nonmorbid and can be taught to nonprofessional health workers; however, its effectiveness depends on the skill and experience of the examiner. Whether routine annual screening by rectal examination reduces prostate cancer mortality remains to be determined.

Transrectal Ultrasound (TRUS) 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. One report found that ultrasound has a low sensitivity and specificity with regard to the values necessary for screening.14 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 among ultrasound-positive subjects in whom rectal and PSA examinations are normal is extremely low.15 Because of low specificity and sensitivity, transrectal ultrasound is relegated to a role in the diagnostic work-up of an abnormal screening test. The cost and poor performance characteristics 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. Transrectal ultrasound guidance is the most frequent method of directing prostate needle biopsy as there is some suggestion that the yield of biopsy is improved with such guidance.16 With the virtually simultaneous clinical acceptance of transrectal ultrasound, spring-loaded biopsy devices, and the proliferation of PSA screening in the late 1980s, the number of prostate cores obtained for patients with either an abnormal DRE or PSA was most commonly 6, using a 'sextant' method of sampling the prostate.17 There is evidence that the predictable increase in cancer detection rates that would be expected by increasing the number of biopsy cores beyond 6 does occur; e.g., biopsies with 12 or 15 cores would increase the proportion of biopsied men having cancer detected by 30% to 35%.18,19 The extent to which such increased detection will reduce morbidity and mortality from the disease or increase the fraction of men treated unnecessarily is at present unknown.

Prostate-Specific Antigen (PSA)
A more promising screening test is measurement of serum PSA. This test has been examined in several observational settings, both for initial diagnosis of disease and as a tool to monitor for recurrence after initial therapy, and for prognosis of outcomes after therapy.20 Parameter estimates for this test include sensitivity in the range of 70%.20 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.21-24 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 which may or may not result in mortality reduction. For lung cancer, no mortality benefit resulted.25 The possibility of identifying an excessive number of false positives in the form of benign prostatic lesions requires, however, that the test be evaluated carefully. A nested case-control prospective study with 10 years of follow-up reported that a single elevated PSA greater 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 significant. Forty-two percent were extracapsular at diagnosis.26 Experience with repeat PSA screening suggests that tumors detected on follow-up examinations are of lower clinical stage and grade.27 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.28 Lower cutoff PSA values are, however, associated with a high proportion of negative biopsies (false positives).29 An initial PSA of less than 2.5 ng/ml is associated with a very low risk of cancer detection within a 4-year follow- up.27,30 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.

Methods to Improve the Performance of the Early Detection of Prostate Cancer:

Complexed PSA and Percent Free PSA
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 from total. 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 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%, respectively.31 However, the preponderance of evidence concerning the utility of complexed and percent PSA is not clear and 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 to 10 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%.32 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.33 Similar findings were reported in another large series.34

PSA Density
As 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,35 subsequent evaluations have failed to confirm any clinically useful association.36,37

PSA Density of the Transition Zone
Some studies have demonstrated that PSA is best adjusted either to total gland volume or to the volume of the transition zone, noting that in general, PSA production by benign epithelium is related to the volume of such epithelium. The adjustments of PSA density (serum PSA divided by gland volume) or PSA density of the transition zone (serum PSA divided by the volume of the transition zone) have been suggested to adjust for these benign sources of PSA. One study prospectively evaluated 559 men with PSA levels between 4.0 and 10.0 ng/ml. A total of 217 of these men were ultimately found to have prostate cancer and 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, respectively).38 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.39

Age-adjusted PSA
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 greater than 33% while retaining 95% of any survival advantage gained by early diagnosis.40 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 missing cancers in older men has prevented uniform acceptance of this approach.

PSA Velocity
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.41 In a follow-up study that used serum collected serially from men without known prostate cancer (2 groups with benign prostatic hyperplasia, one diagnosed by histology and the other clinically, both with PSA levels less than or equal to 10 ng/ml, and a third group with no more than one PSA exceeding 10 ng/ml), it was reported that averaging 3 PSA changes measured at 2-year intervals could be useful for cancer discrimination, while changes measured at 3- or 6-month intervals were volatile and nonspecific, perhaps because of a biologic fluctuation of PSA which may be as high as 30%.42,43 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.44

Alteration of PSA Cutoff Level
A number of authors have begun to explore 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.28 Several collaborating European jurisdictions are conducting prostate cancer screening trials. Both Rotterdam (the Netherlands) and Finland are among them. In Rotterdam data for 7,943 screened men between the ages of 55 and 74 have been reported. Of the 534 men who had PSA levels between 3.0 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.45 In Finland, 15,685 men were screened and 14% of screened men had PSA levels of 3.0 ng/ml or greater. All men with PSA above 4.0 ng/ml were recommended to diagnostic follow-up by digital rectal examination, 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 PSA between 3.0 and 3.9 ng/ml (all biopsied) 22 (3%) had cancer. Of the 1116 men with screening PSA between 4.0 and 9.9, 247 (22%) had cancer, and of the 226 men with screening PSA of 10 or greater, 139 (62%) had cancer.46 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 a PSA level between 3.0 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 5, and pathologic pT3 disease in 6 cases.29 Several variables can affect PSA levels in men. Certain 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.47,48 Some authors have suggested that ejaculation and digital rectal examination can affect PSA levels but subsequent examination of these variables have found that they do not have a clinically significant effect on PSA.49

Frequency of Screening
The optimal frequency and age range for PSA (and DRE) testing are unknown.40,50,51

Types of Tumors Detected by Prostate Cancer Screening
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.52 Most of these tumors are well-differentiated and microscopic in size. Conversely, evidence suggests that tumors of potential clinical significance are larger and higher grade.53 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 alfa blockers and finasteride); and (2) an increase in detection of peripheral zone tumors due to the incorporation of transrectal ultrasound-guided prostate biopsies. As transition zone tumors are predominantly low-volume and low-grade and as peripheral zone tumors have a preponderance of moderate- 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 through 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.54 It is possible, however, that there was a shift in diagnostic criteria over this period.

Factors That May Influence PSA Levels
Diet
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.55,56 Other possible dietary influences include selenium, vitamin E, vitamin D, lycopene, and isoflavones.57 Family History In a Finnish study of 2,099 prostate cancer patients, 302 individuals were identified with 2 or more family members affected by prostate cancer.58 Two hundred nine asymptomatic men from these families were studied to determine the frequency of test abnormality and prostate cancer incidence. Serum PSA was elevated in 10% and prostate cancer or high grade prostatic intraepithelial neoplasia (PIN) were identified in 3.3% and 1%, respectively. The risk of elevated PSA or ultimate diagnosis of prostate cancer was greatest among families with a history of prostate cancer development before age 60. A similar study was conducted in Sweden and evaluated 5,706 sons of Swedish men who had been diagnosed with prostate cancer between 1959 and 1963. While the cumulative risk of developing prostate cancer in the general population by ages 60, 70 and 80 were 0.45%, 3%, and 10%, respectively, the associated age-specific risks for sons of men with prostate cancer were 5%, 15%, and 30%, respectively.59
Race
The impact of race on PSA and tumor volume was evaluated in a large series of patients undergoing radical prostatectomy in whom whole-mount histology was used for the prostate sections. After adjustment for age, stage, pathologic stage, Gleason score, and volume of benign disease, PSA and tumor volume were both higher among African American men.60 Physician Behaviors Related to Screening
A variety of variables affect the likelihood of a recommendation for prostate cancer screening from a physician. One thousand three hundred sixty-nine primary care physicians in Washington State were surveyed to determine patterns of PSA screening. 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 among this population.61 Providing Information to the Public, to Patients, and to Their Families A number of investigators have studied knowledge and preferences of men and their families with regards to prostate cancer screening. One of the most comprehensive analyses interviewed physicians, patients, and their families regarding the sort of information they each felt should be made available prior to prostate cancer screening with PSA and DRE. The investigator found that each group could reach consensus on the minimum amount of information that should be made available to a patient to help him decide whether to have PSA or DRE screening for prostate cancer.62 Randomized, Prospective Clinical Trials of Screening for Prostate Cancer While 2 large randomized clinical trials are currently ongoing to assess whether early detection of prostate cancer can reduce mortality from the disease,63,64 a Canadian trial has been published that was reported to have been performed in a randomized, prospective manner. In this study, 46,193 men, identified from the electoral rolls of Quebec City and its metropolitan area, were randomized to either be approached for PSA and DRE screening or not. A total of 30,956 men were randomized to screening while a total of 15,237 were randomized to observation. (It appears that these men were unaware that they had been randomized in a 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, of the 30,956 men who were randomized to screening, 7,155 actually underwent screening while 23,801 did not. Of the 15,237 who were randomized to observation, 982 actually underwent screening while 14,255 did not. One hundred thirty-seven deaths were noted among the 38,056 men who did not undergo screening compared to only 5 deaths among the 8,137 men who underwent screening. Using an intention-to-treat analysis based upon the study arm to which the individual was originally randomized, however, there was no difference in mortality (there were 73 deaths among the 15,237 men who were randomized to observation compared to 140 deaths among the 31,300 randomized to screening.) Because of noncompliance, this study does not answer the question whether early detection with PSA and DRE will reduce prostate cancer mortality.65

Population Observations on Early Detection, Incidence, and Prostate Cancer Mortality
While DRE has been a staple of medical practice for many decades, PSA did not come into common use until about 1988 for the early diagnosis of prostate cancer. Following the national dissemination of the practice of early detection, 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 significantly lower rates of prostate cancer diagnosis.66 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 (NCI) 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. As the test diffused, 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.67 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 a decrease observed in mortality rates. In Olmsted County, Minnesota, for example, age-adjusted prostate cancer mortality rates increased from 25.8 per 100,000 men in the population during the period 1980 to 1984 to a peak of 34 per 100,000 during 1989 to 1992; they subsequently decreased to 19.4 per 100,000 during 1993 to 1997.68 Similar observations have been made elsewhere in the world,69,70 leading some to hypothesize that the mortality decline is related to PSA testing. In Canada (Quebec province), however, examinations of the association between the size of the rise in incidence rates (from 1989 to 1993) and the size of the decrease in mortality rates (from 1995 to 1999), by birth cohort and residential grouping, showed no correlation between these 2 variables.70 This study suggests that, at least over this time frame, the decline in mortality is not related to widespread PSA testing. Since the evidence in this respect is inconsistent, it remains unclear whether the cause of these mortality trends is chance, early detection, improved treatments, or a combination of effects.

Simulation Models
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 Prostate, Lung, Colorectal, and Ovarian cancer study. The changes in prostate cancer mortality could not be explained entirely by PSA screening alone.71 Cause-of-death-misclassification was 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 as due to prostate cancer would fall as would the overall rate of prostate cancer death.72 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.41,73,74 Further, there is a possibility of unnecessary morbidity associated with diagnosis and treatment of many prostate cancer lesions. A meta-analysis of 6 expectant series demonstrates that patients with low-grade disease experience prolonged survival with deferred therapy.75 The incidence of prostate cancer found at autopsy steadily increases for each decade after age 50 years, and many of these lesions are clinically silent. Some progress has been made in predicting the biologic behavior of these tumors, but despite improved understanding of the biologic potential of prostate cancer as it relates to histologic grade and tumor volume, the necessity to diagnose or treat a given case of prostate cancer cannot be proven at this time. Decision analyses using the Markov model yield variable treatment outcomes due to the uncertainty regarding metastatic rates expected for prostate cancer and uncertainty about treatment efficacy.76-78 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 to observation.79 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.80 Screening and subsequent treatment of a large number of detected prostate cancers could have substantial risks and morbidity that include urinary incontinence, urethral strictures, erectile dysfunction, rectal injury, and a small but finite incidence of treatment-related mortality.81,82 The dilemma is shared by investigators in other countries.83 A simulation model based on available evidence suggests that if there is a benefit to screening, this benefit decreases with age.84 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 transrectal ultrasound and serum tumor markers (including PSA) for routine screening in asymptomatic men.76,81 While awaiting results of current studies, physicians and men (and their partners) are faced with the dilemma of whether or not 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.62 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 deaths from prostate cancer, and, among experts, the recommendation to screen is controversial. An NCI multicenter trial is ongoing to test the effect of early detection by digital rectal examination and PSA on reducing mortality. A trial of screening is also being performed in Europe.63,85

1. Scardino PT: Early detection of prostate cancer. Advances in Urologic Ultrasound 16(4): 635-655, 1989.

2. Gilbertsen VA: Cancer of the prostate gland: results of early diagnosis and therapy undertaken for cure of the disease. JAMA: Journal of the American Medical Association 215(1): 81-84, 1971.

3. Jenson CB, Shahon DB, Wangensteen OH: Evaluation of annual examinations in the detection of cancer: special reference to cancer of the gastrointestinal tract, prostate, breast, and female generative tract. JAMA: Journal of the American Medical Association 174(14): 1783-1788, 1960.

4. Chodak GW, Schoenberg HW: Early detection of prostate cancer by routine screening. JAMA: Journal of the American Medical Association 252(23): 3261-3264, 1984.

5. Chodak GW, Keller P, Schoenberg HW: Assessment of screening for prostate cancer using the digital rectal examination. Journal of Urology 141(5): 1136-1138, 1989.

6. Donohue RE, Fauver HE, Whitesel JA, et al.: Staging prostatic cancer: a different distribution. Journal of Urology 122(3): 327-329, 1979.

7. Wajsman Z, Chu TM: Detection and diagnosis of prostatic cancer. In: Murphy GP ed.: Prostatic cancer. Littleton, Massachusetts: 1987, pp 94-99.

8. Thompson IM, Zeidman EJ: Presentation and clinical course of patients ultimately succumbing to carcinoma of the prostate. Scandinavian Journal of Urology and Nephrology 25(2): 111-114, 1991.

9. Beemsterboer PM, Kranse R, de Koning HJ, et al.: Changing role of 3 screening modalities in the European randomized study of screening for prostate cancer (Rotterdam). International Journal of Cancer 84(4): 437-441, 1999.

10. Schroder FH, van der Maas P, Beemsterboer P, et al.: Evaluation of the digital rectal examination as a screening test for prostate cancer. Journal of the National Cancer Institute 90(23): 1817-1823, 1998.

11. Jacobsen SJ, Bergstralh EJ, Katusic SK, et al.: Screening digital rectal examination and prostate cancer mortality: a population-based case-control study. Urology 52(2): 173-179, 1998.

12. Richert-Boe KE, Humphrey LL, Glass AG, et al.: Screening digital rectal examination and prostate cancer mortality: a case-control study. Journal of Medical Screening 5(2): 99-103, 1998.

13. Friedman GD, Hiatt RA, Quesenberry CP, et al.: Case-control study of screening for prostatic cancer by digital rectal examinations. Lancet 337(8756): 1526-1529, 1991.

14. Waterhouse RL, Resnick MI: The use of transrectal prostatic ultrasonography in the evaluation of patients with prostatic carcinoma. Journal of Urology 141(2): 233-239, 1989.

15. Cooner WH, Mosley BR, Rutherford CL, et al.: Clinical application of transrectal ultrasonography and prostate specific antigen in the search for prostate cancer. Journal of Urology 139(4): 758-761, 1988.

16. Renfer LG, Schow D, Thompson IM, et al.: Is ultrasound guidance necessary for transrectal prostate biopsy? Journal of Urology 154(4): 1390-1391, 1995.

17. Hodge KK, McNeal JE, Stamey TA: Ultrasound guided transrectal core biopsies of the palpably abnormal prostate. Journal of Urology 142(1): 66-70, 1989.

18. Levine MA, Ittman M, Melamed J, et al.: Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. Journal of Urology 159(2): 471-476, 1998.

19. Eskew LA, Bare RL, McCullough DL: Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. Journal of Urology 157(1): 199-203, 1997.

20. Partin AW, Oesterling JE: The clinical usefulness of prostate specific antigen: update 1994. Journal of Urology 152(5, Part 1): 1358-1368, 1994.

21. Catalona WJ, Smith DS, Ratliff TL, et al.: Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA: Journal of the American Medical Association 270(8): 948-954, 1993.

22. Babaian RJ, Mettlin C, Kane R, et al.: The relationship of prostate-specific antigen to digital rectal examination and transrectal ultrasonography: findings of the American Cancer Society National Prostate Cancer Detection Project. Cancer 69(5): 1195-1200, 1992.

23. Brawer MK, Chetner MP, Beatie J, et al.: Screening for prostatic carcinoma with prostate specific antigen. Journal of Urology 147: 841-845, 1992.

24. Mettlin C, Murphy GP, Lee F, et al.: Characteristics of prostate cancers detected in a multimodality early detection program. Cancer 72(5): 1701-1708, 1993.

25. Collins MM, Barry MJ: Controversies in prostate cancer screening: analogies to the early lung cancer screening debate. JAMA: Journal of the American Medical Association 276(24): 1976-1979, 1996.

26. Gann PH, Hennekens CH, Stampfer MJ: A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA: Journal of the American Medical Association 273(4): 289-294, 1995.

27. Smith DS, Catalona WJ, Herschman JD: Longitudinal screening for prostate cancer with prostate-specific antigen. JAMA: Journal of the American Medical Association 276(16): 1309-1315, 1996.

28. Smith DS, Carvalhal GF, Mager DE, et al.: Use of lower prostate specific antigen cutoffs for prostate cancer screening in black and white men. Journal of Urology 160(5): 1734-1738, 1998.

29. Lodding P, Aus G, Bergdahl S, et al.: Characteristics of screening detected prostate cancer in men 50 to 66 years old with 3 to 4 ng./ml. prostate specific antigen. Journal of Urology 159(3): 899-903, 1998.

30. Harris CH, Dalkin BL, Martin E, et al.: Prospective longitudinal evaluation of men with initial prostate specific antigen levels of 4.0 ng./ml. or less. Journal of Urology 157(5): 1740-1743, 1997.

31. Brawer MK, Meyer GE, Letran JL, et al.: Measurement of complexed PSA improves specificity for early detection of prostate cancer. Urology 52(3): 372-378, 1998.

32. 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. Journal of General Internal Medicine 15(10): 739-748, 2000.

33. 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): 558-565, 1998.

34. Pannek J, Rittenhouse HG, Chan DW, et al.: The use of percent free prostate specific antigen for staging clinically localized prostate cancer. Journal of Urology 159(4): 1238-1242, 1998.

35. Benson MC, Whang IS, Pantuck A, et al.: Prostate specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. Journal of Urology 147(3 pt 2): 815-816, 1992.

36. Bangma CH, Grobbee DE, Schroder FH: Volume adjustment for intermediate prostate-specific antigen values in a screening population. European Journal of Cancer 31A(1): 12-14, 1995.

37. Babaian RJ, Kojima M, Ramirez EI, et al.: Comparative analysis of prostate specific antigen and its indexes in the detection of prostate cancer. Journal of Urology 156(2): 432-437, 1996.

38. Djavan B, Remzi M, Zlotta AR, et al.: Combination and multivariate analysis of PSA-based parameters for prostate cancer prediction. Techniques in Urology 5(2): 71-76, 1999.

39. 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. The Prostate 37(3): 133-137, 1998.

40. Etzioni R, Cha R, Cowen ME: Serial prostate specific antigen screening for prostate cancer: a computer model evaluates competing strategies. Journal of Urology 162(3 pt 1): 741-748, 1999.

41. Carter HB, Pearson JD, Metter EJ, et al.: Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA: Journal of the American Medical Association 267(16): 2215-2220, 1992.

42. Carter HB, Pearson JD, Waclawiw Z, et al.: Prostate-specific antigen variability in men without prostate cancer: effect of sampling interval on prostate-specific antigen velocity. Urology 45(4): 591-596, 1995.

43. Woolf SH: Screening for prostate cancer with prostate-specific antigen: an examination of the evidence. New England Journal of Medicine 333(21): 1401-1405, 1995.

44. Brawer MK, Beatie J, Wener MH, et al.: Screening for prostatic carcinoma with prostate specific antigen: results of the second year. Journal of Urology 150(1): 106-109, 1993.

45. Schroder 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.

46. Maattanen L, Auvinen A, Stenman U, et al.: Three-year results of the Finnish prostate cancer screening trial. Journal of the National Cancer Institute 93(7): 552, 2001.

47. Andriole GL, Guess HA, Epstein JI, et al.: Treatment with finasteride preserves usefulness of prostate-specific antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial. Urology 52(2): 195-202, 1998.

48. DiPaola RS, Zhang H, Lambert GH, et al.: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. New England Journal of Medicine 339(12): 785-791, 1998.

49. Stenner J, Holthaus K, Mackenzie SH, et al.: The effect of ejaculation on prostate-specific antigen in a prostate cancer-screening population. Urology 51(3): 455-459, 1998.

50. Ross KS, Carter HB, Pearson JD, et al.: Comparative efficiency of prostate-specific antigen screening strategies for prostate cancer detection. JAMA: Journal of the American Medical Association 284(11): 1399-1405, 2000.

51. Carter HB, Landis PK, Metter EJ, et al.: Prostate-specific antigen testing of older men. Journal of the National Cancer Institute 91(20): 1733-1737, 1999.

52. Sakr WA, Haas GP, Cassin BF, et al.: The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. Journal of Urology 150(2 pt 1): 379-385, 1993.

53. Stamey TA, McNeal JE, Yemoto CM, et al.: Biological determinants of cancer progression in men with prostate cancer. JAMA: Journal of the American Medical Association 281(15): 1395-1400, 1999.

54. Schwartz KL, Grignon DJ, Sakr WA, et al.: Prostate cancer histologic trends in the metropolitan Detroit area, 1982 to 1996. Urology 53(4): 769-774, 1999.

55. Fleshner NE, Klotz LH: Diet, androgens, oxidative stress and prostate cancer susceptibility. Cancer and Metastasis Reviews 17(4): 325-330, 1998-99.

56. Clinton SK, Giovannucci E: Diet, nutrition, and prostate cancer. Annual Review of Nutrition 18: 413-440, 1998.

57. Thompson IM, Coltman CA Jr, Crowley J: Chemoprevention of prostate cancer: the prostate cancer prevention trial. The Prostate 33(3): 217-221, 1997.

58. Matikainen MP, Schleutker J, Morsky P, et al.: Detection of subclinical cancers by prostate-specific antigen screening in asymptomatic men from high-risk prostate cancer families. Clinical Cancer Research 5(6): 1275-1279, 1999.

59. Gronberg H, Wiklund F, Damber JE: Age specific risks of familial prostate carcinoma. Cancer 86(3): 477-483, 1999.

60. Moul JW, Connelly RR, Mooneyhan RM, et al.: Racial differences in tumor volume and prostate specific antigen among radical prostatectomy patients. Journal of Urology 162(2): 394-397, 1999.

61. Edlefsen KL, Mandelson MT, McIntosh MW, et al.: Prostate-specific antigen for prostate cancer screening. Do Physician Characteristics affect its use? American Journal of Preventive Medicine 17(1): 87-90, 1999.

62. Chan EC, Sulmasy DP: What should men know about prostate-specific antigen screening before giving informed consent? American Journal of Medicine 105(4): 266-274: 1998.

63. Denis LJ: Prostate cancer screening and prevention: "realities and hope". Urology 46(suppl 3A): 56-61, 1995.

64. Gohagan JK, Levin DL, Prorok JC et al., eds.: The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Controlled Clinical Trials 21(6 suppl): 249S-406S, 2000.

65. Labrie F, Candas B, Dupont A, et al.: Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. The Prostate 38(2): 83-91, 1999.

66. 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 and Control 9(5): 519-527, 1998.

67. 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): 444-449, 1998.

68. 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. Journal of Urology 161(2): 529-533, 1999.

69. 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): 417-424, 2001.

70. Perron L, Moore L, Bairati I, et al.: PSA screening and prostate cancer mortality. Canadian Medical Association Journal 166(5): 586-591, 2002.

71. 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. Journal of the National Cancer Institute 91(12): 1033-1039, 1999.

72. 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. Journal of the National Cancer Institute 91(12): 1025-1032, 1999.

73. Johansson JE, Holmberg L, Johansson S, et al.: Fifteen-year survival in prostate cancer. A prospective, population-based study in Sweden. JAMA: Journal of the American Medical Association 277(6): 467-471, 1997.

74. Whitmore WF: Localised prostatic cancer: management and detection issues. Lancet 343(8908): 1263-1267, 1994.

75. Chodak GW, Thisted RA, Gerber GS, et al.: Results of conservative management of clinically localized prostate cancer. New England Journal of Medicine 330(4): 242-248, 1994.

76. Fleming C, Wasson JH, Albertsen PC, et al.: A decision analysis of alternative treatment strategies for clinically localized prostate cancer. JAMA: Journal of the American Medical Association 269(20): 2650-2658, 1993.

77. 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): 445-461, 1995.

78. Beck JR, Kattan MW, Miles BJ: A critique of the decision analysis for clinically localized prostate cancer. Journal of Urology 152(5, Part 2): 1894-1899, 1994.

79. Lu-Yao GL, Yao SL: Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 349(9056): 906-910, 1997.

80. Gronberg 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): 374-378, 1997.

81. Kramer BS, Brown ML, Prorok PC, et al.: Prostate cancer screening: what we know and what we need to know. Annals of Internal Medicine 119(9): 914-923, 1993.

82. Stamey TA, Prestigiacomo A, Komatsu K: Physiological variation of serum prostate specific antigen (PSA) from a screening population in the range of 4-10 ng/ml using the Hybritech Tandem-R PSA assay. Proceedings of the American Urological Association 153(4, suppl): A-765, 420A, 1995.

83. Menegoz F, Colonna M, Exbrayat C, et al.: A recent increase in the incidence of prostatic carcinoma in a French population: role of ultrasonography and prostatic specific antigen. European Journal of Cancer 31A(1): 55-58, 1995.

84. Coley CM, Barry MJ, Fleming C, et al.: Early detection of prostate cancer: part II: estimating the risks, benefits, and costs. Annals of Internal Medicine 126(6): 468-479, 1997.

85. Schroder FH, Bangma CH: The European randomized study of screening for prostate cancer (ERSPC). British Journal of Urology 79(suppl 1): 68-71, 1997.

86. Crawford ED, Leewansangtong S, Goktas S, et al.: Efficiency of prostate-specific antigen and digital rectal examination in screening, using 4.0 ng/ml and age-specific reference range as a cutoff for abnormal values. The Prostate 38(4): 296-302, 1999.

Risk Factors for Prostate Cancer Development

Age
It is well-established that prostate cancer incidence increases dramatically with increasing age. While a very unusual disease in men before age 50, rates increase exponentially thereafter. The registration rate by age cohort in England and Wales increased from 8 (per thousand population) in men 50 to 56 to 68 (per thousand) in men 60 to 64, 260 (per thousand) in men 70 to 74, and peaked at 406 (per thousand) in men 75 to 79.1 The death rate (per thousand) in 1992 in the 50 to 54, 60 to 64, and 70 to 74 aged cohorts in this same population was 4, 37, and 166, respectively.1 At all ages, incidence of blacks exceeds those of whites. In general, the age-related increase in prostate cancer rates parallels total cancer rates in the United States.2

Family History
Approximately 15% of men with a diagnosis of prostate cancer will be found to have a first-degree male relative (brother, father) with prostate cancer, compared to approximately 8% of the U.S. population.3 It has been estimated that approximately 9% of all prostate cancers may result from heritable susceptibility genes.4 Several authors have completed segregation analyses, and although a single, rare autosomal gene has been suggested to cause cancer in some of these families, the burden of evidence suggests that the inheritance is considerably more complex.5,6 Further study has demonstrated that, controlling for all other tumor variables, treatment of the primary tumor is more likely to fail in men with a family history of prostate cancer.7

Hormones
The development of the prostate is dependent upon the secretion of testosterone by the fetal testis. Testosterone causes normal virilization of the wolffian duct structures and internal genitalia and is acted upon by the enzyme 5 alpha- reductase (5AR) to form dihydrotestosterone (DHT). DHT has a fourfold to 50- fold greater affinity for the androgen receptor than testosterone, and it is DHT that leads to normal prostatic development. Children born with abnormal 5AR (due to a change in a single base pair in exon 5 of the normal type II 5AR gene), are born with ambiguous genitalia (variously-described as hypospadias with a blind-ending vagina to a small phallus) but masculinize at puberty due to the surge of testosterone production at that time. Clinical, imaging, and histologic studies of kindreds born with 5AR deficiency have demonstrated a small, pancake-appearing prostate with an undetectable prostate-specific antigen (PSA) and no evidence of prostatic epithelium.8 Long-term follow-up demonstrates that neither benign prostatic hyperplasia (BPH) nor prostate cancer develop. Other evidence suggesting that the degree of cumulative exposure of the prostate to androgens is related to an increased risk of prostate cancer includes:
1. Neither BPH nor prostate cancer have been reported in men castrated prior to puberty.9
2. Androgen levels generally parallel prostate cancer risk in various populations of men. Although there are conflicting data, a number of studies have demonstrated that levels of testosterone and, especially dihydrotestosterone, are highest in black males, of intermediate levels in white males, and lowest in native Japanese.10-12 The risks for prostate cancer in these ethnic groups directly parallel these androgen levels.
3. Androgen deprivation in almost all forms leads to involution of the prostate, a fall in PSA levels, apoptosis of prostate cancer and epithelial cells, as well as a clinical response in prostate cancer patients.13,14

Race
The risk of prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese. Survival is also related to ethnicity with 5-year survivals of whites with localized, regional, or metastatic prostate cancer being 94.7%, 86.6%, and 29.6%, respectively, compared to rates of 87.8%, 69.3%, and 22.7%, respectively, for blacks.15 Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to care may play a role in disease outcomes.16

Dietary Fat
An interesting observation is that although the incidence of latent (occult, histologically evident) prostate cancer is similar throughout the world, clinical prostate cancer varies from country to country by as much as 20- fold.17 Previous ecologic studies have demonstrated a direct relationship between a country's prostate cancer-specific mortality rate and average total calories from fat consumed by the country's population.18,19 Studies of immigrants from Japan have demonstrated that native Japanese have the lowest risk of clinical prostate cancer, first generation Japanese-Americans have an intermediate risk, and subsequent generations have a risk comparable to the U.S. population.20,21 Animal models of explanted human prostate cancer have demonstrated decreased tumor growth rates in animals fed a low-fat diet.22,23 Evidence from many case-control studies has generally found an association between dietary fat and prostate cancer risk 24-26, although studies have not uniformly reached this conclusion.27-29 In a review of published studies of the relationship between dietary fat and prostate cancer risk, among descriptive studies, approximately half found an increased risk with increased dietary fat and half found no association.30 Among case-control studies, again, about half of the studies found an increased risk with increasing dietary fat, animal fat, and saturated and monounsaturated fat intake while approximately half found no association. Only in studies of polyunsaturated fat intake were there 3 reported studies of a significant negative association between prostate cancer and fat intake. In general, fat of animal origin seems to be associated with the highest risk.16,31 In a series of 384 patients with prostate cancer, the risk of cancer progression to an advanced stage was greater in men with a high fat intake.32 The announcement in 1996 that cancer mortality rates had fallen in the United States prompted one suggestion that this may be due to decreases in dietary fat over the same time period.33,34 The explanation for this possible association between prostate cancer and dietary fat is unknown. Several hypotheses have been advanced including:
1. Dietary fat may increase serum androgen levels, thereby increasing prostate cancer risk. This hypothesis is supported by observations from South Africa and the United States that changes in dietary fat change urinary and serum levels of androgens.35,36
2. Certain types of fatty acids or their metabolites may initiate or promote prostate carcinoma development. The evidence for this hypothesis is conflicting, but one study suggests that linoleic acid (omega-6 polyunsaturated fatty acid) may stimulate prostate cancer cells while omega-3 fatty acids inhibit cell growth.37
3. An observation made in an animal model is that male offspring of pregnant rats fed a high-fat diet will develop prostate cancer at a higher rate than animals fed a low-fat diet.38 This observation may explain some of the variations in prostate cancer incidence and mortality among ethnic groups as an observation has been made that first trimester androgen levels in pregnant blacks are higher than those in whites.39

Diet: Fruits and Vegetables
Increased dietary intake of fruits and vegetables has been associated with a reduced risk of prostate cancer in some studies. One study evaluated 1619 prostate cancer cases and 1618 controls in a multicenter, multi-ethnic population. The study found that intake of legumes, yellow-orange, and cruciferous vegetables was associated with a lower risk of prostate cancer.40

Cadmium Exposure
Cadmium exposure is occupationally seen associated with nickel-cadmium batteries and cadmium recovery plant smelters as well as in association with cigarette smoke.41 The earliest studies of this agent documented what seemed to be an association, but better-designed studies have failed to note an association.42,43

Dioxin Exposure
Dioxin (TCDD or 2,3,7,8 tetrachlorodibenzo-p-dioxin) is a contaminant of an herbicide used in Vietnam. This agent is similar to many components of herbicides used in farming. In the review of the linkage between dioxin and prostate cancer risk by the National Academy of Sciences Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides, only 2 articles were found on prostate cancer with sufficient numbers of cases and follow-up to allow analysis.44,45 Their analysis of all available data suggest that the association between dioxin exposure and prostate cancer is not conclusive.46

References:

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4. Gronberg H, Isaacs SD, Smith JR, et al.: Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAMA: Journal of the American Medical Association 278(15): 1251-1255, 1997.

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8. Imperato-McGinley J, Gautier T, Zirinsky K, et al.: Prostate visualization studies in males homozygous and heterozygous for 5alpha-reductase deficiency. Journal of Clinical Endocrinology and Metabolism 75(4): 1022-1026, 1992.

9. Isaacs JT: Hormonal balance and the risk of prostatic cancer. Journal of Cellular Biochemistry 16H(suppl): 107-108, 1992.

10. Ellis L, Nyborg H: Racial/ethnic variations in male testosterone levels: a probable contributor to group differences in health. Steroids 57(2): 72-75, 1992.

11. Ross RK, Bernstein L, Lobo RA, et al.: 5-alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet 339(8798): 887-889, 1992.

12. Wu AH, Whittemore AS, Kolonel LN, et al.: Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada. Cancer Epidemiology, Biomarkers and Prevention 4(7): 735-741, 1995.

13. Peters CA, Walsh PC: The effect of nafarelin acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatic hyperplasia. New England Journal of Medicine 317(10): 599-604, 1987.

14. Kyprianou N, Isaacs JT: Expression of transforming growth factor-beta in the rat ventral prostate during castration-induced programmed cell death. Molecular Endocrinology 3(10):1515-1522, 1989.

15. Ries LA, Miller BA, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1991: tables and graphs. Bethesda, Md: National Cancer Institute, 371. NIH Pub. No. 94-2789, 1994.

16. Optenberg SA, Thompson IM, Friedrichs P, et al.: Race, treatment, and long-term survival from prostate cancer in an equal-access medical care delivery system. JAMA: Journal of the American Medical Association 274(20): 1599-1605, 1995.

17. Wynder EL, Mabuchi K, Whitmore WF Jr: Epidemiology of cancer of the prostate. Cancer 28(2): 344-360, 1971.

18. Armstrong B, Doll R: Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. International Journal of Cancer 15(4): 617-631, 1975.

19. Rose DP, Connolly JM: Dietary fat, fatty acids and prostate cancer. Lipids 27(10): 798-803, 1992.

20. Haenszel W, Kurihara M: Studies of Japanese migrants, I: mortality from cancer and other disease among Japanese in United States. Journal of the National Cancer Institute 40(1): 43-68, 1968.

21. Shimizu H, Ross RK, Bernstein L, et al.: Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. British Journal of Cancer 63(6): 963-966, 1991.

22. Wang Y, Corr JG, Thaler HT, et al.: Decreased growth of established human prostate LNCaP tumors in nude mice fed a low-fat diet. Journal of the National Cancer Institute 87(19): 1456-1462, 1995.

23. Connolly JM, Coleman M, Rose DP: Effects of dietary fatty acids on DU145 human prostate cancer cell growth in athymic nude mice. Nutrition and Cancer 29(2): 114-119, 1997.

24. Ross RK, Shimizu H, Paganini-Hill A, et al.: Case-control studies of prostate cancer in blacks and whites in southern California. Journal of the National Cancer Institute 78(5): 869-874, 1987.

25. Kolonel LN, Yoshizawa CN, Hankin JH: Diet and prostatic cancer: a case-control study in Hawaii. American Journal of Epidemiology 127(5): 999-1012, 1988.

26. Whittemore AS, Kolonel LN, Wu AH, et al.: Prostate cancer in relation to diet, physical activity, and body size in blacks, whites, and Asians in the United States and Canada. Journal of the National Cancer Institute 87(9): 652-661, 1995.

27. Giovannucci E: Epidemiologic characteristics of prostate cancer. Cancer 75(suppl 7): 1766-1777, 1995.

28. Mettlin C, Selenskas S, Natarajan N, et al.: Beta-carotene and animal fats and their relationship to prostate cancer risk: a case-control study. Cancer 64(3): 605-612, 1989.

29. Severson RK, Nomura AM, Grove JS, et al.: A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Research 49(7): 1857-1860, 1989.

30. Zhou JR, Blackburn GL: Bridging animal and human studies: what are the missing segments in dietary fat and prostate cancer? American Journal of Clinical Nutrition 66(suppl): 1572S-1580S, 1997.

31. Rose DP, Boyar AP, Wynder EL: International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer 58(11): 2363-2371, 1986.

32. Bairati I, Meyer F, Fradet Y, et al.: Dietary fat and advanced prostate cancer. Journal of Urology 159(4): 1271-1275, 1998.

33. Cole P, Rodu B: Declining cancer mortality in the United States. Cancer 78(10): 2045-2048, 1996.

34. Wynder EL, Cohen LA: Correlating nutrition to recent cancer mortality statistics. Journal of the National Cancer Institute 89(4): 324, 1997.

35. Hill P, Wynder EL, Garbaczewski L, et al.: Diet and urinary steroids in black and white North American men and black South African men. Cancer Research 39(12): 5101-5105, 1979.

36. Hamalainen E, Adlercreutz H, Puska P, et al.: Diet and serum sex hormones in healthy men. Journal of Steroid Biochemistry 20(1): 459-464, 1984.

37. Rose DP, Connolly JM: Effects of fatty acids and eicosanoid synthesis inhibitors on the growth of two human prostate cancer cell lines. The Prostate 18(3): 243-254, 1991.

38. Kondo Y, Homma Y, Aso Y, et al.: Promotional effect of two-generation exposure to a high-fat diet on prostate carcinogenesis in ACI/Seg rats. Cancer Research 54(23): 6129-6132, 1994.

39. Henderson BE, Bernstein L, Ross RK, et al.: The early in utero oestrogen and testosterone environment of blacks and whites: potential effects on male offspring. British Journal of Cancer 57(2): 216-218, 1988.

40. Kolonel LN, Hankin JH, Whittemore AS, et al.: Vegetables, fruits, legumes and prostate cancer: a multiethnic case-control study. Cancer Epidemiology, Biomarkers and Prevention 9(8): 795-804, 2000.

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42. Sanchez AG, Antona JF, Urrutia M: Geochemical prospection of cadmium in a high incidence area of prostate cancer, Sierra de Gata, Salamanca, Spain. The Science of the Total Environment 116(3): 243-251, 1992.

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45. Bertazzi PA, Zocchetti C, Pesatori AC, et al.: Ten-year mortality study of the population involved in the Seveso incident in 1976. American Journal of Epidemiology 129(6): 1187-1200, 1989.

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Opportunities for Prevention

Hormonal Prevention
The evidence that lifetime hormonal influences may affect prostate cancer risk has led to the initiation of a large, randomized, placebo-controlled trial of finasteride (an inhibitor of 5 alpha-reductase) to determine if this agent can reduce the incidence of prostate carcinoma.1 The results of this study will not be available until approximately 2004. In general, agents that are used for hormonal therapy of existing prostate cancers would be unsuitable for prostate cancer chemoprevention due to the cost and wide variety of side effects including sexual dysfunction, osteoporosis, and vasomotor symptoms (hot flushes).2 It is possible, however, that newer antiandrogens may play a role as preventive agents in the future.3

Dietary Prevention With a Low-Fat Diet
It is unknown whether dietary modification through the use of a low-fat, plant- based diet will reduce prostate cancer risk. While this outcome is unknown, multiple additional benefits may be gleaned by such a diet to include a lower risk of hyperlipidemia, better control of blood pressure, and a lower risk of cardiovascular disease - all of which may merit adoption of such a diet.

Chemoprevention
Several agents, including alpha-tocopherol, selenium, lycopene, difluoromethylornithine (DFMO),4-8 vitamin D,9-11 and isoflavonoids,12,13 have shown potential in either clinical or laboratory studies for chemoprevention of prostate cancer. Based mainly on clinical trial results, alpha-tocopherol, selenium, and lycopene are receiving the greatest public health interest and are highlighted in our chemoprevention discussions below.

Chemoprevention With Vitamin E (Alpha-Tocopherol)
In 1986, while studying the effect of adriamycin on the human prostatic cancer cell line DU-145, it was also found that alpha-tocopherol may have a possible effect.14 The study, employing d-alpha-tocopheryl acid succinate, found that not only did it enhance the cytotoxic effect of adriamycin but also inhibited cell growth when used alone. This inhibition was dose-dependent. Finally, these properties were noted at doses which are routinely attained in plasma.15 These same doses have been demonstrated to have no effect on normal mouse fibroblasts.16,17 In a similar study using the Nb rat prostate adenocarcinoma model, it was found that the combination of adriamycin-vitamin E resulted in a lower average final tumor volume when compared to control animals.18 A nested case-control study of serum micronutrients from a cohort of 6,860 Japanese-American men analyzed 142 confirmed cases of prostate cancer, comparing them with a similar number of controls.19 Although the difference did not reach statistical significance, the odds ratio for gamma-tocopherol was 0.7 (95% confidence interval 0.3-1.5). In a study of 2,974 male workers in Basel, Switzerland, low levels of lipid-adjusted plasma of vitamin E were associated with a statistically significantly increased risk for lung cancer.20 Additionally, it was noted in male smokers that low levels of vitamin E were associated with a higher risk of prostate cancer. The effect of the RRR-alpha-tocopheryl succinate derivative of vitamin E (vitamin E succinate - VES) on 3 metastatic human prostate cancer cell lines was studied: LNCaP, PC-3, and DU-145.21 It was found that VES inhibited cell growth and DNA synthesis in all cell lines in a dose-dependent manner. In a similar manner, the effect of dl-alpha-tocopherol in CRL-1740 prostate cancer cells was studied.22 It was observed that even at 0.1 mM vitamin E, the prostate cancer cell line demonstrated growth suppression. When studying tritiated-thymidine incorporation in the prostate cell line, it was found that vitamin E supplementation reduced DNA synthesis. Additionally, analysis of high-molecular weight DNA indicated that apoptotic changes were ongoing and may have been due to vitamin E supplementation. Not all studies of alpha-tocopherol have found the agents to be effective. Using the DMAB-initiated rate prostate cancer model in F344 rats, the effect of 6 naturally occurring antioxidants on carcinogenesis was studied.23 Using dietary 2 ppm selenium and 1% alpha-tocopherol, no differences were noted in atypical hyperplasia or carcinoma rates in the study groups compared with control animals. In a large nested case-control study, serum obtained in 1974 from 25,802 persons in Washington County, Maryland was studied.24 Serum levels of tocopherol were compared between 103 men who developed prostate cancer during 13 years of follow-up to 103 control subjects matched for age and race. No association was found between tocopherol levels and cancer risk. The largest assessment of the impact of alpha-tocopherol on prostate cancer risk came from the Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study. This prostate cancer analysis was secondary to the ATBC study's primary objective of assessing whether alpha-tocopherol and/or beta-carotene could reduce incidence of lung cancer in male smokers.25 The ATBC study was prompted by multiple observations that populations with higher intakes of diets rich in alpha-tocopherol and beta-carotene had a lower risk of cancer.26,27 Conducted in 14 geographic areas in southwestern Finland, the ATBC study was a randomized, double-blind, placebo-controlled comparison of alpha-tocopherol and beta-carotene. The study employed a 2 x 2 factorial design, and each participant received 2 capsules. Specifically, participants were divided into 4 similar study arms/groups: 1 receiving beta-carotene and placebo, 1 receiving alpha-tocopherol and placebo, 1 receiving both active agents, and 1 receiving 2 placebo capsules. The form of alpha-tocopherol in this study was dl-alpha tocopherol acetate. A total of 29,133 men were enrolled. The daily doses of alpha-tocopherol and beta-carotene were 50 mg and 20 mg, respectively. Median follow-up was 6.1 years (based on a total of 169,751 man-years). Mean patient age was 57.2 years. Cancers in participants were identified through the Finnish Cancer Registry. In their 1994 report,14 the ATBC study authors concluded that 5 to 8 years of dietary supplementation with alpha-tocopherol produced no reduction and with beta-carotene produced a statistically significant increase in lung cancer incidence in male smokers. A secondary analysis revealed that there were substantially fewer prostate cancers in participants who were randomized to receive alpha-tocopherol (99 prostate cancers) than in those who were not randomized to receive alpha-tocopherol (151 prostate cancers). These results translate into an incidence of 11.7 cases per 10,000 person-years (with alpha- tocopherol) versus an incidence of 17.8 cases per 10,000 person-years (without alpha-tocopherol). Recognizing that the data from the ATBC study may only apply to smokers, another study analyzed self reported vitamin E use in smokers and nonsmokers in the Health Professionals Follow-up Study.28 While in smokers and men who had quit smoking the risk of metastatic or fatal prostate cancer was lower among men who consumed at least 100 IU of vitamin E daily, no difference in prostate cancer was seen in nonsmokers. Two clinical trials conducted in Linxian, China 29,30, also tested alpha- tocopherol, along with selenium (discussed below) and various other agents, in humans. The Linxian general population trial involved approximately 30,000 subjects and had a very complicated factorial design involving various combinations of vitamins and minerals primarily to reduce the incidence and/or mortality of all cancers (not necessarily prostate cancer). Although the trial was not positive in respect to its primary objectives, secondary analyses indicated that one combination, which included selenium (50 ug/day in a yeast supplement), alpha-tocopherol (30 mg/day), and beta-carotene (15 mg/day), was associated with a statistically significantly lower total mortality rate, a statistically nonsignificant 13% reduction in the all-cancer mortality rate, and a statistically significantly lower gastric cancer (cardia plus noncardia) mortality rate (a major cancer in Linxian). A second, far smaller Linxian trial (in approximately 3,300 subjects) tested a combination of these 3 agents along with several additional vitamins and minerals (versus placebo) in preventing esophageal/gastric cardia cancer in patients with esophageal dysplasia. The treatment arm did not reduce the cancer risk, and a statistically nonsignificant 18% increase in overall gastric (cardia and noncardia) cancer mortality occurred. Prostate cancer mortality was not reported. It is difficult to compare results of the 2 Linxian trials, however, because the trials differed in scale, subject characteristics, and study agents (additional agents in the latter trial may have affected the activity of selenium, alpha-tocopherol, and beta-carotene indicated in the former trial). It also is difficult to know how either trial would apply to the United States, with a very different (generally far lower) risk in the general population.

Chemoprevention With Selenium
Selenium is an essential trace element in humans and in other species.31-33 A substantial volume of data suggest that supplementation with selenium reduces the risk of a variety of cancers in chemically-induced cancers 34-52, in spontaneous animal tumors 53, and in transplanted animal tumor lines.54 Studies of geographical areas with varying dietary selenium content have demonstrated an inverse relationship between selenium intake and cancer risk.55,56 Similarly, in a study of environmental selenium levels (forage crop concentrations of selenium), an inverse relationship was again noted.57 Epidemiologic studies have had mixed results with statistically significant (again, inverse) relationships encountered in some studies 58-73 while others have not encountered a statistically-higher risk in patients with low selenium levels or a low selenium intake.74-82 In a case-control study, serum samples collected in 1973 from 111 subjects who developed cancer during the subsequent 5 years were studied and compared with serum samples from 210 cancer-free subjects matched for age, race, sex, and smoking history.60 Subjects were obtained from a cohort of 10,940 men enrolled in the Hypertension Detection Follow-up Programme. Mean serum selenium level was lower in cancer cases (0.129 +/- SEM 0.002 ug/ml) than in controls (0.126 +/- 0.002 ug/ml). The association between low selenium level and cancer was strongest for gastrointestinal and prostate cancer. The mechanism of action of selenium is not clear, but there are a number of hypotheses. In cell culture, it reduces the effect of a number of described mutagens 83-87 and may alter the metabolism of other carcinogens.88-92 A variety of other potential actions which have been suggested include effects on the immune and endocrine systems, production of cytotoxic selenium metabolites, initiation of apoptosis, inhibition of protein synthesis, protection against the action of free radicals and oxidative damage through the action of selenium as an antioxidant as it is incorporated into glutathione peroxidase, as well as inhibition of specific enzymes.25,93-96 A multi-institutional study designed to prevent skin cancer randomized a group of 1,312 patients with a history of basal cell or squamous cell carcinoma of the skin to either 200 ug selenium per day (as selenized yeast) or placebo (nonselenized yeast).97 Although the study began in 1983, additional funding subsequently allowed the ascertainment of rates of other cancers in the 2 study groups. Baseline serum PSA levels in both arms were also evaluated. This evaluation indicated that 12.4% of the selenium and 10.2% of the placebo group had prestudy serum PSAs greater than 4.0 ng/ml. After enrollment, plasma selenium concentrations increased by approximately 67% in the selenium-treated patients. After an average follow-up of 6.4 years, cancer incidence rates were tabulated for both groups. The table below lists the various tumors studied, numbers of tumors in the 2 study arms, hazard ratio, and p values, which were derived from the Cox proportional hazard model, adjusted for age, sex, and smoking status at randomization. Selenium-treated patients experienced only about one third as many prostate tumors as did patients receiving placebo. It is important to note that no patient experienced toxicity due to selenosis, a side effect that has been reported in association with chronic feeding of inorganic and certain organic forms of selenium at levels above 5 ppm.98

Cancer Site	Selenium	Placebo	Hazard Ratio	p value
Lung	17	31	56	05
Prostate	13	35	.35	.001
Colorectal	8	19	.39	.03
Head/neck	6	8	.77	.64
Bladder	8	6	1.27	.66
Esophageal	2	6	.30	.14
Breast	9	3	2.95	.11
Other carcinoma	5	9	.54	.27
Total carcinoma	59	104	.54	<.001
Melanoma	8	8	.92	.87
Leukemia	8	5	1.50	.48
Other noncarcinoma	3	3	.99	.99
Total noncarcinomas	19	16	1.16	.65

Total cancers

119

.61

<.001

Chemoprevention With Lycopene
Evidence exists that a diet with a high intake of fruits and vegetables is associated with a lower risk of cancer. Which, if any, micronutrients may account for this reduction is unknown. One group of nutrients often postulated as having chemoprevention properties is the carotenoids. Lycopene is the predominant circulating carotenoid in Americans and has a number of potential activities including an antioxidant effect.99 It is encountered in a number of vegetables, most notably tomatoes, and is best absorbed if these products are cooked and in the presence of dietary fats or oils. The earliest studies of the association of lycopene and prostate cancer risk were generally negative before 1995 with only one study of 180 case subjects showing a reduced risk.100-103 In 1995, an analysis of the Physicians' Health Study found a one-third reduction in prostate cancer risk in the group of men with the highest consumption of tomato products compared to the group with the lowest level of consumption, which they attributed to the lycopene content of these vegetables.104 This large analysis prompted several subsequent studies, the results of which were mixed.105,106 A review of the published data concluded that the evidence is weak that lycopene is associated with a reduced risk because previous studies were not controlled for total vegetable intake (i.e., separating the effect of tomatoes from vegetables in general), dietary intake instruments are poorly able to quantify lycopene intake, and other potential biases.107 Specific dietary supplementation with lycopene remains to be demonstrated to reduce prostate cancer risk.

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22. Sigounas G, Anagnostou A, Steiner M: dl-alpha-tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells. Nutrition and Cancer 28(1): 30-35, 1997.

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Neurologic Complications of Prostate Cancer

RAMSIS BENJAMIN, M.D., M.P.H., Keck School of Medicine of the University of Southern California, Los Angeles, California

Neurologic complications continue to pose problems in patients with metastatic prostate cancer. From 15 to 30 percent of metastases are the result of prostate cancer cells traveling through Batson's plexus to the lumbar spine. Metastatic disease in the lumbar area can cause spinal cord compression. Metastasis to the dura and adjacent parenchyma occurs in 1 to 2 percent of patients with metastatic prostate cancer and is more common in those with tumors that do not respond to hormone-deprivation therapy. Leptomeningeal carcinomatosis, the most frequent form of brain metastasis in prostate cancer, has a grim prognosis. Because neurologic complications of metastatic prostate cancer require prompt treatment, early recognition is important. Physicians should consider metastasis in the differential diagnosis of new-onset low back pain or headache in men more than 50 years of age. Spinal cord compression requires immediate treatment with intravenously administered corticosteroids and pain relievers, as well as prompt referral to an oncologist for further treatment.

Prostate cancer is second only to lung cancer as the leading cause of cancer-related deaths in men.1 Histologic evidence of prostate adenocarcinoma is present in 30 percent of men more than 50 years of age and in 70 percent of men more than 80 years old. About 9.5 percent of men will have a clinical diagnosis of prostate cancer in their lifetime, and 2.9 percent will succumb to this malignancy.2,3
Although most men with prostate cancer have asymptomatic, indolent disease, central nervous system (CNS) complications often occur with advanced metastatic disease4,5 (Table 1).4-6 CNS involvement may present as back pain caused by spinal cord compression resulting from bone metastasis via the paravertebral venous plexus or, less commonly, as headache or neurologic changes caused by the hematogenous spread of prostate cancer to the brain. Paraneoplastic syndromes, including neuropathies (sensory, peroneal, etc.), cerebellar ataxia, and limbic and brain-stem encephalitides, may also occur; discussion of these rare complications is beyond the scope of this article.7,8

TABLE 1 More Common Neurologic Complications in Patients with Metastatic Prostate Cancer*

Complication (incidence, %)	Clinical clues (incidence, %)	Treatment options
Spinal cord compression caused by metastasis (7)	Localized back pain (90 to 95) Weakness (75 to 80)Autonomic dysfunction (57)Sensory changes (50)	Dexamethasone sodium phosphate (Decadron): 16 to 100 mg administered as an intravenous bolus; then 4 mg given intravenously four times dailyfor 3 days; tapered over about 14 days Morphine, hydromorphone (Dilaudid), fentanyl (Duragesic), or oxycodone (Roxicodone) for pain management Oncology referral
Brain metastasis (1 to 2)	No symptoms (?) Headaches (34) Motor deficits (26) Altered mental status (23)Seizures (8)	Dexamethasone, as above, if magnetic resonance image shows edema Anticonvulsants (not as prophylaxis, and not phenytoin [Dilantin] if radiotherapyis anticipated, because of the risk of Stevens-Johnson syndrome withconcomitant treatment) Oncology referral

? = unknown. *--The rarer neurologic complications include paraneoplastic syndromes such as peroneal neuropathy (peroneal nerve palsy related to local metastasis), cerebellar ataxia, limbic encephalitis and brain-stem encephalitis. Information from references 4, 5, and 6.

Lesions in the brain and spinal cord require prompt treatment. Hence, family physicians need to consider metastatic prostate cancer in the differential diagnosis of new-onset back pain or headache in men more than 50 years of age.

Anatomy and Metastasis of Prostate Cancer
The pudendal nerve innervates the few striated muscles within the prostatic capsule. The parasympathetic nerves emanate from S2 to S4 and form the pelvic nerve. The sympathetic preganglionic nerves, which reside in the thoracolumbar region between T6 and L2, provide the major neural input to the prostate and reach the pelvis through the hypogastric nerve .
Prostate cancer has been shown to metastasize by following the venous drainage system through the lower paravertebral plexus, or Batson's plexus.4,9 Although hematogenous spread of other malignancies is most commonly to the lungs and liver, 90 percent of prostatic metastases involve the spine, with the lumbar spine affected three times more often than the cervical spine. Prostate cancer also spreads to the lungs in about 50 percent of patients with metastatic disease, and to the liver in about 25 percent of those with metastases.4
Epidural metastases are the result of contiguous spread from lesions of the calvaria to the meninges. Because of the protective layer of the dura mater, subdural and intraparenchymal metastases from prostate cancer are rare .

Spinal Metastasis
Sites of spinal metastases from prostate cancer are illustrated in Figure 3. Metastases that lead to spinal cord compression are usually located in the vertebral column (85 percent of cases) or the paravertebral space (10 to 15 percent of cases).10

SYMPTOMS
The symptoms of spinal cord compression include progressive radicular pain that is aggravated by movement. This pain can be confused with the pain caused by an osteodegenerative process of the spine. However, reclining does not alleviate back pain in patients with spinal cord compression resulting from metastatic prostate cancer. Back pain is present in nearly all patients with prostate cancer that has metastasized to the spine. Percussion over the involved vertebral body may evoke tenderness.
Muscle weakness evolves over a few days to weeks after the initial pain. Weakness usually affects the proximal muscles of the lower extremities and may or may not involve sensory loss. Autonomic dysfunction can cause urinary retention or, less frequently, bladder or bowel incontinence.

DIAGNOSIS
In 85 to 90 percent of patients with epidural cord compression, plain-film radiographs of the spine detect abnormalities such as collapse or erosion of the vertebral body or pedicle, but these findings are not specific.10 If spinal cord compression is suspected, magnetic resonance imaging (MRI) should be performed on an emergency basis. If MRI is not available, computed tomographic (CT) myelography can be used. Neuroimaging of the entire spine is necessary because epidural tumors may develop at different levels of the spine.11
Cerebrospinal fluid (CSF) examination is not very helpful and is rarely required for the diagnosis of spinal cord compression if MRI is available. CSF examination has a high false-negative rate for the detection of malignant cells.
The serum prostate-specific antigen (PSA) level is highly predictive of bone metastasis. If the serum PSA level is above 100 ng per mL, the positive predictive value is 74 percent. If the serum PSA level is less than 10 ng per mL, the negative predictive value is 98 percent.12 The CSF PSA level may prove useful for identifying intradural metastasis of prostate cancer in patients with an as yet unestablished primary tumor or with multiple malignancies. The medical literature contains a report of a 79-year-old man with lumbosacral pain who repeatedly had normal serum PSA levels and neuroimaging studies, but a CSF PSA level that was elevated to 29 ng per mL; MRI studies ultimately detected spinal metastasis from prostate cancer.13

TREATMENT
Treatment should be initiated as soon as spinal cord compression is diagnosed. With prompt treatment, there is an 89 to 100 percent likelihood of preserved ambulation in patients who present without walking difficulties. The likelihood of subsequent ambulatory function drops to 39 to 83 percent in patients who present with impaired ambulation, and to 10 to 20 percent in those who present with paralysis.14,15
Treatment involves reducing or alleviating pain as well as maintaining overall neurologic function. By using a combination of pharmaceutical and nonpharmaceutical modalities, physicians can achieve pain control in 85 to 95 percent of patients.16 Opioid medication is the mainstay of therapy for patients with severe, debilitating pain. Regimens using morphine, hydromorphone (Dilaudid), fentanyl (Duragesic), and oxycodone (Roxicodone) should follow the analgesic "ladder" developed by the World Health Organization, with rescue doses of an opioid available to manage breakthrough pain.16,17
Intravenously administered corticosteroids help to decrease cord edema and pain, retain motor function, and improve outcome after treatment. In one placebo-controlled study,18 corticosteroids improved ambulatory function from 63 percent to 81 percent in patients with high-grade radiologic lesions. After six months, 59 percent of the steroid-treated patients still ambulated, compared with 33 percent of placebo-treated patients; however, median survival remained equal. Nonetheless, dexamethasone sodium phosphate (Decadron) is the treatment of choice in patients with spinal cord compression caused by metastatic prostate cancer.
The dosing of dexamethasone is somewhat controversial. Depending on the severity of the lesion, investigators have recommended an intravenous bolus dose (loading dose) ranging from 16 to 100 mg, followed by 4 to 24 mg given intravenously four times daily for three days; tapering is accomplished by reducing the dosage by one third every three days during radiotherapy.19 High-dose dexamethasone therapy with a bolus dose of 96 to 100 mg has side effects that outweigh the benefits over use of a 16-mg loading dose with a 14-day taper.20,21 Furthermore, the 16-mg regimen does not have a significant difference in the number of patients having pain, bladder dysfunction, or inability to walk.20,21
Surgical decompression is usually reserved for patients with a solitary spinal lesion (which is seldom the situation in metastatic prostate cancer). In hormone-naïve patients, corticosteroids and androgen ablation therapy are given priority, followed by radiotherapy in patients who become refractory to corticosteroids and hormone-deprivation therapy. At this juncture, a medical oncologist should be involved.

The treatment of spinal cord compression generally improves motor strength and function in patients with metastatic prostate cancer. However, there is a 45 percent risk of another episode of compression at the same site or a new site within two years.11

Brain Metastasis
Brain metastasis is rare in prostate cancer and occurs late in the course of the disease. It usually represents the failure of hormone-deprivation therapy and the presence of disseminated disease.
Data collected before the importance of PSA values was recognized indicate that the average time from the diagnosis of prostate cancer to the occurrence of metastasis is 19 months for bone metastasis, 35 months for lung metastasis, and 60 months for brain metastasis.22,23 The long time between diagnosis and brain involvement strongly favors the cascade theory of tumor spread. Metastasis to the brain can occur by way of Batson's plexus or by direct extension from adjacent structures such as the sphenoid bone or sinuses.24
The most common intracranial sites of prostate cancer metastasis are the leptomeninges (67 percent), cerebrum (25 percent), and cerebellum (8 percent).22 Other primary cancers, such as lung and breast tumors, are more likely to have intraparenchymal metastases than leptomeningeal involvement.

SYMPTOMS
Patients rarely present with neurologic symptoms as the first manifestation of prostate cancer. Presentation with a solitary brain metastasis as the only site of prostate cancer spread is even more rare. Leptomeningeal metastasis (or carcinomatosis) is usually clinically silent, although it can present with deficits in multiple anatomic sites.25

DIAGNOSIS
No test other than gadolinium-enhanced MRI is required to exclude or confirm the presence of brain metastases. Compared with CT scanning, MRI is more sensitive in detecting multiple metastases, especially at the gray-white junction.26

TREATMENT
Unless seizures occur, the use of prophylactic anticonvulsants, particularly phenytoin (Dilantin), is not encouraged.27,28 In combination with radiotherapy, phenytoin may cause Stevens-Johnson syndrome (erythema multiforme major).28 Dexamethasone therapy should be started early, and referral to an oncologist is warranted.
A two-week course of radiotherapy is the most common treatment for patients with multiple brain metastases or leptomeningeal involvement. Surgical removal of a solitary lesion usually extends survival.29
Various stereotactic radiosurgical techniques, including the proton beam, gamma knife, linear accelerator (LINAC) X-knife and multileaf collimators with intensity modulators, are becoming more widely available. Because these modalities provide a precise beam of radiation, damage to surrounding normal tissue is limited.30
Brain metastasis is associated with a poor prognosis. Once prostate cancer has spread to the brain, the one-year survival rate is 18 percent, with an average survival of 7.6 months.6,29

The Author
RAMSIS BENJAMIN, M.D., M.P.H., is currently a neuro-oncology fellow at Massachusetts General Hospital, Boston. He received his medical degree from Rush Medical College of Rush University, Chicago, and earned a master of public health degree from Johns Hopkins University School of Hygiene and Public Health, Baltimore, where he was an affiliate of the preventive medicine residency program at Johns Hopkins University School of Medicine. Dr. Benjamin recently completed a neurology residency at the Keck School of Medicine of the University of Southern California, Los Angeles.

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