Huang thoroughly discredits this concept and goes on to point out the limitations of the various study methods, including observational studies, case-control studies, and cohort studies. He suggests that only randomized, carefully controlled studies can address these important issues.

Nutritional studies are difficult to perform because of the inherent heterogeneity of any study population, the variations in individual lifestyles, and the quantitative and qualitative complexity in food and food products. Laboratory studies in animal models provide important leads in designing, conducting, and interpreting large studies in humans, but translating data from animal studies to humans is often fraught with error. These difficulties explain why so many contradictory reports exist that confuse physicians, as well as the public.

The principal message from nutritional studies in humans has been an endorsement of the benefits of a diet consisting mainly vegetables, fruits, grains, and fish, combined with restricted caloric intake and exercise. Such a diet provides multiple micronutrients packaged in their most effective form. For example, whole-grain bread provides fiber, iron, vitamin E, and folate. Fruit juices such as pomegranate juice provide antioxidants.

In contrast, supplements contain micronutrients that are usually pharmacologically or synthetically produced and are ingested in isolation. They are not as well absorbed as nutrients contained in food, nor do they have the advantage of the nutrient interactions that occur in a food source.

Other aspects of diet may increase prostate cancer risk. Foods that should be minimized include red meat, fat, and milk. ^[2]

No studies have indicated that these diet recommendations would be of benefit in altering the growth of an existing cancer. However, evidence has shown that these dietary measures are effective in reducing the risk of death from cardiovascular disease. Interestingly, every prostate-cancer study with survival as the endpoint has found that most patients die of causes other than prostate cancer, mostly cardiovascular disease. Therefore, the possible merits of nutritional measures in preventing prostate cancer are compounded by their proven merits in preventing and managing cardiovascular disease.

Ideally, individuals should adopt this type of diet when they are young. Unfortunately, this has not been happening; even with all of the publicity about the dangers of an improper diet, rates of obesity and diabetes are increasing. ^[3]

Nevertheless, the diagnosis of prostate cancer can be a trigger for dietary improvement. In an interview study from the United Kingdom, Avery et al found that over half of men diagnosed with prostate cancer reported making dietary changes, primarily to promote general or prostate health or to facilitate coping. Interest in dietary advice was high. Men whose treatment choice was active surveillance were especially likely to modify their diet and regard diet as an adjunct therapy. ^[4]

Analysis of a cancer registry in the United States, which included men with prostate cancer, showed that patient-clinician information engagement leads to increased consumption of fruits and vegetables by cancer patients. These dietary changes resulted in part from patients’ information seeking from nonmedical channels. ^[5]

Nondietary factors in prostate cancer

Nondietary factors that play an etiologic role in prostate cancer include various hormonal perturbations, genetic predisposition to cancer, and oxidative deoxyribonucleic acid (DNA) damage caused by chronic prostate inflammation.

Although DNA damage is common, various repair systems ordinarily correct the problem. The inability of the various DNA-repair mechanisms to function properly allows an altered cell to proceed through cell division instead of being corrected or eliminated. One such system is the glutathione S -transferase P1-1 (GSTpi) repair mechanism, which has been found to be functionally inactive in men with prostate cancer.

Prostate cancer has become such a frequently diagnosed condition that much research has been undertaken to understand its etiologic factors and how its onset can be prevented or delayed. Although the primary risk factor for developing prostate cancer is aging, the role of diet and nutrition in the development and progression of this and other cancers has received increasing attention. ^[6]

In 1982, The National Academy of Science presented convincing evidence concerning the relationship between dietary fat and cancer. ^[8] All of the subsequent epidemiologic studies, animal-model studies, and investigations into the biochemical and molecular biologic processes that involve cancer have emphasized the role that diet plays in the process of carcinogenesis.

• Limit or avoid dairy products
• Avoid grilled, fried, and broiled meats
• Emphasize fruits and vegetables

One such diet is the Mediterranean diet, which consists largelly of fruits and vegetables, nuts, grains, olive oil, and chicken and seafood. A systematic review and meta-analysis of observational studies of the Mediterranean diet found that the highest adherence to this diet was significantly associated with a lower risk of mortality from prostate cancer (risk ratio 0.96, 95% confidence index 0.92–1.00), as well as several other cancers. ^[10]

Diet is perhaps the most important factor that an individual can control. The strongest dietary factor associated with prostate cancer seems to be obesity. The significant prevalence of overeating and the resultant obesity, coupled with other risk factors, may explain the increasing incidence of prostate cancer. A report from the International Agency for Research on Cancer indicated that 10% of all cancers in the United States are related to obesity. Epidemiologic studies have indicated that 27.6% of men and 33.4% of women are considered obese (as defined by a body mass index [BMI] >30kg/m²).

Numerous studies have shown that obese men have a greater risk of dying of prostate cancer, developing a more aggressive cancer, and experiencing disease recurrence after surgery or radiation therapy. The Cancer Prevention Study demonstrated that men with a BMI greater than 32.5kg/m² were 35% more likely to die of prostate cancer than men whose BMI was less than 25%. Overweight men who lose weight seem to reduce their risk of developing prostate cancer.

Per-capita fat consumption is highest in males in North America and Western Europe, and rates of prostate-cancer deaths are also highest in these regions. (The typical American male obtains about one third of his daily energy intake from dietary fat.) Conversely, the countries in the Pacific Rim have the lowest fat consumption and the lowest death rates.

Whittemore et al studied the relationship of diet, physical activity, and body size in black, white, and Asian men living in North America and found that the only factor that correlated with prostate cancer was the amount of dietary fat. ^[11] The same was true in Hawaiian men; the highest prevalence of prostate cancer was in men with the highest intake of saturated fat. ^[12]

Interestingly, the introduction of Western diets in Japan, where the traditional diet is low in fat, has led to an increased incidence of aggressive prostate cancer. Giovannucci et al reported that men who consumed high levels of fat were more likely not only to develop prostate cancer but also to develop a more aggressive form of the disease. ^[13]

In an animal study by Wang et al, a low-fat diet decreased the growth of prostate tumor cells. ^[14]These investigators injected prostate cancer cells from the androgen-sensitive cell line (LNCaP cells) into nude mice. Initially, all of the animals were placed on a diet in which 40% of their caloric intake came from fat. When the tumors were established and measurable, the diet was changed. Tumor growth was markedly inhibited in the animals in whom dietary fat contributed no more than 20% of the total caloric intake. There was no significant difference in total ingested calories between the 2 groups.

The correlation between obesity and prostate cancer has also been emphasized by studies of metabolic syndrome, which refers to a group of conditions that includes central adiposity, hypertension, dyslipidemia, and high serum glucose levels. Men with metabolic syndrome have been shown to have a higher incidence of prostate cancer.

Fatty acids

The correlation between fat consumption and the risk of prostate cancer seems to depend on the specific types of fat and their constituent fatty acids. Fatty acids can be separated into 3 classes on the basis of their carbon-carbon bonds, as follows:

• Saturated fatty acids, such as stearic acid, contain no carbon-carbon double bonds.
• Monounsaturated fatty acids, such as oleic acid, have a single carbon-carbon bond.
• Polyunsaturated fatty acids, including linoleic acid and eicosapentaenoic acid, have 2 or more carbon-carbon bonds.

Trans fat is an industrially created unsaturated fat that is neither necessary nor beneficial. Trans fat may be monounsaturated or polyunsaturated.

Fatty acids are generally found in foods and in fat deposits as triglycerides or neutral fat, in which 3 fatty acids are esterified to a single molecule of glycerol. In cell membranes, fatty acids exist as phospholipids, in which one of the fatty esters is replaced by a head group such as choline, serine, or inositol. Phospholipids are integral components of cellular membranes; they are responsible for maintaining cellular integrity and for regulating membrane enzymes, cell-signaling processes, and the construction of cellular receptors.

Fatty acids provide a source of concentrated energy for cellular metabolic needs through the sequential removal and oxidation of 2-carbon units. The complete oxidation of a fatty acid provides 9kcal per gram of fat; in contrast, protein and carbohydrates provide 4kcal per gram. Separating the intrinsic effects of fat intake from those associated with high caloric intake is difficult because of the high energy content of fatty acids.

Saturated fat constitutes the largest proportion of fat in Western diets and is consumed primarily in animal-derived foods. Although the intake of animal fats and saturated fats correlates with prostate cancer risk, this association is not as strong when adjusted for total energy intake.

In addition, a direct cause and effect has not been established. Several mechanisms have been suggested to explain the relationship between saturated fatty acids and prostate cancer. They involve insulinlike growth factor-1 (IGF-1), hormone metabolism, and free-radical damage. A low-fat diet seems to correlate with lower levels of IGF-1, testosterone, and estradiol levels and higher levels of insulinlike growth factor–binding protein 1 and sex hormone–binding globulin.

Omega fatty acids

Much attention has been devoted to the benefits of the omega-3 and the deleterious effects of the omega-6 long-chain unsaturated fatty acids. The marine omega-3 fatty acids are potent antioxidants that have demonstrated a beneficial effect in the development of prostate cancer, based on results from animal and epidemiologic studies. Whether the omega-3 fatty acids or the ratio between omega-3 and omega-6 is important has not been elucidated.

MacLean and colleagues reviewed 38 articles describing the effects of dietary supplementation of omega-3 on cancer risk. ^[15] They found no correlation between consumption of omega-3 dietary supplements and the incidence of intestinal tumors, bladder cancer, lymphoma, ovarian cancer, or pancreatic cancer. In their analysis of prostate cancer, they found 1 estimate of decreased risk and 1 of increased risk for advanced cancer. Fifteen other estimates showed no association.

Ritch et al studied a group of 148 Jamaican men because of the high incidence of cancer death and the very high intake of omega-6 fatty acids in this population. ^[16] They evaluated the relationship between the intake of dietary fatty acids and prostate cancer biopsy grade and volume and concluded that omega-6 fatty acids stimulated prostate cancer cell growth, whereas omega-3 fatty acids inhibited cancer cell growth.

Hormones and BMI

Prostate cancer is considered to be one of the cancers influenced by the hormonal environment. Perturbations in the sex steroids seem to play an important role in the genesis of prostate cancer, as they do in breast cancer. A greater BMI has been shown to be associated with lower serum levels of testosterone and sex hormone–binding globulin and with higher levels of estradiol. Serum levels of androstenedione are decreased, but the peripheral conversion of androstenedione to estrone and estradiol is increased.

Epidemiologic studies have suggested a correlation between red-meat intake and prostate cancer. Giovannucci et al reported that men with the highest intake of red meat were 2.64 times as likely to develop prostate cancer as men with the lowest intake. ^{[13, 17]}

The association between meat consumption and prostate cancer is particularly strong with meats that are cooked at high temperatures and charred, including processed meats such as sausages, bacon, and hot dogs. Longer cooking times, increased temperature, barbecuing, and frying of such meats produce larger amounts of compounds such as heterocyclic amines and N -nitrosamines. For example, the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is found in grilled beef, pork, chicken, lamb, fish, and processed meats. Heterocyclic amines and N -nitrosamines have been added to the list of potential carcinogens by the US Department of Health and Human Services.

In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, Cross et al found that neither the total amount of meat ingested nor the type of meat (ie, red, white) consumed was associated with prostate cancer risk. However, ingestion of more than 10 g daily of very–well-done meat increased the likelihood of disease by 1.4 times over no consumption. Moreover, men who were in the highest quintile for PhIP consumption were 1.2 times more likely to develop prostate cancer. ^[18]

Total energy consumption may be another important factor in the development of prostate cancer. Excessive caloric intake, regardless of its source, may lead to obesity, which correlates with an increased risk of prostate cancer.

Mukherjee et al demonstrated that in castrated and noncastrated mice, regardless of castration (which alone diminishes cancer growth), all of the groups in which energy intake was restricted developed cancers that were smaller and slower growing, had decreased microvessel density, and had a decreased cell-proliferation index. ^[19] In this study, cancer cells from the Dunning R3327-H and from LNCaP were transplanted into severe combined immunodeficiency (SCID) mice. Diet was not restricted in one group. A second group was castrated and subdivided into 2 subgroups—one with an energy-intake restriction of 20% and one with a restriction of 40%. Finally another group was not castrated but had caloric restriction.

On the basis of the results of a transgenic mouse model, Huffman et al ^[20] concluded that the ability of caloric restriction to inhibit cancer development and progression is partially mediated by changes in energy balance, body mass, and body composition rather than just caloric intake. This implies that the risk of developing prostate cancer depends more on excess caloric retention, which leads to obesity, rather than just excessive caloric consumption.

Although these data are compelling in animal models that can be carefully controlled, whether these results can be expected in humans is unknown.

An intriguing theory suggests a role for insulin in the promotion of cancer. Obese men with diabetes have been found to be less likely to develop prostate cancer. Insulin is an important growth factor, and levels of insulin growth factor and its receptor have been shown to be elevated in persons with prostate cancer. Keeping insulin values low may retard the growth rate of prostate cancer cells; this can be achieved only through diet.

A glycemic index has been developed for persons with diabetes, so that they can take advantage of the small amounts of insulin they may produce. This index ranks carbohydrates in different foods on a scale of 0-100, depending on how much those foods increase blood sugar levels after consumption. The consumption of low-glycemic foods lowers blood sugar levels and decreases insulin production. According to this theory, low levels of insulin growth factor would prevent cancer cells from growing as rapidly.

In the 1920s, Ohsawa popularized the concept of a macrobiotic diet, which produces about the lowest glycemic index. This stringent diet consists primarily of whole grains and vegetables. Even most fruits are excluded. In contrast, the diabetic diet restricts only those foods with the highest glycemic index, which includes foods such as the following:

• Dates
• Corn flakes
• Jelly beans
• Doughnuts
• White bread
• Table sugar
• White rice

Klein and colleagues at the Cleveland Clinic have produced a working hypothesis that shows the link between inflammation and prostate cancer. ^[21]Prostatic inflammation is associated with oxidative stress, which stimulates the production of reactive oxidative species (ROS) and reactive nitrogen species (RNS). These bind to DNA and cause mutations. Oxidative stress derived from endogenous and exogenous sources are associated with DNA damage that occurs with aging and plays a role in carcinogenesis. Polyunsaturated fatty acids induce the production of ROS, resulting in the formation of lipid radicals that can cause DNA damage. Semen can also be oxidative, because of the occasional presence of leukocytes and a substantial amount of polyunsaturated fatty acids.

Several mechanisms that can prevent and repair oxidative damage have been identified. Antioxidant enzymes such as phospholipase A-2 remove altered fatty acids, ROS, and RNS, preventing mutations. This one example of the beneficial effects of dietary antioxidants provides evidence that the consumption of foods that promote the production of ROS and RNS should be limited or avoided.

Vance et al reported that dietary antioxidant intake was inversely associated with levels of thioredoxin 1 (Trx 1), an enzyme and subcellular indicator of redox status, in benign prostate tissue in men with incident prostate cancer. Trx 1 levels were positively associated with the Gleason score in these patients. Thus, antioxidant intake may affect the redox status within prostate tissue, which in turn may influence prostate cancer aggressiveness. ^[22]

All of the dietary nutrients that may reduce the risk of developing prostate cancer are readily available. Whether substituting or adding dietary supplements is advantageous continues to be investigated. The general consensus is that any nutrient that is contained in food is better than an artificial supplement. However, quantifying the amount of these nutrients in serum and tissues has been difficult. Therefore, the necessary amount of a given supplement is unknown. Conflicting reports that are confusing to the public and to physicians frequently appear in the media. Differences in study populations, methodology, and interpretation of data complicate the comparison of studies.

Antioxidants such as beta carotene, vitamin A, and vitamin E are being taken with the goal of reducing oxidative damage and its potentially harmful effects. Many primary and secondary prevention trials have been conducted, but whether these supplements reduce oxidative damage is uncertain.

In a meta-analysis of 68 randomized trials involving 232,606 participants, Bjelakovic and colleagues found that beta carotene, vitamin A, and vitamin E significantly increased mortality rates whether taken alone or in combination. As for vitamin C and selenium, the investigators concluded that these antioxidants require further study. ^[23]

A study by Klein et al found a significant increase in the risk of prostate cancer among healthy men who took a dietary supplement of vitamin E. ^[24]

The Physicians’ Health Study II, a long-term, randomized, controlled trial involving male physicians, found that neither vitamin E nor vitamin C supplementation reduced the risk of cancer, whether prostate or otherwise. ^[25]

Carotenoids

Carotenoids are micronutrient antioxidants that are found in orange or yellow fruits and vegetables and in some dark, leafy vegetables, such as spinach and Brussels sprouts. The most common dietary carotenoids include beta carotene, alpha carotene, beta cryptoxanthin, lutein, zeaxanthin, and lycopene.

Lycopene, a beta carotene, is the most efficient antioxidant in this group and is the predominant carotenoid in the plasma and in various tissues, including the prostate. It is found in watermelon, tomato and all tomato-based products, pink grapefruit, apricots, papaya, guava, and persimmons. Carrots contain high levels of carotene but contain little lycopene.

Four large clinical trials that evaluated the role of beta carotene and the risk of developing prostate cancer indicated, in general, that the risk of prostate cancer is reduced in men with low serum levels of beta carotene who are treated with supplements. A high intake of tomato products (10 or more servings weekly) was associated with a 35% decreased risk of advanced prostate cancer; this was independent of fruit, vegetable, and olive oil intake.

Additional studies have reported that the incident risk of prostate cancer was reduced by 25-80%. Some other studies did not find this association, but some of these were conducted in populations in whom lycopene intake may have been too low to make an association. Studies comparing high and low intake of tomatoes reported a 10-20%, statistically significant reduction in prostate cancer risk in men with high intake. Cooked tomato products had a stronger effect than raw tomato products.

The other carotenoids seem to be beneficial but not to the degree that has been reported with lycopene. Lu et al reported a 70-80% reduction in prostate cancer risk in men with high levels of plasma lutein, beta-cryptoxanthin, and zeaxanthin. ^[26] The incidence of prostate cancer in men with low baseline levels of serum beta carotene or lycopene was reduced when their serum levels were corrected, but the risk was increased in those in whom the levels were already higher.

Cruciferous vegetables

Broccoli, cauliflower, cabbage, Brussels sprouts, bok choy, and kale have high levels of the anticarcinogenic phytochemicals sulforaphane and indole-3 carbinol. These nutrients induce the production of antioxidant enzymes that can protect cells from oxidative damage. Sulforaphane helps to induce apoptosis in damaged cells. In animal studies, indole-3 carbinol has been shown to exhibit antiproliferative and antimetastatic properties.

Findings from a study by Canene-Adams and coworkers implied that plant-derived nutrients are more beneficial in combination than alone. ^[27] The investigators studied the antitumor activity in the Dunning prostate-cancer animal model. They fed rats various combinations of tomatoes and broccoli and found that tumor growth was significantly reduced owing to reduced cancer cell proliferation and increased apoptosis.

Selenium

Selenium is an essential, nonmetallic trace element that is widely distributed throughout the body. It is a component of multiple antioxidant enzymes and participates in various functions. Epidemiologic studies indicate that selenium is a potential prostate cancer preventive and decreases the growth rate of prostate cancer cells. Plasma, serum, and tissue levels of selenium are inversely associated with the risk of developing prostate cancer.

Selenium is found in Brazil nuts, walnuts, fish (including canned tuna and shellfish), beef, turkey, chicken, eggs, whole grains, garlic, onions, broccoli, cabbage, and mushrooms. One of the problems in obtaining adequate dietary selenium is that the level of selenium in a given plant depends on the soil in which it is growing. For example, produce from the Imperial Valley has a higher selenium content than plants grown elsewhere.

Selenium has several forms, each of which may produce differing biologic effects. The protective activities of selenium compounds are thought to be mediated through a metabolite of selenium called methylselenol. Selenomethionine modulates transcript levels of genes involved in cell-cycle and apoptosis pathways, androgen signaling, signal transduction, and transcriptional regulation. At high concentrations, selenomethionine decreases expression of prostate-specific antigen (PSA). Studies with methylselenic acid have shown that similar biologic pathways are affected, but gene expression has distinct differences.

Animal experiments and epidemiologic evidence suggest that selenium has an anticarcinogenic effect due to its action on apoptotic pathways, inhibition of cell proliferation, and antiangiogenesis. Several studies have reported that high selenium levels confer a 50-65% reduction in the risk of prostate cancer over low selenium levels. The Nutrition Prevention of Cancer (NPC) trial reported that the incidence of prostate cancer in men who received selenium supplements was 50% less than in men who received placebo.

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) studied the effects of selenium (in the form of selenomethionine, 200μg daily) and vitamin E alone and in combination in over 35,000 men, but the study was terminated after an average of 5.5 years (SELECT was planned to include 7-12 years of follow-up) when initial results indicated no significant difference between the supplementation and placebo arms. There was a statistically insignificant trend toward more prostate cancer cases in men taking only vitamin E and more cases of diabetes in men taking only selenium. ^[28]

In their examination of the disparity between the results of the NPC trial and SELECT, the SELECT investigators noted that the NPC trial participants had deficient levels of selenium, and those with the lowest baseline selenium levels derived the most preventive effect, whereas SELECT participants generally were replete in selenium at baseline.

Vitamin E

Vitamin E is a mixture of various antioxidant tocopherols that are particularly effective against unsaturated fatty acids and that protect against oxidative cell membrane damage. It also seems to lower testosterone levels. Vitamin E is a lipid-soluble antioxidant found in vegetable oils, nut oils (eg, almonds, cottonseeds, safflowers, sunflowers), hazelnuts, sweet potatoes, whole grains, and leafy vegetables. Gamma tocopherol is the most prevalent form of vitamin E in the diet, whereas alpha tocopherol, found in dietary supplements, is the most biologically available form.

A report by Crispen et al supported the role of vitamin E as a chemopreventive. The investigators studied the mechanism of action of alpha-tocopherol succinate (vitamin E succinate). ^[29] They studied the transcription factors nuclear factor kappa B (NF-kappa-B) and activator protein-1 (AP-1), which are known to contribute to the development and progression of prostate cancer by regulating the genes involved in proliferation, apoptosis, angiogenesis, and metastasis. Their experiments with vitamin E succinate treatment revealed an inhibition of NF-kappa-B but an augmentation of AP-1. They also found that this treatment reduced the expression of interleukin (IL)–6, IL-8, and vascular endothelial growth factor (VEGF) and suppressed cell adhesion. Androgen-dependent LNCaP cells were sensitized to androgen deprivation.

The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study reported a 30-40% decrease in prostate cancer incidence and mortalityin men receiving 50 IU of alpha tocopherol daily, compared with placebo. ^[30] The preventive effect of alpha tocopherol supplementation continued several years post-trial and resulted in lower prostate cancer mortality. ^[31] The Health Professionals Follow-up Study reported a decreased risk of advanced prostate cancer. In both of these studies, the benefit was identified only in smokers. Studies of gamma tocopherol have shown variable responses.

The Prostate, Lung, Colorectal, and Ovarian Screening trial (PLCO) studied dietary vitamin E, beta carotene, and vitamin C intake and evaluated prostate cancer risk, but the results did not provide strong evidence for the ingestion of large amounts of antioxidants, either from the diet or from supplements, for the prevention of prostate cancer, although smokers did derive some benefit. This was a questionnaire study, and the doses reported by the participants varied.

The SELECT trial found no protective effect from vitamin E, taken alone or in combination with selenium. ^[28]

Vitamin D

The major and most important source of vitamin D is sunlight, but this vitamin is also contained in dairy products, eggs, vitamin D–fortified cereals, and fatty fish (such as salmon and tuna). Many men are vitamin-D deficient, and this substance can readily be measured in the serum.

In epidemiologic studies, associations of vitamin D levels and prostate cancer risk have been inconsistent. Analysis of 1,695 cases and 1,682 controls from the Prostate Cancer Prevention Trial showed that vitamin D may have different effects for different stages of prostate cancers, with higher serum levels of 25-hydroxyvitamin D (25[OH]D) modestly increasing risk of Gleason 2-6 disease but more substantially reducing risk of Gleason 8-10 prostate cancer. ^[32]

An epidemiologic study Giovannucci et al showed that most of the protective effect of vitamin D came from sunlight, and even a modest exposure to sunlight can provide adequate levels of vitamin D. Dietary supplements are available for persons in whom sunlight is not available or is restricted. However, the recommended dose of 400 IU daily is too low to maintain skeletal health and probably has limited anticancer effects. A dose of 400 IU raises serum levels a very small amount (3 ng/mL). Serum levels can be obtained and the dose titrated to reach normal levels.

In a 3-month study of vitamin D – deficient African-American men, an estimated dosage of 1640 IU/d of vitamin D₃ was needed to raise the plasma 25(OH)D concentration to ≥ 20 ng/mL in ≥ 97.5% of participants, and 4000 IU/d was needed to achieve concentrations ≥ 33 ng/mL in ≥ 80% of subjects. ^[33]

High-dose vitamin D has been combined with docetaxel (Taxotere) chemotherapy in the treatment of androgen-independent cancer in men. A new formulation of calcitriol, DN-101, has been used in clinical trials; this combination has shown benefit compared with docetaxel or high-dose vitamin D alone.

Isoflavones (soy)

Soy is a rich source of the isoflavones genistein, daidzein, and equol, which have been shown to affect cell-growth pathways and angiogenesis. Isoflavones have also been shown to affect the production and metabolism of androgen and estrogens, which play an important role in the development and progression of prostate cancer.

The traditional Western diet includes minimal soy consumption; as a result, few epidemiologic studies that provide useful recommendations have been performed. In animal studies, isoflavones have been shown to have a beneficial effect in the prevention and reduction in the growth rate of prostate cancer.

Polyphenols (green tea)

Polyphenols are found in varying amounts in most fruits and vegetables, as well as in green tea and red wine. These agents act via antioxidant, antiproliferative, and antiangiogenesis pathways and have proapoptotic effects.

Some of the more popular polyphenols have been the catechins in green tea, which have been shown to inhibit cancer cell growth in animal and epidemiologic studies. Epigallocatechin (EGCG), which is a principal ingredient in green tea leaves, interferes with biochemical reactions associated with cellular proliferation and enhances apoptosis. EGCG is a potent inhibitor of the carcinogenic heterocyclic amines (PhIP), which are produced from overcooked or charred meat. ^{[34, 35, 36, 37, 38]}

Commercially prepared green-tea extracts contain 60% polyphenols, the source of bioflavonoids, which are potent antioxidants. A study by Betuzzi et al suggested that such extracts may discourage the development of prostate cancer. The investigators administered either a placebo or 600 mg/day of green-tea extract to 60 men with high-grade prostatic intraepithelial neoplasia (HGPIN), a potential precursor for prostate cancer. ^[39] All of the men underwent repeat biopsy after 1 year, and only one of the 30 men in the treated group was found to have a cancer, compared with nine of the 30 in the placebo-treated group.

Calcium

Higher milk intake has been consistently shown to be associated with an increased risk of developing advanced prostate cancer. Whether this is related to the high fat content in milk or to the amount of calcium, or possibly to increased serum levels of insulin-like growth factor-I (IGF-I) has not been clarified. ^{[40, 9]}

Giovannucci et al hypothesized that the high calcium intake could lower 1,25(OH)2 vitamin-D levels, which would promote increased dedifferentiation of the cancer cells. ^[41] They examined the records of 47,750 men who were participating in the Health Professionals Follow-up Study. They found that dietary or supplemental calcium was independently associated with increased risk. More importantly, calcium intake of greater than 1500 mg daily was associated with lower vitamin-D2 levels and a higher risk of developing an aggressive cancer.

Gao et al also provided evidence suggesting that cancer risk is associated with calcium intake, ^[42] but Severi and colleagues obtained data from the Melbourne Collaborative Cohort Study that did not support this contention. ^[43] The interpretation of these findings is that calcium is good, but that too much may be harmful.

Zinc

Zinc is commonly used as a dietary supplement. Healthy individuals with a balanced diet consume about 11mg of zinc daily. Zinc is found in meat and nuts and in vegetables such as chickpeas and beans. Many individuals consume large amounts of supplemental zinc because of the possible health benefits that have been promoted by commercial interests.

The findings that zinc levels are decreased in men with prostate cancer and that zinc suppresses prostate cancer cell growth and invasion have led to the hypothesis that zinc may play a protective role. However, the Health Professionals Follow-Up Study showed an increased risk of prostate cancer in men who consumed more than 100 mg daily. ^[44] High-dose zinc has been shown to promote prostate cancer development. Studies of persons taking large amounts of zinc have also reported adverse effects on the urinary tract.

In a study of the relationship between zinc intake in black men and risk of prostate cancer by Mahmoud et al, prostate cancer patients had lower zinc intake, with a mean of 11 mg/day versus 14 mg/day, but comparison of tertiles of zinc intake showed a non-significant, non-linear increase in prostate cancer. A dose-response meta-analysis of 17 studies by these authors showed a non-linear trend in the relationship between zinc intake and prostate cancer. ^[45]

Ornish et al showed that in men with early, low-grade prostate cancer, lifestyle intervention consisting of a vegan diet supplemented with antioxidants, aerobic exercise, and stress-management techniques can lower PSA levels by a modest 0.25ng/mL (or 4%). ^[46]However, a reduction in PSA production does not always mean that the cancer cells have become inactive.

Dietary modifications, coupled with exercise and lifestyle modifications, may affect cancer growth rates. These measures can be used in concert with accepted therapy. Relying on diet alone to treat prostate cancer is unrealistic.

Source