1. health and fitness
2. disease
3. cancer

Thurairaja_EU Urological Review 24/05/2011 12:22 Page 19
Current Issues Preventive Urology
Preventive Urology for Prostate Conditions
Ramesh Thurairaja,1 Edward Jefferies2 and Rajendra Persad3
1. Specialist Registrar in Urology, Southmead Hospital; 2. Specialist Registrar in Urology, Royal United Hospital;
3. Consultant Urological Surgeon, Bristol Royal Infirmary
Abstract
The approach to clinical medicine has evolved from managing acute events to incorporating therapeutic strategies to prevent medical
conditions and their negative effects. Preventive medicine stems from evidence identifying risk reduction and the lowering of negative events.
Recently, there has been a growing interest in this concept within the field of urology as a result of clinical trials, longer life expectancy and
public interest. Prostate conditions are a common cause for acute and chronic complaints in men and can have medical, psychological
and financial consequences. This review focuses on evidence surrounding prostatitis, benign prostatic hyperplasia and prostate cancer,
addressing methods and outcomes of prevention for these conditions. ‘Prevention is better than cure’ only if the evidence justifies the concept.
Keywords
Preventive urology, prostate, lifestyle changes, chemoprevention
Disclosure: The authors have no conflicts of interest to declare.
Received: 16 December 2010 Accepted: 21 February 2011 Citation: European Urological Review, 2011;6(1):19–25
Correspondence: Ramesh Thurairaja, Department of Urology, Southmead Hospital, North Bristol NHS Trust, Westbury-on-Trym, Bristol, BS10 5NB, UK.
E: rthurairaja@doctors.org.uk
In today’s economic climate, rising rates of unemployment and growing
numbers of uninsured people are exacerbating health problems and
disparities in care provision. As the healthcare delivery systems move
toward more managed care or medical rationing, clinical skills in health
promotion will become increasingly valuable. Preventive medicine has
already proven itself to significantly contribute to avoiding the negative
outcomes of cardiovascular and cerebrovascular events.1–6 This review
focuses on evidence from historic and contemporary urological studies
to rationalise whether preventive urology should be encouraged in
urological management.
Rationale, Levels of Prevention
and Implementation
Prevention strategies may reduce clinically insignificant conditions and
in so doing potentially prevent the side effects of treatment for these
conditions. These measures could also result in cost savings relating to
intervention and could possibly help to avoid the psychological effects
of the disease process and the consequences of treatment.7,8
Primary prevention strategies aim to prevent the development of
disease. Most population-based health promotion activities are
primary preventive measures. Secondary prevention strategies
attempt to diagnose and treat an existing disease in its early stages
before it results in significant morbidity. Tertiary preventive
treatments aim to reduce the negative impact of established disease
by restoring function and reducing disease-related complications,
while quaternary prevention describes the set of health activities that
mitigate or avoid the consequences of unnecessary or excessive
interventions by the health system.9 Urological practice has, until
recently, been centred on curative medicine or tertiary prevention.
With life expectancy figures having doubled in the past century and
© TOUCH BRIEFINGS 2011
overall mortality rates declining, preventive medicine seems destined
to take on a more important role, both for clinical and economic
purposes and should be encouraged in urological practice.10–12 Urology
as a speciality has been slow to embrace the idea of prevention,
although in the past two decades there has been a growing interest in
changing its perception.
Ideally, by focusing on target populations rather than mass
screening, the concept of preventive urology can be instituted.
Family history, age, lifestyle and symptom severity could be triggers
for initiating prevention. This may take the form of conservative
management through patient information, advice on lifestyle
modification and pharmacotherapy.
Prostate Conditions
The prevalence of prostatitis and the proportion of visits to urology
clinics is approximately 8%.13,14 In 2000, excluding pharmaceutical
spending, the cost of diagnosing and treating prostatitis in the US was
estimated to be over US$80million.15 Furthermore, 14% of men who
made medical claims for the treatment of prostatitis missed work.15
Chronic prostatitis has also been shown to affect mental and physical
domains of health-related quality of life.16 These statistics clearly
underscore the broad and far-reaching effect on patient quality of life
and the economic impact of this condition.
Bladder outlet obstruction (BOO) secondary to benign prostatic
hyperplasia (BPH) is one of the most common medical conditions in
older men. It represents up to a 40% clinical risk for urinary retention
in a man’s lifetime.17 BOO is the most prevalent condition in the ageing
male, affecting 14 million men in the US at an annual cost of
US$4billion to treat.17 BPH is more commonly diagnosed because
19
Thurairaja_EU Urological Review 24/05/2011 12:23 Page 20
Current Issues Preventive Urology
of increased life expectancy and a greater tendency today to seek
medical advice at an earlier stage of the disease.
Prostate cancer is now one of the principal medical problems facing
the male population. In Europe, an estimated 2.6 million new cases of
cancer are diagnosed each year.18 Prostate cancer more often affects
elderly men and is thus a bigger health and economic concern in
developed countries. With growing interest in early diagnosis and
screening, the medical and cost implications are due to rise.
suffer from chronic prostatitis.32 Supplementation does not increase
prostatic fluid levels, however and there is no evidence that zinc helps
treat infections or symptoms, or prevents future episodes of category
2 prostatitis. Cranberry juice, conversely, is felt to be a protective
agent against UTIs as it prevents E. coli attaching to the uroepithelial
cells and reduces the biofilm load.33,34 No placebo-controlled trial has
proven its protective effect in men against category 2 prostatitis. On
the contrary, having an acidic pH, cranberry juice may perpetuate
symptoms of prostatitis since men with this condition are sensitive to
an acid load in their diet.
Prostatitis
Prostatitis is a common condition with an estimated one in two
men encountering this condition in their lifetime.19 Although the term
prostatitis literally means ‘prostatic inflammation’, inflammation is not
always present and neither is infection. In 2002, the National Institute of
Health (NIH) proposed a four-category subclassification of prostatitis:20
For category 3 prostatitis, phytotherapeutic agents have shown great
potential. These agents have antioxidant and anti-inflammatory
characteristics and therefore it is felt that they are beneficial in this
patient group. The best-studied phytotherapy agents in this category
include quercetin, rye pollen and Saw palmetto (Serenoa repens) .
• category 1 – acute bacterial prostatitis;
• category 2 – chronic bacterial prostatitis;
• category 3 – chronic abacterial prostatitis/chronic pelvic
pain syndrome;
• 3a – inflammatory (>10 white blood cells per high powered field
[WBC/hpf] in expressed secretions);
• 3b – non-inflammatory (<10WBC/hpf in expressed secretions); and
• category 4 – asymptomatic inflammatory prostatitis
Quercetin is a bioflavanoid found in many of the food products that
patients with prostatitis avoid – onions, spices, cranberry and citrus
fruits. A small randomised controlled trial assessed patients’ chronic
prostatitis symptom index (CPSI), a validated symptom score, following
supplementation with quercetin 500mg twice daily or placebo. It found
that, compared to 7% of the placebo group, 35% of patients in the
quercetin group had an improved CPSI score. In addition to this,
the quercetin group had a 67% improvement in score, compared
to 25% in the placebo group (a 25% improvement in CPSI score
identifies clinical improvement).35,36 Common side effects of quercetin
Only 5% of men suffer from bacterial prostatitis, with the majority
(95%) having non-bacterial prostatitis.21,22 Reasons for this include the
antibacterial factor within seminal fluid as well as the immune system
dispatching lymphocytes and eosinophils, resulting in the eventual
demise of bacteria due to hydrogen peroxide.23 Controversially, chronic
abacterial prostatitis has been linked to ‘occult’ bacterial invasion,
fungal infections, genetic conditions, hormonal imbalance, ageing,
chemical irritants and auto-immunity; while the non-inflammatory
condition has been postulated to be a result of spasm of the pelvic floor
musculature, stress and intra-prostatic urinary reflux.19,24,25
The most commonly isolated organism for acute and chronic bacterial
prostatitis is Escherichia coli (E. coli), but other Gram-negative
organisms, such as Klebsiella, Proteus and Pseudomonas have also
been identified. Gram-positive Enterococcus species may also be
isolated. In sexually active men, particularly those <35-years-old,
Neisseria gonorrhoeae and Chlamydia trachomatis are usually
isolated. The mainstay of bacterial prostatitis treatment is therefore
antibiotics and appropriate supportive care. There is some evidence
that recurrent urinary tract infections (UTIs) in women may be
reduced by probiotic treatment.26–28 This preventive strategy may
therefore be useful in not only preventing category 1 and 2 prostatitis
but also allowing patients to avoid the common and considerable side
effects of short- and long-term antibiotic therapy. With a third of
non-bacterial prostatitis responding to antibiotic therapy, probiotics
may also be used in category 3 prostatitis.29,30 Clinical experience
has suggested that alpha-blockers may have a role in preventing
recurrences of category 3 prostatitis. The only large randomised,
double blind, placebo controlled trial of patients with category 3
prostatitis (alfuzosin 10mg versus placebo), however, showed no
statistically significant reduction in symptoms.31
Zinc is the major component of the antibacterial factor found in
seminal fluid. An early study showed reduced levels in patients who
20
include nausea and tingling, particularly when this supplement is
taken on an empty stomach. Quercetin binds to the DNA gyrase
site on E. coli, where quinolone antibiotics bind, so quercetin could
theoretically interfere with quinolone antibiotics and the two should
not be used together.37
Studies using the rye pollen preparation Cernilton and Saw palmetto
have claimed that symptoms improve in patients with chronic
prostatitis. Results from placebo controlled randomised trials of
patients supplemented with Cernilton and Saw palmetto have been
presented at the American Urology Association (AUA) meetings in the
past decade. One study has shown that when using a validated
symptom score, patients with category 3 prostatitis had a statistically
significant improvement in pain and quality of life when supplemented
with Cernilton compared to those who had placebo.38 In another
study, when supplementing with Saw palmetto, a mild improvement
in CPSI scores was seen in 75% of patients and a moderate to marked
improvement in 55% of patients, compared to 20 and 16% in the
placebo group, respectively.39
Benign Prostatic Hyperlasia
BPH is a common and often bothersome condition that affects ageing
men. Based on histological assessment from autopsy studies, it has
been shown that BPH change is inevitable with age.40 The prevalence of
BPH in males ranges from 40% in the fifth decade to 90% in the ninth
decade.40 Although BPH is often associated with lower urinary tract
symptoms (LUTS), only 25–50% of men with BPH complain of LUTS.
These are a major burden for the ageing male population, however and
their prevalence will continue to grow with increasing life expectancy
trends. Bothersome LUTS can occur in up to 30% of men over the age
of 65 years. In accordance, BPH has been defined as a life-altering
urinary condition that potentially requires medical or surgical
intervention and may not only be predictable but also preventable.41
EUROPEAN UROLOGICAL REVIEW
Thurairaja_EU Urological Review 24/05/2011 12:23 Page 21
Preventive Urology for Prostate Conditions
BPH is most often associated with prostate enlargement (volume
>30ml), deteriorating voiding patterns and eventually long-term
complications including acute urinary retention (AUR) and BPH
bleeding requiring surgery.42–44 Although only 2.5% of symptomatic
men with BPH who were treated with a watchful waiting approach
suffered from AUR, the Olmstead County study found that in randomly
selected men, the incidence of AUR was 13.7% in the average
60-year-old man over a 10-year period. This is high compared to lower
incidence of stoke (7.2%) or myocardial infarction (5.1%) in this group.45
BPH bleeding has not been studied as frequently as AUR but is
probably as common and may be even more problematic to manage.
The concept of BPH prevention developed from large prospective
studies evaluating medical therapies for the condition. To propose
BPH prevention, specific concepts need to be universally accepted:41
• BPH is progressive and as a disease entity will lead to long-term
and life-changing complications;
• it can be predicted in advance; and
• it can be prevented or altered with lifestyle, medical or
surgical interventions.
• elevated serum low-density lipoprotein (LDL) cholesterol, defined
as ≥130–140mg/dL;
• decreased serum high-density lipoprotein (HDL) cholesterol
(<40mg/dL); and
• increased serum triglycerides (≥150mg/dL).
These factors are components of both the metabolic syndrome and
diabetes. This observation raises the possibility that an abnormal lipid
profile may also be connected to BPH pathogenesis. Clinical studies,
however, have been equivocal. A Swedish cohort study concluded
that in men with BPH, a larger prostate volume was associated
with lower HDL cholesterol and higher LDL cholesterol levels; while an
Indian case study reported similar profiles in men undergoing
BPH surgery.57,58 Contrasting results were seen in other studies
where no associations were noted, including a cohort US Air Force
Veterans study.59
As seen in community-based studies, BPH is progressive and can lead
to complications. To predict BPH disease risk and progression, age,
serum prostate-specific antigen (PSA), prostate volume and flow
indices remain valuable. While older men are at a higher risk of
disease progression and AUR, men with larger prostates have higher
PSA values and so are at greater risk of progression.46 The Proscar
Some studies have found correlations between atherosclerosis
and BPH. A recent study on prostatic perfusion rates showed that
men with lower prostatic perfusion rates secondary to atherosclerosis
had larger mean prostate volumes while those with diabetes and PVD
reported significantly higher international prostate symptom scores.60
Heart disease, diabetes mellitus and metabolic-syndrome factors
have all been associated with more rapid annual increase in prostatic
growth rates and an increased risk of BPH.61 As a result of these
ongoing associations, there should be an emphasis on optimising
blood pressure, lipid profile and serum glucose levels in order to
maintain adequate health.
long-term efficacy and safety study (PLESS) concluded that
progression occurred in men with prostate volumes of >40ml and
PSA >1.4ng/ml.47
Other factors influencing BPH outcomes may include physical activity,
alcohol and coffee consumption and diet supplementation (see Table 1).
Of all indices, serum PSA has been found to be the most valuable
index of disease progression after excluding prostate cancer, as
shown in the PLESS trial. In an analysis by Roehrborn et al. on
worldwide BPH trials including 3,700 placebo-treated patients, PSA
was the most robust predictor of AUR and even outperformed a
complex decision matrix.48
Nomograms to predict disease progression, such as one constructed
using data from the dutasteride phase III programme, have a
predictive accuracy of >70%.
With these predictive tools and focusing on target populations based
on age, family history and race, what interventions can be used to
prevent BPH disease progression? As seen with chronic conditions
such as diabetes mellitus, hypertension and heart disease, BPH
affects men’s quality of life.49,50 Men with BPH are more likely to
suffer from depression than their peers.51 The natural history of BPH
stems from a multifactorial process that is common to cardiovascular
disease. Factors that contribute to cardiovascular disease and the
metabolic syndrome – such as obesity, diabetes, glucose intolerance,
dyslipidaemia, hypertension and peripheral vascular disease (PVD) –
are also thought to be risk factors for BPH.52–55 Although there is a lack
of evidence on the influences of lifestyle on BPH progression, limited
studies suggest that primary prevention through lifestyle changes
may be beneficial.
Abnormal concentrations of lipids are a well-studied risk category for
cardiovascular disease. Abnormalities included are:56
EUROPEAN UROLOGICAL REVIEW
A systematic review and meta-analysis performed by Parsons and
Kashefi reported that physical activity reduces the risks of BPH
and LUTS. 62 The degree of physical activity was an important
contributory factor, with moderate to vigorous exercise significantly
reducing the risks compared to a light workout. They also added
that the BPH/LUTS complex may be associated with modifiable
risk factors of cardiovascular disease and suggested that increased
physical activity may prevent or attenuate these conditions.
Sexual activity does not seem to be causally related, although a large
multinational study has suggested that men with increasing LUTS
have increasing sexual and ejaculatory disturbances.63
Alcohol has been postulated to reduce plasma testosterone and
therefore induces an inhibitory effect on BPH. This has been
highlighted in a recent study from Switzerland where it was found
that in men between 65 and 80 years, although smoking had no effect
on BPH outcomes, there was a strong negative association between
alcohol intake and those requiring surgical intervention compared to a
positive correlation with coffee consumption.64 The author concluded
that the increased LDL-cholesterol as a result of coffee constituents
may be part of the pathophysiology of BPH and that, if so, further
studies are required to see whether a reduction in coffee intake can
potentially reduce BPH progression.
In terms of dietary supplementation, considering that BPH is not
a life-threatening condition, using drugs composed of natural
ingredients (phytotherapeutic agents) with low perceived side effect
21
Thurairaja_EU Urological Review 24/05/2011 12:23 Page 22
Current Issues Preventive Urology
Table 1: Effects of Dietary Supplementation
and Lifestyle Changes
Acupuncture
Minimal to no impact found in preliminary studies
Aspirin/nonsteroidal
May be associated with reduced risk
anti-inflammatory drugs
Alcohol
Moderate alcohol consumption may reduce risk
Caffeine
Excess intake of caffeine may increase risk
Calcium and vitamin D
May lower PSA velocity,
supplements
but the impact on prostetic hyperplasia is unknown
Cholesterol/lipid levels
High total cholesterol, LDL cholesterol or
triglyceride levels and/or lower HDL cholesterol
levels may increase the risk and progression of
BPH, whereas cholesterol-lowering medications
may reduce risk
Diabetes mellitus
Increased insulin/glucose levels may stimulate
prostate growth
Diet (overall)
Lower overall caloric intake may reduce risk
Other dietary
Sitosterol, Pygeum africanum, rye pollen, stinging
supplements
nettle and South African Star grass have
preliminary evidence showing they improve mild
symptoms of BPH but have not been tested in
large randomised trials
Fat (dietary)
Increased fibre
Omega-3 fatty acids may reduce risk
Fibre consumption, especially soluble fibre, may
reduce PSA levels but the impact on BPH
prostate size and in so doing lowered the risk of AUR and BPH-related
surgery compared to placebo.69 In addition to this, the beneficial effect
of 5ARIs in prostatic bleeding was highlighted by Miller and Puchner.70
Surgical intervention was usually required to control prostatic
bleeding; however, the sustained effect of an 5ARI through the
reduction in microvessel density within the prostate has provided not
only a less invasive alternative but a potentially preventive option.
Two large randomised-controlled trials within the past decade have
outlined the value of medical intervention in preventing disease
progression. The Medical therapy of prostatic symptoms (MTOPS)
study found that, compared to placebo, finesteride reduced disease
progression and the risk of AUR by 34 and 68%, respectively.
Combination therapy with the alpha-blocker doxazosin provided
the greatest effect, reducing BPH progression and AUR risk by 66
and 81%, respectively.71 The Combination of Avodart and Tamsulosin
(COMBAT) study similarly found strong evidence for combination
therapy.72 Combining the alpha-blocker tamsulosin with dutasteride
reduced the relative risk of disease progression and AUR- or
BPH-related surgery by 31 and 20%, respectively, compared to the
5ARI alone. Although evidence has shown that medical intervention
can alter BPH disease progression, there is still a void when
addressing medical therapy in BPH prevention, therefore future
studies are required.
is unknown
Fruits and vegetables
Fruits and especially vegetables may reduce risk
Obesity
Greater weight may increase risk, especially
greater waist-to-hip ratio
Physical activity/excercise
Increased regular physical activity may reduce risk
Plant oestrogens
Soy and other dietary sources of plant
oestrogens may reduce the risk of BPH
BPH = benign prostatic hyperplasia; LDL = low-density lipoprotetin; HDL = high-density
lipoprotein; PSA = prostate-specific antigen.
profiles is attractive to patients. The proposed mechanisms of action
of phytotherapeutic agents include:65
•
•
•
•
•
•
anti-androgenic effect;
anti-oestrogenic effect;
inhibition of 5α-reductase;
α-adrenergic receptor antagonism;
anti-inflammatory effect; and
inhibition of prostatic cell proliferation.
Patients should, however, be informed that herbal remedies such
as Saw palmetto fruit, African plum tree (Pygeum africanum) bark and
stinging nettle (Urtica dioica) roots have no proven advantage over
conventional medication or even placebo in treating BPH, while other
products such as zinc may even be damaging.66 The Complementary
and alternative medicine for urological symptoms (CAMUS) trial with
3,300 participants is assessing the short and long-term effects of
Seronoa repens, African plum tree extract, an α-adrenergic blocker
and placebo, with outcome data expected in 2011.67 A list of dietary
supplementation and lifestyle interventions that alter BPH risk are
listed in Table 1.68
Therapeutic intervention with conventional medication has been
shown to lower the risk of BPH progression. BPH is a complex process
but is primarily influenced by androgens. One of the first large-scale
randomised-controlled trials (PLESS) showed that the anti-androgenic
effects of a 5-alpha reductase inhibitor (5ARI), finesteride, reduced
22
Finally, is there any place for prophylactic surgical intervention?
BPH-related surgery includes:
• minimally-invasive therapies (e.g. thermo- and microwave therapy,
high-intensity frequency ultrasound);
• laser ablative and enucleation therapies;
• trans-urethral resection; and
• open procedures.
Although surgical interventions have provided better clinical outcomes
than medical interventions, these effects are usually seen in patients
with advanced BPH and severe symptoms or in patients following
AUR. In addition to this, there is the side effect profile from surgery that
cannot be ignored. Early intervention could, however, potentially
negate the pathological and cost issues surrounding chronic urinary
retention, renal impairment and dependence on dialysis. Since there
have not as yet been any studies on surgical prophylaxis, this form of
management will continue to be controversial.
As with any intervention, potential negative impacts have to be
addressed. The disadvantages of medical intervention include:41
• drug side effects for alpha-blockers (e.g. headaches, dizziness,
postural hypotension and retrograde ejaculation) and 5ARIs (e.g.
gynaecomastia and loss of libido);
• limited or poor drug efficacy; and
• long-term costs.
Prostate Cancer
As a result of improving healthcare and technology, patient awareness
and the advent of PSA testing, prostate cancer is now one of the most
prominent medical conditions in the male population, with the annual
prevalence in Europe being estimated at >2.5 million, according to EAU
guidelines. It constitutes 11% of male cancers and 9% of cancer deaths
in Europe.18,73 Importantly, this condition affects elderly men and is a
EUROPEAN UROLOGICAL REVIEW
Thurairaja_EU Urological Review 24/05/2011 12:24 Page 23
Preventive Urology for Prostate Conditions
greater concern in developed countries, where it comprises 15%
of male cancers.74 With life expectancy improving, the population of
prostate cancer patients may grow. Furthermore, despite suggestions
of prostate cancer over-diagnosis and over-treatment, a high
intervention rate still persists. This ubiquitous condition and its rising
mortality rates therefore make it an ideal condition to target using
prevention strategies.
addition to this, there is still a lack of evidence as to the type of
activity, its parameters and time periods to be undertaken for this
risk reduction. It is also unclear whether the reduction is modified by
other variables, including age, race and family history. There is
some evidence that the beneficial effect of physical activity is greater
in patients with advanced prostate cancer and for higher levels of
physical activity.79,82,83
Screening
The European prospective investigation into cancer and nutrition
(EPIC) trial identified dietary factors associated with cancers. This
study discovered that a high intake of dairy protein and calcium from
dairy products and high serum concentration of insulin-like growth
factor 1 were associated with an increased risk of prostate cancer.84,85
There was, however, a lack of association between prostate cancer
incidence and total fruit and vegetable intake.86 The Selenium and
vitamin E cancer prevention trial (SELECT) randomised over 35,000
healthy men to take selenium, vitamin E, both supplements or
placebo.87 Results from this trial showed that neither supplement
alone nor in combination had a beneficial effect on prostate cancer
prevention. There has been some evidence, however, that soy and
isoflavanoids have a beneficial effect in non-Western men. This is
thought to be a result of phytoestrogens and tyrosine kinase inhibition
causing apoptosis, limited cell growth and reduced inflammation.88–90
Green tea from the Camellia sinensis plant, through the proposed
mechanism of antioxidant activity and 5ARI activity, has been shown
to have a potentially positive effect on advanced prostate cancer.91,92
Prostate cancer screening has been the subject of intense scrutiny,
leading to it being included in the European randomised study of
screening for prostate cancer (ERSPC), the Prostate, lung, colorectal
and ovarian (PLCO) screening trial and the Gothenburg trial, which
included participants from the previously reported ERSPC trial.75–77
The ERSPC study confirmed that PSA-based screening reduced the
rate of death from prostate cancer by 20%, but was associated with a
higher risk of over-diagnosis. It showed that 1,410 men would require
screening and 48 additional cases would need treatment to prevent
one death from prostate cancer.75
The PLCO trial, after seven to 10 years of follow-up, concluded that the
rate of death from prostate cancer was very low and that there were
no significant differences in the screened and unscreened population
in terms of prostate cancer deaths. Despite this, crucial shortcomings
in this trial were highlighted in both patient populations, particularly
with the impact of the PSA dilution effect on eventual outcomes.76
Chemoprevention
The Gothenburg trial clearly showed that prostate cancer mortality
was reduced by more than half over a 14-year follow-up period in
the screened population compared to the control group. Once again,
however, the trial highlighted the issue of over-diagnosis risk in
this population.77
A recent systemic review and meta-analysis on all the relevant
contemporary screening studies concluded that existing evidence
from randomised controlled trials does not support the use of routine
screening in prostate cancer. Despite this, it acknowledged that
there is evidence that screening aids in early prostate cancer diagnosis
and treatment and reduces mortality.78 This comes at a price, with
over-diagnosis, over-treatment and downstream adverse events. What
the study has not addressed is the issue of at-risk patient populations,
such as hereditary prostate cancer and Afro-Caribbean males, who
would benefit from screening. It does not address concerns about the
rising prostate cancer mortality and life expectancy worldwide either.
A number of observations from various epidemiological studies have
suggested associations between prostate cancer and lifestyle, dietary
or pharmacological interventions. Although factors such as age,
ethnicity and genetics are not modifiable, lifestyle modifications and
chemoprevention have become an important approach in reducing
the mortality and economic burden due to a condition that has
a high incidence, prevalence, cost of treatment, disease- and
treatment-related mortality.
Factors that Affect Risk
There is inconsistent evidence regarding the association between
physical activity and prostate cancer, with about a third of studies
indicating a protective effect of activity on cancer risk.79–81 The
magnitude of the risk reduction is modest, ranging from 10–20%. In
EUROPEAN UROLOGICAL REVIEW
Chemoprevention for prostate cancer is defined as the use of specific
natural or synthetic agents to reverse, suppress or prevent the
carcinogenic process, thereby preventing the development of
clinically evident disease. Androgens help maintain the normal
secretory and metabolic functions of the prostate. These hormones
contribute to the carcinogenic process of prostate cancer as well as
BPH. Pharmacological agents that alter circulating androgen levels or
inhibit 5-α reductase have potential as chemopreventive agents
because testosterone, after conversion to 5-α-dihydrotestosterone,
controls prostate mitotic activity and results in prostate cancer
and BPH pathogenesis. Both finesteride (selective inhibition for
type II 5-α-reductase) and dutasteride (inhibition of type I and II
5-α-reductase) have been used to treat LUTS associated with BPH.
Their role as chemopreventive agents was investigated in two large,
well-publicised randomised trials93,94 designed to assess their impact on
the prevalence of confirmed cancer over a specified period of time.
The Prostate cancer prevention trial (PCPT) was the hallmark study
on chemoprevention of prostate cancer.93 This trial randomised
patients to finesteride or placebo and followed these patients over a
seven-year period. The results showed a 24.8% relative risk reduction
in prostate cancer with finesteride compared to placebo. In the
results there was the particularly significant finding of a 25.5%
increase in the diagnosis of high-grade (Gleason score ≥7) prostate
cancer in the finesteride group. As a result, this has created concern
in the use of this medication. Post hoc analyses and interpretations
have, however, concluded that the effects of reduced prostate
volume in modelling studies and the increase in PSA/digital rectal
examination (DRE) predictive accuracy in the finesteride arm may
explain the increased detection of high-grade disease in this group.
On closer inspection, markers of the disease profile (perineural
invasion, bilateral disease, percentage of positive cores) were worse
23
Thurairaja_EU Urological Review 24/05/2011 12:24 Page 24
Current Issues Preventive Urology
in the placebo group and when subjects from both the placebo and
finesteride groups underwent radical prostatectomy for their disease.
A greater number of cases of high-grade disease were identified in
the placebo group.
The Reduction by dutasteride of prostate cancer events (REDUCE)
trial, as in the PCPT trial, randomised men to treatment with
dutasteride or placebo and followed them up over a four-year
period.94 Patients in this trial were at higher risk of prostate cancer,
having had a negative biopsy within six months of joining the trial.
The results confirmed a relative risk reduction for prostate cancer of
22.8% for dutasteride over placebo, similar to data from the PCPT
trial. The major difference between these two trials was that in
the REDUCE trial dutasteride did not significantly affect the diagnosis
of high-grade disease prevalence. When Gleason 8–10 cancers were
identified, no difference in incidence was found at the two-year
point, but at the four-year mark there were 12 patients in the
dutasteride group in comparison to a single patient from the placebo
group. The authors noted that by two years, a substantially higher
number of patients with Gleason 5–7 disease had been removed
from the placebo group in comparison to the dutasteride group.
This could conceivably have influenced the difference between
both groups for patients with higher Gleason scores. Aside from
the cancer outcomes, there was an increase in all cardiac events in
the dutasteride arm, which caused concern. A similar side effect
profile to finesteride (erectile dysfunction, abnormal ejaculation and
abnormal sexual function) was also seen with this drug.
Presently, opinion from an expert guideline panel95 is that 5ARIs can
be considered in chemoprevention for prostate cancer, but key issues
should be highlighted including:
• the fact that 5ARIs reduce the incidence of prostate cancer but do
not eliminate it completely;
• the uncertainty that remains surrounding the increased risk of
high-grade disease;
• their effect on mortality is unclear;
• significant sexually-related side effects still persist with 5ARIs; and
• the well-documented beneficial effects for men with BPH-related
LUTS will persist.
An editorial by Walsh has unearthed many interesting and crucial
points about these trials.96 In the PCPT trial, the percentage of
positive biopsies in the placebo group (25%) substantially exceeded
the lifetime risk of prostate cancer (17%), which suggests that many
of the tumours were likely to be clinically insignificant. In addition to
this, in the REDUCE trial the reduction in prostate cancer in the
1.
2.
3.
4.
5.
24
Downs JR, Clearfield M, Weis S, et al., Primary prevention of
acute coronary events with lovastatin in men and women
with average cholesterol levels: results of the
AFCAPS/TexCAPS, JAMA, 1998;279:1615–22.
Scandinavian Simvastatin Survival Study Group, Randomized
trial of cholesterol lowering in 4444 patients with coronary
heart disease: the Scandinavian Simvastatin Survival Study
(4S), Lancet, 1994;344:1383–9.
Long-term Intervention with Pravastatin in Ischaemic Disease
(LIPID) Study Group, Prevention of cardiovascular events and
death with pravastatin in patients with coronary heart
disease and a broad range of initial cholesterol levels,
N Engl J Med, 1998;339:1349–57.
Sacks FM, Pfeffer MA, Moye LA, et al., for the Cholesterol
and Recurrent Events Trial Investigators, Effect of pravastatin
on coronary events after myocardial infarction in patients
with average cholesterol levels, N Engl J Med,
1996;335:1001–9.
Shepherd J, Cobbe SM, Ford I, et al., for the West of Scotland
dutasteride arm was limited to the incidence of Gleason 5–6 cancers,
with no significant reduction in less differentiated tumours (Gleason
scores 7–10) that are more likely to be lethal.94 This finding is similar
to results from the random biopsies in the PCPT, which showed no
decrease in high-grade disease.93 Both finesteride and dutasteride
treat LUTS, reduce prostate volume and reduce PSA readings by 50%
or more.96 This may leave patients with a false sense of security in
terms of prostate cancer prevention. It should therefore be made
clear to patients that these medications merely shrink tumours that
have low lethal potential alone and do not prevent prostate cancer.
In addition, 5ARIs do not reduce the risk of a positive biopsy in
patients with an elevated PSA level or abnormal DRE. Patients should
be educated about the effects on PSA and should not fall into a false
sense of security about prostate cancer prevention.
Over the past decade, prostatic inflammation has been implicated as
a major risk factor for prostate cancer. Population studies have found
an increased relative risk of prostate cancer in men with a history of
previous prostatitis.97 Almost all BPH specimens show inflammatory
infiltrates on histological examination and the cycolooxygenase-2
and nuclear factor-kappa B inflammatory pathways are overexpressed in prostate adenocarcinomas.98–100 Thus, there has been
interest in targeting these pathways to possibly prevent prostate
cancer. Several studies using NSAIDs have been carried out but have
shown relatively modest reductions in prostate cancer (~10%).101 A
recently published study of 51,529 US male healthcare professionals
found a similar 15% decrease in prostate cancer, but more
importantly, a significant decrease in high-grade (28%) and lethal
(29%) prostate cancer risk when taking at least two adult-strength
(75mg) aspirin tablets per week.102
Conclusions
Prostate conditions are common in today’s urological practice and
will increase in prevalence to be a health expenditure burden in many
countries. Through preventive measures in the form of screening,
case-selection, patient education, lifestyle and diet changes and
finally through conventional and complementary therapies, these
conditions may be better managed. There could also be a potential
reduction in prevalence, disease progression and morbidities
associated with both the disease process and possible side effects of
invasive treatment in the future.
Although the potentials of preventive urology have been highlighted,
uncertainties surrounding methods, outcomes and cost efficacy still
remain. Future trials addressing these issues should therefore be
encouraged. n
Coronary Prevention Study Group, Prevention of coronary
heart disease with pravastatin in men with
hypercholesterolemia, N Engl J Med, 1995;333:1301–7.
6. Paciaroni M, Bogousslavsky J, Statins and stroke prevention,
Expert Rev Cardiovasc Ther, 2009;7(10):1231–43.
7. Ormond BA, Spillman BC, Waidmann TA, et al., Potential
national and state medical care savings from primary disease
prevention, Am J Public Health, 2011;101(1):157–64.
8. Manson SC, Benedict A, Pan F, et al., Potential economic
impact of increasing low dose asprin usage on CVD in the
US, Curr Med Res Opin, 2010;26(10):2365–73.
9. Gofrit ON, Shemer J, Leibovici D, et al., Quaternary
prevention: a new look at an old challenge, Isr Med Assoc J,
2000;2(7):498–500.
10. Borgaarts J, Long-range Trends in Adult Mortality Trends:
Models and Projection Methods, Population Council Working
Paper No. 192, 2004. Available at:
www.popcouncil.org/pdfs/wp/192.pdf
(accessed 24 March 2011).
11. Carey JR, Judge DS, Life span extension in humans is
self-reinforcing: a general theory of longevity, Population and
Development Review, 2001;27(3):411–36.
12. Cutler D, Meara E, Changes in the age distribution of
mortality over the 20th Century. In: Wise D (ed), Perspectives
on the Economics of Aging, Chicago, University of Chicago
Press, 2003.
13. Krieger JN, Lee SW, Jeon J, et al., Epidemiology of prostatitis,
Int J Antimicrob Agents, 2008;31(Suppl. 1):S85–S90.
14. Collins MM, Stafford RS, O’Leary MP, et al., How common is
prostatitis? A national survey of physician visits, J Urol,
1998;159(4):1224–8.
15. Pontari MA, Joyce GF, Wise M, et al.; Urologic Diseases in
America Project, Prostatitis, J Urol, 2007;177(6):2050–7.
16. McNaughton Collins M, Pontari MA, O’Leary MP, et al.,
Quality of life is impaired in men with chronic prostatitis:
the Chronic Prostatitis Collaborative Research Network,
J Gen Intern Med, 2001;16(10):656–62.
17. Djavan B, Eckersberger E, Finkelstein J, et al., Benign
EUROPEAN UROLOGICAL REVIEW
Thurairaja_EU Urological Review 24/05/2011 12:24 Page 25
Preventive Urology for Prostate Conditions
prostatic hyperplasia: current clinical practice, Prim Care,
2010;37(3):583–9.
18. Bray F, Sankila R, Ferlay J, et al., Estimates of cancer
incidence and mortality in Europe in 1995, Eur J Cancer,
2002;38(1):99–166.
19. Schaeffer AJ, Landia JR, Knauss JS, et al., Demographic and
clinical characteristics of men with chronic prostatitis: the
National Institutes of Health Chronic Prostatitis Cohort Study,
J Urol, 2002;168:593–8.
20. Krieger JN, Nyberg LJ, Nickel JC, NIH consensus definition and
classification of prostatitis, JAMA, 1999; 282: 236–7.
21. Nickel JC, Prostatitis and related conditions. In: Walsh PC,
Retik AB, Vaughan Jr ED, et al. (eds), Campbell’s Urology, 8th ed,
Philadelphia, WB Saunders, 2002:603–30.
22. Hua VH, Williams DH, Schaeffer AJ, Role of bacteria in
chronic prostatitis/chronic pelvic pain syndrome,
Current Prostate Reports, 2005;3:87–93.
23. Fair WR, Couch J, Wehner N, Prostatic antibacterial factor:
identity and significance, Urology, 1976;7:169–77.
24. Pontari MA, Ruggieri MR, Mechanisms in prostatitis/chronic
pelvic pain syndrome, J Urol, 2004;172:839–45.
25. Hetrick DC, Ciol MA, Rothman I, et al., Musculoskeletal
dysfunction in men with chronic pelvic pain syndrome type
III: a case-control study, J Urol, 2003;170:828–31.
26. Heczko PB, Strus M, Kochan P, Critical evaluation of probiotic
activity of lactic acid bacteria and their effects, J Physiol
Pharmacol, 2006;57(Suppl. 9):5–12.
27. Reid G, Bruce AW, Probiotics to prevent urinary tract
infections: the rationale and evidence, World J Urol,
2006;24:28–32.
28. Falagas ME, Betsi GI, Tokas T, et al., Probiotics for prevention
of recurrent urinary tract infections in women: a review of
the evidence from microbiological and clinical studies, Drugs,
2006;66:1253–61.
29. Alexander RB, Propert KJ, Schaeffer AJ, et al., Ciprofloxacin
or tamsulosin in men with chronic prostatitis/chronic pelvic
pain syndrome: a randomized, double-blind trial,
Ann Intern Med, 2004;141:581–9.
30. Nickel JC, Downey J, Clark J, et al., Levofloxacin for chronic
prostatitis/chronic pelvic pain syndrome in men: a
randomized placebo-controlled multicenter trial, Urology,
2003;62:614–7.
31. Nickel JC, Krieger JN, McNaughton-Collins M, et al.; Chronic
Prostatitis Collaborative Research Network, Alfuzosin and
symptoms of chronic prostatitis-chronic pelvic pain
syndrome, N Engl J Med, 2008;359(25):2663–73.
32. Fair WR, Couch J, Wehner N, Prostatic antibacterial factor.
Identity and significance, Urology, 1976;7:169–77.
33. Di Martino P, Agniel R, David K, et al., Reduction of
Escherichia coli adherence to uroepithelial bladder cells after
consumption of cranberry juice: a double-blind randomized
placebo-controlled cross-over trial, World J Urol, 2006;24:21–7.
34. Di Martino P, Agniel R, Gaillard JL, et al., Effects of cranberry
juice onuropathogenic Escherichia coli in vitro biofilm
formation, J Chemother, 2005;17:563–5.
35. Shoskes DA, Zeitlin SI, Shahed A, et al., Quercetin in men
with category III prostatitis: a preliminary, prospective,
double-blind, placebo-controlled trial, Urology, 1999;54:960–3.
36. Propert KJ, Litwin MS, Wang Y, et al., Responsiveness of the
National Institutes of Health Chronic Prostatitis Symptom
Index (NIH-CPSI), Qual Life Res, 2006;15:299–305.
37. Plaper A, Golob M, Hafner I, et al., Characterization of
quercetin binding site on DNA gyrase, Biochem Biophys Res
Commu, 2003;306:530–6.
38. Schneider H, Ludwig M, Horstmann A, et al., The efficacy of
Cernilton in patients with chronic pelvic pain syndrome
(CP/CPPS) type NIH IIIa: a randomized, prospective,
double-blind, placebo controlled study, J Urol,
2006;176(Suppl):abstract 105.
39. Reissigl A, Pointner J, Marberger M, et al., Multicenter
Austrian trial on safety and efficacy of phytotherapy in the
treatment of chronic prostatitis/chronic pelvic pain
syndrome, Presented at: AUA 98th Annual Meeting: Abstract
103937, 26 April 2003.
40. Berry SJ, Coffey DS, Walsh PC, et al., The development of
human benign prostatic hyperplasia with age, J Urol,
1984;132:474–9.
41. Marks LS, Roeherborn CG, Andriole GL, Prevention of benign
prostatic hyperplasia disease, J Urol, 2006; 176:1299–306.
42. Rhodes T, Girman CJ, Jacobsen SJ, et al., Longitudinal
prostate growth rates during 5 years in randomly selected
community men 40 to 79 years old, J Urol, 1999;161:1174–9.
43. Girman CJ, Panser LA, Chute CG, et al., Natural history of
prostatism: urinary flow rates in a community-based study,
J Urol, 1993;150:887–92.
44. Homma Y, Imajo C, Takahahi S, et al., Urinary symptoms and
urodynamics in a normal elderly population, Scand J Urol
Nephrol Suppl, 1994;157:27–30.
45. Jacobsen SJ, Girman CJ, Lieber MM, Natural history of benign
prostatic hyperplasia, Urology, 2001;58(6 Suppl. 1):5–16.
46. Wright EJ, Fang J, Metter EJ, et al., Prostate specific antigen
predicts the long-term risk of prostate enlargement: results
from the Baltimore Longitudinal Study of Aging, J Urol,
2002;167:2484–7.
EUROPEAN UROLOGICAL REVIEW
47. Roehrborn CG, McConnell JD, Lieber M, et al.; for the PLESS
Study Group, Serum prostate-specific antigen concentration
is a powerful predictor of acute urinary retention and need
for surgery in men with clinical benign prostatic hyperplasia,
Urology, 1999;53:473–80.
48. Roehrborn CG, Malice MP, Cook TJ, et al., Clinical predictors
of spontaneous acute urinary retention in men with LUTS and
clinical BPH: a comprehensive analysis of the pooled placebo
groups of several large clinical trials, Urology, 2001;58:210–6.
49. Parsons JK, Carter HB, Partin AW, et al., Metabolic factors
associated with benign prostatic hyperplasia, J Clin Endocrinol
Metab, 2006;91:2562–8.
50. Michel MC, Heemann U, Schumacher H, et al., Association of
hypertension with symptoms of benign prostatic hyperplasia,
J Urol, 2004;172:1390–3.
51. Clifford GM, Farmer RD, Drug or symptom-induced
depression in men treated with alpha 1-blockers for benign
prostatic hyperplasia? A nested case-control study,
Pharmacoepidemiol Drug Saf, 2002;11:55–61.
52. Gibbons EP, Colen J, Nelson JB, et al., Correlation between
risk factors for vascular disease and the American Urological
Association Symptom Score, BJU Int, 2007;99:97–100.
53. Parsons JK, Modifiable risk factors for benign prostatic
hyperplasia and lower urinary tract symptoms: new
approaches to old problems, J Urol, 2007;178:395–401.
54. Lee S, Min HG, Choi SH, et al., Central obesity as a risk factor
for prostatic hyperplasia, Obesity (Silver Spring),
2006;14:172–9.
55. Dahle SE, Chokkalingam AP, Gao YT, et al., Body size and
serum levels of insulin and leptin in relation to the risk of
benign prostatic hyperplasia, J Urol, 2002;168:599–604.
56. Parsons JK, Bergstrom J, Barrett-Connor E, Lipids,
lipoproteins and risk of benign prostatic hyperplasia in
community dwelling men, BJU Int, 2008;101(3):313–8.
57. Hammarsten J, Hogstedt B, Holthuis N, et al., Components of
the metabolic syndrome-risk factors for the development of
benign prostatic hyperplasia, Prostate Cancer Prostatic Dis,
1998;1(3):157–62.
58. Nandeesha H, Koner BC, Dorairajan LN, et al.,
Hyperinsulinemia and dyslipidemia in non-diabetic benign
prostatic hyperplasia, Clin Chim Acta, 2006;370(1–2):89–93.
59. Gupta A, Gupta S, Pavuk M, et al., Anthropometric and
metabolic factors and risk of benign prostatic hyperplasia: a
prospective cohort study of Air Force veterans, Urology,
2006;68(6):1198–205.
60. Berger AP, Deibl M, Leonhartsberger N, et al., Vascular
damage as a risk factor for benign prostatic hyperplasia and
erectile dysfunction, BJU Int, 2005;96(7):1073–8.
61. Hammarsten J, Högstedt B, Holthuis N, et al., Components of
the metabolic syndrome-risk factors for the development of
benign prostatic hyperplasia, Prost Cancer Prostatic Dis,
1998;1(3):157–62.
62. Parsons, JK, Kashefi C, Physical activity, benign prostatic
hyperplasia, and lower urinary tract symptoms, Eur Urol, 2008;
53:1228–35.
63. Rosen RC, Fitzpatrick JM; ALF-LIFE Study Group, Ejaculatory
dysfunction in men with lower urinary tract symptoms
suggestive of benign prostatic hyperplasia, BJU Int,
2009;104(7):974–83.
64. Gass R, Benign prostatic hyperplasia: the opposite effects of
alcohol and coffee intake, BJU Int, 2002;90:649–54.
65. Kirby R, Lepor H, Evaluation and non-surgical management of
benign prostatic hyperplasia. In: Wein AJ, Kavoussi LR, Peters
CA, et al. (eds), Campbell-Walsh Urology, 9th edition,
Philadelphia: WB Saunders, 2007:2766–802.
66. Johnson AR, Munoz A, Gottlieb JL, et al., High dose zinc
increases hospital admissions due to genitourinary
complications, J Urol, 2007;177:639–43.
67. Lee J, Andriole G, Avins A, et al., Redesigning a large-scale
clinical trial in response to negative external trial results: the
CAMUS study of phytotherapy for benign prostatic
hyperplasia, Clin Trials, 2009;6(6):628–36.
68. Moyad MA, Lowe FC, Educating patients about lifestyle
modifications for prostate health, Am J Med,
2008;121(8 Suppl. 2):S34–42.
69. McConnell JD, Bruskewitz R, Walsh P, et al, The effect of
finasteride on the risk of acute urinary retention and the
need for surgical treatment among men with benign
prostatic hyperplasia. Finasteride Long-Term Efficacy and
Safety Study Group, N Engl J Med, 1998;338:557–63.
70. Miller MI, Puchner PJ, Effects of finasteride on haematuria
associated with benign prostatic hyperplasia: long-term
follow-up, Urology, 1998;51:237–40.
71. McConnell JD, Roehrborn CG, Bautista OM, et al., The
long-term effect of doxazosin, finasteride, and combination
therapy on the clinical progression of benign prostatic
hyperplasia, N Engl J Med, 2003;349:2387–98.
72. Roehrborn CG, Siami P, Barkin J, et al.; CombAT Study Group,
The effects of combination therapy with dutasteride and
tamsulosin on clinical outcomes in men with symptomatic
benign prostatic hyperplasia: 4-year results from the
CombAT study, Eur Urol, 2010;57(1):123–31.
73. Black RJ, Bray F, Ferlay J, et al., Cancer incidence and
mortality in the European Union: cancer registry data and
estimates of national incidence for 1990, Eur J Cancer,
1997;33(7):1075–107.
74. Parkin DM, Bray FI, Devesa SS, Cancer burden in the year
2000: the global picture, Eur J Cancer, 2001;37(Suppl. 8):S4–66.
75. Schroder FH, Hugosson J, Roobol MJ, et al., Screening and
prostate-cancer mortality in a randomized European study,
N Engl J Med, 2009;360(13):1320–8.
76. Andriole GL, Grubb RL 3rd, Buys SS, et al., Mortality results
from a randomized prostate-cancer screening trial,
N Engl J Med, 2009;260(13):1310–9.
77. Hugosson J, Carlsson S, Aus G, et al., Mortality results from
the Göteborg randomised population-based prostate-cancer
screening trial, Lancet Oncol, 2010;11:725–32.
78. Djulbegovic M, Beyth RJ, Neuberger MM, et al., Screening for
prostate cancer: systematic review and meta-analysis of
randomised controlled trials, BMJ, 2010;14(341):c4543.
79. Monninkhof EM, Elias SG, Vlems FA, et al., Physical activity
and breast cancer: a systematic review, Epidemiology,
2007;18(1):137–57.
80. Pan SY, DesMeules M, Energy intake, physical activity,
energy balance, and cancer: epidemiologic evidence, Methods
Mol Biol, 2009;472:191–215.
81. Moore SC, Peters TM, Ahn J, et al., Physical activity in
relation to total, advanced, and fatal prostate cancer,
Cancer Epidemiol Biomarkers Prev, 2008;17:2458–66.
82. IARC Working Group, IARC Handbook of Cancer Prevention, Volume
6: Weight Control and Physical Activity, Lyon: IARC, 2002.
83. World Cancer Research Fund and the American Institute for
Cancer Research, Food, Nutrition, Physical Activity, and the
Prevention of Cancer: a Global Perspective, Washington, DC,
American Institute for Cancer Research, 2007.
84. Allen NE, Key TJ, Appleby PN, et al., Serum insulin-like
growth factor (IGF)-I and IGF-binding protein-3 concentrations
and prostate cancer risk: results from the European
Prospective Investigation into Cancer and Nutrition, Cancer
Epidemiol Biomarkers Prev, 2007;16(6):1121–7.
85. Allen NE, Key TJ, Appleby PN, et al., Animal foods, protein,
calcium and prostate cancer risk: the European Prospective
Investigation into Cancer and Nutrition, Br J Cancer,
2008;98(9):1574–81.
86. Key TJ, Allen N, Appleby P, et al., Fruits and vegetables and
prostate cancer: no association among 1, 104 cases in a
prospective study of 130, 544 men in the European
Prospective Investigation into Cancer and Nutrition (EPIC),
Int J Cancer, 2004;109:119–24.
87. Lippman SM, Goodman PJ, Klein EA, et al., Designing the
selenium and vitamin E cancer prevention trial (SELECT),
J Natl Cancer Inst, 2005;97(2):94–102.
88. Gruber CJ, Tschugguel W, Schneeberger C, et al., Production
and actions of estrogens, N Engl J Med, 2002;346:340–52.
89. Schulman CC, Ekane S, Zlotta AR, Nutrition and prostate
cancer: evidence or suspicion?, Urology, 2001;58:318–34.
90. Fair WR, Fleshner NE, Heston W, Cancer of the prostate: a
nutritional disease?, Urology, 1997;50:840–8.
91. Smith TJ, Hong JY, Wang ZY, et al., How can carcinogenesis
be inhibited?, Ann NY Acad Sci, 1995;768:82–90.
92. Ahmad N, Feyes DK, Nieminen AL, et al., Green tea
constituent, epigallocatechin-3-gallate and induction of
apoptosis and cell cycle arrest in human carcinoma cells,
J Natl Cancer Inst, 1997;89:1881–6.
93. Thompson IM, Goodman PJ, Tangen CM, et al., The influence
of finasteride on the development of prostate cancer,
N Engl J Med, 2003;349(3):215–24.
94. Andriole GL, Bostwick DG, Brawley OW, et al., Effect of
dutasteride on the risk of prostate cancer, N Engl J Med,
2010;362:1192–202.
95. Kramer BS, Hagerty KL, Justman S, et al., Use of 5alphareductase inhibitors for prostate cancer chemoprevention:
American Society of Clinical Oncology/American Urological
Association 2008 Clinical Practice Guideline, J Urol,
2009;181(4):1642–57.
96. Walsh PC, Chemoprevention of prostate cancer, N Engl J Med,
2010;362:1237–8.
97. Palapattu GS, Sutcliffe S, Bastian PJ, et al., Prostate
carcinogenesis and inflammation: emerging insights,
Carcinogenesis, 2005;26:1170–81.
98. Kramer G, Mitteregger D, Marberger M, Is benign prostatic
hyperplasia (BPH) an immune inflammatory disease?, Eur Urol,
2007;51:1202–16
99. Maliner-Stratton MS, Klein RD, Udayakumar TS, et al.,
Interleukin-1beta-induced promatrilysin expression is
mediated by NFkappaB-regulated synthesis of interleukin-6 in
the prostate carcinoma cell line, LNCaP, Neoplasia,
2001;3(6):509–20.
100. Gupta S, Srivastava M, Ahmad N, et al., Over-expression of
cyclooxygenase-2 in human prostate adenocarcinoma,
Prostate, 2000;42:73–8.
101. Mahmud S, Franco E, Aprikian A, Prostate cancer and use of
nonsteroidal anti-inflammatory drugs: systematic review and
meta-analysis, Br J Cancer, 2004;90:93–9.
102. Dhillon PK, Kenfield SA, Stampfer MJ, et al., Long-term aspirin
use and the risk of total, high-grade, regionally advanced and
lethal prostate cancer in a prospective cohort of health
professionals, 1988-2006, Int J Cancer, 2011;128(10):2444–52.
25