Purpose of This PDQ Summary
Summary of Evidence

Benefits from Finasteride Chemoprevention Harms from Finasteride Chemoprevention Benefits and Harms of Other Prevention Interventions

Significance

Incidence and Mortality

Risk Factors for Prostate Cancer Development

Age Family History Hormones Race Dietary Fat Dairy and Calcium Intake Multivitamin Use Cadmium Exposure Dioxin Exposure

Opportunities for Prevention

Hormonal Prevention Dietary Prevention With Fruit, Vegetables, and a Low-Fat Diet Chemoprevention         Chemoprevention with vitamin E (alpha-tocopherol)         Chemoprevention with selenium         Chemoprevention with lycopene

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Purpose of This PDQ Summary

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

Information about the following is included in this summary:

• Prostate cancer incidence and mortality statistics and information about prostate cancer risk factors.
• Interventions for prostate cancer prevention.
• Benefits and harms of interventions to prevent prostate cancer.

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

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

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Summary of Evidence

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

Based on solid evidence, chemoprevention with finasteride reduces the incidence of prostate cancer, but the evidence is inadequate to determine whether chemoprevention with finasteride reduces mortality from prostate cancer.

Description of the Evidence

• Study Design: Evidence obtained from randomized controlled trials.
• Internal Validity: Good for the outcome of incidence, poor for the outcome of mortality.
• Consistency: Not applicable.
• Direction and Magnitude of Effect: Absolute reduction in incidence over 7 years was 6% (24.4% with placebo and 18.4% with finasteride); relative risk reduction for incidence was 24.8% (95% confidence interval [CI], 18.6%–30.6%). There was no difference in the number of men dying from prostate cancer in the two groups, though the number of deaths was small.
• External Validity: Fair, because of small numbers of African American and Hispanic men.

Men in the finasteride group had statistically significantly more erectile dysfunction, loss of libido, and gynecomastia than men in the placebo group. Men in the finasteride group had a statistically significant incidence of high-grade (Gleason sum 8–10) cancers during the study.[1] Whether this was a histological artifact or not is uncertain.

Description of the Evidence

• Study Design: Evidence obtained from randomized controlled trials.
• Internal Validity: A randomized controlled trial of finasteride for the prevention of prostate cancer used an interview (rather than a patient-completed questionnaire) to examine erectile dysfunction and libido during treatment (rather than both before and during treatment).
• Consistency: Good (evidence other than the randomized controlled trial supports these effects).
• Direction and Magnitude of Effect: Statistically significant increases in the following outcomes were observed in the finasteride group (an additional 9% of men in the finasteride group discontinued therapy at least temporarily because of one of these side effects):
  • Percentage in finasteride group versus percentage in placebo group:
    • Reduced volume of ejaculate (60.4% vs. 47.3%).
    • Erectile dysfunction (67.4% vs. 61.5%).
    • Loss of libido (65.4% vs. 59.6%).
    • Gynecomastia (4.5% vs. 2.8%).
• External Validity: Fair, because of small numbers of African American and Hispanic men.

There is inadequate evidence to determine whether the prevention strategies of dietary change (i.e., reducing dietary fat or increasing fruits and vegetables), or vitamin E (alpha-tocopherol), selenium, or lycopene supplementation, are effective in reducing prostate cancer incidence or mortality.

Description of the Evidence

• Study Design for Vitamin E and Selenium: Evidence obtained from randomized controlled trials, in this case secondary endpoints from randomized trials.
• Study Designs for the Other Interventions: Evidence obtained from cohort or case-control studies. Evidence obtained from ecologic and descriptive studies (e.g., international patterns studies, time series).
• Internal Validity: Fair.
• Consistency: Poor.
• Direction and Magnitude of Effect: Uncertain.
• External Validity: Fair.

References

1. Thompson IM, Goodman PJ, Tangen CM, et al.: The influence of finasteride on the development of prostate cancer. N Engl J Med 349 (3): 215-24, 2003.  [PUBMED Abstract]
   
   

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Significance

Incidence and Mortality

Carcinoma of the prostate is the most common tumor in men in the United States, with an estimated 186,320 new cases and 28,660 deaths expected in 2008.[1] A wide range of estimates of the impact of the disease are notable. The disease is histologically evident in as many as 34% of men in their fifth decade and in up to 70% of men aged 80 years and older.[2,3] Prostate cancer will be diagnosed in almost one fifth of U.S. men during their lifetime, yet only 3% of men will be expected to die of the disease.[4] The estimated reduction in life expectancy of men who die of prostate cancer is approximately 9 years.[5]

The extraordinarily high rate of clinically occult prostate cancer in the general population compared with the 20-fold lower likelihood of death from the disease indicates that many of these cancers have low biologic risk. Concordant with this observation are the many series of patients with prostate cancer managed by surveillance alone with relatively good survival rates at 5 and 10 years of follow-up.[6] Data demonstrate, however, that with prolonged 10-year follow-up of moderately differentiated (which constitute the majority of tumors detected [7]) and poorly differentiated tumors, there is a substantial risk of disease progression and death from prostate cancer.[8]

Because of marked variability in tumor differentiation from one microscopic field to another, many pathologists will report the range of differentiation among the malignant cells that are present in a biopsy using the Gleason grading system. This grading system includes five histologic patterns distinguished by the glandular architecture of the cancer. The architectural patterns are identified and assigned a grade from 1 to 5 with 1 being the most differentiated and 5 being the least differentiated. The sum of the grades of the predominant and next most prevalent will range from 2 (well-differentiated tumors) to 10 (undifferentiated tumors).[9,10] Systematic changes to the histological interpretation of biopsy specimens by anatomical pathologists have occurred during the prostate-specific antigen (PSA) screening era (i.e., since about 1985) in the United States.[11] This phenomenon, sometimes called “grade inflation,” is the apparent increase in the distribution of high-grade tumors in the population over time but in the absence of a true biological or clinical change. It is possibly the result of an increasing tendency for pathologists to read tumor grade as more aggressive, resulting in a higher preponderance to treat these cancers aggressively.[12]

Treatment options available for prostate cancer include radical prostatectomy, external-beam radiation therapy, brachytherapy, cryotherapy, androgen deprivation with luteinizing hormone-releasing hormone analogs and/or antiandrogens, intermittent androgen deprivation, cytotoxic agents, and surveillance. Of all the means of management, only radical prostatectomy has been found to be superior to surveillance in men with localized prostate cancer in terms of reduced rates of metastases (relative hazard = 0.63; 95% CI, 0.41–0.96) and disease specific (relative hazard = 0.5; 95% CI, 0.27–0.91) and overall mortalities.[13] However, the relative efficacy of radical prostatectomy to the other forms of treatment has not been adequately addressed.[14] Confounding issues in the treatment of prostate cancer include side effects with treatment, inability to predict the natural history of a given cancer, patient comorbidity that may affect an individual’s likelihood of surviving long enough to be at risk for disease morbidity and mortality, and an increasing body of evidence suggesting that careful PSA monitoring following treatment may indicate a substantial fraction of treatment failures.[15]

Because of considerable uncertainty regarding the efficacy of treatment and the difficulty with selecting patients for whom there is a known risk of disease progression, opinion in the medical community is divided regarding screening for carcinoma of the prostate. While both digital rectal examination and PSA screening have demonstrated reasonable performance characteristics (sensitivity, specificity, and positive predictive value) for the early detection of prostate cancer, the lack of evidence that screening and treatment affects ultimate population morbidity or mortality has led many organizations to eschew screening.

The tremendous impact of prostate cancer on the U.S. population, as well as the financial burden of the disease both for patients and society, has led to an increased interest in primary disease prevention.

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. Last accessed October 1, 2008. 
   
   
2. Sakr WA, Haas GP, Cassin BF, et al.: The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 150 (2 Pt 1): 379-85, 1993.  [PUBMED Abstract]
   
   
3. Hølund B: Latent prostatic cancer in a consecutive autopsy series. Scand J Urol Nephrol 14 (1): 29-35, 1980.  [PUBMED Abstract]
   
   
4. Ries LAG, Harkins D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2003. Bethesda, Md: National Cancer Institute, 2006. Also available online. Last accessed October 07, 2008. 
   
   
5. Horm JW, Sondik EJ: Person-years of life lost due to cancer in the United States, 1970 and 1984. Am J Public Health 79 (11): 1490-3, 1989.  [PUBMED Abstract]
   
   
6. Whitmore WF Jr, Warner JA, Thompson IM Jr: Expectant management of localized prostatic cancer. Cancer 67 (4): 1091-6, 1991.  [PUBMED Abstract]
   
   
7. Orozco R, O'Dowd G, Kunnel B, et al.: Observations on pathology trends in 62,537 prostate biopsies obtained from urology private practices in the United States. Urology 51 (2): 186-95, 1998.  [PUBMED Abstract]
   
   
8. D'Amico AV, Moul J, Carroll PR, et al.: Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol 21 (11): 2163-72, 2003.  [PUBMED Abstract]
   
   
9. Gleason DF, Mellinger GT: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 111 (1): 58-64, 1974.  [PUBMED Abstract]
   
   
10. Gleason DF: Histologic grading and clinical staging of prostatic carcinoma. In: Tannenbaum M: Urologic Pathology: The Prostate. Philadelphia, Pa: Lea and Febiger, 1977, pp 171-197. 
    
    
11. Albertsen PC, Hanley JA, Barrows GH, et al.: Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 97 (17): 1248-53, 2005.  [PUBMED Abstract]
    
    
12. Thompson IM, Canby-Hagino E, Lucia MS: Stage migration and grade inflation in prostate cancer: Will Rogers meets Garrison Keillor. J Natl Cancer Inst 97 (17): 1236-7, 2005.  [PUBMED Abstract]
    
    
13. Holmberg L, Bill-Axelson A, Helgesen F, et al.: A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 347 (11): 781-9, 2002.  [PUBMED Abstract]
    
    
14. Middleton RG, Thompson IM, Austenfeld MS, et al.: Prostate Cancer Clinical Guidelines Panel Summary report on the management of clinically localized prostate cancer. The American Urological Association. J Urol 154 (6): 2144-8, 1995.  [PUBMED Abstract]
    
    
15. Moul JW: Prostate specific antigen only progression of prostate cancer. J Urol 163 (6): 1632-42, 2000.  [PUBMED Abstract]
    
    

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Risk Factors for Prostate Cancer Development

Age

Prostate cancer incidence increases dramatically with increasing age. Although it is a very unusual disease in men younger than 50 years, rates increase exponentially thereafter. The registration rate by age cohort in England and Wales increased from eight per thousand population in men aged 50 to 56 years to 68 per thousand in men aged 60 to 64 years, 260 per thousand in men aged 70 to 74 years, and peaked at 406 per thousand in men aged 75 to 79 years.[1] In this same population, the death rate per thousand in 1992 in cohorts of men aged 50 to 54 years, 60 to 64 years, and 70 to 74 years was 4, 37, and 166, respectively.[1] At all ages, incidence of prostate cancer in blacks exceeds those of whites.[2]

Approximately 15% of men with a diagnosis of prostate cancer will be found to have a first-degree male relative (e.g., brother, father) with prostate cancer, compared with approximately 8% of the U.S. population.[3] Approximately 9% of all prostate cancers may result from heritable susceptibility genes.[4] Several authors have completed segregation analyses, and though 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.[5-7]

The development of the prostate is dependent upon the secretion of dihydrotestosterone (DHT) 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 DHT. DHT has a 4-fold 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 because of 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) level 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 the following:

1. Neither BPH nor prostate cancer have been reported in men castrated prior to puberty.[9]



2. Androgen deprivation in almost all forms leads to involution of the prostate, a fall in PSA levels, apoptosis of prostate cancer and epithelial cells, and a clinical response in prostate cancer patients.[10,11]

Ecological studies have found a correlation between serum levels of testosterone, especially DHT, and overall risk of prostate cancer among African American, white, and Japanese males.[12-14] However, evidence from prospective studies of the association between serum concentrations of sex hormones, including androgens and estrogens, does not support a direct link.[15] A collaborative analysis of 18 prospective studies, pooling prediagnostic measures on 3,886 men with incident prostate cancer and 6,438 control subjects, found no association between the risk of prostate cancer and serum concentrations of testosterone, calculated-free testosterone, dihydrotestosterone sulfate, androstenedione, androstanediol glucuronide, estradiol, or calculated-free estradiol.[15] A caution for interpreting the data is the unknown degree of correlation between serum levels and prostate tissue level. Androstanediol glucuronide may most closely reflect intraprostatic androgen activity and this measure was not associated with the risk of prostate cancer. This lack of association affirms that risk stratification cannot be made on serum hormone concentrations.

The risk of developing and dying from prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese. [16,17] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to health care may play a role in disease outcomes.[18]

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.[19] 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.[20,21] 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.[22,23] Animal models of explanted human prostate cancer have demonstrated decreased tumor growth rates in animals who are fed a low-fat diet.[24,25] Evidence from many case-control studies has found an association between dietary fat and prostate cancer risk,[26-28] though studies have not uniformly reached this conclusion.[29-31] 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.[32] Among case-control studies, 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 three studies reported 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.[18,33] 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.[34] The announcement in 1996 that cancer mortality rates had fallen in the United States prompted the suggestion that this may be caused by decreases in dietary fat intake over the same time period.[35,36]

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 intake change urinary and serum levels of androgens.[37,38]



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.[39]



3. An observation made in an animal model is that male offspring of pregnant rats who are fed a high-fat diet will develop prostate cancer at a higher rate than animals who are fed a low-fat diet.[40] This observation may explain some of the variations in prostate cancer incidence and mortality among ethnic groups; an observation has been made that first trimester androgen levels in pregnant blacks are higher than those in whites.[41]

In a meta-analysis of ten cohort studies (eight from the United States and two from Europe), it was concluded that men with the highest intake of dairy products (relative risk [RR] = 1.11; 95% confidence interval [CI], 1.00–1.22; P = .04) and calcium (RR = 1.39; 95% CI, 1.09–1.77; P = .18) were more likely to develop prostate cancer than men with the lowest intake. The pooled RRs of advanced prostate cancer were 1.33 (95% CI, 1.00–1.78; P = .055) for the highest versus lowest intake categories of dairy products and 1.46 (95% CI, 0.65–3.25; P > .2) for the highest versus lowest intake categories of calcium. High intake of dairy products and calcium may be associated with an increased risk of prostate cancer although the increase may be small.[42]

Regular multivitamin use has not been associated with the risk of early or localized prostate cancer.[43]

Cadmium exposure is occupationally associated with nickel-cadmium batteries and cadmium recovery plant smelters and is associated with cigarette smoke.[44] The earliest studies of this agent documented an apparent association, but better-designed studies have failed to note an association.[45,46]

Dioxin (2,3,7,8 tetrachlorodibenzo-p-dioxin or TCDD) is a contaminant of an herbicide used in Vietnam. This agent is similar to many components of herbicides used in farming. A 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, found only two articles on prostate cancer with sufficient numbers of cases and follow-up to allow analysis.[47,48] The analysis of all available data suggests that the association between dioxin exposure and prostate cancer is not conclusive.[49]

References

1. Epidemiological aspects. In: Kirby RS, Christmas TJ, Brawer MK: Prostate Cancer. London, England: Mosby, 1996, pp 23-32. 
   
   
2. Cancer incidence in the United States (SEER) age-specific rates. In: Harras A, Edwards BK, Blot WJ, eds.: Cancer Rates and Risks. 4th ed. Bethesda, Md: National Cancer Institute, 1996, pp 22. 
   
   
3. Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. Prostate 17 (4): 337-47, 1990.  [PUBMED Abstract]
   
   
4. Grönberg H, Isaacs SD, Smith JR, et al.: Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAMA 278 (15): 1251-5, 1997.  [PUBMED Abstract]
   
   
5. Carter BS, Steinberg GD, Beaty TH, et al.: Familial risk factors for prostate cancer. Cancer Surv 11: 5-13, 1991.  [PUBMED Abstract]
   
   
6. Schaid DJ, McDonnell SK, Blute ML, et al.: Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62 (6): 1425-38, 1998.  [PUBMED Abstract]
   
   
7. Bauer JJ, Srivastava S, Connelly RR, et al.: Significance of familial history of prostate cancer to traditional prognostic variables, genetic biomarkers, and recurrence after radical prostatectomy. Urology 51 (6): 970-6, 1998.  [PUBMED Abstract]
   
   
8. Imperato-McGinley J, Gautier T, Zirinsky K, et al.: Prostate visualization studies in males homozygous and heterozygous for 5 alpha-reductase deficiency. J Clin Endocrinol Metab 75 (4): 1022-6, 1992.  [PUBMED Abstract]
   
   
9. Isaacs JT: Hormonal balance and the risk of prostatic cancer. J Cell Biochem Suppl 16H: 107-8, 1992.  [PUBMED Abstract]
   
   
10. Peters CA, Walsh PC: The effect of nafarelin acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatic hyperplasia. N Engl J Med 317 (10): 599-604, 1987.  [PUBMED Abstract]
    
    
11. Kyprianou N, Isaacs JT: Expression of transforming growth factor-beta in the rat ventral prostate during castration-induced programmed cell death. Mol Endocrinol 3 (10): 1515-22, 1989.  [PUBMED Abstract]
    
    
12. Ellis L, Nyborg H: Racial/ethnic variations in male testosterone levels: a probable contributor to group differences in health. Steroids 57 (2): 72-5, 1992.  [PUBMED Abstract]
    
    
13. 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): 887-9, 1992.  [PUBMED Abstract]
    
    
14. 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 Epidemiol Biomarkers Prev 4 (7): 735-41, 1995 Oct-Nov.  [PUBMED Abstract]
    
    
15. Roddam AW, Allen NE, Appleby P, et al.: Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 100 (3): 170-83, 2008.  [PUBMED Abstract]
    
    
16. Ries LAG, Eisner MP, Kosary CL, et al., eds.: SEER Cancer Statistics Review, 1975-2002. Bethesda, Md: National Cancer Institute, 2005. Also available online. Last accessed February 12, 2009. 
    
    
17. Bunker CH, Patrick AL, Konety BR, et al.: High prevalence of screening-detected prostate cancer among Afro-Caribbeans: the Tobago Prostate Cancer Survey. Cancer Epidemiol Biomarkers Prev 11 (8): 726-9, 2002.  [PUBMED Abstract]
    
    
18. 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 274 (20): 1599-605, 1995 Nov 22-29.  [PUBMED Abstract]
    
    
19. Wynder EL, Mabuchi K, Whitmore WF Jr: Epidemiology of cancer of the prostate. Cancer 28 (2): 344-60, 1971.  [PUBMED Abstract]
    
    
20. Armstrong B, Doll R: Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer 15 (4): 617-31, 1975.  [PUBMED Abstract]
    
    
21. Rose DP, Connolly JM: Dietary fat, fatty acids and prostate cancer. Lipids 27 (10): 798-803, 1992.  [PUBMED Abstract]
    
    
22. Haenszel W, Kurihara M: Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States. J Natl Cancer Inst 40 (1): 43-68, 1968.  [PUBMED Abstract]
    
    
23. Shimizu H, Ross RK, Bernstein L, et al.: Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer 63 (6): 963-6, 1991.  [PUBMED Abstract]
    
    
24. Wang Y, Corr JG, Thaler HT, et al.: Decreased growth of established human prostate LNCaP tumors in nude mice fed a low-fat diet. J Natl Cancer Inst 87 (19): 1456-62, 1995.  [PUBMED Abstract]
    
    
25. Connolly JM, Coleman M, Rose DP: Effects of dietary fatty acids on DU145 human prostate cancer cell growth in athymic nude mice. Nutr Cancer 29 (2): 114-9, 1997.  [PUBMED Abstract]
    
    
26. Ross RK, Shimizu H, Paganini-Hill A, et al.: Case-control studies of prostate cancer in blacks and whites in southern California. J Natl Cancer Inst 78 (5): 869-74, 1987.  [PUBMED Abstract]
    
    
27. Kolonel LN, Yoshizawa CN, Hankin JH: Diet and prostatic cancer: a case-control study in Hawaii. Am J Epidemiol 127 (5): 999-1012, 1988.  [PUBMED Abstract]
    
    
28. 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. J Natl Cancer Inst 87 (9): 652-61, 1995.  [PUBMED Abstract]
    
    
29. Giovannucci E: Epidemiologic characteristics of prostate cancer. Cancer 75 (Suppl 7): 1766-1777, 1995. 
    
    
30. 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): 605-12, 1989.  [PUBMED Abstract]
    
    
31. 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 Res 49 (7): 1857-60, 1989.  [PUBMED Abstract]
    
    
32. Zhou JR, Blackburn GL: Bridging animal and human studies: what are the missing segments in dietary fat and prostate cancer? Am J Clin Nutr 66 (6 Suppl): 1572S-1580S, 1997.  [PUBMED Abstract]
    
    
33. 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): 2363-71, 1986.  [PUBMED Abstract]
    
    
34. Bairati I, Meyer F, Fradet Y, et al.: Dietary fat and advanced prostate cancer. J Urol 159 (4): 1271-5, 1998.  [PUBMED Abstract]
    
    
35. Cole P, Rodu B: Declining cancer mortality in the United States. Cancer 78 (10): 2045-8, 1996.  [PUBMED Abstract]
    
    
36. Wynder EL, Cohen LA: Correlating nutrition to recent cancer mortality statistics. J Natl Cancer Inst 89 (4): 324, 1997.  [PUBMED Abstract]
    
    
37. 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 Res 39 (12): 5101-5, 1979.  [PUBMED Abstract]
    
    
38. Hämäläinen E, Adlercreutz H, Puska P, et al.: Diet and serum sex hormones in healthy men. J Steroid Biochem 20 (1): 459-64, 1984.  [PUBMED Abstract]
    
    
39. Rose DP, Connolly JM: Effects of fatty acids and eicosanoid synthesis inhibitors on the growth of two human prostate cancer cell lines. Prostate 18 (3): 243-54, 1991.  [PUBMED Abstract]
    
    
40. 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 Res 54 (23): 6129-32, 1994.  [PUBMED Abstract]
    
    
41. 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. Br J Cancer 57 (2): 216-8, 1988.  [PUBMED Abstract]
    
    
42. Gao X, LaValley MP, Tucker KL: Prospective studies of dairy product and calcium intakes and prostate cancer risk: a meta-analysis. J Natl Cancer Inst 97 (23): 1768-77, 2005.  [PUBMED Abstract]
    
    
43. Lawson KA, Wright ME, Subar A, et al.: Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J Natl Cancer Inst 99 (10): 754-64, 2007.  [PUBMED Abstract]
    
    
44. Pienta KJ: Epidemiology and etiology of prostate cancer. In: Raghavan D, Scher HI, Leibel SA, eds.: Principles and Practice of Genitourinary Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1997, pp 379-385. 
    
    
45. García Sánchez A, Antona JF, Urrutia M: Geochemical prospection of cadmium in a high incidence area of prostate cancer, Sierra de Gata, Salamanca, Spain. Sci Total Environ 116 (3): 243-51, 1992.  [PUBMED Abstract]
    
    
46. Boffetta P: Methodological aspects of the epidemiological association between cadmium and cancer in humans. In: Nordberg GF, Herber RF, Alessio L, eds.: Cadmium in the Human Environment: Toxicity and Carcinogenicity. Lyon, France: International Agency for Research on Cancer, 1992, pp 425-434. 
    
    
47. Fingerhut MA, Halperin WE, Marlow DA, et al.: Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N Engl J Med 324 (4): 212-8, 1991.  [PUBMED Abstract]
    
    
48. Bertazzi PA, Zocchetti C, Pesatori AC, et al.: Ten-year mortality study of the population involved in the Seveso incident in 1976. Am J Epidemiol 129 (6): 1187-200, 1989.  [PUBMED Abstract]
    
    
49. Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides.: Veterans and Agent Orange: Update 1996. In: Washington DC, National Academy Press, 1996. 
    
    

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Opportunities for Prevention

Hormonal Prevention

The Prostate Cancer Prevention Trial, a large randomized placebo-controlled trial of finasteride (an inhibitor of alpha-reductase), was performed in 18,882 men aged 55 years or older. At 7 years, the incidence of prostate cancer was 18.4% in the finasteride group versus 24.4% in the placebo group, a relative risk reduction of 24.8% (95% confidence interval [CI], 18.6%–30.6%; P < .001). The finasteride group had more patients with Gleason grade 7 to 10, but the clinical significance of Gleason scoring is uncertain in conditions of androgen deprivation.[1] High-grade cancers were noted in 6.4% of finasteride patients, compared with 5.1% of men receiving a placebo. The increase in high-grade tumors was seen within 1 year of finasteride exposure and did not increase over time.[2]

Finasteride decreases the risk of prostate cancer but may also alter the detection of disease through effects on prostate-specific antigen (PSA) and decreased prostate volume (24%), creating a detection bias.[3] In men receiving finasteride, varying adjustment factors may be needed to determine whether PSA is in the normal range.[4] There may be an artifactual histological effect of finasteride on Gleason scoring.

It is possible that finasteride induced the development of high-grade epithelial neoplasia, but this has not been demonstrated.[3] With a finasteride-induced development of high-grade prostate cancer, a gradual and progressive increase in the number of high-grade tumors would have been expected over the 7 years, compared with placebo; however, this was not the case. The increase in high-grade tumors was seen within 1 year of finasteride exposure and did not increase over time.[2]

In general, agents that are used for hormonal therapy of existing prostate cancers would be unsuitable for prostate cancer chemoprevention because of the cost and wide variety of side effects including sexual dysfunction, osteoporosis, and vasomotor symptoms (hot flushes).[5] Newer antiandrogens may play a role as preventive agents in the future.[6]

Results from studies of the association between dietary intake of fruits and vegetables and risk of prostate cancer are not consistent. A study evaluated 1,619 prostate cancer cases and 1,618 controls in a multicenter, multiethnic population. The study found that intake of legumes and yellow-orange and cruciferous vegetables was associated with a lower risk of prostate cancer.[7]

The European Prospective Investigation into Cancer and Nutrition examined the association between fruit and vegetable intake and subsequent prostate cancer. After an average follow-up of 4.8 years, 1,104 men developed prostate cancer among the 130,544 male participants. No statistically significant associations were observed for fruit intake, vegetable intake, cruciferous vegetable intake, or the intake of fruits and vegetables combined.[8]

One study of dietary intervention over a 4-year period with reduced fat and increased consumption of fruit, vegetables, and fiber had no impact on serum PSA levels.[9] 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.

Several agents, including alpha-tocopherol, selenium, lycopene, difluoromethylornithine,[10-14] vitamin D,[15-17] and isoflavonoids,[18,19] 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 the chemoprevention discussions below.

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.[20] The study, employing d-alpha-tocopheryl acid succinate, found that not only did it enhance the cytotoxic effect of adriamycin, but it also inhibited cell growth when used alone. This inhibition was dose-dependent. Finally, these properties were noted at doses that are routinely attained in plasma.[21] These same doses have been demonstrated to have no effect on normal mouse fibroblasts.[22,23] In a similar study using the Nb rat prostate adenocarcinoma model, the combination of adriamycin-vitamin E resulted in a lower average final tumor volume when compared with control animals.[24]

A nested case-control study of serum micronutrients from a cohort of 6,860 Japanese-American men analyzed 142 confirmed cases of prostate cancer and compared the cases with a similar number of controls.[25] Although the difference did not reach statistical significance, the odds ratio for gamma-tocopherol was 0.7 (95% CI, 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 significant increased risk for lung cancer.[26] Additionally, male smokers who had 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 three metastatic human prostate cancer cell lines was studied: LNCaP, PC-3, and DU-145.[27] It was found that VES inhibited cell growth and deoxyribonucleic acid (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.[28] 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 caused by vitamin E supplementation.

Not all studies of alpha-tocopherol have found the agents to be effective. Using the 3,2'-dimethyl-4-aminobiphenyl initiated rate prostate cancer model in F344 rats, the effect of six naturally occurring antioxidants on carcinogenesis was studied.[29] 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.[30] Serum levels of tocopherol were compared between 103 men who developed prostate cancer during 13 years of follow-up to 103 control patients 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 the incidence of lung cancer in male smokers.[31] 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.[32,33] 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 two capsules. Specifically, participants were divided into four similar study arms/groups: one receiving beta carotene and placebo, one receiving alpha-tocopherol and placebo, one receiving both active agents, and one receiving two 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,[20] 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 randomly assigned to receive alpha-tocopherol (99 prostate cancers) than in those who were not randomly assigned 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.[34] 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,[35,36] also tested alpha-tocopherol, along with selenium (discussed below) and various other agents, in humans. The Linxian general population trial involved approximately 30,000 patients 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 µg/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 significant lower gastric cancer (cardia plus noncardia) mortality rate (a major cancer in Linxian). A second, smaller Linxian trial (with approximately 3,300 patients) tested a combination of these three agents 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 two Linxian trials, however, because the trials differed in scale, patient 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 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.

Selenium is an essential trace element in humans and other species.[37-39] A substantial volume of data suggests that supplementation with selenium reduces the risk of a variety of cancers in chemically induced cancers,[40-58] in spontaneous animal tumors,[59] and in transplanted animal tumor lines.[60] Studies of geographical areas with varying dietary selenium content have demonstrated an inverse relationship between selenium intake and cancer risk.[61,62] Similarly, in a study of environmental selenium levels (forage crop concentrations of selenium), an inverse relationship was again noted.[63] Epidemiologic studies have had mixed results with statistically significant (inverse) relationships encountered in some studies [64-79] while others have not encountered a statistically higher risk in patients with low selenium levels or a low selenium intake.[80-88]

In a case-control study, serum samples collected in 1973 from 111 patients who developed cancer during the subsequent 5 years were studied and compared with serum samples from 210 cancer-free people matched for age, race, sex, and smoking history.[66] Study participants 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 ± standard error of the mean [SEM] 0.002 µg/mL) than in controls (0.136 ± SEM 0.002 µg/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 cultures, it reduces the effect of a number of described mutagens [89-93] and may alter the metabolism of other carcinogens.[94-98] A variety of other potential actions that 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.[31,99-102]

A multi-institutional study designed to prevent skin cancer randomly assigned a group of 1,312 patients with a history of basal cell or squamous cell carcinoma of the skin to either 200 µg selenium per day (as selenized yeast) or placebo (nonselenized yeast).[103] Although the study began in 1983, additional funding subsequently allowed the ascertainment of rates of other cancers in the two 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 two 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. No patient experienced toxicity caused by selenosis, a side effect that has been reported in association with chronic feeding of inorganic and certain organic forms of selenium at levels greater than 5 ppm.[104] Only those participants with baseline plasma-selenium concentrations in the lowest two tertiles (<123.2 ng/mL) had statistically significant reductions in prostate cancer incidence. A statistically significant interaction between baseline plasma selenium and treatment was detected.[105]

Because preliminary data suggest that both selenium and vitamin E may reduce the risk of prostate cancer, a large randomized, prospective, double-blind study has been designed to determine whether selenium and vitamin E can reduce the risk of prostate cancer among healthy men. Enrollment for the Selenium and Vitamin E Cancer Prevention Trial (SELECT) began in 2001 [106] and completed accrual in 2004. More than 35,000 men have been enrolled and will be on study for at least 7 years. Final results are anticipated in 2013.[107]

Other clinical trials of selenium in humans include the two studies conducted in Linxian, China [35,36] that are discussed in the Chemoprevention with Vitamin E (Alpha-Tocopherol) section.

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.[108] 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-control patients showing a reduced risk.[30,109-111] 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 when compared with the group with the lowest level of consumption, which was attributed to the lycopene content of these vegetables.[112] This large analysis prompted several subsequent studies, the results of which were mixed.[113,114] 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), dietary intake instruments are poorly able to quantify lycopene intake, and other potential biases.[115] Specific dietary supplementation with lycopene remains to be demonstrated to reduce prostate cancer risk.

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76. Calautti P, Moschini G, Stievano BM, et al.: Serum selenium levels in malignant lymphoproliferative diseases. Scand J Haematol 24 (1): 63-6, 1980.  [PUBMED Abstract]
    
    
77. McConnell KP, Jager RM, Bland KI, et al.: The relationship of dietary selenium and breast cancer. J Surg Oncol 15 (1): 67-70, 1980.  [PUBMED Abstract]
    
    
78. Clark LC, Graham GF, Crounse RG, et al.: Plasma selenium and skin neoplasms: a case-control study. Nutr Cancer 6 (1): 13-21, 1984.  [PUBMED Abstract]
    
    
79. Fex G, Pettersson B, Akesson B: Low plasma selenium as a risk factor for cancer death in middle-aged men. Nutr Cancer 10 (4): 221-9, 1987.  [PUBMED Abstract]
    
    
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82. Menkes MS, Comstock GW, Vuilleumier JP, et al.: Serum beta-carotene, vitamins A and E, selenium, and the risk of lung cancer. N Engl J Med 315 (20): 1250-4, 1986.  [PUBMED Abstract]
    
    
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84. Schober SE, Comstock GW, Helsing KJ, et al.: Serologic precursors of cancer. I. Prediagnostic serum nutrients and colon cancer risk. Am J Epidemiol 126 (6): 1033-41, 1987.  [PUBMED Abstract]
    
    
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87. Ringstad J, Jacobsen BK, Tretli S, et al.: Serum selenium concentration associated with risk of cancer. J Clin Pathol 41 (4): 454-7, 1988.  [PUBMED Abstract]
    
    
88. Coates RJ, Weiss NS, Daling JR, et al.: Serum levels of selenium and retinol and the subsequent risk of cancer. Am J Epidemiol 128 (3): 515-23, 1988.  [PUBMED Abstract]
    
    
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90. Norppa H, Westermarck T, Laasonen M, et al.: Chromosomal effects of sodium selenite in vivo. I. Aberrations and sister chromatid exchanges in human lymphocytes. Hereditas 93 (1): 93-6, 1980.  [PUBMED Abstract]
    
    
91. Shamberger RJ, Beaman KD, Corlett CL, et al.: Effect of selenium and other antioxidants on the mutagenicity of malonaldehyde. [Abstract] Fed Proc 37 (3): A-265, 261, 1978. 
    
    
92. Jacobs MM, Matney TS, Griffin AC: Inhibitory effects of selenium of the mutagenicity of 2-acetylaminofluorene (AAF) and AAF derivatives. Cancer Lett 2 (6): 319-22, 1977.  [PUBMED Abstract]
    
    
93. Shamberger RJ, Baughman FF, Kalchert SL, et al.: Carcinogen-induced chromosomal breakage decreased by antioxidants. Proc Natl Acad Sci U S A 70 (5): 1461-3, 1973.  [PUBMED Abstract]
    
    
94. Griffin AC: Role of selenium in the chemoprevention of cancer. Adv Cancer Res 29: 419-42, 1979.  [PUBMED Abstract]
    
    
95. Daoud AH, Griffin AC: Effects of selenium and retinoic acid on the metabolism of N-acetylaminofluorene and N-hydroxyacetylamino-fluorene. Cancer Lett 5 (4): 231-7, 1978.  [PUBMED Abstract]
    
    
96. Marshall MV, Rasco MA, Griffin AC: Effects of selenium on benzo(a)pyrene metabolism. [Abstract] Fed Proc 37: A-628, 1383, 1978. 
    
    
97. Rasco MA, Jacobs MM, Griffin AC: Effects of selenium on aryl hydrocarbon hydroxylase activity in cultured human lymphocytes. Cancer Lett 3(5/6): 295-301, 1977. 
    
    
98. Marshall MV, Arnott MS, Jacobs MM, et al.: Selenium effects on the carcinogenicity and metabolism of 2-acetylaminofluorene. Cancer Lett 7 (6): 331-8, 1979.  [PUBMED Abstract]
    
    
99. Combs GF Jr, Scott ML: Nutritional interrelationships of vitamin E and selenium. BioScience 27(7): 467-473, 1977. 
    
    
100. Rotruck JT, Pope AL, Ganther HE, et al.: Selenium: biochemical role as a component of glutathione peroxidase. Science 179 (73): 588-90, 1973.  [PUBMED Abstract]
     
     
101. Chow CK: Nutritional influence on cellular antioxidant defense systems. Am J Clin Nutr 32 (5): 1066-81, 1979.  [PUBMED Abstract]
     
     
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Changes To This Summary (08/26/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Risk Factors for Prostate Cancer Development

Added text to state that ecological studies have found a correlation between serum levels of testosterone, especially DHT, and overall risk of prostate cancer among African American, white, and Japanese males (cited Ellis et al. as reference 12, Ross et al. as reference 13, Wu et al. as reference 14, and Roddam et al. as reference 15).

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