Prostate Cancer, Nutrition, and Dietary Supplements
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Although nutrition plays a role in the development of prostate cancer, no specific diet can prevent or eradicate this disease. Prostate cancer, like other cancers, is an extremely complex process. No single factor (eg, diet) can explain the various facets of this disease. Nevertheless, the use of diet and dietary supplements for reducing the risk of developing prostate cancer or for treating prostate cancer continues to engage the interest of patients and researchers. [1]
Before discussing or recommending a dietary or lifestyle pattern that may help prevent prostate cancer or inhibit its progression, it would seem prudent to touch on probability, which should inform discussions of the role of nutrition in the prevention of any disease. Reviewing the most common causes of morbidity and mortality allows for an easier understanding of dietary changes that should be recommended in general.
Recommendations should be simple, logical, practical, and at the very least probability-based, similar to any other evidence-based medicine topic. Additionally, with any general dietary and lifestyle recommendations, the maxim “first do no harm” should also apply, given the history of some past recommendations—especially in the area of dietary supplements whose risk was ultimately found to outweigh their benefit.
In the United States, as in virtually every region of the world, cardiovascular disease (CVD) is the number one overall cause of mortality; indeed, CVD has been the leading cause of death in the US every single year since 1919. [2] Cancer is the second leading cause of death in the US and in most developed countries, and is expected to mirror the number of deaths from CVD in the future in various regions of the world. Currently, however, more than 300,000 US men die of CVD every year, [3] whereas fewer than 30,000 die from prostate cancer. [4]
Thus, for the average US man, CVD prevention should take precedence over prostate cancer prevention, based on probability and cumulative research. Fortunately, most of what is known concerning lifestyle and dietary change for CVD prevention appears to directly apply to cancer prevention. [5, 6]
The largest US and worldwide trials of pharmaceutical-based prostate cancer primary prevention exemplify the urgent need for a more proper and balanced perspective. For example, results of the Prostate Cancer Prevention Trial (PCPT) garnered attention plus controversy regarding the use of finasteride daily versus placebo to reduce the risk of prostate cancer. [7, 8, 9, 10] However, the results also provided information that has not received adequate exposure and debate in the medical literature: Of the more than 18,000 men included in this randomized trial, 5 men died from prostate cancer in the finasteride and in the placebo arm, but 1123 men in total died. [7] Thus, prostate cancer was responsible for less than 1% of the deaths; the majority of deaths were from CVD and other non-prostate causes.
The largest clinical trial ever conducted on the use of dietary supplements to prevent cancer was the selenium and vitamin E supplementation randomized trial (SELECT). [11] It was terminated approximately 7 years early because of a lack of efficacy, and even a potential negative impact with these supplements at the dosages used. Once again, CVD represented the primary cause of mortality overall in this study, with over 500 deaths from this cause compared with a single death from prostate cancer in 5 years of follow-up. In short, every prostate cancer study with survival as the endpoint has found that most patients die of causes other than prostate cancer, mostly CVD.
With that in mind, the lifestyle recommendations proffered in this article are intended to serve CVD and prostate health simultaneously. Lifestyle or dietary changes that can potentially impact all-cause morbidity and mortality rather than just disease-specific morbidity and mortality again appear to provide the greatest benefit-to-risk ratio. The principal message from nutritional studies in humans has been an endorsement of the benefits of a diet consisting mainly of vegetables, fruits, fiber, and fish, combined with restricted caloric intake and/or exercise to maintain or achieve a healthy weight.
These measures have been associated with a reduced cancer mortality, although no studies have indicated that they can slow the growth of an existing cancer. [12] However, evidence has shown that these dietary measures are effective in reducing the risk of death from CVD. Therefore, the possible merits of nutritional measures in preventing prostate cancer are compounded by their proven merits with regard to CVD.
Ideally, individuals should adopt this type of diet when they are young. Unfortunately, that has not been happening; even with the widespread publicity about the dangers of an improper diet, rates of obesity and diabetes are increasing. [13]
The diagnosis of prostate cancer can be a trigger for dietary improvement, however. 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. [14]
Interestingly, clinicians dealing with prostate cancer patients are at times understandably questioned by these same patients or their family members about what they can tell their sons about prostate cancer prevention, now that there is a family history of the disease. In such cases, the emphasis on reducing CVD risk to as close to zero as possible is often initially surprising to patients and their families, but when the preventive effect on both CVD and cancer—the so-called 2-for-1 benefit—is explained, it seems likely to increase the chances of compliance within the family.
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 at least 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. [15]
Heart-healthy dietary patterns appear to be garnering the most attention for their efficacy in preventing prostate cancer or other cancer. They also appear to have the added benefit of increasing longevity or reducing all-cause mortality. One example is the Mediterranean diet, which consists largely of fruits and vegetables, nuts, grains, olive oil, and chicken and seafood (lean sources of protein). 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. [12]
This is not meant to imply that a Mediterranean diet offers the only route to heart-healthy changes. Rather, there are numerous dietary patterns that promote improvement in parameters such as blood pressure, cholesterol and blood glucose levels, and weight/waist size, and arguably could impact prostate cancer incidence. The patient’s personal preferences and likelihood of adherence should help guide the decision of which pattern to follow. This is especially relevant when discussing weight loss and obesity.
Obesity is one of the strongest dietary/lifestyle factors associated with prostate cancer. Numerous studies have shown that obese men have a greater risk of developing more aggressive prostate cancer, experiencing disease recurrence despite surgery or radiation therapy, and dying of prostate cancer. [16] For example, in the Health Professionals Follow-up Study (HPFS), long-term weight gain after a diagnosis of localized prostate cancer was associated with an increased risk of lethal prostate cancer in non-smokers. [17]
Another issue that needs more attention is the correlation between obesity and prostate size or volume. [18] Since weight gain can increase prostate size, it can also reduce the ability of standard biopsies to detect cancer at an earlier stage. Also, with increasing prostate size comes increased secretion of prostate-specific antigen (PSA) from non-cancerous prostate tissue, thus providing a more potentially confusing picture for the clinician and patient. If preventing weight gain could reduce prostate enlargement in some men, that alone could provide substantial clinical benefits.
Some of the best data to support an ideal weight loss diet also can be derived from cardiovascular medicine research, such as the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) study, which was one of the longest (2-years) randomized trials. [19, 20, 21] The results of this and other studies suggest that the “end justifying the means” philosophy appears to be the most beneficial. In other words, as long as an individual can maintain reduced caloric consumption over the long term and weight loss actually occurs, the cardiovascular benefits appear to be similar regardless of the type of diet or macronutrient distribution involved.
Again, adherence is key. Whether a reduced-calorie, low-fat, higher-fat, moderate-protein, or higher-protein approach is selected should be based on individual preference, knowing that long-term significant weight loss (the end result) substantiates the method chosen (the means).
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 prostate cancer 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. [22] The same was true in Hawaiian men; the highest prevalence of prostate cancer was in men with the highest intake of saturated fat. [23]
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. [24]
In an animal study by Wang et al, a low-fat diet decreased the growth of prostate tumor cells. [25] 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 which 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.
If higher fat intakes are associated with prostate cancer in older studies, why do more recent and more extensive cohort studies and a meta-analysis [26] show minimal to no correlation at best? Perhaps the reduction in saturated fat and replacement with unsaturated fats has provided protection, as was observed in numerous cardiovascular studies. [27] Perhaps it is the need to adjust for countless variables, such as smoking status, overall caloric intake, age, family history, physical activity levels, alcohol consumption, types of fat (eg, omega-3, omega-6), fruit, vegetable, and fiber consumption, and fat-soluble nutrient intake. Thus, it is possible that in older studies, fat consumption may have been a marker or indicator for unhealthy overall behavior (eg, higher caloric intake, less physical activity, smoking).
Still, it is intriguing that numerous clinical trials have begun examining the impact of higher fat consumption or a ketogenic diet on prostate cancer progression. It seems plausible that if higher fat intake can lead to heart-healthy parameter changes (eg, reduced blood pressure, cholesterol, blood sugar, weight/waist size, inflammation) then the potential for success should somewhat rival what is observed with other heart-healthy dietary programs.
At the other extreme, many adverse cardiovascular risk factors appear to increase prostate cancer risk and/or aggressiveness. For example, men with metabolic syndrome have been shown to have a higher incidence of prostate cancer, and potentially more aggressive disease at the time of diagnosis. [28]
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, as noted above.
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, for example, 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. The POUNDS LOST trial suggests similar changes in some of these metabolic markers with a reduced caloric intake and weight loss. [20]
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, in animal and epidemiologic studies. Whether the omega-3 fatty acids themselves or the ratio between omega-3 and omega-6 is important has not been elucidated.
Some nutrient tests, such as these omega-index measurements, are promoted to suggest that a favorable alteration reduces disease risk. In fact, the value of these omega-marker tests in prostate cancer is controversial and needs further study. Some cohort studies suggest reduced risk of aggressive prostate cancer with increasing consumption of omega-3.
Other blood marker data from trials such as the Prostate Cancer Prevention Trial suggest increased risk of prostate cancer with greater omega-3 intake, which was an ancillary observation but still important follow in the future, especially in regard to the impact of supplemental omega-3 and cancer risk. [29, 30] Multiple studies of omega-3 fatty acids and heart health are being conducted, and their results and secondary endpoints should provide more clarity in the area of cancer research.
Although marine sources of omega-3 fatty acids receive a good deal of attention, perhaps because of the popularity of these dietary supplements, healthy plant sources of omega-3 fatty acids exist (eg, nuts, seeds). These also appear to be heart healthy and provide other healthy components such as fiber, which has been associated with a lower risk of prostate cancer in some studies.
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 higher body mass index (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.
The increase in BMI and change in hormone status could shift the human body into a pro-inflammatory state, which also could be a cause for concern. In addition, the potentially large reductions in testosterone that can occur with weight gain could provide a partial androgen deprivation akin to the androgen deprivation therapy used for advanced prostate cancer. While in the short term this could reduce the risk of an incident prostate cancer, in the long term it could increase the risk of aggressive disease. [31]
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. [24, 32]
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. [33]
Like fat consumption, meat consumption may simply be a marker of an overall unhealthy lifestyle in some individuals. Consumption of fried food, which has been suggested to increase the risk for prostate cancer, may be a similar marker of risk. [34] Nevertheless, given the documented link between fried food consumption and increased risk of cardiovascular disease, including a recommendation to limit consumption of fried food would seem reasonable advice for a patient seeking to reduce prostate cancer risk.
Meat consumption cannot be construed as an “all or nothing” exercise, however, since the popularity of higher protein and so-called paleo diets has provided another path whereby individuals can lose weight and potentially improve heart health. However, men who currently consume substantial amounts of meat or processed meat and who are gaining weight or are unable to lose weight may find that shifting their diet toward leaner meats or to a plant-based diet could be beneficial.
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. [35] 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 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. [36] 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 similar results can be expected in humans is unknown. However, the favorable data from cardiovascular research suggests that using reduced total energy consumption to maintain or achieve a healthy weight would provide significant value.
An intriguing theory suggests a role for insulin in the promotion of 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 comprises foods with a very low 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, such as the following:
The renewed focus on the role of insulin in preventing or slowing the progression of prostate cancer and other cancers is exemplified by the interest in using metformin for that purpose. [6, 37, 38] Nevertheless, while the Diabetes Prevention Program trial demonstrated that metformin has the ability to prevent type 2 diabetes, an underappreciated finding of that trial was the profound reduction in diabetes risk produced by lifestyle changes (a low-fat diet with total caloric reduction of 450 calories/day and 150 minutes of exercise/week). In fact, lifestyle changes proved significantly more effective than metformin for diabetes prevention (58% versus 31% reduction). [39] Once again, this illustrates the value of an integrated approach to health promotion and disease prevention.
Klein and colleagues at the Cleveland Clinic have produced a working hypothesis that shows the link between inflammation and prostate cancer. [40] 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. [41]
In general, risk factors for cardiovascular disease (eg, elevation in weight, blood pressure, and blood cholesterol and glucose levels) involve increased chronic inflammation. Several drugs with established roles in cardiovascular prevention have pleiotropic effects that include anti-inflammatory activity and are being studied for prevention of prostate and other cancers, as well as for adjuvant cancer treatment. Notable examples are statins, aspirin, and metformin (SAM). [6]
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 dietary supplement. In addition, several dietary supplements that are marketed as antioxidents have the potential, if used in excess, to increase the risk and/or progression of prostate cancer. [6, 31, 42, 43] No high-quality study has shown that any supplement can significantly reduce the risk for, or progression of, prostate cancer.
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.
The reliability of nutrient testing is also an issue. Countless nutrient or antioxidant tests are offered today to consumers who are concerned about cancer, yet the validity of many of these tests—especially as they relate to cancer and other “hard endpoints”—is unknown. Unanswered questions include the following:
Those and other critical questions should be answered before consumers spend their money on these tests. A few examples can help illustrate the complexity of nutrient testing, which has yet to be fully appreciated.
For example, use of dietary supplements containing large amounts of biotin (marketed as promoting healthy hair, skin, and nails) may interfere with a variety of laboratory tests that are biotin based. High biotin intake may result in artifactually low results on PSA assays, as well as other cancer marker tests (eg, CA125, CA15-3, CEA, CA19). (False increases in thyroid function test results and vitamin B12 assays have also been reported. [44] )
Given the plethora of tests that may be impacted, patients should be advised to stop taking an individual biotin supplement at least 3 days (and perhaps ideally 1 week) before blood testing. Multivitamins that include biotin are usually not a cause for concern.
Systemic inflammation may result in low values on tests for nutrients such as zinc; selenium; and vitamins B6, C, A, and D. [45] This effect may skew interpretation of research findings because it can suggest that a nutrient deficiency increases the risk for a particular disease when in fact the disease itself is decreasing the measured nutrient level.
Vitamin D blood measurements, in particular, may be reduced not only by inflammation but by obesity, smoking, depression, cancer, and lack of physical activity. [43, 45, 46, 47] This could partly explain the lack of an effect of supplementation in some major clinical trials; that is, the inflammatory state may be creating the appearance of a vitamin D insufficiency or deficiency in individuals with adequate vitamin D intake.
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 the following:
Lycopene is one of the predominant carotenoids in 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.
Clinical trials that evaluated the role of beta carotene and the risk of developing prostate cancer have 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. However, those findings were generally not from the trials’ primary endpoints.
Overall, individual beta-carotene supplements have proved disappointing in their ability to reduce cancer risk. In fact, two large phase III clinical trials (the Alpha-Tocopherol, Beta-Carotene Cancer Prevention [ATBC] [48] and the Beta-Carotene and Retinol Efficacy Trial [CARET] [49] ) raised the possibility that beta-carotene supplements may increase the risk of lung cancer in current smokers, and the Age-Related Eye Disease Study 2 (AREDS2) suggested a potential increase in the risk of lung cancer in former smokers. [50]
Note that beta-carotenes from dietary sources have not been associated with an increased risk of lung cancer. Patients concerned about beta-carotene study results can be reassured that the adverse findings apply only to individual dietary supplements.
A high intake of tomato products (10 or more servings weekly) has been 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%. Other studies did not find this association, but some of those were conducted in populations in whom lycopene intake may have been too low to make an association. [51]
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. [51]
In contrast with those older dietary data, however, current data (from pooled analysis of prospective studies and updated robust epidemiologic studies) suggest that consumption of tomato products, as well as most other fruits and vegetables, has minimal to no effect on prostate cancer risk. [52, 53] Regardless, the potential for fruits and vegetables to reduce cardiovascular risk and potentially assist with weight loss should be emphasized while more research in the area of cancer prevention is being conducted. Other carotenoids such as lutein, beta-cryptoxanthin, and zeaxanthin need more research.
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. [54] 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.
However, as with beta-carotenes, recent pooled prospective studies have found that consumption of cruciferous vegetables has minimal effect on prostate cancer risk. [55] Again, however, this does not negate the general findings that vegetables are not only heart healthy but are the cornerstone of many potentially successful weight loss dietary plans.
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 in California 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, 200 μg 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. [56]
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.
Additionally, clinical trials of individual selenium supplements in patients at high risk for prostate cancer or with localized prostate cancer have demonstrated no impact on disease progression, and even the possibility of increased risk for disease progression and mortality with high-dose supplementation. [57, 58, 59, 60, 61] This is another reason no individual high-dose antioxidant supplement can currently be promoted for reducing prostate cancer risk.
Of further interest is that in the SELECT trial, selenium supplementation did not reduce prostate cancer risk in men with baseline low selenium status but selenium supplementation in men already replete with selenium from dietary sources increased their risk for aggressive prostate cancer. [62] Again, these findings support the value of emphasizing dietary sources of selenium over individual supplement use for prostate cancer prevention.
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, almond, cottonseed, safflower, sunflower), 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.
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study reported a 30-40% decrease in prostate cancer incidence and mortality in men receiving 50 IU of alpha tocopherol daily, compared with placebo. [63] The preventive effect of alpha tocopherol supplementation continued several years post-trial and resulted in lower prostate cancer mortality. [64] 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.
It should be noted that the risk for some nutrient deficiencies is higher in current smokers than in nonsmokers. This suggests the study of whether improving the status of some primary antioxidant nutrients in smokers would reduce the risk for prostate cancer. Of course, regardless of what such research might determine, the impact of quitting smoking on reduction of all-cause morbidity and mortality should be heavily emphasized over any discussion of potential supplementation.
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. Ultimately, SELECT found a significant increase in the risk of prostate cancer in healthy men who took a vitamin E supplement. [56]
To the credit of the SELECT research group, participant follow-up continued (54,464 added person-years), which provided data on outcomes after cessation of dietary supplementation. [65] This follow-up period revealed potential harm from supplement use, and perhaps helped change the perception that dietary supplement use in healthy populations is innocuous.
A significant (P=0.008; hazard ratio [HR]=1.17) increased risk of prostate cancer was found in the vitamin E group, but not in the selenium or combination intervention arm. More concerning was a trend toward increased risk of Gleason 7 or higher disease in the intervention arms compared with the placebo group, although that did not reach statistical significance in any group. The increased risk of prostate cancer with vitamin E began to emerge after only 3 years, and was found to be consistent for low- and high-grade disease types—so conceivably, the risk might have attained statistical significance if the trial had continued for several more years.
The negative results from SELECT cannot be explained by bias or increased biopsy rates. Rather, they suggest that the dietary supplements themselves are the issue, and the confidence intervals have only continued to narrow with time.
The Physicians’ Health Study II (PHSII), a long-term, randomized, controlled trial involving male physicians, found that neither vitamin E nor vitamin C supplementation reduced the risk of prostate cancer or other cancers. [66] The potential for vitamin E supplements to increase the risk of bleeding events (hemorrhagic stroke, HR=1.74; p=0.04) was also observed in this trial. [67]
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. Serum 25-hydroxyvitamin D assays are readily available, and many men test as vitamin-D deficient. As discussed above, however, that assay can be influenced by multiple intrinsic and extrinsic factors (eg, smoking, obesity, inflammation). Consequently, this test should not be widely advocated until further validation with so-called hard clinical endpoints has been accomplished.
Guidelines on vitamin D from the Institute of Medicine (IOM), published in 2011, set the Recommended Dietary Allowance for vitamin D at only 600 IU (800 IU in those age 71 and older), because of the concern for toxicity (eg, hypercalcemia, hypercalciuria, nephrolithiasis) and the lack of impressive data to advocate for higher amounts. [68, 69] Admittedly, the IOM recommendations have not been without controversy. [70]
Vitamin D appears to have some of the same historical embellishment issues that occurred before randomized trials of other dietary supplements for prostate cancer, when some clinicians and patients believed that “the more the better”. In fact, results of studies of vitamin D for prostate cancer prevention have not been consistently impressive, and several studies have found no impact or potential harm at higher blood levels. [71, 72, 73]
Vitamin D is important for bone health, but recommendations for higher intakes to support prostate health have not been supported by strong clinical trial evidence. Vitamin D tends to mimic the function of a hormone, which is why caution should be followed because the potential for a U-shaped risk curve (similar to that seen with other hormones, and even alcohol) does exist for men’s health.
It may be tempting to endorse the general findings of an increased risk of prostate cancer mortality with lower vitamin D blood status, but again the issues with the assay and the history of prostate cancer supplements being discredited argue for a “first do no harm” approach until larger trials are published that give further insight. Clinical trials such as the VITamin D and OmegA-3 TriaL (VITAL) [74] should be published soon and they will provide further insight into the benefits and limitations of vitamin D supplementation to prevent cancer.
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 amounts of soy, and 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.
Still, not enough data have accumulated to recommend soy products for prostate cancer prevention. However, soy can be a part of a protein-based or plant-based diet to reduce the risk of cardiovascular disease.
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. [75, 76, 77]
Some preliminary epidemiologic data support increasing green tea and/or EGCG consumption to reduce the risk of prostate cancer. [78] In addition, some preliminary research also suggests that coffee consumption may help to prevent prostate cancer or aggressive prostate cancer. [79] Still, the question remains whether these low-caloric beverages have tangible anti-cancer properties or are just markers of overall healthy behaviors that could cumulatively be responsible for a lower prostate cancer risk. This will be difficult to answer any time soon, but consuming low-caloric beverages to help maintain or achieve a healthy weight is a reasonable recommendation.
Initial observational data on pomegranate juice or extracts suggested a benefit for prostate cancer prevention. Placebo-controlled trials have not demonstrated a consistent impact on prostate cancer, however, and pomegranate juice can contain larger amounts of calories than beverages such as green tea. Thus, the use of pomegranate for prostate cancer prevention cannot currently be supported. [80, 81, 82]
Higher milk intake has been shown to be associated with an increased risk of developing advanced prostate cancer. Whether this is related to the high fat or even caloric 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. [83, 84]
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. [85] Their examination of the records of 47,750 men who were participating in the Health Professionals Follow-up Study 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, [86] but Severi and colleagues obtained data from the Melbourne Collaborative Cohort Study that did not support this contention. [87] The interpretation of these findings is that calcium is good, but that too much may be harmful.
Consumers and clinicians need to be aware of the increasing fortified and natural sources of calcium in the food supply and ideally should work with a dietician to calculate their average daily intake of dietary calcium from foods and beverages (eg, fish, vegetables, milk alternatives). For example, numerous milk alternatives—such as almond, cashew, hemp, and soy milk—contain 400-500 mg of calcium per 8 ounces.
Randomized trials in the general population (eg, the Women’s Health Initiative trials) have shown that many individuals consume the recommended amounts of dietary calcium (1000-1200 mg/day) and thus have no need for dietary supplementation. [43] In addition, normalizing calcium intake using dietary sources carries no significant or consistent increased risk of stone disease compared with excessive intake of calcium supplements, which has been associated with an increased risk of stone disease, as well as constipation.
Zinc is commonly used as a dietary supplement. Healthy individuals with a balanced diet consume about 11 mg 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. [88] 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. [89] Thus, there is no compelling reason to supplement with zinc for prostate health; the amount contained in the diet, with or without a multivitamin (usually the recommended daily allowance), is normally sufficient.
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 prostate-specific antigen (PSA) levels by a modest 0.25 ng/mL (or 4%). [90] However, a reduction in PSA production does not always mean that the cancer cells have become inactive.
One of the most interesting, and possibly underappreciated, observations from the Ornish trial is that dietary changes alone appeared to reduce low-density lipoprotein (LDL) cholesterol levels as much as a low to moderate dose of a statin. Indeed, cardiovascular health could be tantamount to prostate health.
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, but using diet to improve overall quality and length of life, especially in regard to the leading cause of mortality in men and women, is realistic and should be constantly encouraged and embraced. With dietary supplements and cancer prevention, the current mantras of “first do no harm” and “less is more” appear to make more sense. There appear to be more supporting data for using individual dietary supplements to reduce specific side effects of cancer treatment, such as taking American ginseng to reduce cancer-related fatigue (CRF). [91, 92]
In addition, only one extensive randomized, placebo-controlled trial has studied the cancer-preventive effect of a single daily multivitamin (Centrum Silver) in healthy men. The Physicians’ Health Study II (PHSII), which followed over 14,000 participants for 11.2 years, found an 8% reduction in the risk of cancer with multivitamin use (a primary endpoint). [93]
Although the reduction was statistically significant, some would argue that it is not clinically significant. Nevertheless, PHSII showed no increase in prostate cancer incidence or mortality in the multivitamin arm. In fact, there was a non-significant reduction in those outcomes, especially in men with a baseline history of cancer, and a non-significant reduction in fatal cancers overall. Other secondary benefits were found, such as a small but significant reduction in cataracts. [94]
Multivitamin use also has the ability to reduce subtle deficiencies, as may develop in patients taking medications (eg, metformin, histamine 2 blockers, proton pump inhibitors) that can profoundly reduce levels of important nutrients such as vitamin B12 and magnesium. [95]
However, patients who want to use multivitamins for prostate cancer prevention should be warned that more is not better: in some of the largest epidemiologic studies, taking more than one multivitamin pill per day has been associated with an increased risk of aggressive prostate cancer. [96]
Seeking dietary and lifestyle solutions that promote cardiovascular health is a sound guide to measures that could also potentially reduce the risk of prostate cancer. Prominent among those is exercise. Substantial and compelling data support the ability of regular exercise to help prevent prostate cancer or reduce its progression—and this in the context of reducing all-cause morbidity and mortality. If for no other reason, the mental health improvement observed with exercise should encourage readers to incorporate regular physical activity to potentially reduce stress, anxiety, and depression.
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Mark A Moyad, MD, MPH Research Associate, Phil F Director of Complementary and Alternative Medicine, Department of Urology, University of Michigan Medical Center
Disclosure: Received honoraria from Abbott Labs for speaking and teaching; Received consulting fee from Farr Labs for consulting; Received consulting fee from Guthy Renker for consulting; Received royalty from Guthy Renker for other.
Stanley A Brosman, MD Clinical Professor, Department of Urology, University of California, Los Angeles, David Geffen School of Medicine
Stanley A Brosman, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Urological Association, Society for Basic Urologic Research, Society of Surgical Oncology, Society of Urologic Oncology, Western Section of the American Urological Association, Association of Clinical Research Professionals, American Society of Clinical Oncology, International Society of Urology, International Society of Urological Pathology
Disclosure: Nothing to disclose.
Edward David Kim, MD, FACS Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center
Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, Sexual Medicine Society of North America, Tennessee Medical Association
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Endo, Avadel.
Gamal Mostafa Ghoniem, MD, FACS Professor of Urology, Chief, Division of Female Urology, Pelvic Reconstructive Surgery, and Voiding Dysfunction, Department of Urology, University of California, Irvine, School of Medicine
Gamal Mostafa Ghoniem, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urogynecologic Society, American Urological Association, International Continence Society, International Urogynaecology Association, and Society of Urodynamics and Female Urology
Disclosure: Astellas Honoraria Speaking and teaching; Coloplasty Consulting fee Board membership; Uroplasty Consulting fee Consulting
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Prostate Cancer, Nutrition, and Dietary Supplements
Research & References of Prostate Cancer, Nutrition, and Dietary Supplements|A&C Accounting And Tax Services
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