Risk Factors

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Demographic Factors

Over 80% of prostate tumors in the US are diagnosed among men over age 65,8 and the incidence of prostate cancer increases exponentially

South AMERICA

"Garbados Trinidad and Tobago "8 a ha mas "Cuba "Venezuela "Costa Rica "Argentina "Colombia

North AMERICA

"Canada

United States of A mérita

OCEANIA

New Zealand

EUROPE

"Norway

"Switzerland "Sweden "Denmark "Belgium Portugal Finland Estonia Netherlands Croatia Czech Republic Austria

UK, England,and Wales France Germany "Lithuania Spain "Slovakia "Italy "Poland Belarus Russia

ASIA

"Israel "Japan "Philippines "Korea, South

Source: http://www-depdb.iarc.fr/who/menu.htm * Rates are from 1994

Fig. 2. Age-adjusted mortality rates (per 100,000 person-years) for prostate cancer in 38 countries, 1998.

with advancing age — an increase that is faster than that for any other malignancy (Table 1). Estimates from the Surveillance, Epidemiology, and End Results (SEER) program from 1996-2000 indicate that for US men under 65 years of age and 65 years and over, age-adjusted prostate cancer incidence rates were 56.8 and 974.7 per 100,000 person-years, respectively.2

Racial/Ethnic Variation

Another consistently observed but poorly understood risk factor is ethnicity. African-Americans have the highest incidence rate in the world, roughly 60 times that of the ethnic group with the world's lowest rates, in Shanghai, China1 (Fig. 1).

Adjustment of incidence rates for prevalence of latent disease at autopsy and proportion of localized tumors among all cancers of the prostate revealed that Japanese men still experience a markedly lower incidence than Americans, indicating that the international variation cannot be explained by differences in detection alone.9 This bolsters the results of migrant studies suggesting that ethnic factors, including genetic, lifestyle, and environmental factors, may affect prostate cancer risk and explain many of the differences in risk between high- and low-risk populations.9'10

Hormonal, Behavioral and Lifestyle Factors

Hormones and Growth Factors

Androgens play a key role in the development and maintenance of the prostate gland; however, the precise role of androgens in the etiology of prostate cancer is unclear. Prostate cancer is notably absent in castrated men, and laboratory studies show that administration of testosterone induces prostate cancer in rats and that androgens promote cell proliferation and inhibit prostate cell death.11-13 However, epidemiologic data supporting a role of androgens are inconclusive.14-16 To date, over 13 prospective studies have investigated the role of circulating androgens, and only one was able to show that men with higher serum testosterone levels have a higher risk of prostate cancer.17 More comprehensive reviews of this topic are reported elsewhere.14-16 Studies of genetic markers involved in the androgen pathways offer further insight into this avenue of research, and are reviewed later in this chapter.

In addition to androgens, insulin-like growth factors (IGFs), insulin and vitamin D have been implicated in prostate cancer. IGF-I and IGF-II are polypeptides that function as both tissue growth factors and endocrine hormones with mitogenic and anti-apoptotic effects on prostate epithelial cells. There are at least six known IGF binding proteins (IGFBPs) that can bind to IGFs and thus prevent activation of the IGF receptor, which mediates IGF effects. At least nine epidemiologic studies have evaluated the roles of the IGF axis in prostate cancer, and most have reported a positive association with IGF-I and an inverse association with IGFBP3.18'19 However, the role of IGF-II is less clear.

Vitamin D is a steroid hormone obtained primarily from dermal synthesis in response to sunlight exposure. Vitamin D and its analogs have potent anti-proliferative, pro-differentiative, and pro-apoptotic effects on prostate cancer cells. In addition, vitamin D inhibits prostate tumor growth in vivo. In general, laboratory data are consistent and support the hypothesis that vitamin D may protect against prostate cancer. However, results from epidemiologic studies investigating serum vitamin D levels have been inconsistent.20 The reasons for these conflicting results are unclear.

Diet

Ecologic studies have shown a strong correlation between the incidence of prostate cancer and dietary fat intake.21 A western diet has been linked to a higher risk of prostate cancer, and it has been suggested that the western diet, high in fat, increases production and availability of both androgen and estrogen, while Asian (low-fat, high-fiber) and vegetarian diets lead to lower circulating levels of these hormones.21

Fat is the most studied dietary factor in relation to prostate cancer. Most epidemiologic studies have investigated the role of total, saturated, and/or animal fat. Findings from these studies suggest a possible positive association with monounsaturated, animal and saturated fats, and an inverse association with omega-3 fat. The results for polyunsaturated fat are less consistent.22,23 Consumption of meat, particularly red meat, is also consistently linked to an increased risk of prostate cancer. However, it is unclear whether the excess risk is due to the fat content in red meat, mutagens such as heterocyclic amines that are induced during high-temperature cooking of meat products, animal proteins, or other unidentified factors.24

Several epidemiologic studies have also investigated whether intake of fatty fish, rich in potentially tumor-inhibitory marine fatty acids, is associated with reduced prostate cancer risk. However, a recent review of 17 studies, including eight prospective studies, found suggestive but inconsistent results, possibly due to inadequate assessment of fish intake or lack of information on specific marine fatty acids, particularly the polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids,25 in these studies.

Although consumption of fruits and vegetables is associated with a reduced risk of several cancers, their role in prostate cancer is less clear. The only consistent finding is an inverse association with consumption of tomatoes and tomato paste, which has been largely attributed to the antioxidant effect of lycopene.26 Cruciferous and allium vegetables have been implicated. A recent review concluded that there is modest evidence that intake of cruciferous vegetables, including broccoli, cabbage, cauliflower, and Brussels sprouts, is inversely associated with prostate cancer risk, possibly due to their content of isothiocyanates.27 Intake of allium vegetables, including onions, garlic, and chives, was associated with a reduced risk in a case-control study in China.28 This protective effect may be due to the tumor inhibitory properties of organosulfur compounds.

Dietary calcium, from either dairy intake or supplements, has also been linked to prostate cancer. Because of its role in regulation of vitamin D synthesis, calcium may down-regulate vitamin D's anti-proliferative effects on prostate cancer. However, the epidemiologic evidence for calcium is as yet unclear, complicated by differences in assessment of calcium (dietary intake versus circulating levels).29 Recent data suggest a threshold effect in that only very high calcium intake (> 2000mg/day) appears to be associated with disease.30

Chronic excess of zinc, another mineral obtained largely through dietary supplements, may be positively associated with prostate cancer risk, although in vitro studies demonstrating mitogenic effects of zinc on prostate cancer suggest that it may reduce risk.31

A large body of epidemiological evidence, including observational, case-control, cohort and randomized controlled clinical trials, supports the hypothesis that selenium may prevent prostate cancer in humans.32 Molecular data show that selenium prevents clonal expansion of tumors by causing cell cycle arrest, promoting apoptosis, and modulating p53-dependent DNA repair mechanisms. Clinical trials have also shown that vitamin E supplementation is associated with a reduced risk of prostate cancer.33'34 Currently a clinical trial is under way to test the chemopre-ventive efficacy of these two compounds.35

Obesity

In epidemiologic studies, overall obesity is usually measured by body mass index (weight in kg divided by the square of height in meters, kg/m2) and abdominal obesity by the ratio of waist to hip circumference. The findings on overall obesity are mixed. However, recent data suggest that abdominal obesity may be associated with an increased risk of prostate cancer even in relatively lean men.36,37 In addition, higher serum levels of insulin were associated with an increased risk of prostate cancer in China,38 and higher serum levels of leptin were associated with larger tumor volume (> 5 cm3).39 Although the role of obesity in prostate cancer is not clearly defined, future studies should attempt to clarify it further because obesity is linked to numerous putative risk factors for prostate cancer, including high intakes of meat and fat intake, hormone metabolism, and serum level IGFs and insulin. Furthermore, the prevalence of obesity correlates with prostate cancer risk across populations. It is likely that obesity may thus provide a link between westernization and increased prostate cancer risk. With the epidemic of obesity in both developed and developing countries, the role of obesity needs to be clarified further.

Physical Activity

Physical activity may decrease levels of total and free testosterone, reduce obesity, and enhance immune function,40 all of which may lead to protection from prostate cancer. However, perhaps due to challenges in classifying physical activity and/or identifying the age/time period at which activity may be most protective, results from numerous epidemiologic studies are equivocal.40'41

Occupation

Occupation is highly correlated with socioeconomic status and lifestyle factors. There is a large body of literature on prostate cancer and occupation, and one consistent result from these studies is that farmers and other agricultural workers have a 7-12% increased risk.42,43 While this excess could reflect lifestyle factors such as increased intake of meat and fats, chemical exposures may also play a role. These chemicals, which have a wide variety of poorly characterized effects, may include fertilizers, solvents, pesticides and herbicides.44 Organochlorines present in many pesticides and herbicides can affect circulating hormone levels; however the epidemiologic evidence linking specific pesticide or herbicide exposures to prostate cancer is weak. In addition to agriculture, workers in the heavy metals industry, rubber manufacturing, and newspaper printing may be at elevated risk,42 suggesting that exposure to certain chemicals common in these work environments may increase the risk of prostate cancer.

Vasectomy

Several, but not all, studies investigating the association between vasectomy and prostate cancer risk suggest a modest positive association. The role of vasectomy remains controversial, however, since most studies are unable to exclude the possible effect of detection bias: men undergoing vasectomies are more likely to have prostate cancer detected than men who do not. Vasectomy is linked to elevations in anti-spermatozoa antibodies, decreased seminal hormone concentrations and decreased prostatic secretion.45 Whether these conditions can influence prostate carcinogenesis needs to be clarified.

Chronic Inflammation

Evidence for chronic inflammation and prostate cancer is just emerging,46 but an association of prostate cancer with chronic inflammation of the prostate (chronic prostatitis) has long been suspected. Inflammation is frequently found in prostate biopsy specimens obtained from both radical prostatectomy and surgical treatment for BPH,47,48 however, epidemiologic findings have been mixed. A recent meta-analysis of 11 studies of prostatitis and prostate cancer reported an overall relative risk of 1.6.49

Results from pathologic and molecular surveys suggest that the earliest stages of prostate cancer may develop in lesions generally associated with chronic inflammation.50'51 De Marzo et al. showed that almost all forms of focal prostatic glandular atrophy, thought to be precursors of prostatic adenocarcinoma, are proliferative, and that such proliferative inflammatory atrophy (PIA) lesions often contain inflammatory infiltrates and are frequently found adjacent to or near high-grade prostatic intraepithelial neoplasia (PIN).50'51 Inflammation may lead to tumorigenesis by stimulating angiogenesis, enhancing cell proliferation, and damaging DNA through radical oxygen species such as nitric oxide.

Additional support for a role for chronic inflammation in prostate cancer comes from the observation that a higher intake of fish and use of aspirin and other non-steroidal anti-inflammation drugs (NSAIDs) has been associated with reduced prostate cancer risk.52 In two large prospective studies, higher intake of fish was associated with a lower risk of total prostate cancer and metastatic prostate cancer.53,54 Abundant in fatty fish, omega-3 fatty acids are known antagonists of arachidonic acid and suppress the production of pro-inflammatory cytokines.55 In addition, use of anti-inflammatory agents, especially NSAIDs such as ibuprofen or aspirin, has been related to lower prostate cancer risk in epi-demiologic studies,56-58 and a recent meta-analysis of 12 of these studies concluded that aspirin use was associated with a 15% reduction in prostate cancer risk.59 Taken together, these data suggest chronic inflammation may increase the risk of prostate cancer. However, there are few epidemiologic studies investigating this directly, possibly due to the difficulty in diagnosing chronic prostatitis and in measuring cytokine levels reliably in serum samples. This is likely to be a fruitful area for future research.

Sexually Transmitted Diseases

Chronic inflammation induced by bacterial or viral agents has been implicated as a potential underlying mechanism for the link between STDs and prostate cancer. One recent large, population-based study showed two- to three-fold increased prostate cancer risks associated with STDs, particularly syphilis and recurrent gonorrhea infections.60 Other studies reported associations of human papillomavirus-16, -18 and -33 serology with an increased risk of prostate cancer.61,62 In addition, epidemiological data are accumulating to suggest that sexual history may be associated with prostate cancer risk,63 and a recent meta-analysis of 17 studies concluded that increased sexual frequency and number of partners are associated with increased prostate cancer risk.49

Benign Prostatic Hyperplasia

The relationship between BPH and prostate cancer is not well established. BPH is currently not considered a precursor to prostate cancer, since prostate cancer occurs mostly in the peripheral zone of the prostate and BPH is more common in the transition and periurethral zones. However, because both conditions are common in elderly men, and because they may coexist within the prostate, they appear to share risk profiles, making it difficult to elucidate the independent role, if any, of BPH in prostate cancer etiology. Detection bias also complicates investigation: excess prostate cancer risk in men who are symptomatic for BPH may be simply a reflection of the increased intensity of evaluation and medical surveillance in such patients. In addition, in most epidemiologic studies, it has been difficult to completely rule out the presence of BPH in control populations, since the prevalence of BPH is very common in elderly men. Due in part to these limitations, the epidemiologic evidence for BPH as a risk factor for prostate cancer remains weak and inconsistent,64 with the largest study to date (over 85,000 BPH patients) showing only a marginally elevated risk of prostate cancer versus the general population (< 2% in 10 years).65

Other Factors

Several other risk factors, such as smoking, use of alcohol, diabetes and liver cirrhosis, have been investigated, but their roles in prostate cancer are weak or unclear based on data in the current literature.66-68

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