1. Nutrition and Dietetics, School of Human Movement Studies, The University of Queensland, Queensland.
2. Nutrition Services, The Wesley Hospital, Queensland.
3. School of Human Movement Studies, The University of Queensland, Queensland.
Prostate cancer is a growing epidemic worldwide and the sixth most common cause of death from cancers in men. Diet and lifestyle factors have been associated with prostate cancer risk, but limited evidence supports their effect on prostate cancer progression post diagnosis. The majority of clinical trials conducted studied men in the lowest severity category of ‘active surveillance’. A small number of studies show differences in the response to diet and/or lifestyle intervention depending on the severity of disease. There are inconsistencies in the quantities of intervention, nutrient/s provided, dietary intake methods, trial lengths and follow-up times. Interventions including substantial fat and energy restrictions risk nutrient deficiencies, particularly iron and zinc, and have inconsistent adherence rates. Dietary changes to modify nutrient profiles, for example, the ratio of n-3:n-6 fats, appear to have more potential than those that restrict specific food groups or macronutrients. Evidence suggests a combination of weight management and lycopene (30mg per day), soy isoflavones or flaxseed supplementation may contribute to delaying prostate cancer proliferation for men on ‘active surveillance’. Studies of these nutrients as adjunctive therapies to weight management interventions in men with locally advanced or advanced disease with metastases are needed to ascertain the effect on prognosis and quality of life.
Cancer of the prostate gland is the second most commonly diagnosed cancer in men, and accounts for 6% of total cancer deaths in males.1 Prostate cancer severity is classified using the standard staging scale (I-IV) and the Gleason score (range 2 to 10), with 10 being the most aggressive form.2 The Gleason total score is a combination of two sub-scores: (i) most common tissue pattern (range 1-5) and (ii) second most common tissue pattern (range 1-5). Gleason scores of less than or equal to 6 are considered the least aggressive (low grade), while Gleason scores of 7 are intermediate and 8-10 are high grade. Prostate cancer has the highest incidence in Australia and New Zealand at 104 per 100,000 while South-Central Asia has the lowest incidence, at 4 per 100,000.1 This may be related to the high prevalence of prostate specific antigen (PSA) testing and follow-up biopsies in Australia and New Zealand; however, several diet and lifestyle factors and their resulting metabolic effects are becoming increasingly implicated in the development of prostate cancer.
The approach of ‘active surveillance’ or ‘watchful waiting’ involves the monitoring of PSA levels at regular short-term intervals. It is sometimes appropriate for men with a Gleason score ≤6. Once the Gleason score is ≥7, treatment may range from radical prostatectomy, radiation therapy or a combination of these with Androgen Deprivation Therapy (ADT), if there is locally advanced disease or advanced disease with metastases.2 Receptors for testosterone are competitively inhibited by the oestrogen-like agents in ADT and this reduces the inflammatory process exacerbated by free testosterone binding with these receptors in prostate tissue, thereby slowing the growth of the tumour.2,3 A substantial side-effect of ADT is that the hormonal changes predispose patients to a range of metabolic risk factors, including weight gain, abdominal obesity, insulin resistance and cardiovascular disease, culminating in the metabolic syndrome.3 Diet and lifestyle changes known to assist in alleviating symptoms of the metabolic syndrome may be beneficial in improving quality of life for men with advanced prostate cancer on ADT. Furthermore, since progression of the disease is associated with higher waist circumference and velocity of weight gain,4 minimising the metabolic side-effects is important for limiting this process.
Prostate cancer is a growing epidemic worldwide.5 The associations of prostate cancer prevention with diet and lifestyle factors in observational studies and the potential for limiting the detrimental side-effects of ADT suggest that further investigation into the effects of food and nutrients as adjunctive therapy is warranted. The purpose of this paper is to review the quality of the latest scientific evidence on the benefits of specific foods, nutrients, nutritional supplements, and diet and lifestyle interventions for three groups of prostate cancer patients: (i) early stage, locally confined; (ii) locally advanced (regionally invasive); and (iii) advanced (distant metastatic).
A search of Medline, PubMed, ScienceDirect, CINAHL, Health Source (Nursing/Academic) was conducted between September 2010 and March 2011 for articles published within the last 20 years. Search terms used included, prostate cancer, nutrition, diet, dietary supplements and complementary/alternative medicine. Exclusion criteria were animal and cell studies, pre-diagnostic studies of prostate cancer and an absence of information regarding the stage of prostate cancer. Articles were designated levels of evidence using the National Health and Medical Research Council Evidence Hierarchy.6 Of the 109 articles retrieved, 40 were selected for inclusion in this review due to their relevance to nutrition and prostate cancer progression. In further review, articles were excluded if there was only one paper available on the topic, as this precluded comparison of findings. Nineteen studies were included in the final review.
A summary of the studies examining prostate cancer progression as a result of dietary interventions is presented in table 1.
Seven studies examined the effects of diet and/or lifestyle modification on the progression of prostate cancer. One of the interventions was a vegan diet, including: daily soy (unspecified amount or fermentation) and fortified soy protein powder, 58g; fish oil (3g, proportion of eicosapentanoic acid [EPA]/docosahexanoic acid [DHA] not defined); vitamin E (400IU, type not defined); selenium (200mcg); vitamin C (2g); 30 minutes of walking six days per week; stress management activities; and attendance at an intervention support group for an hour per week.9 This combination of nutrients was associated with a 4% reduction of PSA in the intervention group, compared to a 6% increase in PSA in the control group, but there were no differences in serum testosterone or prostate cancer cell apoptosis. It is unclear which component of the intervention contributed to this effect, or if it was as a result of synergism of all components. After one year, adherence to the intervention was 95%, with 45% adherence to the control diet, measured using a food frequency questionnaire.9
Two recent feasibility studies examined adherence to diet and/or exercise interventions. Men with advanced stage prostate cancer on ADT showed reductions in total fat, saturated and monounsaturated fat intake and total energy after a 12 week lifestyle program, as reported in three day diet diaries.11 Adherence to this dietary pattern after six months was not reported. In a study of telephone counselling, men on ‘active surveillance’ increased their intake of cruciferous vegetables and tomatoes, whole grains, beans and legumes as reported by 24 hour recall, with higher plasma levels of carotenoids after six months.10 Similar outcomes were obtained from other studies with comparable dietary guidance and follow-up times,7,8 but there was no significant change in disease progression outcomes, only small changes in PSA doubling time.8 This occurred in another study, along with changes in gene expression for fat and carbohydrate metabolism and the insulin-like growth factor (IGF-1) in prostate tissue. However, due to the mixture of interventions utilised (low fat, plant-based diet; stress management; moderate exercise; psychosocial support), it is unclear which strategy led to this effect, or if it was simply due to energy restriction and weight loss.12 There are reported adherence issues throughout the intervention and follow-up periods of similar interventions.11,13 Poor adherence has been linked to weight gain after an initial weight loss at three months, with subsequent re-rising of PSA.13 This has prompted investigation of whether certain dietary compounds are more powerful than others and may serve as helpful adjunctive therapies, rather than having to rely on such a significant, potentially non-sustainable, energy restriction.
Lycopene is a red carotenoid pigment found predominantly in tomatoes, and is the most efficient antioxidant when compared to other carotenoids and vitamin E.25 It is highly concentrated in the prostate gland and consumption of 30mg per day has been associated with reduced rates of prostate cancer risk and progression in observational studies.26 In a study comparing the prostate tissue of 24 men with benign prostatic hyperplasia or prostate cancer pre and post-prostatectomy, consumption of 30mg lycopene per day as 200g spaghetti sauce (3/4 cup) for three weeks prior to prostatectomy resulted in an increase in apoptotic prostate cells and higher rates of cell death.14 When prostate tissue was compared between cases and controls (no additional lycopene prior to prostatectomy), no significant difference in apoptotic cells or cell death was detected.14 Although the timeframe was short, adherence to this intervention was good, with patients receiving 82% of the planned lycopene dose pre-surgery.
Another study, the Molecular Effects of Nutritional Supplements Trials, investigated whether 30mg lycopene or 3g fish oil per day for three months could alter the expression of IGF-1 or cyclooxygenase 2 (COX-2), which have been associated with inflammatory pathways and prostate cancer progression in observational studies.16 IGF-1 has been associated with cancer growth and metastasis and is a novel target of therapies to reduce cancer progression.27 IGF-1 and COX-2 expression has been reduced by lycopene in breast and colorectal cancer.28,29 However, in this study of men on ‘active surveillance’, there was no difference in gene expression for either pathway between the intervention or placebo groups after three months. Similarly, a small case-control study examined the effect of either >25mg lycopene per day (n=20), 40g soy protein supplement per day (n=21) or a combination of both for four weeks (n=41) on IGF-1 and PSA outcomes in men with localised prostate cancer. There was no effect on IGF-1 levels, but a trend towards reduction in PSA doubling time occurred for some men (p=0.08) during both interventions.15 It is unclear which intervention had the greater effect.
Phytoestrogens comprise isofavonoids and lignans.30 Epidemiological data suggest the isoflavone content of soy is protective against prostate cancer, as men in Asian countries where soy is regularly consumed have much lower rates of the disease. However, within two generations of living in the US and consuming diets lower in isoflavones, Asian men have a substantially higher rate of prostate cancer compared with those in Asia.31 The mechanism of action of soy isoflavones is quite well characterised in vitro, but less understood in vivo, due to the paucity of clinical trials conducted in humans. Some published literature suggests that isoflavones may exert an estrogenic effect and lower testosterone levels,30 however a recent meta-analysis showed that increasing soy protein or isoflavone intake had no effect on testosterone levels in men.32 An Australian clinical trial showed reductions in total PSA and the ratio of free to total PSA (-15.5%; p<0.05) after men consumed 117mg daily soy isoflavones from 50g soy grits baked into bread.18 An additional reduction in free to total PSA (-10%) occurred when 20g linseed was added to the soy (p<0.01).
Another study demonstrated that 60mg soy isoflavones per day for 12 weeks in patients with early-stage prostate cancer was associated with non significant overall reductions in free testosterone and serum total PSA compared with the placebo group, suggesting it may have had an anti-proliferative effect;17 but this study was of short duration. Conversely, a 12-week randomised control trial administered 20g soy protein (160mg soy isoflavones) or 20g whole milk protein (control) in a group of men with advanced prostate cancer who were on ADT.19 There were no differences in inflammatory markers (adipokines [leptin, resistin], interleukin-6, TNF-α or C-reactive protein) or serum testosterone levels between the groups.
Flaxseeds contain Alpha Linolenic Acid (ALA), a plant-based omega-3 fatty acid which is a precursor to eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), as well as lignans, which belong to the phytoestrogen group. A randomised control trial compared the effects of a low fat diet (<20% energy), a flaxseed-supplemented diet (30g) and a low fat diet supplemented with flaxseeds (<20% energy; 30g) for 30 days prior to prostatectomy on the progression of prostate cancer.20 Men on low fat diets had significant reductions in serum cholesterol with no other effects. Prostate tissue from men on low fat diets supplemented with flaxseeds or on usual diets supplemented with flaxseeds showed significantly lower prostate cancer proliferation rates compared to the pre-intervention biopsy. These findings were consistent with those obtained in a previous feasibility study,21 however, there were no differences in PSA or IGF-1 levels in any of the intervention groups.20 Flaxseed supplementation did not alter erythrocyte or prostate tissue levels of ALA, however EPA levels were higher, suggesting the ALA had already been converted to EPA.
Zinc contributes to DNA repair and apoptosis, immune system function and is highly concentrated in the prostate gland.23 In a large, population-based cohort study, higher intakes of zinc were associated with reductions in prostate cancer mortality, particularly for localised disease.23 ‘High’ intake referred to the highest quartile of intake in this study of more than 15.6 mg, quantified through food frequency questionnaires. A recent study analysed post-prostatectomy tissue samples from 40 men and lower concentrations of zinc and iron in prostate tissue were associated with a higher likelihood of rising PSA post-prostatectomy.22
Limited trials have focused on the effect of folate levels and folic acid supplementation in prostate cancer. In one randomised control trial aiming to prevent colorectal adenomas using folic acid supplements, new diagnoses of prostate cancer occurred in 9.7% of the intervention group, compared with 3.3% of the control group.33 A recent study compared prostate tissue folate levels in 19 cases post-prostatectomy with 25 controls and examined associations with serum folate levels in both groups.24 Men with prostate cancer had significantly higher serum folate levels (taken fasting at prostatectomy) in their cancerous and non-cancerous tissue when compared with controls. Of interest is that there was no significant difference in serum folate results between men taking folic acid supplements (39.5%) compared to those who were not.
Studies involving vegan diets have prescribed total fat as 10% of energy with inconclusive effects, since the studies have been conducted with concomitant other interventions.9,12 The emerging associations of tissue levels of zinc and iron with lower prostate cancer mortality and likelihood of biochemical recurrence is important.22,23 Interventions emphasising vegan diets risk inadequate supply of iron and zinc as well as other nutrients. It is important to note that the Australian recommended dietary intake for zinc for adult males is 14mg/day, while the upper level of intake is 40mg.34 Although zinc has been shown to have positive associations with prostate cancer mortality, it is critical that the upper level is not exceeded by the consumption of rich food sources and/or multiple supplements, as some observational studies show consumption of more than 100mg per day is associated with a higher risk of death from prostate cancer.23
The issue of fat restriction compared with modifying the fat profile of the diet remains uncertain. In the study by Demark-Wahnefried, Polascik and George et al. (2008), supplementing the diet with ALA from flaxseed had more effect on reducing prostate cancer proliferation rates than the low fat diet in isolation.20 Other studies suggest that the conversion of ALA to EPA and DHA is more efficient in the presence of lower levels of linoleic acid ie. diets lower in total fat.35 ALA and linoleic acid (eg. meat, dairy, nuts, seeds, avocados) compete as substrates for the enzyme, delta-5-desaturase.36 The product of delta-5-desaturase action on ALA is EPA and DHA, while the product of delta-5-desaturase action on linoleic acid produces arachidonic acid, a precursor to prostaglandin PG2 which stimulates inflammatory pathways.36 This suggests that any dietary intervention to reduce prostate cancer progression and systemic inflammation needs to consider the context of the whole diet and that change to nutrient profiles, rather than the elimination of food groups, is more appropriate. Instead of excluding meat and dairy foods, for example, recommendations to consume lean and low fat sources of nutrients may be more appropriate.
There is some evidence to suggest that folate is protective for cells in a precancerous state, but once cells turn cancerous, folate can stimulate cancer proliferation.37 This has significant implications for men with prostate cancer, particularly those who are consuming plant-based diets, or fortified cereals, rich in folate. However, there were no clinical trials available for inclusion in this review; all of the existing data is cross-sectional and sample sizes are small, therefore no conclusions can be drawn about folate and prostate cancer at present.
There was some evidence for the promotion of apoptosis and prostate cancer cell death after three weeks of lycopene supplementation as tomato sauce (3/4 cup),14 however studies investigating the effect of short interventions on IGF-1 and COX-2 inflammatory pathways were inconclusive. Other studies of mixed interventions of soy and lycopene could not decipher which was associated with reductions in PSA doubling time,15 therefore conducting further studies of longer duration with single ingredients may be warranted.
Soy products may have a role in reducing PSA levels in patients with early-stage prostate cancer, however it is unclear whether fermented (miso, tempeh, soy sauce) or non-fermented (soy milk, tofu) soy is more effective. Unfermented soy products contain phytates and trypsin inhibitors, which may limit the absorption of calcium, zinc, iron and magnesium. Given the importance of these nutrients for general health and the association of adequate iron and zinc with healthy prostate tissue, consuming more fermented rather than non-fermented soy products may be beneficial. However, more clinical studies are needed in this area, particularly as the response to soy differed between men with early-stage and advanced prostate disease.
There is substantial epidemiological data on nutritional factors influencing prostate cancer risk, but clinical trials on diet and lifestyle interventions to slow prostate cancer progression once in situ are limited. Most studies differ in the quantities of intervention nutrient provided, trial length and follow-up time, which precludes direct comparison of findings. No studies report on the processing methods or bioavailability of the nutrients and serum or tissue markers of dietary adherence or absorption are used rarely. Dietary intake measures have either relied on food frequency questionnaires, three-day food diaries or 24 hour recalls, which are unreliable at the individual level and should not be used in isolation to quantify individual nutrient consumption.38 Multiple methods should be utilised to enable triangulation of the data, particularly when sample sizes are small.
There is a clear opportunity for further research into the modification of dietary patterns, lifestyle and nutrient profiles in men with prostate cancer. The majority of clinical trials conducted have studied men in the lowest prostate cancer severity category of ‘active surveillance’. In the few trials that have included men with advanced disease on ADT, interventions appear to have different effects compared to those with less severe disease. No clinical trials of weight management or nutritional therapy have been conducted in men with advanced prostate cancer on ADT in order to prevent and/or alleviate the range of metabolic side-effects. Results indicate that a combination of weight management and lycopene (30mg per day), soy isoflavones or flaxseed supplementation may contribute to delaying prostate cancer proliferation, as results were promising for men on ‘active surveillance’. It is important to conduct trials of these nutrients as adjunctive therapies to weight management interventions in men with locally advanced or advanced disease with metastases to ascertain the effect on prognosis and quality of life.
The authors thank Professor Sandra Capra for comments on the manuscript draft.
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33. Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, et al. Folic Acid and Risk of Prostate Cancer: Results from a Randomized Clinical Trial. J Natl Cancer Inst. 2009;101:432-5.