Chapter 34 Prostate disease and cancer
Introduction
Clinicians encounter in clinical practice 3 common diseases of the prostate, namely, benign prostatic hypertrophy (BPH), prostate cancer and prostatitis (inflammation of the prostate).
Benign prostatic hypertrophy (BPH)
BPH is a common, often worrisome condition that affects ageing men.1 Approximately 60% of men in the Baltimore Longitudinal Study of Ageing2 demonstrated some degree of clinical BPH by age 60.3 Autopsy studies have confirmed microscopic evidence of BPH in 40% of men aged 50–60 years, and 90% of men aged 80 to 90 years.3 The profound impact of this condition spans all ethnic/racial groups, and African American and Latino men are affected to at least a similar degree as white European American men.3 BPH has been found to have an effect on quality of life (QOL) similar to that of other chronic diseases such as diabetes mellitus, hypertension, and heart disease.4–7 Also, depressive mood is more likely to occur in men with BPH.8 Despite the high prevalence of BPH, its specific cause is unknown, but the evidence suggests a multi-factorial process comparable to that of other chronic diseases, perhaps such as cardiovascular disease.9, 10, 11 The risk factors for BPH include high blood pressure, low levels of high-density lipoprotein cholesterol, increased weight gain (associated with waist-to-hip ratio increases), and peripheral arterial disease.10–15
Prostate cancer
Early estimates from autopsy data have reported that in Western countries, approximately 30–40% of all men will develop microscopic prostate cancer during their lifetime.16, 17 However, as the growth of most prostate cancers is slow, the risk of developing overt clinical disease in the US has been reported to be approximately 8–10% (lifetime risk), and the risk of actually dying from prostate cancer is approximately 3%, whereas the autopsy-based prevalence is 80% by the age of 80 years. Furthermore, epidemiological data from the US suggests that for a 50 year-old man with a life expectancy of a further 25 years, there is a 40–45% lifetime risk of having microscopic cancer.17, 18
In recent years, the veritable epidemic of prostate cancer has probably resulted from the widespread use of prostate-specific antigen (PSA) testing which allows the earlier diagnosis in men who have not yet developed symptoms. As an example, it is estimated that in 2005 in the USA there will be approximately 235 000 new diagnoses of prostate cancer and 29 000 deaths.17, 18, 19
In Australia, prostate cancer is the underlying cause of 4.3% of all male deaths registered in 2004.20 The median age of death from prostate cancer is 80.4 years. Prostate cancer is primarily a disease of men over the age of 50 years, and the trend towards an ageing worldwide population is likely to lead to an increased incidence of cases of prostate cancer. In 2004 in Australia there were 15, 759 new cases and 2,792 deaths from prostate cancer (∼18%).20 Approximately 11% of men in Australia will develop prostate cancer in their lifetime.21
Prostatitis
Prostatitis is the most common reason why men see a urologist with 1 in 2 men experiencing this condition in their lifetime. Prostatitis can be acute or chronic, bacterial, non-bacterial or inflammatory, plus non-inflammatory.22 More than 90% of symptomatic patients have chronic prostatitis and/or chronic pelvic pain syndrome. Very little is known about the aetiology of chronic abacterial prostatitis. It is possible that this form of prostatitis may be some form of autoimmune disease.
Bacterial prostatitis is treated using conventional approaches. The other forms of prostatitis are best managed using an integrative approach, as with other chronic medical problems.
Risk factors for prostate cancer
Alcohol
High alcohol consumers such as those that drink more than 10 drinks per day have triple the risk for development of prostate cancer.23 Another study reported that men who drank 4 glasses of red wine, 4 times weekly, had 50% reduction in relative risk of prostate cancer.24 This study reported that middle-aged men showed a relative risk reduction of 6% for each additional glass of red wine consumed per week.24 This study also demonstrated that consumption of alcohol above this level may increase risk of prostate cancer.
Meat and dairy
Studies have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins and the subsequent risk for prostate cancer.25 A recent study has investigated individual patient data from 12 prospective studies.26 This study investigated prostate cancer risk with relevance to IGFs, and their binding proteins. The study reported that men with high blood levels of IGF-1 were up to 40% more likely to develop prostate cancer than those with low levels. The conclusion was that high circulating IGF-I concentrations were associated with a moderately increased risk for prostate cancer.25 However, there were limitations with the study and these included that IGF-1 concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer could have varied among the studies.
Occupational exposure
Herbicides and pesticides are 2 common xenobiotics (chemicals and toxins that are foreign to the body) that can increase prostate cancer risk by causing DNA damage and altering hormone metabolism. Over 60 studies have investigated the relationship between farming and prostate cancer, and have generally shown an elevated risk for farmers.27
Endocrine disrupters — substances that mimic natural hormones — are xenobiotics that also increase prostate cancer risk, but also disrupt hormone metabolism. Endocrine disrupters include polychlorinated, biphenyls or PCBs (used to make plastic), ink, electrical and electronic equipment, and plasticizers (substances used to make plastic food-wrap more pliable). Dairy and beef products contain fat which can be contaminated with toxic pesticide and hormone residues which can act as endocrine disruptors.28, 29
Lifestyle
Benign prostatic hyperplasia and prostate cancer
Lifestyle modifications have received minimal attention in the medical literature, however, a limited number of studies seem to suggest a consistent beneficial impact of lifestyle interventions that can prevent BPH or cancer and that lifestyle interventions may diminish the progression of existing disease.30 The incidence of clinical prostate disease is around 30 times higher in Western men than in Eastern men of similar age.30 Recently, it was reported that excess Body Mass Index (BMI) has been associated with adverse outcomes in prostate cancer, and hyperinsulinaemia is a candidate mediator of increased risk.31 The study concluded that elevated BMI levels and a high plasma concentration of C-peptide both predisposed men who had been previously diagnosed with prostate cancer to an increased likelihood of dying of their disease.31 Furthermore, that in those patients with both factors, the survival outcome from the disease was with the lowest probability.
Prostate cancer
There is strong edpimiological evidence that links the development of prostate cancer to a Western type lifestyle.22 Furthermore, that there are specific components of the Western diet such as low fibre/high meat/high saturated fat consumptions that may have clinical significance in the late stages of tumour growth, promotion and disease progression.
A small study that investigated a plant based diet in combination with a mindfulness based stress reduction program reported significant reduction in the rate of PSA increase and slowed the rate of tumour progression in patients with biochemically proven recurrent prostate cancer.32 A recent and more robust study investigated lifestyle in patients with prostate cancer.33 Participation was in The Prostate Cancer Lifestyle Trial, a 1-year randomised controlled clinical trial that consisted of 93 patients with early-stage prostate cancer (Gleason score <7, PSA 4–10 ng/mL) who were undergoing active surveillance. The study reported that lifestyle and dietary changes could be important in delaying or even avoiding conventional treatment.
Mind–body medicine
Lifestyle changes and stress reduction
Psychosocial interventions can improve quality of life (QOL) and significantly improve survival in patients diagnosed with prostate cancer.34 A pilot study that enrolled prostate cancer patients into a mindfulness based stress reduction program reported enhanced QOL and decreased stress symptoms and also resulted in beneficial changes in hypothalamic-pituitary-adrenal (HPA) axis functioning.35 The study demonstrated that mental relaxation, stress management, ways to develop self-esteem and spirituality, imagery techniques and problem solving improved prognosis with the active group living twice as long as the men in the control group.35 The effects of comprehensive lifestyle changes from multiple Ornish research reports36–41 has demonstrated that patients with prostate cancer participating in the Prostate Cancer Lifestyle Trial gain significant quality of life benefits. A study investigating a reduction in PSA levels demonstrated inhibition of the human cell line–LNCaP cell growth, and fewer prostate cancer-related clinical events at the end of 1 year compared with control participants.36 The in vitro growth of the prostate cancer cells was inhibited 8 times more than in the control group using the serum from these patients. Another aspect of the Ornish study found that needle biopsy of prostate in the experimental group had significant changes in their prostate cancer genes and also increase in telomerase activity.36 Hence an enhanced understanding of the molecular response to comprehensive lifestyle changes by prostate cancer cells is further warranted.37, 38
The Ornish study of early stage prostate cancer patients,39 for instance, that randomised 93 men with prostate cancer (PSA 4–10ng/mL, cancer Gleeson scores < 7.0) to an intervention group versus a control group (no expectation of dietary or lifestyle changes), and observed over 1 year reported overall disease improvement. During the study time, the intervention group made vigorous lifestyle changes, namely, adhered to a vegan diet, daily moderate aerobic exercise and stress management techniques, weekly group support and daily supplementation of fish oil (3g/day), vitamin E (400IU/day), selenium (200mcg/day) and vitamin C (2g/day). The growth of prostate cancer cells were inhibited by 70% in the intervention group compared with 9% in the control. None of the patients in the intervention group required further conventional treatment and overall PSA dropped by 4%, compared with 6 patients in the control group requiring further conventional treatment and demonstrating an average increase of PSA of 6%. Diet and lifestyle changes may be the primary contributing factors, but it is hard to separate this benefit from the concomitant use of supplements.39 A further study with a plant-based diet, high in fibre and low in saturated fat, combined with a stress management technique (mindfulness-based stress reduction) was able to decrease the rate of PSA increase and may slow the rate of tumour progression in cases of biochemically recurrent prostate cancer.40 An additional recent study by this group further highlights the importance that plant based nutrition may have on slowing progression or preventing the development of prostate cancer.41 This study suggested that a very–low–fat vegan diet increased intake of protective dietary factors and that it simultaneously may decrease intake of pathogenic dietary factors.
Nutrients and risk of prostate cancer
A recent observational study has highlighted serious concerns with the high use of multivitamins in men, increasing the risk of advanced prostate cancer.42 The study enrolled 295 344 men aged 50–71 years who were cancer free over 1995–1996. Over a 5-year follow-up, 10 241 men were diagnosed with prostate cancer. The study demonstrated a 32% increase risk of advanced prostate cancer and a 98% increase risk of fatal prostate cancer among men ingesting multivitamins more than 7 times per week! This association was strongest in men with a family history of prostate cancer or those who took individual micronutrients such as selenium, beta-carotene or zinc. Unfortunately, they did not detail the exact quantities of multivitamins taken by those surveyed. The researchers acknowledge limitations of this study include its lack of information regarding duration of multivitamin use, information which may have helped to determine whether associations were limited to long-time users and that small case numbers limited their ability to investigate 3-way interactions among multivitamin use, single supplement use, and family history of prostate cancer. Furthermore, the authors speculate that the adverse effect of multivitamin supplements in combination with supplemental zinc on prostate cancer risk could be due to non-essential, potentially harmful trace elements contained in zinc supplements, such as cadmium, a known carcinogen. The authors did acknowledge that previous research demonstrated a positive association of multivitamin and mineral use amongst men (with PSA<3) leading to a marked reduction in prostate cancer risk, even up to 52% compared with placebo.
Physical activity/exercise
A recent study demonstrated that men who were more active had less lower urinary tract symptoms.15 More intense exercise, such as running and participating in sport activity, can significantly reduce the symptoms of BPH. In the Health Professionals Follow-up Study, after adjusting for age, race, ethnicity, alcohol intake, diet and smoking, it was found that men who were more active were also less likely to have BPH symptoms or surgery for the condition.15
Biologically plausible mechanisms exist to explain the protective effect of physical activity on the development of prostate cancer; the epidemiological data supporting this hypothesis is still incomplete.44 It is relevant to know whether exercise is indoors or outdoors, the latter providing an opportunity for increased vitamin D production through sun exposure.
Exercise can improve immunity, and reduce stress and depression, increase exposure to sunlight, all of which could increase protection against prostate cancer. Some evidence indicates that physical activity cannot only decrease the chance of prostate cancer, but may slow its progression.45 Resistance exercise in men receiving androgen deprivation therapy for prostate cancer reduces fatigue and improves QOL, and muscular fitness.46
Exercise is protective against BPH and prostate cancer. Men walking 2 to 3 hours per week have 25% lower risk of BPH. Exercise has been found to be protective and in 1 study in men younger than 60, found those that exercised were 4 times less likely to develop prostate cancer.47
Pelvic floor exercises for urinary incontinence following prostatectomy
The loss of urine should be evaluated by a clinician as it can have complicated sequelae.
Pelvic floor exercises and re-education of patients may help prevent and reduce the incidence of urinary incontinence after prostate surgery.48 A recent randomised prospective study investigating the benefit of implementing pelvic floor muscle exercises 30 days prior to surgery demonstrated efficacy.49 The study concluded that preoperative pelvic floor muscle exercises could improve early continence and quality of life outcomes in men following radical prostatectomy for prostate cancer.
Nutritional influences
Vegetables, legumes, soy and fruit
Diet plays an important role in the development of prostate disease.50 There is now a significant amount of research that strongly suggests that nutrition is closely linked with prostate health.30, 50–55 A diet rich in fruit, vegetables and fish and low in meat is likely to protect against BPH and prostate cancer.51–55 High meat, fat and possibly milk intake51, 52 and polyunsaturated fatty acids53–55 are also risk factors. According to a recent study of 6000 men over 30 years of age, high consumption of fatty fish, such as salmon, herring and mackerel was reported to be associated with a 50% reduced risk of prostate cancer.56 Men who ate no fish had a 2–3 fold higher risk of developing prostate cancer than men who ate moderate or high amounts. These benefits are further established in a recent epidemiological review that reported that the benefits were due to high omega-3 fatty acids contained in fatty fish57 which proved to inhibit the growth of prostate cancer cells in previous in vitro studies, albeit the exact mechanisms remain unclear.
In those countries where legumes and soy are the main protein source consumed in large amounts, BPH and the reported prostate cancer incidence is very low.58 It has been reported and hypothesised that soy is rich in isoflavones which actively concentrates in the prostate gland, regulates activity of androgens and oestrogens by acting on oestrogen receptors, and the isoflavonoids, genestein and diadzein are known to inhibit the enzyme 5-alpha-reductase.50, 58–60 This then prevents the development of BPH, and may explain the lower rates of prostate cancer in Asian countries. In BPH, there is an increase in dihydrotestosterone (DHT) and DHT receptors. The conversion of testosterone to DHT is mediated by 5-alpha-reductase. This enzyme inhibition can prevent the development of BPH.
Broccoli and cruciferous vegetables
Epidemiological studies suggest men who consume at least 1 portion of cruciferous vegetables (such as broccoli, cauliflower, cabbage and brussel sprouts) per week are at lower risk of the incidence of prostate cancer.52, 61 Diets rich in broccoli may reduce the risk of prostate cancer according to a 12-month study that randomised men to either a broccoli-rich or a pea-rich diet.62 The researchers quantified and interpreted changes in global gene expression patterns in the human prostate gland by biopsy before, during and after the 12-month diet and biopsies of the prostate were taken. Whilst the underlying mechanism for this observation is still not clear, the authors postulated that consuming broccoli interacts with GSTM1 genotype to result in complex changes to signalling pathways associated with inflammation and carcinogenesis in the prostate. It was proposed that these changes may be mediated through the chemical interaction of isothiocyanates with signalling peptides in the plasma. The report describes broccoli interacting with oncogenic signalling pathways in the prostate.62
Fish, omega-3 fatty acids
The type of fat in the diet plays a role in prostate cancer risk. Oily fish may help to reduce the risk of prostate cancer as omega-3 fatty acids appear to have inhibitory effects on tumour cells whereas omega-6 fatty acids (those contained in margarines rather than gamma-linolenic acid contained in evening primrose and borage seed oil) may have stimulatory effects. Omega-3 fatty acids can influence 5-alpha-reductase activity. Canola products increase the rate of prostate cancer and it is thought to be due to the instability with heat of alpha linolenic acid in canola. Also, omega-3 fatty acids found in fish are protective most probably due to their anti-inflammatory action through their influence on prostaglandins and leukotrienes.63
A small study examined the effects on men with dietary changes rich in plant-based foods and fish and its effect on QOL and PSA over 3 months.64 The intervention group significantly reduced the consumption of saturated fats, dairy foods and animal proteins, and increased consumption of vegetable proteins. The researchers concluded that men with an increasing PSA level after primary treatment were able to make a change to a prostate-healthy diet, accompanied by increases in QOL. No significant difference was found in the log PSA slope between the 2 groups; however, the PSA doubling time increased substantially in the intervention group compared with that in the controls.64 Further studies are required with larger samples.
Dairy products
A large study found the risk of BPH was significantly lower in men with a high intake of total vegetables, dark yellow vegetables, other vegetables, tofu and red meat and a greater risk with increasing intake of high-fat dairy products.65 It is thought that a high intake of calcium foods and dairy products is associated with an increased risk of prostate cancer by lowering concentrations of 1,25-dihydroxyvitamin D(3),66, 67 1,25(OH2D3), a hormone thought to protect against prostate cancer. The Physicians’ Health Study, a cohort of male US physicians in an 11-year follow-up study, documented 1012 incident cases of prostate cancer among 20 885 men. After adjustment for baseline age, BMI, smoking, exercise, and randomised treatment compared with men consuming less than or equal to 1–2/day servings of dairy products, those consuming >2.5 servings had an increase relative risk of prostate cancer by 34%.66 Men consuming >600mg/day of calcium had a 32% higher risk of prostate cancer. Of interest, at baseline, men who consumed >600mg Ca/day from skim milk had lower plasma 1,25(OH2D3) concentrations than did those consuming less than or equal to 150mg Ca/day, which explains the lack of protection towards developing prostate cancer. However, a recent large meta-analyses has concluded that the case-control analyses using calcium as the exposure of interest demonstrated no association with increased risk of prostate cancer in the review.68 Dietary intake of vitamin D also was not related to prostate cancer risk. Moreover, the data from observational studies did not support an association between dairy product use and an increased risk of prostate cancer.68
Soy milk
Drinking soy milk (several glasses per day) lowered risk of prostate cancer by 70% in 1 study.50, 69 Soy contains cancer-fighting substances called isoflavones, especially genistein which inhibits prostate cancer growth. Soy can inhibit oestrogen, cell growth, block activity of 5-alpha-reductase and tyrosine-specific protein kinase, plus reduce angiogenesis.
Phytoestrogens have been shown to cause prominent prostate cancer apoptosis in a human study.70 The major difference between Asian and US diets is the consumption of soy-based food stuffs. Soy protein powder decreases serum testosterone levels in healthy men and acts as an estrogen receptor (ER)-beta agonist, possibly inducing a biological effect to reduce the risk for prostate cancer development.71 This, however, needs to be carefully verified.
In general, there is support for the intake of legumes and yellow-orange plus cruciferous vegetables being inversely related to the risk of prostate cancer.72 Decreased prostate cancer risk has been found in Seventh-Day Adventists who have high intakes of lycopenes, lentils and peas.69 In general, multiple servings of fruit have also been shown to be inversely related to progression of prostate cancer.51
Pomegranate juice
Pomegranate juice is a major source of phytochemicals, and when consumed by men with a rising PSA after surgery or radiotherapy for their prostate cancer, it caused a statistically significant prolongation of PSA doubling with time.73 Approximately 2 x 30mls of pomegranate juice was consumed daily over the 2-year period of the trial. The serum of the men taking pomegranate also influenced in vitro prostate cancer cell proliferation and apoptosis, as well as oxidative stress.73
Special foods and teas
Green tea (Camellia sinensis)
Tea produced from the leaves of the plant Camellia sinensis along with water, is the most widely consumed beverage in the world.74 Alterations in the manufacturing process result in black, green, and oolong tea, which account for approximately 75%, 23%, and 2% of the global production, respectively. Even though each of these non-herbal teas is derived from the same source, different processing techniques render them chemically different from each other.74
Green tea has been reported in numerous recent reviews to be of benefit in preventing prostate diseases.75–80 According to a recent study79 with 404 men living in Southeast China, it was reported that compared to non-green tea drinkers, the risk of prostate cancer was 62% lower in all tea drinkers. Those who drank more than 3 cups daily reduced their risk by 63% and 88% for those who had consumed green tea for more than 40 years and 91% lower for those who consumed more than 1.5kg of tea leaves yearly.80 Green tea suppresses prostate cancer cells in vitro.
Lycopene
Based largely on the scientific evidence from epidemiologic, in vitro, animal and human clinical trials data, it is evident that lycopene, a non-provitamin A carotenoid, is a promising agent for the chemo-prevention of prostate cancer.81, 82 Lycopene is a natural plant compound found predominantly in tomatoes.
In the Health Professionals Follow-up study that followed just over 47 000 middle-aged male practitioners since 1986, a significant difference was reported in prostate cancer incidence in men with a high dietary intake of lycopene with a relative risk reduced to 0.84, even after adjusting for other risk factors such as smoking and other dietary factors.83 The main source of lycopene in the study was from tomato sauce. Men who ate the most sauce had the highest lycopene levels and lower prostate cancer rates. Another study found that men who consumed tomato sauce-based pasta dishes for 3 weeks before radical prostatectomy, had increased lycopene levels in blood and prostate, reduction in serum PSA levels and damage to prostate cancer cells.83 Recently the US Food and Drug Administration stated that lycopene was not associated with a reduced risk of prostate, lung, colorectal, breast, cervical or endometrial cancer.84 The role of lycopene in the area of prostate cancer prevention subsequent to this study was defended by an expert commentary.85
Garlic (Allium sativum)
Animal and in vitro studies provide evidence of an anti-carcinogenic effect of active ingredients in garlic.86, 87 A significant protective effect has also been noted in men with a consumption of >10g/day of allium vegetables.88 After adjusting for age and intake for other foods, high consumption of garlic and scallions were associated with the greatest protective effects.88
Pumpkin seeds (Curcurbita pepo)
A German multi centre study with 2245 patients diagnosed with BPH (Stage I to II) investigated the therapeutic use and safety of a pumpkin seed extract.89 Urinary symptoms were recorded by the International-Prostate-Symptom-Score according to the American Urological Association, the influence on quality of life has been recorded by a QOL index. Patients were treated for 12 weeks with 1–2 capsules per day containing 500mg of a pumpkin seed extract (15–25:1). The prostate symptom score decreased by 47.4% and QOL improved by 46.1% during therapy.
An early double-blind, placebo-controlled study of 3 months duration in 53 patients with BPH demonstrated that a daily intake of 4800mg of Cucurbita pepo (pumpkin seed) combined with the herb Serenoa repens (saw palmetto) showed significant improvement in objective and subjective parameters such as micturition time, frequency, dysuria, urinary flow (6.7 to 9.7 ml) as well as a reduction in residual volume by 32%. No side-effects were noted.90
A more recent double-blind, placebo-controlled study of 12 months duration in 47 patients with BPH demonstrated that a daily intake of 4800mg of Cucurbita pepo (pumpkin seed oil at a dose of 320mg/day) combined with the herb Serenoa repens (saw palmetto oil at a dose of 320mg/day) when compared with placebo or the 2 oils given singly. The study showed significant improvement in the international prostate symptom score (both oils singly or in combination), quality of life (both oils singly or in combination), serum prostate specific antigen (oil combination alone), prostate volume (no improvement) and maximal urinary flow rate improvement with both oils.91
Turmeric (Curcumin)
Curcumin is known to be a COX-2 inhibitor and can induce apoptosis of prostate cancer cells, as well as enhancing cytotoxicity of chemotherapeutic agents, and conferring radio-sensitising effects on prostate cancer cells.92 Curcumin can induce apoptosis in both androgen-dependent and androgen-independent prostate cancer cells by inhibiting tyrosine kinase activity of epidermal growth factor receptor, and depletes this protein.93 Curcumin may be a novel modality by which one can interfere with the signal transduction pathways of the prostate cancer cell and prevent it from progressing to its hormone refractory state.
