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NCI/PDQ® Health professionals: Prostate Cancer Prevention (PDQ®)
National Cancer Institute
Last Modified: March 29, 2012

TABLE OF CONTENTS


Overview

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


Benefits From Finasteride and Dutasteride Chemoprevention

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

Magnitude of Effect: Absolute reduction in incidence for more than 7 years with finasteride was 6% (24.4% with placebo and 18.4% with finasteride); relative risk reduction (RRR) 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.

In the dutasteride trial, using the restricted crude rate absolute risk reduction was 5.1% at 4 years, and RRR was 22.8% (95% CI, 15.2%29.8%, P < .001). There was no difference in prostate cancer or overall mortality, though the number of deaths was small and none were due to prostate cancer. The reduction in prostate cancer incidence occurred primarily in Gleason 5 to 6 cancers. 1 The reduction in incidence primarily in less aggressive cancers (i.e., Gleason 56) and not in more aggressive cancers (i.e., Gleason 710) raises the question of whether this reduction in incidence would lead to any reduction in mortality. This question is presently unanswered.

  • Study Design: Two randomized controlled trials; one for finasteride and one for dutasteride.
  • Internal Validity: Good for the outcome of incidence, poor for the outcome of mortality.
  • Consistency: Good.
  • External Validity: The studies focused on different populations. The finasteride trial enrolled men with a prostate-specific antigen (PSA) more than 3 ng/mL, constituting the majority of U.S. men, but men with a lower risk of cancer. In the dutasteride trial, men were at somewhat higher risk, with a PSA of 2.5 to 10.0 and a prior negative biopsy. As such, results are generalizable primarily to these respective populations.


Harms From Finasteride and Dutasteride Chemoprevention


Finasteride

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 810) cancers during the study. 2 Whether this was a histological artifact or not is uncertain.

Magnitude of Effect: Statistically significant increases in the following outcomes were observed in the finasteride group (a greater fraction of men in the finasteride group [36.8%] temporarily discontinued treatment at some time during the study for reasons other than death or a diagnosis of prostate cancer than in the placebo group [28.9%]):

  • 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%).


Dutasteride

Overall, 4.3% of men in the dutasteride group compared with 2% of men in the placebo group discontinued the trial because of drug-related adverse events (P < .001).Men in the dutasteride group had a higher incidence of decreased libido, loss of libido, decreased semen volume, erectile dysfunction and gynecomastia than men in the placebo group. 1

Magnitude of Effect: Increases in the following outcomes were observed in the dutasteride group:

  • Percentage in dutasteride group versus percentage in placebo group:
    • Decreased libido (3.3% vs. 1.6%).
    • Loss of libido (1.9% vs. 1.3%).
    • Decreased semen volume (1.4 vs. 0.2%).
    • Erectile dysfunction (9.0% vs. 5.7%).
    • Gynecomastia (1.9% vs. 1.0%).

  • Study Design: Two randomized controlled trials; one for finasteride and one for dutasteride.
  • Internal Validity: Good: The finasteride trial used two subject-completed sexual functioning instruments administered at enrollment, randomization, 6 months, and annually over the 7-year study. The dutasteride trial administered a sexual functioning instrument after completion of placebo run-in and annually thereafter.
  • Consistency: Good (evidence other than the randomized controlled trial supports these effects).
  • External Validity: As above, the studies evaluated two different populations: PSA less than or equal to 3 ng/mL in the finasteride trial and PSA of 2.5 to 10.0 ng/mL with a prior negative biopsy in the REDUCE trial. The results are most generalizable to these two populations.


Other Prevention Interventions

The Selenium and Vitamin E Cancer Prevention Trial (SELECT [NCT00006392]) was a large randomized placebo-controlled trial of vitamin E and selenium. It showed no reduction in prostate cancer period prevalence, but an increased risk of prostate cancer with vitamin E alone. 3

Magnitude of Effect: Compared with the placebo group in which 529 men developed prostate cancer, there was a statistically significant increase in prostate cancer in the vitamin E group (620 cases) but not in the selenium plus vitamin E group (555 cases) or in the selenium group (575 cases). The magnitude of increase in prostate cancer risk with vitamin E alone was 17%.

  • Study Design for Vitamin E and Selenium: Randomized, placebo-controlled trial of selenium (200 g/d from L-selenomethionine), vitamin E (400 IU/d of all-rac-[alpha]-tocopheryl acetate), or both.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

References:

  1. Andriole GL, Bostwick DG, Brawley OW, et al.: Effect of dutasteride on the risk of prostate cancer. N Engl J Med 362 (13): 1192-202, 2010. [PUBMED Abstract]
  2. 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]
  3. Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011. [PUBMED Abstract]


Significance

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Incidence and Mortality

Carcinoma of the prostate is the most common tumor in men in the United States, with an estimated 241,740 new cases and 28,170 deaths expected in 2012. 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 compared with about 3% of men who 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 lower-risk (i.e., Gleason 6 and some low-volume Gleason 7 tumors) prostate cancer managed by surveillance alone with high survival rates at 5 and 10 years of follow-up. 6 Data demonstrate, however, that with longer follow-up, higher-grade cancers are associated with a greater risk of prostate cancer death. 7 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 for a period of 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, focal ablation, androgen deprivation with luteinizing hormone-releasing hormone analogs and/or antiandrogens, intermittent androgen deprivation, cytotoxic agents, and active surveillance. Of all the means of management, only radical prostatectomy has been tested in a randomized clinical trial to assess survival benefit. In this study, prostatectomy was found to be superior to surveillance in men with localized prostate cancer in terms of reduced rates of metastases (relative hazard [RH] = 0.63; 95% confidence interval [CI], 0.410.96) and disease specific (RH = 0.5; 95% CI, 0.270.91) and overall mortalities. 13 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 with careful PSA monitoring following treatment, a substantial fraction of patients may suffer disease recurrence . 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, conflicting outcomes of randomized trials examining the impact of screening on mortality has led to some organizations to recommend for and others to recommend against screening. 16 17

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

References:

  1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
  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. Hílund B: Latent prostatic cancer in a consecutive autopsy series. Scand J Urol Nephrol 14 (1): 29-35, 1980. [PUBMED Abstract]
  4. Altekruse SF, Kosary CL, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2007. Bethesda, Md: National Cancer Institute, 2010. Also available online [PUBMED Abstract]
  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. Cooperberg MR, Carroll PR, Klotz L: Active surveillance for prostate cancer: progress and promise. J Clin Oncol 29 (27): 3669-76, 2011. [PUBMED Abstract]
  7. Lu-Yao GL, Albertsen PC, Moore DF, et al.: Outcomes of localized prostate cancer following conservative management. JAMA 302 (11): 1202-9, 2009. [PUBMED Abstract]
  8. Jones CU, Hunt D, McGowan DG, et al.: Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med 365 (2): 107-18, 2011. [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. [PUBMED Abstract]
  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]
  16. Thompson I, Thrasher JB, Aus G, et al.: Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol 177 (6): 2106-31, 2007. [PUBMED Abstract]
  17. Screening for Prostate Cancer. Rockville, Md: U.S. Preventive Services Task Force, 2011. Available online [PUBMED Abstract]


Risk Factors for Prostate Cancer Development

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Age

Prostate cancer incidence escalates 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


Family History

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 6 7


Hormones

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
  3. The results of two large-scale chemoprevention trials using 5AR inhibitors (finasteride and dutasteride) demonstrate that intraprostatic androgens modulate prostate cancer risk. In both studies, reductions in overall prostate cancer risk were identified although with increased risk of high-grade disease. 12 13

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. 14 15 16 However, evidence from prospective studies of the association between serum concentrations of sex hormones, including androgens and estrogens, does not support a direct link. 17 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. 17 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.


Race

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. 18 19 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. 20


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. 21 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. 22 23 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. 24 25 Animal models of explanted human prostate cancer have demonstrated decreased tumor growth rates in animals who are fed a low-fat diet. 26 27 Evidence from many case-control studies has found an association between dietary fat and prostate cancer risk, 28 29 30 though studies have not uniformly reached this conclusion. 31 32 33 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. 34 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. Fat of animal origin seems to be associated with the highest risk. 20 35 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. 36 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 during the same time period. 37 38

Two studies were conducted within the Prostate Cancer Prevention Trial in which prospective nutritional information was collected and all subjects were recommended to undergo biopsy. Findings included that, among 9,559 subjects there was no association between any supplement or nutrient (including fat) and risk of prostate cancer overall but the risk of high-grade cancer was associated with high intake of polyunsaturated fats. In a subset of 1,658 cases and 1,803 controls, specific fatty acids were examined and docosahexaenoic acid was associated with risk of high-grade disease while trans-fatty acids (TFA) 18:1 and TFA 18:2 were inversely associated with risk of high-grade disease. These large scale studies suggest a complex relationship between nutrients such as fat and risk of prostate cancer. 39 40

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. 41 42
  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. 43
  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. 44 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. 45


Dairy and Calcium Intake

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], 1.001.22; P = .04) and calcium (RR = 1.39; 95% CI, 1.091.77; 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, 1.001.78; P = .055) for the highest versus lowest intake categories of dairy products and 1.46 (95% CI, 0.653.25; 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. 46


Multivitamin Use

Regular multivitamin use has not been associated with the risk of early or localized prostate cancer. 47 However, in this large (295,344 men) study, there was a statistically significantly increased risk of advanced and fatal prostate cancer among men with excessive use of multivitamins.


Folate

The Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas, was conducted between July 6, 1994, and December 31, 2006. In a secondary analysis, the authors addressed the effect of folic acid supplementation on the risk of prostate cancer. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.07.8) years and asked periodically to report all illnesses and hospitalizations. 48 Supplementation with 1 mg of folic acid was associated with an increased risk of prostate cancer. However, dietary and plasma levels among nonmultivitamin users were inversely associated with risk. These findings highlight the potentially complex role of folate in prostate carcinogenesis. 48 49


Cadmium Exposure

Cadmium exposure is occupationally associated with nickel-cadmium batteries and cadmium recovery plant smelters and is associated with cigarette smoke. 50 The earliest studies of this agent documented an apparent association, but better-designed studies have failed to note an association. 51 52


Dioxin Exposure

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. 53 54 The analysis of all available data suggests that the association between dioxin exposure and prostate cancer is not conclusive. 55

References:

  1. Epidemiological aspects. In: Kirby RS, Christmas TJ, Brawer MK: Prostate Cancer. London, England: Mosby, 1996, pp 23-32. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. Grínberg 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]
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  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. Andriole GL, Bostwick DG, Brawley OW, et al.: Effect of dutasteride on the risk of prostate cancer. N Engl J Med 362 (13): 1192-202, 2010. [PUBMED Abstract]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. 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]
  18. Altekruse SF, Kosary CL, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2007. Bethesda, Md: National Cancer Institute, 2010. Also available online [PUBMED Abstract]
  19. 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]
  20. 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]
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  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
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  30. 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]
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  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. Bairati I, Meyer F, Fradet Y, et al.: Dietary fat and advanced prostate cancer. J Urol 159 (4): 1271-5, 1998. [PUBMED Abstract]
  37. Cole P, Rodu B: Declining cancer mortality in the United States. Cancer 78 (10): 2045-8, 1996. [PUBMED Abstract]
  38. Wynder EL, Cohen LA: Correlating nutrition to recent cancer mortality statistics. J Natl Cancer Inst 89 (4): 324, 1997. [PUBMED Abstract]
  39. Kristal AR, Till C, Platz EA, et al.: Serum lycopene concentration and prostate cancer risk: results from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 20 (4): 638-46, 2011. [PUBMED Abstract]
  40. Kristal AR, Arnold KB, Neuhouser ML, et al.: Diet, supplement use, and prostate cancer risk: results from the prostate cancer prevention trial. Am J Epidemiol 172 (5): 566-77, 2010. [PUBMED Abstract]
  41. 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]
  42. Hímílíinen 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]
  43. 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]
  44. 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]
  45. 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]
  46. 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]
  47. 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]
  48. Figueiredo JC, Grau MV, Haile RW, et al.: Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst 101 (6): 432-5, 2009. [PUBMED Abstract]
  49. Kristal AR, Lippman SM: Nutritional prevention of cancer: new directions for an increasingly complex challenge. J Natl Cancer Inst 101 (6): 363-5, 2009. [PUBMED Abstract]
  50. 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. [PUBMED Abstract]
  51. 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]
  52. 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. [PUBMED Abstract]
  53. 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]
  54. 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]
  55. 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. [PUBMED Abstract]


Opportunities for Prevention

Back Up


Hormonal Prevention

The Prostate Cancer Prevention Trial (PCPT), 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 (RRR) 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 during this time period. 2

Finasteride decreases the risk of prostate cancer but may also alter the detection of disease through effects on prostate-specific antigen (PSA), prostate digital rectal examination, and decreased prostate volume (24%), creating a detection bias. 3 Adjustment of PSA in men taking finasteride preserves the performance characteristics for cancer detection. 4

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 for more than 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 during this time period. 2 An analysis of the PCPT data adjusted for the sources of detection bias found that finasteride reduced the incidence of Gleason 5 to 7 and Gleason 3 to 4 prostate cancer, but not Gleason 2 to 3 or Gleason 8 to 10. The reduction in the incidence of Gleason 7 (22%) was less than the reduction in the incidence of Gleason 5 (58%) and Gleason 6 (52%). 5 An analysis using different methodologies found an overall reduction of both low-grade (Gleason <6) and high-grade (Gleason >7) cancers. 6

The Reduction by Dutasteride of Prostate Cancer Events trial randomly assigned 8,231 men aged 50 to 75 years at higher risk of prostate cancer (i.e., PSA 2.510.0) with one recent negative prostate biopsy to dutasteride at 0.5 mg daily or to placebo. The primary endpoint was prostate cancer diagnosed by prostate biopsy at 2 years and 4 years after randomization. After 4 years, among the 6,729 men (82% of initial population) who had at least one prostate biopsy, 25.1% of the placebo group and 19.9% of the dutasteride group had been diagnosed with prostate cancer, a statistically significant difference (absolute risk reduction = 5.1% and RRR = 22.8% [95% CI, 15.2%29.8%]). The RRR in years 3 to 4 was similar to the RRR in years 1 to 2. The difference between the groups was entirely due to a reduction in prostate cancers with Gleason score 5 to 7. For years 3 to 4 there was a statistically significant increase in the dutasteride group compared with the placebo group in prostate cancers with Gleason score 8 to 10 (12 cancers in dutasteride group vs. 1 cancer in placebo group). 7

Overall, there was no statistically significant difference of high-grade tumors for Gleason 8 to 10 cancers in years 1 to 4 (29 vs. 19, 0.9 vs. 0.6%; P = .15). However, in a retrospective analysis there was a statistically significant difference between years 3 to 4. Because this is a small retrospective subgroup, the finding of an increase in Gleason 8 to 10 cancers is of uncertain validity. However, the finding of no reduction in these cancers is more significant. 7

There are several plausible explanations for the failure of finasteride or dutasteride to reduce the incidence of Gleason 8 to 10 cancers. Because of this uncertainty, the evidence is currently insufficient to determine the effect of prophylaxis with these drugs on prostate cancer mortality.

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). 8 Newer antiandrogens may play a role as preventive agents in the future. 9

A Cochrane systematic review of all published studies of clinical outcome investigations of the prostate preventive effects of 5-alpha-reductase (5AR) inhibitors through 2010 that were at least one year in duration concluded that finasteride and dutasteride reduce the risk of being diagnosed with prostate among men who are screened regularly for prostate cancer. The review also concluded that mortality effects could not be assessed from these studies and that persistent use of these agents increased sexual and erectile dysfunction. The review was based on MEDLINE and Cochrane Collaboration Library computerized searches through June 2010 using Medical Subject Headings terms and text words finasteride,' dutasteride,' neoplasms,' azasteroids,' reductase inhibitors' and enzyme inhibitors' to identify randomized trials. Eight studies met the inclusion criteria. Only the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events study were designed to assess the impact of 5AR inhibitors on prostate cancer period prevalence. Reviews of all eight studies concluded that compared with placebo, 5AR inhibitors resulted in 25% relative risk (RR) reduction in prostate cancers detected for cause' [RR = 0.75; 95% CI, 0.670.83 and 1.4% absolute risk reduction (3.5% vs. 4.9%)]. Six trials of 5AR inhibitors versus placebo assessed prostate cancers detected overall. Among these there was a 26% RR reduction favoring 5AR inhibitors [RR = 0.74; 95% CI, 0.551.00 and 2.9% absolute risk reduction (6.3% vs. 9.2%)]. There were reductions across age, race, and family history. One placebo-controlled trial of men considered at greater risk for prostate cancer based on age, elevated PSA and previous suspicion of prostate cancer leading to a prostate biopsy reported that dutasteride did not reduce prostate cancers detected for cause based on needle biopsy but did reduce risk of overall incident prostate cancer detected by biopsy by 23% [RR = 0.77; 95% CI, 0.70.85 and absolute risk reduction 16.1% vs. 20.8%]. There were reductions across age, family history of prostate cancer, PSA level, and prostate volume subgroups. The Cochrane review defined for-cause' cancers as:

  1. Suspected clinically from symptoms, abnormal digital rectal exam (DRE), or PSA and confirmed on biopsy.
  2. Study protocol recommended biopsy, but it was not done and the end of study biopsy showed prostate cancer.
  3. The end of study biopsy with PSA less than 4 ng/mL and/or suspicious DRE showed prostate cancer. 10


Dietary Prevention With Fruit, Vegetables, and a Low-fat Diet

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. 11

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. 12

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. 13 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 diseaseall of which may merit adoption of such a diet.


Chemoprevention

While several agents, including alpha-tocopherol, selenium, lycopene, difluoromethylornithine, 14 15 16 17 18 vitamin D, 19 20 21 and isoflavonoids, 22 23 have shown potential in either cli

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