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R EVI E W A R T IC L E BJUI Prostate cancer and diet: food for thought? BJU INTERNATIONAL Satoshi Hori, Elizabeth Butler* and John McLoughlin† Department of Uro-oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, *Department of Nutrition, Penny Brohn Cancer Care, Chapel Pill Lane, Bristol, and †Departments of Urology, West Suffolk Hospital, Bury St. Edmunds and Addenbrooke’s Hospital, Cambridge, UK Accepted for publication 12 August 2010 What’s known on the subject? and What does the study add? There has been increasing recognition that diet plays an important role in the pathogenesis of prostate cancer. Despite this, the largely heterogenous nature of prostate cancer and nutritional research often means that no definitive conclusions can be drawn for those seeking answers in this important topic. In this review article, we summarize the key evidence available in this topic to date. Although we found mounting evidence on certain nutritional components being important in prostate cancer prevention and progression, further high quality studies are needed to fully understand the complex nature of diet and prostate cancer. • There is now increasing evidence that diet plays a major role in prostate cancer biology and tumorigenesis. • In a health conscious society, it is becoming increasingly common for Urologists to be asked about the impact of diet on prostate cancer. • In the present review, we explore the current evidence for the role of different dietary components and its’ effect on prostate cancer prevention and progression. • A literature search was conducted using PubMed® to identify key studies. • There was some evidence to suggest that green tea, isoflavones, lycopenes, cruciferous vegetables and omega 3 polyunsaturated fatty acid intake to be beneficial in the prevention and/or progression of prostate cancer. • There was also evidence to suggest that a high total fat, meat (especially well cooked) and multivitamin intake may be associated with an increased risk of developing prostate cancer. • To date publications have been highly heterogeneous and variable in quality and design. More robust, high quality research trials are needed to help us understand the complex relationship between diet and prostate cancer. KEYWORDS diet, dietary supplements, prostatic neoplasms, prevention, recurrence INTRODUCTION Prostate cancer is the commonest male malignancy in the UK with 46 924 new cases reported in 2008 and is the second leading cause of mortality after lung cancer [1]. There is now increasing recognition that the Western diet, together with other lifestyle factors such as physical activity levels, may be a significant risk factor in the development of prostate cancer. The Western diet tends to be high in animal products and processed, refined foods resulting in a high intake of saturated fats, processed polyunsaturated fats (such as the trans fats) and refined carbohydrates. In addition, the Western diet is often low in fresh vegetables, fruit, pulses and whole grains resulting in a low intake of fibre and phytonutrients. Overall, the Western diet is often calorie-dense but lacking in certain essential nutrients. By contrast, in Far Eastern countries, e.g. Japan and China, where the incidence of prostate cancer is lower, the traditional diet is mainly plant-based and minimally processed or refined. Relatively small amounts of animal products accompany the vegetables, fruit and other plant foods and overall the diet is lower in calories than the Western diet but is likely to contain greater amounts of certain essential nutrients. Particular foods that feature more heavily in a traditional Far Eastern diet 1348 © BJU INTERNATIONAL © 2 0 11 T H E A U T H O R S 2 0 11 B J U I N T E R N A T I O N A L | 1 0 7 , 1 3 4 8 – 1 3 6 0 | doi:10.1111/j.1464-410X.2010.09897,10321.x PROSTATE CANCER AND DIET that may have an impact on prostate cancer risk include green tea, soy and cruciferous vegetables. Epidemiological studies on migrant populations from Japan and China to the USA have found that the rate of prostate cancer in these men was higher compared with men in their native countries. By the second generation, their incidence rate was fast approaching those of the average American [2,3]. These studies suggest a strong environmental factor in the development of prostate cancer. With an ever increasing source of information available from the internet and mass media, our patients have become better informed about the health benefits associated with dietary and lifestyle modifications. Indeed the sheer number of studies available on this subject means that there are often no clear-cut answers for patients and their family seeking answers regarding the effect of diet and prostate cancer. Thus, it is of importance that Urologists are aware of the current evidence to appropriately counsel patients seeking advice on this frequently asked topic. In the present article, we focus on reviewing the current evidence for different dietary components and its’ impact on prostate cancer prevention and progression. METHODS A literature search was performed on PubMed® until May 2010 to identify key studies investigating the association between dietary components and prostate cancer. The search terms included: diet, dietary, nutrition, supplement, prostate, prostatic neoplasm, prevention, progression, green tea, polyphenol, soy, phytooestrogen, tomato, lycopene, vegetable, vitamin, selenium, calcium, dairy, fish, omega-3, omega-6, fatty acid, fat, meat, heterocyclic amine and carbohydrate. The search was limited to publications in the English language. To limit the size of this review, results from randomised controlled trials (RCTs) were © favoured over observational studies due to the higher quality of methodological design. Additionally, results from systematic reviews or meta-analysis of RCTs/observational studies were given preference to quoting individual studies where appropriate. Lifestyle interventions and prostate cancer was not included in our search as it is beyond the scope of this article. RESULTS Green tea Green tea plays a major role in the oriental diet and has been consumed in the Far East for several thousand years. Green tea, derived from the plant Camellia sinensis, contains polyphenolic compounds, which have previously been suggested to decrease the risk and slow the progression of prostate cancer in vitro and in vivo [4]. The most abundant and the best studied polyphenolic compound is (−)-epigallocatechin-3-gallate (EGCG), an antioxidant that is 25–100 times more potent than Vitamin C and E [5]. Suggested mechanisms of the anti-tumourigenic action of green tea include apoptosis and cell cycle arrest via alterations in the mitogen-activated protein kinase, phosphatidylinositol-3-kinase (PI3K)/Akt and protein kinase C pathways, inhibition of inflammatory pathways [nuclear factor κB and cyclooxygenase-2 (COX-2)] and modulation of the insulin-like growth factor (IGF) and androgen receptor (AR) axes [6]. To date, clinical studies have yielded some promising results. A large prospective cohort study of 49 920 men aged 40–69 years and their green tea consumption habits was conducted by the Japan Public Health Centre between 1990 and 2004 [7]. During this time, there were 404 cases of newly diagnosed prostate cancer of which 114 cases were advanced, 271 were localized and 19 were of an undetermined stage. The results indicate that there may be a dose-dependent decrease in the risk of advanced prostate cancer in men who consume > 5 cups of green tea per day [relative risk (RR) 0.52]. Bettuzzi et al. [8] in a small proof-of-principle trial, set out to assess the efficacy of daily green tea supplement in patients at a higher risk of developing prostate cancer. In all, 60 patients with highgrade prostatic intraepithelial neoplasia (HGPIN) were randomized to receive daily green tea supplementation vs placebo. The authors reported that there was a highly significant reduction in the incidence of prostate cancer in the group given daily green tea supplements compared with the group who took placebo alone [nine of 30 (30%) vs one of 30 (3%)]. In addition, the PSA values in the green tea supplement group remained constantly lower than those given placebo alone, although this was not statistically significant. A few studies have also investigated the role of green tea in patients with confirmed prostate cancer. In a multicentre, single-arm, open-label Phase II trial, the effect of green tea powder supplementation was evaluated in 42 patients with metastatic castrationresistant prostate cancer (CRPC) [9]. Of the 42 patients evaluated in this study, only one 2 0 11 T H E A U T H O R S BJU INTERNATIONAL © 2 0 11 B J U I N T E R N A T I O N A L 1349 H O R I ET AL. to the same conclusion [odds ratio (OR) 0.69, 95% CI 0.57–0.84]. had a > 50% reduction in PSA level after supplementation with green tea powder. For the rest of the cohort, there was a median increase of 43% in PSA level from baseline to the end of the first month after commencement of supplementation. Another similar study by Choan et al. [10] evaluated the role of green tea supplementation at a dose of 250 mg given orally twice daily in patients with CRPC. This study also yielded disappointing results, with no patients achieving a significant reduction in their PSA levels. In conclusion, although green tea appears to have some benefit in the prevention of prostate cancer, there is no data currently supporting the increased consumption of green tea amongst men with confirmed prostate cancer. Soy phytooestrogens Interest in soy phytooestrogens stem mainly from epidemiological findings that a lower incidence of prostate cancer occurs in Far Eastern countries where the consumption of soy products are typically high. Phytooestrogens are a group of biologically active plant compounds with a chemical structure similar to oestradiol [11] of which, isoflavones are the most important. Food sources rich in isoflavones include soy bean, tofu, kidney beans, chick peas, lentils and peanuts. Isoflavones have been shown to alter the expression of numerous genes associated with prostate cancer [12] and is postulated to work mainly through its’ oestrogenic effect, binding to oestrogen receptors and thereby suppressing cellular proliferation and promoting differentiation in vitro and in vivo [13]. Several clinical studies have investigated the role of isoflavones in prostate cancer prevention. A metaanalysis by Yan and Spitznagel [14] ‘Several clinical studies have investigated the based on eight role of isoflavones in prostate cancer prevention’ observational studies, examined the relationship between soy isoflavone intake and the risk of developing prostate cancer. That study concluded that when individual study results were pooled, the overall risk estimate of developing prostate cancer with high soy consumption was 0.70 (95% CI 0.59–0.83, P < 0.001) indicating an inverse association between soy consumption and risk of prostate cancer. A more recent meta-analysis by Hwang et al. [15] also came 1350 Several small clinical trials have evaluated the effect of consuming a diet rich in soy isoflavones in patients with confirmed prostate cancer. Bylund et al. [16] performed a small RCT on 10 men with confirmed prostate cancer who were on active surveillance. Men in that study were randomized to receive a daily supplement of rye bran bread (phytooestrogen rich food) or to receive wheat bread (control). Although the authors did not report any statistically significant change in PSA levels in the group treated with phytooestrogen, apoptotic markers as measured by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling) method, indicated a significant increase in the group given high phytooestrogen supplementation (P < 0.005). A slightly larger RCT by Kumar et al. [17] of 59 men with prostate cancer on active surveillance yielded similar results, failing to show any beneficial effect of a high phytooestrogen diet and PSA reduction. On the other hand, Dalais et al. [18] performed a double-blind RCT of high phytooestrogen diet (soy) vs low phytooestrogen diet (wheat) in men awaiting radical prostatectomy (RP) and reported a statistically significant decrease in PSA amongst the group who received a high phytooestrogen diet compared with the control group (decrease in PSA level of 12.7% vs an increase of 40%, respectively, P = 0.02). In summary, current evidence indicates a possible protective effect of high phytooestrogen diet in prostate cancer prevention but only limited evidence amongst patients with confirmed prostate cancer. Tomatoes and lycopenes Lycopene is a bright red carotenoid pigment abundantly found in tomatoes, watermelon and grapefruit. In vitro, it has been shown to exert an antiproliferative effect by inhibiting the cell cycle at the G0/G1 phase [19]. It has also been shown to increase the number of IGF-1 binding proteins [20] resulting in a net decrease in serum IGF-1, which has previously been associated with an increased susceptibility to prostate cancer [21]. As such, it has been postulated that lycopene may be beneficial in the prevention and progression of prostate cancer. © BJU INTERNATIONAL © 2 0 11 T H E A U T H O R S 2 0 11 B J U I N T E R N A T I O N A L PROSTATE CANCER AND DIET A meta-analysis of 21 observational studies [22] evaluating the role of lycopene in prostate cancer prevention reported that compared with infrequent consumers of tomato products, those eating a lot of raw tomato and cooked tomato products had a RR of developing prostate cancer of 0.89 (95% CI 0.80–1.00) and 0.81 (95% CI 0.71–0.92), respectively, suggesting that a high intake of tomato products has a modest role in the prevention of prostate cancer. Similarly, there is some evidence to suggest that lycopene supplementation may also be of benefit in men with confirmed prostate cancer. A recent systematic review of eight interventional studies by Haseen et al. [23] has shown an inverse association between lycopene intake and serum PSA levels in six of the studies [24– 29]. It is also worth noting that in one of the studies, a RCT of lycopene and orchidectomy vs lycopene alone in men with metastatic prostate cancer [30], the results have been particularly encouraging with radiological evidence of disease retardation on serial bone scans in the group given lycopene supplementation. However, more recently a small prospective open phase II study of daily lycopene supplementation (15 mg) in men with progressive CRPC did not result in any clinically significant benefit in this group of patients although five of 17 patients had a plateau-like stabilization in their PSA levels [31]. In addition, the USA Food and Drug Administration (FDA) carried out an evidencebased review of the literature in response to the growing number of claims that lycopene is beneficial in reducing certain types of cancer including prostate cancer [32]. In all, 13 observational studies evaluating the association between increased tomato or lycopene supplementation and prostate cancer were evaluated. The FDA concluded that at present, there was only very limited evidence to support an association between tomato/lycopene consumption and reduced risk of prostate cancer. In summary, although there is promising data in the current literature, further large scale RCTs are required to investigate a more concrete beneficial association between lycopene/tomato consumption and prostate cancer. active ingredient in cruciferous vegetable, isothiocyanates (a metabolic derivative of glucosinolates) has been shown to have potent anticancer properties [33–36]. A recent study has shown phenethyl isothiocyanates to repress AR transcription and expression, mediating growth arrest in both androgendependent and androgen-independent prostate cancer cells [37]. Several epidemiological studies have previously reported a reduced incidence of prostate cancer amongst men who have a high consumption of cruciferous vegetables [38–40] but studies that are more recent have failed to show this effect [41–44]. Currently therefore, there is only limited evidence that cruciferous vegetable may play a protective role in the development and progression of prostate cancer. Vitamins Cruciferous vegetables Vitamins are a group of structurally and functionally unrelated organic compounds that are essential for the normal functioning of the body and are present in various different food sources. Foods rich in vitamin A (retinol and carotenes) include cheese, eggs, liver, oily fish, vegetables and fruit. The B vitamins are found in a wide variety of foods. For example, B6 (pyridoxine) is found in pork, chicken, turkey and cod whilst B12 (cobalamin) is found in meat, salmon, cod, milk and cheese. Vitamin C (ascorbic acid) is present in various fruit and vegetables including pepper, broccoli, brussels sprouts, oranges and kiwi, whilst most vitamin D is synthesized from our skin in response to sun light but is also found in eggs, liver, butter and oily fish. Vitamin E is found mainly in plant oils such as soya, corn or olive oil whilst vitamin K is abundant in leafy vegetables such as spinach and broccoli. There is now increasing recognition that vitamins are important not only for the normal functioning of our bodies, but that they also appear to possess several anti-tumorigenic properties in vitro. Possible mechanisms for this includes the activation of pro-apoptotic and cell cycle arrest transcription factors, modulation of epigenetic events, interaction with AR and also through anti-oxidative mechanisms [45]. Cruciferous vegetables are part of the Brassicaceae family which includes horseradish, broccoli, cabbage, brussels sprout, cauliflower, bok choy and wasabi. The Virtually all clinical studies to date have investigated the association of vitamin usage and prevention of prostate cancer. Vitamin A is found principally in two main food forms as © retinol and carotenes. The Carotene and Retinol Efficacy Trial (CARET) was a doubleblind RCT investigating the effects of carotene and retinol supplementation on preventing lung cancer amongst high-risk patients [46]. As a secondary outcome, they were also interested in evaluating the potential association with prostate cancer [47]. Men in the interventional arm who also used additional dietary supplements had an increased RR towards developing an aggressive prostate cancer (RR 1.52, 95% CI 1.03–2.24; P < 0.05) compared with those who did not, although this association disappeared on cessation of the trial. The authors concluded therefore that the excessive use of high-dose vitamins especially when taken in combination may increase the risk of developing aggressive prostate cancer. This association has also been reported in the National Institutes of Health (NIH)-AARP Diet and Health study where excessive multivitamin intake was associated with an increased risk of patients developing advanced or fatal prostate cancer (RR 1.32, 95% CI 1.04–1.67 and RR 1.98, 95% CI 1.07–3.66, respectively) [48]. Several RCTs have evaluated the role of vitamin E either alone or combined with other vitamins. The α-tocopherol, β-carotene Cancer Prevention Study (ATBC) was a large RCT investigating the effect of vitamin A (βcarotene) and/or vitamin E (α-tocopherol) supplementation in the prevention of lung and other cancers [49]. After a median followup of 6 years, there was a 34% reduction in the incidence of prostate cancer amongst participants randomized to vitamin E (αtocopherol) supplementation whilst there was a modest but statistically insignificant increase in prostate cancer risk amongst those patients given vitamin A (β-carotene) supplementation [50]. The authors concluded that vitamin E (α-tocopherol) appears to have a favourable effect in reducing the risk of prostate cancer but that these findings would need to be substantiated in further studies. Unfortunately, subsequent studies on vitamin E have failed to reproduce the initial benefit reported in the ATBC study. Two large observational studies, the Cancer Prevention Study II Nutrition Cohort [51] and the NIHAARP Diet and Health Study [52] both failed to show any beneficial association between vitamin E supplementation and prostate cancer risk. A recent RCT, the Physicians’ 2 0 11 T H E A U T H O R S BJU INTERNATIONAL © 2 0 11 B J U I N T E R N A T I O N A L 1351 H O R I ET AL. Health Study investigated the effect of longterm vitamin C and/or E supplementation on prostate cancer and found that neither vitamins decreased the risk of prostate cancer [53]. The interim results of the much anticipated Selenium and Vitamin E Cancer Prevention Trial (SELECT) have also recently become available [54]. This large, doubleblind, placebo-controlled RCT of 35 533 men randomized to receive selenium, selenium and vitamin E, vitamin E alone, and placebo was terminated early as the interim analysis failed to show any benefit with either components in reducing the risk of prostate cancer. In addition, there was also a trend in the vitamin E group in developing prostate cancer although this association was statistically not significant (P = 0.09). In summary, results from several large observational and RCTs to date have failed to show any beneficial role of vitamin supplements in reducing the risk of prostate cancer. On the contrary, some studies even suggest that multivitamin supplements may be associated with an increased risk of prostate cancer. Selenium Selenium is a trace mineral that serves as an antioxidant, which helps prevent cellular damage from free radicals. It is found in large quantities in Brazil nuts, fish such as tuna and swordfish as well as in molluscs and oysters. In vitro studies have shown selenium to inhibit angiogenesis, inhibit cellular proliferation and induce apoptosis [55]. Earlier enthusiasm for selenium supplementation came from the result of a large scale RCT in the 1990s, the Nutritional Prevention of Cancer trial [56], which was initially set up to investigate the effect of selenium supplementation for prevention of skin cancer recurrence in ‘Dairy products such as milk, butter, cheese and men with a past history of cutaneous yoghurt have all previously been postulated to malignancy. increase the risk of developing prostate cancer’ Although that study did not show any protective effect of selenium againstthe development of skin cancer, it incidentally found that supplementation with 200 μg selenium was associated with a lower incidence of lung, colorectal and prostate cancer. This beneficial effect of selenium against prostate cancer was also reflected in a meta-analysis of 20 epidemiological studies 1352 that showed a significant increase in the incidence of prostate cancer amongst men with low levels of serum selenium [57]. Such findings may be of particular relevance in populations with low levels of selenium in the topsoil such as the UK where ice age glaciers are thought to have washed out a large proportion of the selenium from the topsoil. As most of wheat in the UK is now grown on home soil, this may magnify the dietary deficiency of selenium in the UK population. The studies above initially raised the prospect of using selenium supplementation for chemoprevention of prostate cancer. However, the interim results of the SELECT trial [54] were disappointing, showing no benefit of selenium alone or when combined with vitamin E for prevention of prostate cancer, which led to the early closure of this trial. Recently, the results of another large multicentre phase III RCT using selenium vs placebo in men with HGPIN has proved equally disappointing with no benefit seen in the intervention group receiving selenium supplementation [58]. The role of selenium supplementation in men with an already established diagnosis of prostate cancer was recently studied by Chan et al. [59]. The authors concluded that selenium supplementation in certain patients may result in a more aggressive prostate cancer phenotype especially when patients have an altered genotype for the manganese superoxide dismutase (SOD2) enzyme. These results taken together now challenge the previous notion of a protective role of selenium supplementation with some studies even suggesting the converse. Dairy products and calcium Dairy products such as milk, butter, cheese and yoghurt have all previously been postulated to increase the risk of developing prostate cancer. This increased risk may in part be attributable to the high amount of saturated fat present in dairy products but the more likely mechanism underpinning this association is the relative suppression of 1,25 dihydroxyvitamin D3 (an active form of vitamin D metabolite) in response to the increased levels of plasma calcium associated with a high dairy diet [60]. In vitro studies have shown 1,25 dihydroxyvitamin D3 to halt cellular proliferation and promote apoptosis in © BJU INTERNATIONAL © 2 0 11 T H E A U T H O R S 2 0 11 B J U I N T E R N A T I O N A L PROSTATE CANCER AND DIET several different human cell lines including prostate cancer cell lines [61–66]. In addition, an increased dairy product intake may also influence the levels of circulating IGF-1, which has been shown to increase the risk of developing prostate cancer [67–69]. Clinical studies examining the relationship between dairy product/milk and prostate cancer have revealed conflicting results. A meta-analysis performed by Gao et al. [70] of 16 prospective studies showed a positive, albeit small association between high dairy product, calcium intake and prostate cancer (RR 1.11, 95% CI 1.00–1.22; P = 0.047 and RR 1.39, 95% CI 1.09–1.77; P = 0.018, respectively). Similarly, a more recent meta-analysis of 18 cohort studies [71] also concluded that the consumption of milk and dairy products was associated with a small increased risk of developing prostate cancer (RR 1.13, 95% CI 1.02–1.24). However, on the contrary a large recent meta-analysis of 45 observational studies showed no evidence of an increased risk of developing prostate cancer with increased dairy product (RR 1.06, 95% CI 0.92–1.22) or milk consumption (RR 1.06, 95% CI 0.91–1.23) [72]. In patients with confirmed prostate cancer, the current literature specifically examining the relationship between dairy product consumption and prostate cancer progression is sparse. One study evaluated this effect indirectly by randomizing patients with localized prostate cancer to either attend a series of intensive dietary and cooking classes or not [73]. The randomized group attending these classes was noted to have a significant reduction in the consumption of saturated fat, animal protein and dairy products. Although men randomized to the interventional arm of the study had a PSA level rise similar to those of the control group, there was a substantially longer PSA-doubling time in this group at the 3-month follow-up visit. It remains to be seen therefore in future studies whether alterations in dairy or calcium intake do actually alter the natural history of prostate cancer progression. In summary, there is some conflicting evidence to suggest that a high dairy consumption is associated with an increased risk of prostate cancer. Little is currently known about the effect of dairy consumption and prostate cancer progression. © Fish and omega 3 (n-3) and 6 (n-6) polyunsaturated fatty acids (PUFA) Polyunsaturated fats such as omega 3 and 6 are essential fatty acids derived entirely from the diet, as the body is unable to synthesize these de novo. Oily fish such as tuna, sardine, salmon and trout are an excellent source of omega 3 PUFA whilst food such as eggs, avocado, nuts and most vegetable oils are rich in omega-6 PUFA. Omega-3 PUFA has previously been shown to possess several anticancer properties both in vitro and in vivo. For example, studies using prostate cancer cell lines have shown the inhibitory effect of omega 3 PUFA on both androgen sensitive (LNCaP) and androgen insensitive (PC3) cell lines [74,75]. Omega 3 has also been shown to exert an inhibitory effect on androgen-independent DU145 prostate cancer cells implanted s.c. in nude mice [76,77]. Omega 6 PUFA on the other hand has an adverse effect if taken in excess and has been implicated in the development of several cancers including prostate in vitro and in vivo [78,79]. Omega 6 PUFA (namely arachidonic acid) is converted by COX-2 enzyme into prostaglandin E2, a pro-inflammatory cytokine implicated in the development of several cancers [80]. Omega 3 PUFA competes against omega 6 as a substrate for COX-2 enzyme resulting in the production of prostaglandin E3 [81], which does not possess mitogenic properties [82]. Several clinical studies have been conducted to evaluate the role of omega 3 PUFA and prostate cancer. A few large observational studies have suggested a beneficial association between high fish or omega 3 PUFA consumption and reduced risk of developing prostate cancer [83–85]. For example, Terry et al. [83] investigated the effect of dietary fish intake amongst 6272 Swedish men who were followed-up for 30 years. That study reported that men who ate no fish had a two–three-fold increase in the risk of developing prostate cancer compared with those who consumed large amounts of fish in their diet (RR 2.3, 95% CI 1.2–4.5; P = 0.05). Although most studies suggest omega 3 PUFA to be protective against prostate cancer, there are also studies to the contrary. A review of eight prospective cohort studies and nine case-control studies failed to show any convincing beneficial effect of high fish and omega 3 PUFA intake and prostate cancer [86]. A more recent systematic review also concluded that the current literature does not provide sufficient evidence to suggest a beneficial association between omega 3 PUFA consumption and cancer prevention. One large prospective cohort study even suggested an increased risk of developing advanced prostate cancer with the consumption of a certain type of omega 3 PUFA known as α-linolenic acid from both non-animal and animal sources (RR 2.02, 95% CI 1.35–3.03 and RR 1.53, 95% CI 0.88–2.66, respectively) [85]. A few clinical studies have examined the effect of omega 3 PUFA in patients with prostate cancer. Demark-Wahnefried et al. [87] performed a case-control pilot study to examine whether a diet high in omega 3 PUFA influences biomarkers involved in prostate carcinogenesis. In all, 25 patients with localized prostate cancer who were awaiting RP were recruited and given omega 3 supplementation (flaxseed) together with a low fat diet and were matched to a historical control. Although the study did not show any statistically significant decrease in PSA levels, other markers of prostate cancer activity such as total testosterone and free androgen index decreased significantly in their respective values. More recently, the same group performed a RCT and reported that in those men who received flaxseed supplementation before RP, there was a statistically significant decrease in tumour proliferation rates compared with controls (P < 0.002) [88]. Presently therefore, there is evidence to suggest that fish and omega 3 plays an important role in reducing the risk of prostate cancer development and may also be beneficial amongst men with prostate cancer. Fats High total fat and meat consumption in the Western diet have been linked to an increased risk of prostate cancer in several epidemiological studies [89]. Fats are a wide group of compounds that are chemically comprised of triesters of glycerol and fatty acids and are obtained from a wide variety of animal and plant sources. Examples of edible animal fat include lard, fish oil and butter that are obtained from animal skin, meat or milk. Soya bean, peanut, sunflower, sesame, olive and vegetable oils are some examples of edible plant fats. Total fats, especially from 2 0 11 T H E A U T H O R S BJU INTERNATIONAL © 2 0 11 B J U I N T E R N A T I O N A L 1353 H O R I ET AL. animal sources, have been suggested to increase the risk of developing prostate cancer. The exact mechanism by which dietary fat induces prostate carcinogenesis or prostatic growth is currently unclear. However, it is likely that the hormone IGF-1 plays an important role in dietary fat-induced prostate cancer. Barnard et al. [90] have previously shown in a feeding experiment that the serum obtained from patients given a low fat diet had much lower plasma circulating levels of IGF-1 compared with controls. Interestingly they also found that LNCaP prostate cancer cells grown on serum of these patients grew at a much slower rate compared with those given a normal fat diet, suggesting that IGF-1 plays a major role in determining prostate cancer cell behaviour. A meta-analysis of 29 studies investigating the effect of dietary fat intake and prostate cancer risk was undertaken by Dennis et al. [91]. The authors concluded that although there appears to be a small but significant increase in the risk of developing prostate cancer with dietary fat consumption of > 45 g/day (RR 1.2), the analysis of these studies were problematic due to the large heterogeneity between studies. More recently, the World Cancer Research Fund (WCRF) and the ‘At present, there is little evidence to suggest American Institute that a diet high in fat is associated with for Cancer Research (AICR) also an increased risk of prostate cancer’ published a report evaluating several dietary factors that may be associated with an increased risk of prostate cancer [92]. The authors reported similar difficulties in extrapolating and pooling results from previous studies for a robust conclusion to be reached mainly due to the large variability in study quality and design. However, since the publication of this report in 2007, there have been three large prospective trials that have not shown any correlation between dietary fat intake and the risk of developing prostate cancer [93–95]. Several clinical studies have also examined the effect of reducing total dietary fat intake in the context of maintaining a general healthy diet and lifestyle. A pilot study evaluating the effect of dietary fat restriction combined with flaxseed supplementation in a group of newly diagnosed patients with prostate cancer awaiting RP, observed that 1354 those who were on a low fat and flaxseed diet had a significantly lower total plasma testosterone levels compared with controls [87]. A RCT by Ornish et al. [96] investigated the effects of intensive dietary and lifestyle changes on PSA level trends in patients with confirmed prostate cancer. In the active intervention arm, patients were given a diet low in fat and simple carbohydrates and high in fruit, vegetables, whole grains, legumes and soy products. Additionally, patients in the intervention arm underwent intensive lifestyle modifications, which included stress management techniques, daily meditation and progressive relaxations. Interestingly, patients randomized to the intervention arm had a 4% decrease in PSA levels compared with a 6% increase in the control arm. The authors also found that LNCaP prostate cancer cells that were grown on serum from patients in the intervention group were inhibited almost eight times more than by serum obtained from the control group (70% vs 9%, P < 0.001). The results of that study appear to suggest that simple dietary changes together with a general healthy lifestyle may positively influence the progression of prostate cancer. At present, there is little evidence to suggest that a diet high in fat is associated with an increased risk of prostate cancer. Reduction of dietary fat intake combined with a general healthy diet and lifestyle may be beneficial in slowing down the rate of progression of prostate cancer in certain patients. Carbohydrates Carbohydrates (or saccharides) are a major source of energy accounting for 45–70% of total energy intake and expenditure in humans [97]. Food sources rich in simple carbohydrates include table sugar, corn syrup, fruit, white bread, white pasta, fizzy drinks and cakes, whilst complex carbohydrates can be found in potato and whole grains such as brown rice and whole-wheat products. Carbohydrates, particularly those with a high glycaemic load consumed in excessive amounts result in increased fat stores due to influences on blood glucose and excess calories. This results in a state of relative hyperinsulinaemia and obesity, which has been postulated to increase the risk of developing prostate cancer through higher bioavailability of circulating oestrogen and IGF-1 [69]. Indeed a recent case-control study evaluating the dietary habits of 1294 Italian © BJU INTERNATIONAL © 2 0 11 T H E A U T H O R S 2 0 11 B J U I N T E R N A T I O N A L PROSTATE CANCER AND DIET men found that starch consumption is directly associated with an increased risk of prostate cancer (OR 1.4, 95% CI 1.1–1.8) [98]. The effect of carbohydrate on prostate cancer has been investigated in several in vivo studies [99–101]. Mice injected s.c. with androgen-sensitive LNCaP prostate cancer cells that were fed on a high carbohydrate (40% carbohydrate, 45% fat, 45% protein) diet were heavier (P = 0.003), had higher levels of serum insulin and IGF-1 (P = 0.039) and had a 45% relative increase in prostate cancer tumour volume compared with mice given a low carbohydrate diet (10% carbohydrate, 45% fat, 45% protein) [99]. Even in experiments where body weight was maintained, mice on low carbohydrate (12% fat, 71% carbohydrate, 17% protein) or a no carbohydrate (83% fat, 0% carbohydrate, 17% protein) diet had a significantly prolonged survival compared with mice on a typical Western diet (40% fat, 43% carbohydrate, 17% protein) with a HR of 0.49 (95% CI 0.29–0.79, P = 0.004) and 0.59 (95% CI 0.37–0.93, P = 0.02), respectively [101]. Interestingly, the phospho-Akt:total-Akt ratio in prostate cancer cells from mice in both these studies had increased with a higher carbohydrate consumption, presumably as a result of higher circulating serum insulin and IGF-1 levels [99,101]. The results of these studies therefore seem to suggest that carbohydrate (and not calorie restriction) has a direct influence on prostate cancer biology and growth in vivo. In humans, studies evaluating the direct impact of carbohydrate intake and prostate cancer are currently lacking. In a small feasibility study, Lin et al. [102] examined whether a low fat, low carbohydrate diet (classified according to glycaemic load) can alter the gene expression in prostatic tissues of men awaiting radical RP compared with men who were given a control (Western) diet. In that study, men who were randomised to receive a low-fat low-carbohydrate diet had a significant alteration in several genes involved in cell migration and intracellular signal transduction. The study therefore provides exciting data suggesting that carbohydrate consumption directly alters gene expression in prostatic tissue but is limited by the few cases (eight patients) and lack of multiple intervention arms. In summary, although several studies suggest a possible adverse effect of increased © carbohydrate consumption and prostate cancer, most evidence to date stems from small preclinical studies. Further studies and RCTs are urgently required to investigate the potential role of carbohydrate consumption and prostate cancer in humans. Meat There is now increasing evidence that heterocyclic amines (HCAs) found in cooked meat are crucial carcinogens that have been implicated in the pathogenesis of several human cancers [103]. HCAs are a group of compounds formed during high temperature cooking from the reaction of creatine, amino acids and sugars [104]. 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP) is a type of HCA that has been particularly shown to induce prostate cancer in vivo and is postulated to act on DNA causing subsequent instability and mutagenesis [105]. Several clinical studies have evaluated the relation between increased meat intake and the risk of prostate cancer. Kolonel et al. [89] found in a large epidemiological review of 22 observational studies that several of the evaluated studies had a statistically significant positive correlation between increased meat consumption and the risk of developing prostate cancer. More recently, Zheng and Lee [103] expanded this observation further by reviewing the literature for the association between high HCAs/well done meat and prostate cancer. Of the four published studies reviewed in this article, three [106–108] have consistently shown a positive correlation between very well done meat and risk of developing prostate cancer. In patients with confirmed prostate cancer, it is currently not known whether a high meat intake affects the progression of the disease. However, a recent prospective study of 1294 men with prostate cancer did not identify any association between increased meat consumption and prostate cancer recurrence or progression [109]. Taken together, the current evidence seems to suggest that a high meat diet, particularly if very well cooked, may be associated with an increased risk of developing prostate cancer. The association between high meat consumption and prostate cancer progression is currently unclear. CONCLUSION In an increasingly health conscious society, it is commonplace for Urologists to be asked about what constitutes an ‘ideal’ diet for the prostate. In addition, a growing number of patients consume vitamins, dietary supplements and other complementary medicine remedies in the belief that they are all ‘natural, safe and good for you’ [110]. We found evidence in the present review that certain vitamins for example, when taken in combination can result in an increased risk of aggressive prostate cancer [47,48]. Additionally, recent data from the American Association of Poison Control Centre has shown a stark increase in the number of adverse events and deaths as a result of vitamin, herbal or dietary supplement consumption from 14 006 to 125 595 adverse events and 5–27 deaths between 1983 and 2005, respectively [111]. Patients should therefore be advised of the potential benefits and risks of taking supplements and should be warned that not all supplements or alternative remedies are of benefit. At present, there is no single dietary factor that has been shown to conclusively reduce the risk of developing or delaying the progression of prostate cancer. However, it is increasingly evident that diet plays a major role in the pathogenesis of prostate cancer and that general dietary modification may be of benefit to patients. Also, it is important to note that the current evidence is limited largely due to the heterogeneous nature of the studies, which vary greatly in design and quality. In addition, much of the current nutritional studies assume a traditional linear cause-effect relationship where a single dietary component is investigated for a particular effect. This reductionism approach may not be optimal in the study of complex systems such as diet and health [112]. It is therefore of paramount importance that a concerted effort is made amongst the Urological and Nutritional communities to improve the design of studies and produce more robust, high quality research trials that will help us improve our understanding of the complexities that exist between diet and prostate cancer. Given these limitations however, and based on the analysis of the current literature, we feel that the ‘ideal’ prostate diet would be comprised of a diet low in saturated fat, 2 0 11 T H E A U T H O R S BJU INTERNATIONAL © 2 0 11 B J U I N T E R N A T I O N A L 1355 H O R I ET AL. refined carbohydrates, meat and dairy products with high vegetable, tomatoes (both cooked and uncooked), soy and green tea consumption. In addition, an increasing body of evidence suggests that lifestyle (mainly obesity) is a major risk factor for several cancers including prostate cancer [113]. Patients should therefore also be encouraged to maintain a healthy weight and lifestyle through healthy eating and regular exercise. When educating and discussing the complex nature of diet and prostate cancer with patients, it is useful to use an analogy that has been suggested by Moyad and Lowe [114], who draw attention to the fact that a sedentary Western lifestyle is a major risk factor for both cardiovascular as well as prostatic diseases. ‘Heart healthy equals prostate healthy’ is probably the most effective way of summarizing the importance of healthy dietary intake and lifestyle in patients seeking advice on this important topic. 4 5 6 7 8 ACKNOWLEDGEMENTS Satoshi Hori gratefully acknowledges the financial support given by the Royal College of Surgeons of England Surgical Research Fellowship and the Addenbrooke’s Charitable Trust Oncology Research Fellowship. 9 10 CONFLICT OF INTEREST None declared. 11 REFERENCES 12 1 2 3 World Health Organization/ International Agency for Research on Cancer. GLOBOCAN 2008 (Cancer incidence and mortality worldwide in 2008). Available at: http://globocan.iarc. fr/. 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Am J Med 2008; 121: S34–42 Correspondence: Satoshi Hori, Department of Uro-oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK. e-mail: [email protected] Abbreviations: AR, androgen receptor; ATBC, α-tocopherol, β-carotene cancer prevention study; COX-2, cyclooxygenase-2; CRPC, castrationresistant prostate cancer; FDA, the USA Food and Drug Administration; HCA, heterocyclic amine; HGPIN, high-grade prostatic intraepithelial neoplasia; IGF, insulin-like growth factor; NIH, the National Institutes of Health; OR, odds ratio; PUFA, polyunsaturated fatty acids; RCT, randomised controlled trial; RR, relative risk; RP, radical prostatectomy; SELECT, Selenium and Vitamin E Cancer Prevention Trial. EDITORIAL COMMENT PROSTATE CANCER AND DIET: FOOD FOR THOUGHT? In the above review Hori et al. discuss the complex relationship between dietary composition and prostate cancer prevention and progression. Using a literature review comprising primarily of randomized control trials, the authors summarized key topics relevant to prostate cancer. The role of diet and cancer is complicated, as a diet is composed of both macro- and micronutrients. However, people do not eat nutrients; they eat whole foods such as chicken, vegetables, or fruits. These foods may also contain minerals and be a source of compounds known as phytochemicals. Diet is also composed of calories. Thus, determining which specific factors are linked with cancer is not easy and indeed this may explain the often ‘negative’ findings between diet and prostate cancer, although some common patterns are starting to emerge. The authors nicely review the role of phytochemicals in green tea, soy, and cruciferous vegetables. While the molecular structure of each compound is distinctly different, all share similar antioxidant and anti-inflammatory properties that decrease DNA damage caused by reactive oxygen species and increase apoptosis in cancer cells [1]. Therefore, we suggest perhaps the source of phytochemicals is less important than the amount of overall consumption. For macronutrients, preclinical data suggest there may be a bell-shaped relationship 2 0 11 T H E A U T H O R S BJU INTERNATIONAL © 2 0 11 B J U I N T E R N A T I O N A L 1359