Asian Journal of Andrology (2012) 14, 365374

2012 AJA, SIMM & SJTU. All rights reserved 1008-682X/12 $32.00
www.nature.com/aja

REVIEW

Lifestyle and dietary factors in the prevention of lethal

prostate cancer
Kathryn M Wilson1,3, Edward L Giovannucci1,2,3 and Lorelei A Mucci1,3
The prevention of lethal prostate cancer is a critical public health challenge that would improve health and reduce suffering from this
disease. In this review, we discuss the evidence surrounding specific lifestyle and dietary factors in the prevention of lethal prostate
cancer. We present a summary of evidence for the following selected behavioral risk factors: obesity and weight change, physical
activity, smoking, antioxidant intake, vitamin D and calcium, and coffee intake.
Asian Journal of Andrology (2012) 14, 365374; doi:10.1038/aja.2011.142; published online 16 April 2012
Keywords: epidemiology; diet; life style; obesity; physical activity; prevention; prostate cancer

INTRODUCTION
Prostate cancer is a major contributor to cancer incidence and mortality among men throughout the world, particularly in Westernized
countries.1 Moreover, men with prostate cancer suffer significant
impairments in quality of life,2 both from the disease itself and as a
consequence of treatment. The disease is notable in its considerable
biologic heterogeneity in metastatic potential over a mans lifetime.
This heterogeneity is an important feature of the disease, and efforts to
understand risk factors and predictors of more aggressive disease are
central in prostate cancer research. The prevention of lethal prostate
cancer represents an important public health challenge to reduce suffering from this disease. Moreover, the identification of lifestyle factors
post-diagnosis that influence prostate cancer clinical course is appealing as a means of secondary prevention in combination with therapeutic intervention. In this paper, we present an overview of the
evidence around selected exposures in the prevention of lethal prostate
cancer. Given the diversity of potential factors, we have elected to focus
on lifestyle and dietary factors, and not to discuss the evidence for
pharmacologic agents. Moreover, we highlight compelling factors that
may influence cancer-specific mortality after diagnosis. We present
risk factors for lethal prostate cancer that have received the greatest
scrutiny within epidemiological studies, as well as discuss novel hypotheses for which there is more limited evidence: obesity and weight
change, physical activity, smoking, antioxidant intake, vitamin D and
calcium, and coffee intake.
GLOBAL BURDEN OF PROSTATE CANCER
An overview of the descriptive epidemiology of cancer sets the framework for understanding the global burden of this disease and its
impact from a public health perspective. Moreover, a comparison of
the patterns of incidence and mortality across populations, as well as
trends over time can provide clues about the role of lifestyle factors in
prostate cancer etiology.
1

Incidence
Prostate cancer is the most commonly diagnosed cancer among men
globally, with almost one million new cases each year.3 In the United
States, 240 890 men are expected to be diagnosed in 2011, and an
American mans lifetime risk of prostate cancer is one in six.4
More than any other malignancy, the burden of prostate cancer
shows remarkable worldwide variation (Figure 1), with a more than
60-fold difference in age-adjusted incidence rates between population
groups with the highest (African-American men in the United States)
and the lowest (Japanese and Chinese men living in their native countries) incidence of prostate cancer. Part of the variation in incidence
rates across populations can be explained by differences in screening
practices, particularly screening with prostate-specific antigen (PSA),
which often diagnoses a significant proportion of otherwise latent
prostate cancer. However, geographic differences in prostate cancer
incidence and mortality were apparent prior to the introduction of
PSA screening starting in the early 1990s, highlighting a potential role
of environmental and lifestyle factors in the etiology of this disease.
Results from migrant studies lend additional support to role of lifestyle
factors in prostate cancer incidence. Prostate cancer rates increase
among men moving from low-risk to high-risk countries compared
to those in their native countries.5,6 Prostate cancer mortality rates also
increase, lending further support for non-hereditary causes beyond
any artifactual rise due to screening and enhanced detection.
Incidence rates have increased substantially over time. In the United
States and other Western countries, this is likely due in part to the
adoption of PSA testing. However, incidence rates have also increased
in Japan and some other Asian and Eastern European countries where
PSA testing is not widely used, reflecting changes in other factors7
(Figure 1). PSA screening has also led to a shift in stage presentation,
with concomitant increase in the ratio of localized to advanced disease
cases and a decrease in the age at diagnosis.8 Screening has also led to

Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; 2Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA and
Channing Laboratory, Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115, USA
Correspondence: Dr LA Mucci ([email protected])
Received: 29 November 2011; Revised: 11 January 2012; Accepted: 20 January 2012; Published online: 16 April 2012
3

Lifestyle, dietary factors in the prevention of lethal PCa

KM Wilson et al
366

Figure 1 Trends in age-adjusted prostate cancer incidence rates over time in

selected populations. Data from the International Agency for Research on
Cancer, 2008.

the detection of a significant number of latent lesions that may never

have come to light clinically nor harmed a man during his lifetime.9,10
The introduction of PSA screening has likely resulted in changes in
the observed associations between specific dietary and lifestyle factors
and prostate cancer risk over time. First, different factors may impact
prostate cancer at various stages of progression, and therefore the
associations may differ according to disease clinical characteristics,
such as those defined by cancer stage or tumor grade.11 Indeed, it
seems unlikely that the factors associated with development of indolent cancers would be similar to those associated with cancers demonstrating malignant potential. Since the majority of cancers
diagnosed in the PSA era are well-differentiated tumors with low
metastatic potential, it seems likely that associations observed in
populations in mainly pre-PSA era populations would no longer be
observed with respect to total prostate cancer risk.
Mortality
Based on 2008 data from the International Agency for Research on
Cancer, an estimated 258 000 men died of prostate cancer worldwide,3
with considerable variation in mortality rates among countries
(Figure 2). Prostate cancer is the second most common cause of
cancer death among men in the United States, with 33 720 fatalities
in 2011.4 During the past decade, prostate cancer mortality rates have
shown declines in some countries, most notably in the United States
(Figure 2). The reasons for this decline remain controversial, but may
be attributable in part to earlier detection through PSA screening and
subsequent earlier treatment.12

Figure 2 Trends in age-adjusted prostate cancer mortality rates over time in

selected populations. Data from the International Agency for Research on
Cancer, 2008.
Asian Journal of Andrology

Notwithstanding the considerable mortality associated with this

disease, most men die with and not from their cancer. Many prostate
tumors remain indolent even in the absence of therapy.13,14 Indeed,
cardiovascular disease and other chronic diseases are responsible
for more than three-quarters of deaths among men diagnosed with
localized prostate cancer.
In this paper, we define lethal prostate cancer as a cancer that forms
overt metastases or leads to cancer-specific death. As not all studies
have sufficient follow-up for cancer outcomes, we also present epidemiological studies that focus on surrogate endpoints such as biochemical recurrence, recognizing the potential limitations of this definition
as an endpoint. The prevention of lethal prostate can come from two
means. First, lifestyle or dietary factors at various points in a mans life
may prevent the initiation of a tumor with a lethal potential from ever
forming. This type of primary prevention is appealing as it eliminates
the entire burden of the disease for men. Second, after a man is diagnosed with prostate cancer, lifestyle and dietary factors may influence
a mans clinical course. Secondary prevention is attractive given that 4
million men are prostate cancer survivors living with a cancer diagnosis, of whom 2.4 million are in the United States.4
ESTABLISHED RISK FACTORS FOR PROSTATE CANCER
INCIDENCE
Established risk factors for total prostate cancer risk are few and
include: older age, race and family history. Moreover, there are a
number of genetic risk loci that have been identified and confirmed
in genome-wide association studies.
Older age is one of the strongest risk factors for prostate cancer.
Prostate cancer rarely is diagnosed among men before the age of
40 years, and mortality is relatively rare before the age of 50 years.
As with other epithelial cancers, incidence rates of prostate cancer
increase exponentially from around the age of 55 years and onwards,
a trend observed across multiple populations. Screening with PSA has
led to a shift to an earlier average age of cancer diagnosis, with an
estimated 10 year lead time.
Prostate cancer incidence and mortality rates differ by race/ethnicity.
In the United States, incidence and mortality rates are the highest
among African-American men. African-American men have mortality
rates 2.4 times greater than those of Caucasian men. Both incidence
and mortality rates are lower among Asian/Pacific-Islanders, Native
Americans and Hispanic men than among non-Hispanic whites.4
Men with a family history of prostate cancer are at increased risk of
prostate cancer diagnosis and mortality. Men whose father was diagnosed with prostate cancer have approximately twice the risk as men
without a paternal family history. Having an affected brother increases
the risk almost threefold. A family history in both the father and a
brother increases risk of diagnosis almost ninefold.15 Family history is
also associated with lethal prostate cancer. The risk of death from
prostate cancer is approximately twofold higher for men with a father
or a brother who died of prostate cancer, compared to men with
prostate cancer who do not have a positive family history.16
However, the interpretation of self-reported family history of prostate
cancer has become somewhat more difficult in the PSA era, because of
the correlated exposure to PSA testing within families, and the
increased use of PSA testing among men with a family history of
prostate cancer.17
Data from twin studies suggest that the familial aggregation of
prostate cancer incidence is in large part due to genetic factors.18
Indeed, prostate cancer is estimated to have one of the highest heritability, with more than 40% of prostate cancer variability attributed to

Lifestyle, dietary factors in the prevention of lethal PCa

KM Wilson et al
367

genetic factors. During the last few years, genome-wide association

studies have sought to identify common single-nucleotide polymorphisms (SNPs) associated with prostate cancer incidence.19 To
date, 41 risk loci have been identified and confirmed across multiple
studies, a number of loci greater than any other malignancy. It is
estimated that these 41 loci explain about one-quarter of the variability
if prostate cancer incidence that is attributed to genetic factors. It is
noteworthy that the heritability of prostate cancer appears to be the
results of small positive associations of low-penetrant genetic variants,
rather than large associations with high-penetrance alleles.
The majority of the identified germline risk loci do not appear to be
more strongly associated with lethal or nonlethal prostate cancer.20
However, family studies indicate a familial component of prostate
cancer-specific survival.21 To date, only one genome-wide association
study of lethal prostate cancer has been published.22 Although no
SNPs reached genome-wide significance, three SNPs were associated
with lethal prostate cancer at 1025, and one of the three SNPs was
subsequently validated in an independent cohort. One of the challenges in studying germline variants and prostate cancer survival is
the identification of cohorts with sufficient numbers of cancer-specific
events. Thus, additional collaborative research is needed to estimate
the heritability of prostate cancer survival, as well as larger genomewide association studies of lethal disease.
OVERVIEW OF RISK FACTORS FOR LETHAL PROSTATE
CANCER
Prostate cancer progression to lethal disease likely involves the activation of a number of different biological pathways. Risk factors for
lethal prostate cancer and opportunities for prevention act through
these pathways. In this paper, we focus on obesity and weight change,
physical activity, smoking, antioxidants, vitamin D and calcium.
Obesity
Obesity is a major public health problem globally, with almost 1.5
billion adults estimated to be overweight or obese in 2008.23 The
increase in overweight and obesity in the United States in recent
decades has been well documented. In the 20072008 National
Health and Nutrition Examination Survey (NHANES), which measures height and weight on its participants, 34% of adults over the
age of 20 years were obese defined as having a body mass index
(BMI) o30.0 kg m22.24 In contrast, only 15% of adults were obese
in the 19711980 NHANES I and II studies. The proportion of
adults classified as overweight, with a BMI of 25.029.9 kg m22,
has been fairly constant over this time, at approximately one-third
of the adult population.25
Obesity dysreglates multiple hormonal pathways and is associated
with higher levels of insulin, lower levels of adiponectin, lower levels of
testosterone and higher levels of inflammatory cytokines, all of which
may be factors in prostate cancer progression.2629 From a prevention
perspective, it is notable that weight loss and physical activity are
associated with positive changes in these biomarkers.
The relation between body size and incidence of prostate cancer is
complex.11,26,3033 However, obesity in adulthood has been associated
with worse prostate cancer outcomes in most studies. Obese men are
at higher risk of developing advanced stage prostate cancer and have
higher rates of recurrence and cancer-specific mortality after diagnosis. A meta-analysis of six cohort studies of initially cancer-free
men showed a significant 15% increase (95% confidence interval (CI):
1.061.25) in the risk of fatal prostate cancer for each 5 kg m22
increase in BMI.33 Similarly, among men with prostate cancer, a

5 kg m22 increase in BMI was associated with a 20% (95% CI: 0.99
1.46) increased risk of prostate cancer-specific mortality.33 There was
some heterogeneity between studies included in this meta-analysis,
which may be due to a large proportion of missing data on BMI in
some study populations, and differences in follow-up time and the
underlying prevalence of obesity between studies. Moreover, it is possible that some of the difference in study results is due to the effect of
obesity on PSA levels; there is evidence that PSA concentrations are
lower in obese men due to a larger blood volume, causing hemodilution of PSA levels. As a consequence, the sensitivity of PSA screening
may be decreased among obese versus normal weight men.34,35
The poor prostate cancer outcomes associated with obesity do not
appear to reflect solely differences in the efficacy of screening, as similar associations are seen between obesity and survival among men
with disease, and adjusting for stage and grade at diagnosis. A study
of 2546 men diagnosed with prostate cancer within the Physicians
Health Study found that prostate cancer-specific mortality was significantly associated with prediagnosis BMI26 (Figure 3). The relative
risk of prostate cancer-specific mortality, adjusted for age at diagnosis
and baseline smoking status was 1.5 (95% CI: 1.21.9) for overweight
men and 2.7 (95% CI: 1.64.4) for obese men, compared to those with
a healthy BMI. In this study, prediagnosis levels of C-peptide, a circulating marker of insulin secretion, were also associated with
increased cancer-specific mortality, and men who were both overweight and who had high insulin levels were at particularly increased
risk. It is possible that men who are obese and have higher C-peptide
levels have a more metabolically active obesity than obese men with
lower C-peptide measures, making the combined measure of BMI and
C-peptide levels more predictive of prognosis.
Waist circumference (WC) and waist-to-hip ratio (WHR),
measures of abdominal obesity, have been assessed in fewer studies
than BMI. These measures of central obesity have generally not been
associated with overall prostate cancer incidence. However, there is
some evidence that abdominal obesity is associated with more
advanced disease. In the European Prospective Investigation into
Cancer and Nutrition (EPIC), a large cohort study of over 150 000
men across Europe, WC and WHR were positively associated with
diagnosis of more advanced prostate cancer (stage T3 or T4, or N1
N3, or M1).36 A 5-cm increase in waist circumference was associated
with a 1.06 times greater risk of advanced prostate cancer (95% CI:
1.011.10), and a 0.1-unit greater waist to hip ratio was associated with
a 1.21 times greater risk (95% CI: 1.041.39). Waist circumference was
significantly associated with more aggressive disease in the Melbourne
Collaborative Cohort Study,37 but it was not associated with advanced
stage or high-grade disease in the Health Professionals Follow-up

Figure 3 Prostate cancer-specific survival curves after diagnosis according to

baseline BMI measured in 1982, controlling for age at diagnosis, smoking status,
and time between BMI measurement and cancer diagnosis. From Ma et al.
(2008).26 BMI, body mass index.
Asian Journal of Andrology

Lifestyle, dietary factors in the prevention of lethal PCa

KM Wilson et al
368

Study.38 Because of the high correlation between BMI and measures of

abdominal obesity, it is difficult to separate their effects. The EPIC
study found that the waist circumference associations were stronger
among men with lower BMI, suggesting a possible interaction between
overall and abdominal obesity; however, the number of men in opposite extreme categories of BMI and waist was low.
The role of body size in childhood and early adulthood has also been
studied. The Health Professionals Follow-up Study reported no overall association between childhood body size and prostate cancer risk,
but a significantly lower risk of advanced and metastatic prostate
cancer among men reporting larger body sizes at ages of 5, 10 and
20 years.38 A population-based casecontrol study in California found
similar inverse associations with advanced prostate cancer for overweight and obesity at ages of 10 and 20 years.39 However, two other
population-based casecontrol studies found no associations.40,41 It is
possible that overweight and obesity in childhood and adolescence
impact sex hormone levels during periods of growth and development
important for later prostate cancer risk.

Figure 4 Hazard ratio of PSA recurrence by weight change from 5 years before to
1 year after prostatectomy (Joshu et al.52). PSA, prostate-specific antigen.

Weight change
The question of whether weight loss or weight gain in the time
period just before and after prostate cancer diagnosis has been less
studied than has body size. However, this is an important question,
because if weight loss or weight gain has effects on prostate cancer
survival, it would provide an important modifiable risk factor for
men with prostate cancer. Several prospective cohort studies have
examined adult weight change and the risk of prostate cancer.
Overall, weight gain from early adulthood (age of 18 or 21 years)
to mid-life was not associated with prostate cancer incidence in
all38,4249 but one study.50 However, the AARP-NIH Diet and
Health Study51 found that weight gain from the age of 18 year to
the start of the study (at ages of 5071 years) was significantly
associated with an increased risk of prostate cancer mortality,
although it was not associated with risk of total, localized, or extraprostatic disease, in line with other studies.
Only one study has examined weight change in the period shortly
before and after prostate cancer diagnosis and the risk of recurrence,
measured by a post-treatment PSA increase.52 This retrospective
cohort study found that weight gain from 5 years before treatment
by prostatectomy to 1 year after treatment was associated with a statistically significant increase in recurrence, while weight loss was nonstatistically significantly associated with a lower risk of recurrence
(Figure 4). This study found no indication that physical activity modified the association between weight change and recurrence.

cohort found no association between recreational physical activity

and advanced or high-stage disease; however, activity levels were substantially higher in this cohort, and the reference group included men
with up to 25 Met-hours per week. In this cohort, the relative risk of
advanced disease for the top versus lowest quartile of men (.71 Methours per week vs. f25 Met-hours per week) was 1.2 (95% CI: 0.9
1.7), with a P value for trend across quartiles of 0.16.55 On the other
hand, the NIH-AARP Diet and Health Study found no association
between vigorous exercise and risk of advanced or fatal prostate cancer.56
The association between post-diagnosis physical activity and risk of
prostate cancer mortality or recurrence among men with prostate
cancer has been examined in only two studies. Among 2705 men with
prostate cancer in the Health Professionals Follow-up Study, those who
exercised vigorously for 3 or more hours per week had a 61% lower risk
of prostate cancer-specific mortality than those with less than 1 h per
week of vigorous activity (relative risk (RR): 0.4; 95% CI: 0.20.8).57
Both vigorous and non-vigorous activities were associated with a lower
risk of all-cause mortality among these men with prostate cancer.
A study of prostate cancer progression, including a composite endpoint of biochemical recurrence, secondary treatments, bone metastasis, or cancer death, found that brisk walking was associated with a
lower risk of recurrence (RR: 0.4; 95% CI: 0.20.9) for brisk walking
o3 h per week versus easy walking for ,3 h per week. There was a
suggestion that vigorous physical activity was also associated with a
lower risk of recurrence; however, few men in this study population
engaged in vigorous physical activity.58

Physical activity
Physical activity has not been consistently associated with prostate
cancer incidence. However, several studies have found that leisure
time or recreational physical activity may reduce the risk of aggressive
or advanced prostate cancer. The Health Professionals Follow-up
Study (HPFS)53 and the American Cancer Society Cancer Prevention Study II Nutrition Cohort (CPS II)54 both reported lower
risks of more advanced disease with increasing levels of recreational
physical activity; these associations were independent of BMI. In the
HPFS, men reporting 30 or more metabolic equivalent (Met)-hours
per week of vigorous physical activity had a relative risk for fatal
prostate cancer of 0.59 (95% CI: 0.351.01) compared to men reporting no recreational activity. In the CPS II study, men reporting greater
than 35 Met-hours per week had a relative risk for aggressive cancer
(high stage and/or grade) of 0.69 (95% CI: 0.520.92). The EPIC

Smoking
Total prostate cancer incidence is not consistently associated with
smoking. However, the latest review of evidence by the United
States Surgeon General concluded that smoking is a probable contributor to higher prostate cancer mortality rates.59 Studies of prostate
cancer mortality have consistently found that smoking is associated
with higher risk, with more recent smoking being more strongly associated. In the Health Professionals Follow-up Study, greater pack-years
of smoking in the 10 years prior to prostate cancer diagnosis were
associated with an increased risk of lethal disease, whereas smoking
earlier than that and total lifetime smoking were not associated
with risk.60 However, current smokers report less PSA testing than
non-smokers,61 and the positive associations between smoking and
prostate cancer mortality may be due in part to later diagnosis and
treatment of these cancers among smokers. It is noteworthy that in the

Asian Journal of Andrology

Lifestyle, dietary factors in the prevention of lethal PCa

KM Wilson et al
369

Health Professionals Follow-up Study, the association of prostate cancer with smoking was apparent even before PSA screening became
available.
Smoking may also influence cancer-specific outcomes by influencing response to treatment. Studies in specific treatment populations
have consistently reported worse outcomes for smokers than nonsmokers among prostate cancer patients treated with radiation, androgen deprivation therapy and radical prostatectomy.6266 These studies
were limited by low numbers of prostate cancer-specific deaths, and
some relied on surrogate endpoints such as biochemical recurrence.
To date, only one large prospective study of smoking and cancerspecific mortality among men with prostate cancer has been published.67 Among 5366 men diagnosed with prostate cancer between
1986 and 2006 in the Health Professionals Follow-up Study, there
were 524 prostate cancer deaths. The crude rate of prostate cancerspecific death was higher in current smokers than in never smokers
(15.3 and 9.6 deaths per 1000 person-years, respectively). Adjusting
for possible confounders, the relative risk of prostate cancer-specific
mortality was 1.6 (95% CI: 1.12.3) for current vs. never smokers. The
risk of cancer-specific death was still increased, but attenuated, when
also adjusted for stage and grade that may indicate that part of the
relationship between smoking and prostate cancer mortality is
through its influence on these clinical parameters. Sensitivity analyses
also found an increased risk of prostate cancer-specific mortality for
current vs. never smokers when restricted to men diagnosed with nonmetastatic disease (stages T1T3), and among men reporting a PSA
test prior to diagnosis. Compared to current smokers, former smokers
who quit 10 or more years before diagnosis and former smokers who
had quit less than 10 years ago but smoked less than 20 pack-years
overall had same risk as never smokers, again suggesting that more
recent smoking behavior is the most relevant with respect to prostate
cancer progression.
The possible biological basis for an association between smoking
and risk of fatal prostate cancer or survival among men with prostate
cancer is not clear, but several mechanisms have been proposed.67
Tumor promotion through carcinogens from tobacco smoke is a possibility, with several studies finding prostate cancer-specific mechanisms in animal and in vitro studies. In addition, nicotine may have
epigenetic effects such as on gene methylation patterns, and effects on
angiogenesis and tumor cell proliferation that contribute to initiation
or progression of disease.
Antioxidants
Several dietary antioxidants, including selenium, vitamin E and lycopene/tomato sauce have been investigated with respect to prostate
cancer incidence. Antioxidants are compounds that inhibit the oxidation of other species, thereby limiting the damaging effects of oxidation
in animal tissues. Oxidative stress may damage molecules including
proteins and DNA, and has been implicated in carcinogenesis.
Vitamin E and selenium. Vitamin E generally refers to a group of fatsoluble compounds that include tocopherols and tocotrienols. atocopherol is the biologically most active form, and current dietary
recommendations in the United States are based on a-tocopherol
alone. c-tocopherol is the most common tocopherol in the United
States diet. Possible anticarcinogenic actions of vitamin E include its
ability to reduce DNA damage and inhibit malignant cellular transformation.68,69 In experimental models, derivatives of vitamin E
inhibit growth induce apoptosis70 and enhance therapeutic effects in
human prostate cancer cells.71

Secondary results of the Alpha-Tocopherol Beta-Carotene Cancer

Prevention (ATBC) Study72 showed a 32% reduction in prostate cancer risk among men assigned to a-tocopherol supplementation compared to placebo.73 Another large trial of a variety of nutrients found
that vitamin E (in combination with selenium and b-carotene)
reduced overall cancer mortality.74 These results, along with laboratory evidence and some epidemiologic support, motivated two trials
of the effect of vitamin E supplementation on the risk of prostate
cancer.
The Selenium and Vitamin E Cancer Prevention Trial (SELECT),
planned for 712 years, was stopped early because of lack of efficacy for
risk reduction. The initial report based on an average of 5.5 years of
treatment, found a non-significant suggestion of increased prostate
cancer risk among men receiving 400 IU day21 of a-tocopherol.75
With additional follow-up, the vitamin E group was found to have a
significant increase in prostate cancer risk (RR: 1.17; 99% CI: 1.004
1.36; P50.008, among 1149 cases).76 Interestingly, there was not a
statistically significant increased risk of prostate cancer in the vitamin
E and selenium combination group (hazard ratio (HR): 1.05; P50.46),
suggesting the two may interact. The Physicians Health Study II (PHS
II) conducted contemporaneously with SELECT, found no effect on
the incidence of prostate cancer (HR: 0.97; 95% CI: 0.851.09;
P50.58), with a dose of 400 IU day21 for a median of 8 years of
follow-up.77
Of note, all men in the ATBC trial were smokers, and the prostate
cancers were diagnosed outside the context of PSA screening, and thus,
were generally aggressive. Interestingly, epidemiological studies of vitamin E and prostate cancer risk have had mixed results, generally
pointing towards no overall association, but observed associations have
generally been for advanced cancers and among smokers. In the
VITamins And Lifestyle (VITAL) study, a cohort study specifically
designed to examine supplement use and future cancer risk, a 10-year
average intake of supplemental vitamin E was not associated with a
reduced prostate cancer risk overall, but it was associated with a reduced
risk for advanced prostate cancer (regionally invasive or distant metastatic, n5123) (HR: 0.43; 95% CI: 0.191.0 for 10-year average intake
o400 IU day21 vs. non-use).78 In a prospective study of plasma vitamin E and prostate cancer mortality, there was a reduced risk associated with higher circulating levels limited to smokers, although the
number of cases in the subgroup was small (,30).79 Other epidemiological studies have similarly found a protective association limited to
ever smokers, including prospective studies of dietary vitamin E,80 vitamin E through supplementation on lethal prostate cancer81 and
plasma a-tocopherol levels and aggressive prostate cancer.82
The SELECT and PHS II trials were performed in the PSA screening
era, and had small numbers of current smokers. Thus, neither trial
could address the effect of a-tocopherol specifically on advanced or
fatal prostate cancers, or among current smokers.
The trace element selenium is not an anti-oxidant per se, but plays
an important role as an essential element for the antioxidant enzyme
glutathione peroxidase,83 as well as other selenoproteins involved in
exerting antitumor effects, including apoptosis and inhibition of cellular proliferation.84,85 Dietary intake of selenium depends on the
selenium content of soil in which foods are grown, which varies greatly
by geographic area. Ecologic studies have suggested an inverse association between selenium soil content and prostate cancer incidence.86
Because selenium contents in specific foods vary as a function of the
selenium content of the soil, epidemiological studies of selenium
require biological sampling, primarily measuring levels in blood or
toenails. Since the activity of some selenoenzymes plateau with a
Asian Journal of Andrology

Lifestyle, dietary factors in the prevention of lethal PCa

KM Wilson et al
370

higher selenium level,87 the chemopreventive effect of selenium may

be the greatest in populations with low selenium exposure.88
Like vitamin E, selenium was tested in the SELECT trial based on
secondary results of other randomized trials. The Nutritional
Prevention of Cancer Trial found a 63% reduction in prostate cancer
risk among men taking selenium supplements;89 with additional follow-up time, the protective effect was limited to those with low baseline levels of PSA or selenium.88 Another trial of selenium (with
vitamin E and b-carotene) found a reduction in total cancer mortality
in China.74 As discussed above, the SELECT trial was stopped early due
to lack of efficacy of the supplements. With additional follow-up, there
was still no association between selenium and prostate cancer risk.
(RR: 1.09; 99% CI: 0.931.27; P50.18).
Six prospective biomarker studies have reported significant associations between higher levels of selenium and reduced prostate cancer
risk,9095 particularly for advanced disease.90,91,94 Not all epidemiological studies have reported a protective association of selenium, however.9698 Two recent randomized studies found no effect of selenium
supplementation, alone or in combination, in reducing progression
of high-grade prostatic intraepithelial neoplasia (PIN) to invasive
cancer.99,100
Lycopene and tomato-based products. The relationship of tomatoes in
prostate cancer prevention has been studied extensively in the epidemiological literature, with evidence suggesting a significant benefit
associated with higher intake of tomatoes, particularly cooked tomatoes, or lycopene, a carotenoid with strong anti-oxidant effects.
However, not all studies are supportive, and the association remains
controversial.
A meta-analysis of studies on tomatoes and prostate cancer risk
included results from 11 casecontrol and 10 prospective cohort or
nested casecontrol studies that presented data on the intake of tomatoes, tomato products, or dietary lycopene.101 Compared with men
with low intake of tomato products (the first quantile of intake), the
relative (RR) of prostate cancer among consumers of higher amounts
of raw tomato (the fifth quantile of intake) was 0.89 (95% CI: 0.80
1.00). For cooked tomato products, which are more bioavailable
sources of lycopene than fresh tomatoes,102 the summary RR was
0.81 (95% CI: 0.710.92) comparing extreme categories of intake.
The results from cohort studies generally indicate a 25%30%
reduction in risk of prostate cancer, whereas dietary-based casecontrol studies are not supportive of an association. For example, the
summary RR of prostate cancer from the meta-analysis related to an
intake of one serving/day of raw tomato (200 g) was 0.97 (95% CI:
0.851.10) for the casecontrol studies and 0.78 (95% CI: 0.660.92)
for cohort studies.101
The 2004 meta-analysis found an inverse association in studies of
plasma lycopene and prostate cancer risk, with corresponding summary relative risks of 0.55 (95% CI: 0.320.94) for casecontrol studies
and 0.78 (95% CI: 0.611.00) for cohort studies.101 An additional
nested casecontrol study not included in the meta-analysis found a
modest, not statistically significant, inverse association overall, and a
significantly reduced risk with higher levels of plasma lycopene among
men over 65 years old and among those without a family history of
prostate cancer.103 However, several more recent studies have found
no associations for serum lycopene.104108 It is possible that these
conflicting results are due, in part, to the changing mix of prostate
cancer cases diagnosed in the United States with the advent of PSA
screening.109 As a result of PSA screening, many more prostate cancers
are being diagnosed, including a pool of biologically indolent cancers
Asian Journal of Andrology

which would have gone undiagnosed in previous decades and in older

studies.
Indeed, epidemiological studies generally point to a stronger reduction in risk of advanced stage or lethal prostate cancer, suggesting that
tomato products and lycopene may play a role in prostate cancer
progression. For example, in the Health Professionals Follow-up
Study, the associations comparing high and low consumption of
tomato sauce were 0.75 (0.610.92) for total prostate cancer and
0.66 (0.441.00) for advanced stage disease.110 In the EPIC study based
on 966 total cases and 205 advanced stage cases of prostate cancer,
there was no association between plasma lycopene and overall risk, but
men in the top quintile of plasma lycopene had a significantly reduced
risk of advanced stage prostate cancer (RR: 0.40; 95% CI: 0.19
0.88).108
Although not definitive, the available data suggest that increased
consumption of tomato and tomato-based products is associated with
lower prostate cancer risk and progression. Whether the effect is driven through lycopene or other aspects of tomatoes remains undetermined. The relationship appears to be stronger for advanced prostate
cancer than indolent disease.
Calcium, dairy products and vitamin D
Calcium intake has been associated with an increased risk of prostate
cancer in many but not all epidemiological studies. A meta-analysis of
studies in 2005 found an increased risk of 1.39 (95% CI: 1.091.77), for
extreme categories of intake.111 Several studies have reported stronger
associations between high intake of calcium and risks of aggressive
forms of prostate cancer, defined by high grade, or advanced or lethal
prostate cancer.11,112,113 The role of calcium is further supported by a
recent study among African-American men in California, which
included information on both calcium intake and vitamin D receptor
calcium absorption genotype.114 Men with the vitamin D receptor
Cdx2 GG genotype, poorer absorbers of dietary calcium, had a significantly lower risk of advanced prostate cancer (odds ratio (OR): 0.41;
95% CI: 0.190.90) than those with the AA genotype. Men with higher
intakes of dietary calcium were at increased risk of advanced disease in
this study, and there was a significant genediet interaction, with a
lower risk of advanced cancer among men with the GG genotype and
lower dietary intakes.
The association between serum calcium and risk of prostate cancer
has been studied in three prospective studies. Serum levels of calcium
were associated with an increased risk of fatal disease in NHANES I
and NHANES III.115,116 The adjusted relative risk of fatal prostate
cancer was 2.68 (95% CI: 1.026.99; P50.04) for the top versus bottom tertile of total serum calcium in NHANES. In NHANES III,
similar increases in risk were seen for both total serum calcium and
ionized serum calcium, the biologically active component. A study in a
large cohort of Swedish men found no association between serum
calcium and overall risk of prostate cancer. Unfortunately, advanced
and/or fatal prostate cancer were not able to be studied separately in
this cohort.117 Circulating calcium levels are tightly regulated and are
related to diet only at very high levels of intake, so it is unclear how this
finding related to dietary calcium intake, if at all. However, it suggests a
role for calcium, vitamin D, and perhaps related factors, such as parathyroid hormone, in the etiology of lethal prostate cancer.
Dairy foods, a major dietary source of calcium, have also been
associated with risk, with the 2005 meta-analysis reporting a summary
relative risk of 1.11 (95% CI: 1.031.19) for total dairy, 1.06 (95% CI:
0.911.23) for milk and 1.11 (95% CI: 0.991.25) per serving for
cheese.111 Most,118,119 but not all120,121 studies published since this

Lifestyle, dietary factors in the prevention of lethal PCa

KM Wilson et al
371

meta-analysis have tended to support an association between higher

milk or dairy consumption and prostate cancer risk. The correlation
between dairy foods and calcium and other nutrients creates challenges in trying to disentangle the independent effects of these compounds; however, cohort studies that have tried to separate effects
generally suggest calcium may be the predominant player in explaining positive associations with prostate cancer. This is supported by a
recent study of calcium intake among Singapore Chinese, a population
in which dairy contributes little to total calcium intake. Even in this
population, with comparatively low calcium intakes and in which
vegetables were the main source of calcium, there was a suggestion
of increased risk with higher calcium intakes.122
One proposed mechanism of calcium and prostate cancer is by
suppressing circulating levels of dihydroxyvitamin D (1,25(OH)2D),
the bioactive metabolite of vitamin D. It is involved in regulating
cellular differentiation and proliferation of many cell types, including
prostate epithelia. The main source of vitamin D is endogenous production in the skin resulting from sun exposure, and diet is a secondary source. 1,25(OH)2D is the most biologically active form, whereas
25(OH)D is found in much higher concentrations and better reflects
sun and dietary exposure.123 An alternate hypothesis is that dairy
protein increases levels of Insulin-like Growth Factor,124 which may
thus influence risk of advanced or lethal prostate cancer.125
None of the studies of dietary or supplemental vitamin D have
reported protective effects for prostate cancer incidence,126129 and
most of prediagnostic vitamin D metabolites have also reported null
results.130137 One recent nested casecontrol study of 1000 prostate
cancer cases and 1000 controls within the ATBC study found an
increased risk in the highest versus lowest serum levels of 25(OH)D,
with a relative risk of 1.56 (95% CI: 1.152.12).138
There is some evidence that vitamin D plays a role in prostate cancer
progression. Genetic variants in the vitamin D receptor are associated
with Gleason score139 and genetic variants in the vitamin D pathway
are associated with risk of recurrence or progression and prostate
cancer-specific mortality.140 In addition, high expression of the vitamin D receptor protein in prostate cancer tissue has been associated
with lower risk of lethal cancer among men with prostate cancer in the
Health Professionals Follow-up Study and Physicians Health Study.
Men in the highest vs. lowest quartile of vitamin D receptor expression
had a relative risk of 0.37 (95% CI: 0.140.94), with adjustment for
PSA at diagnosis, Gleason grade and stage.141 Another recent study of
prostate cancer mortality nested in the HPFS and PHS found that
prostate cancer patients with the lowest levels of prediagnostic
25(OH)D had a significantly greater risk of prostate cancer-specific
mortality, with an RR of 1.59 (95% CI: 1.062.39) for the highest vs.
lowest quartiles.142 Prediagnostic vitamin D levels were significantly
associated with both stage and grade in this study. Thus, while vitamin
D exposure does not seem to be associated with lower risk of incident
prostate cancer, several lines of evidence suggest that the vitamin D
pathway may play a role in prostate cancer progression.
Coffee
There are several potential mechanisms by which coffee could be
associated with a lower risk of lethal prostate cancer. Coffee is rich
in several biologically active compounds including caffeine, minerals
and phytochemicals. In observational and animal studies, long-term
coffee drinking has been associated with improved glucose metabolism and insulin secretion in observational and animal studies.143
Moreover, coffee is a potent antioxidant144,145 and intake may be
associated with levels of different sex steroid hormones.146,147

Most prior epidemiological studies of coffee and prostate cancer

have focused on total incidence of disease. There have been to date
three studies that have looked at lethal prostate cancer. Two studies148,149 reported no statistically significant associations of coffee consumption and prostate cancer mortality, although the studies were
limited by a narrow range of coffee consumption, a small number of
cancer-specific deaths, and inadequate adjustment for potential confounding by smoking and other factors. The Health Professionals
Follow-up Study examined 47 911 men who reported intake of regular
and decaffeinated coffee in 1986 and every 4 years thereafter, and
included 642 patients with lethal prostate cancer.150 After adjusting
for potential confounding, men who consumed six or more cups of
coffee per day had an 18% lower risk for prostate cancer overall (RR:
0.82; 95% CI: 0.680.98) and a 60% lower risk of lethal prostate cancer
(RR: 0.40; 95% CI: 0.220.75) compared to nondrinkers. Intriguingly,
the inverse association with lethal cancer was similar for men who
drank either regular or decaffeinated coffee, suggesting that caffeine
is not underlying the link. These intriguing data, while biologically
plausible, need to be confirmed in additional study populations with
large number of events and control for confounding.
SUMMARY
From a public health perspective, the prevention of lethal prostate is a
paramount issue to improve the health of men in the United States and
globally. Moreover, the identification of lifestyle factors after cancer
diagnosis that could improve outcomes is appealing for the 4 million
men currently living with a prostate cancer diagnosis. Research is in
the early stages on both fronts, and research prerequisites include
large, prospective cohort studies with long-term follow-up for cancer
outcomes, detailed and updated questionnaire data, and consideration of the potential biases associated with epidemiological research.
Still, there is now intriguing evidence that several behavioral risk factors may play a role in the prevention of lethal prostate cancer.
COMPETING FINANCIAL INTERESTS
None of the authors has any competing financial interests.

Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer Incidence, Mortality
and Prevalence Worldwide. Lyon: IARC Press; 2004.
2
Steineck G, Helgesen F, Adolfsson J, Dickman PW, Johansson JE et al. Quality of life
after radical prostatectomy or watchful waiting. N Engl J Med 2002; 347: 7906.
3
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, et al. GLOBOCAN 2008 v1.2, Cancer
Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France:
International Agency for Research on Cancer; 2010. Available from: http://
globocan.iarc.fr, accessed on March 6, 2012.
4
Howlader N, Noone A, Krapcho M, Neyman N, Aminou R et al. SEER Cancer Statistics
Review 19752008, National Cancer Institute. Bethesda, MD, http://www.seer.
cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission,
posted to the SEER web site, 2011
5
Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE et al. Cancers of the
prostate and breast among Japanese and white immigrants in Los Angeles County.
Br J Cancer 1991; 63: 9636.
6
Yu H, Harris RE, Gao YT, Gao R, Wynder EL. Comparative epidemiology of cancers of
the colon, rectum, prostate and breast in Shanghai, China versus the United States. Int
J Epidemiol 1991; 20: 7681.
7
Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and
mortality rates and trends. Cancer Epidemiol Biomarkers Prev 2010; 19: 1893907.
8
Etzioni R, Gulati R, Falcon S, Penson D. Impact of PSA screening on the incidence of
advanced stage prostate cancer in the United States: a surveillance modeling
approach. Med Decis Making 2008; 28: 32331.
9
Ciatto S, Gervasi G, Bonardi R, Frullini P, Zendron P et al. Determining overdiagnosis
by screening with DRE/TRUS or PSA (Florence pilot studies, 19911994). Eur J
Cancer 2005; 41: 4115.
10 Etzioni R, Penson DF, Legler JM, di Tommaso D, Boer R et al. Overdiagnosis due to
prostate-specific antigen screening: lessons from U.S. prostate cancer incidence
trends. J Natl Cancer Inst 2002; 94: 98190.

Asian Journal of Andrology

Lifestyle, dietary factors in the prevention of lethal PCa

KM Wilson et al
372
11 Giovannucci E, Liu Y, Platz EA, Stampfer MJ, Willett WC. Risk factors for prostate
cancer incidence and progression in the health professionals follow-up study. Int J
Cancer 2007; 121: 15718.
12 Chu KC, Tarone RE, Freeman, HP. Trends in prostate cancer mortality among black
men and white men in the United States. Cancer 2003; 97: 150716.
13 Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative
management of clinically localized prostate cancer. JAMA 2005; 293: 2095101.
14 Johansson JE, Andren O, Andersson SO, Dickman PW, Holmberg L et al. Natural
history of early, localized prostate cancer. JAMA 2004; 291: 27139.
15 Hemminki K, Czene K. Attributable risks of familial cancer from the Family-Cancer
Database. Cancer Epidemiol Biomarkers Prev 2002; 11: 163844.
16 Brandt A, Sundquist J, Hemminki K. Risk for incident and fatal prostate cancer in men
with a family history of any incident and fatal cancer. Ann Oncol 2012; 23: 2516.
17 Ross LE, Berkowitz Z, Ekwueme DU. Use of the prostate-specific antigen test among
U.S. men: findings from the 2005 National Health Interview Survey. Cancer
Epidemiol Biomarkers Prev 2008; 17: 63644.
18 Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J et al. Environmental and
heritable factors in the causation of canceranalyses of cohorts of twins from
Sweden, Denmark, and Finland. N Engl J Med 2000; 343: 7885.
19 Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S et al. Multiple loci identified in
a genome-wide association study of prostate cancer. Nat Genet 2008; 40: 3105.
20 Pomerantz MM, Freedman ML. Genetics of prostate cancer risk. Mt Sinai J Med 2010;
77: 64354.
21 Hemminki K. Familial risk and familial survival in prostate cancer. World J Urol 2011.
22 Penney KL, Pyne S, Schumacher FR, Sinnott JA, Mucci LA et al. Genome-wide
association study of prostate cancer mortality. Cancer Epidemiol Biomarkers Prev
2010; 19: 286976.
23 Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK et al. National, regional, and
global trends in body-mass index since 1980: systematic analysis of health
examination surveys and epidemiological studies with 960 country-years and 9.1
million participants. Lancet 2011; 377: 55767.
24 Flegal KM, Carroll MD, Ogden CL, Curtin LR et al. Prevalence and trends in obesity
among US adults, 19992008. JAMA 2010; 303: 23541.
25 Ogden CL, Carroll MD. CDC/NCHS Prevalence of Overweight, Obesity, and Extreme
Obesity Among Adults: United States, Trends 19601962 Through 20072008,
2010.
26 Ma J, Li H, Giovannucci E, Mucci L, Qiu W et al. Prediagnostic body-mass index,
plasma C-peptide concentration, and prostate cancer-specific mortality in men with
prostate cancer: a long-term survival analysis. Lancet Oncol 2008; 9: 103947.
27 Li H, Stampfer MJ, Mucci L, Rifai N, Qiu W et al. A 25-year prospective study of plasma
adiponectin and leptin concentrations and prostate cancer risk and survival. Clin
Chem 2010; 56: 3443.
28 Platz EA, Giovannucci E. The epidemiology of sex steroid hormones and their signaling
and metabolic pathways in the etiology of prostate cancer. J Steroid Biochem Mol Biol
2004; 92: 237.
29 de Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H et al. Inflammation in prostate
carcinogenesis. Nat Rev Cancer 2007; 7: 25669.
30 Discacciati A, Orsini N, Andersson SO, Andren O, Johansson JE et al. Body mass index
in early and middle-late adulthood and risk of localised, advanced and fatal prostate
cancer: a population-based prospective study. Br J Cancer 2011; 105: 10618.
31 MacInnis RJ, English DR. Body size and composition and prostate cancer risk:
systematic review and meta-regression analysis. Cancer Causes Control 2006; 17:
9891003.
32 Robinson WR, Poole C, Godley PA. Systematic review of prostate cancers association
with body size in childhood and young adulthood. Cancer Causes Control 2008; 19:
793803.
33 Cao Y, Ma J. Body mass index, prostate cancer-specific mortality, and biochemical
recurrence: a systematic review and meta-analysis. Cancer Prev Res (Phila) 2011; 4:
486501.
34 Banez LL, Hamilton RJ, Partin AW, Vollmer RT, Sun L et al. Obesity-related plasma
hemodilution and PSA concentration among men with prostate cancer. JAMA 2007;
298: 227580.
35 Grubb RL 3rd, Black A, Izmirlian G, Hickey TP, Pinsky PF et al. Serum prostatespecific antigen hemodilution among obese men undergoing screening in the
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer Epidemiol
Biomarkers Prev 2009; 18: 74851.
36 Pischon T, Boeing H, Weikert S, Allen N, Key T et al. Body size and risk of prostate
cancer in the European prospective investigation into cancer and nutrition. Cancer
Epidemiol Biomarkers Prev 2008; 17: 325261.
37 MacInnis RJ, English DR, Gertig DM, Hopper JL, Giles GG. Body size and composition
and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2003; 12: 141721.
38 Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Willett WC. Height, body weight,
and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 1997; 6: 55763.
39 Robinson WR, Stevens J, Gammon MD, John EM. Obesity before age 30 years and risk
of advanced prostate cancer. Am J Epidemiol 2005; 161: 110714.
40 Hsing AW, Deng J, Sesterhenn IA, Mostofi FK, Stanczyk FZ et al. Body size and
prostate cancer: a population-based case-control study in China. Cancer Epidemiol
Biomarkers Prev 2000; 9: 133541.
41 Andersson SO, Baron J, Wolk A, Lindgren C, Bergstrom R et al. Early life risk factors for
prostate cancer: a population-based case-control study in Sweden. Cancer Epidemiol
Biomarkers Prev 1995; 4: 18792.
42 Nomura A, Heilbrun LK, Stemmermann GN. Body mass index as a predictor of cancer
in men. J Natl Cancer Inst 1985; 74: 31923.

Asian Journal of Andrology

43 Cerhan JR, Torner JC, Lynch CF, Rubenstein LM, Lemke JH et al. Association of
smoking, body mass, and physical activity with risk of prostate cancer in the Iowa
651 Rural Health Study (United States). Cancer Causes Control 1997; 8: 22938.
44 Putnam SD, Cerhan JR, Parker AS, Bianchi GD, Wallace RB et al. Lifestyle and
anthropometric risk factors for prostate cancer in a cohort of Iowa men. Ann
Epidemiol 2000; 10: 3619.
45 Schuurman AG, Goldbohm RA, Dorant E, van den Brandt PA. Anthropometry in
relation to prostate cancer risk in the Netherlands Cohort Study. Am J Epidemiol
2000; 151: 5419.
46 Spitz MR, Strom SS, Yamamura Y, Troncoso P, Babaian RJ et al. Epidemiologic
determinants of clinically relevant prostate cancer. Int J Cancer 2000; 89: 25964.
47 onsson F, Wolk A, Pedersen NL, Lichtenstein P, Terry P et al. Obesity and hormonedependent tumors: cohort and co-twin control studies based on the Swedish Twin
Registry. Int J Cancer 2003; 106: 5949.
48 Friedenreich CM, McGregor SE, Courneya KS, Angyalfi SJ, Elliott FG. Casecontrol
study of anthropometric measures and prostate cancer risk. Int J Cancer 2004; 110:
27883.
49 Littman AJ, White E, Kristal AR. Anthropometrics and prostate cancer risk. Am J
Epidemiol 2007; 165: 12719.
50 Hernandez BY, Park SY, Wilkens LR, Henderson BE, Kolonel LN. Relationship of body
mass, height, and weight gain to prostate cancer risk in the multiethnic cohort. Cancer
Epidemiol Biomarkers Prev 2009; 18: 241321.
51 Wright ME, Chang SC, Schatzkin A, Albanes D, Kipnis V et al. Prospective study of
adiposity and weight change in relation to prostate cancer incidence and mortality.
Cancer 2007; 109: 67584
52 Joshu CE, Mondul AM, Menke A, Meinhold C, Han M et al. Weight gain is associated
with an increased risk of prostate cancer recurrence after prostatectomy in the PSA
era. Cancer Prev Res (Phila) 2011; 4: 54451.
53 Giovannucci EL, Liu Y, Leitzmann MF, Stampfer MJ, Willett WC. A prospective study
of physical activity and incident and fatal prostate cancer. Arch Intern Med 2005;
165: 100510.
54 Patel AV, Rodriguez C, Jacobs EJ, Solomon L, Thun MJ et al. Recreational physical
activity and risk of prostate cancer in a large cohort of U.S. men. Cancer Epidemiol
Biomarkers Prev 2005; 14: 2759.
55 Johnsen NF, Tjnneland A, Thomsen BL, Christensen J, Loft S et al. Physical activity
and risk of prostate cancer in the European Prospective Investigation into Cancer and
Nutrition (EPIC) cohort. Int J Cancer 2009; 125: 9028.
56 Moore SC, Peters TM, Ahn J, Park Y, Schatzkin A et al. Physical activity in relation to
total, advanced, and fatal prostate cancer. Cancer Epidemiol Biomarkers Prev 2008;
17: 245866.
57 Kenfield SA, Stampfer MJ, Giovannucci E, Chan JM. Physical activity and survival
after prostate cancer diagnosis in the health professionals follow-up study. J Clin
Oncol 2011; 29: 72632.
58 Richman EL, Kenfield SA, Stampfer MJ, Paciorek A, Carroll PR et al. Physical activity
after diagnosis and risk of prostate cancer progression: data from the cancer of the
prostate strategic urologic research endeavor. Cancer Res 2011; 71: 388995.
59 US Department of Health and Human Services. The Health Consequences of
Smoking. A Report of the Surgeon General. Washington, DC: US Dept of Health
and Human Services; 2004.
60 Giovannucci E, Rimm EB, Ascherio A, Colditz GA, Spiegelman D et al. Smoking and
risk of total and fatal prostate cancer in United States health professionals. Cancer
Epidemiol Biomarkers Prev 1999; 8 (4 Pt 1): 27782.
61 Byrne MM, Davila EP, Zhao W, Parker D, Hooper MW et al. Cancer screening behaviors
among smokers and non-smokers. Cancer Epidemiol 2010; 34: 6117.
62 Pickles T, Liu M, Berthelet E, Kim-Sing C, Kwan W et al. The effect of smoking on
outcome following external radiation for localized prostate cancer. J Urol 2004; 171:
15436.
63 Moreira DM, Antonelli JA, Presti JC Jr, Aronson WJ, Terris MK et al. Association of
cigarette smoking with interval to biochemical recurrence after radical prostatectomy:
results from the SEARCH database. Urology 2010; 76: 121823.
64 Joshu CE, Mondul AM, Meinhold CL, Humphreys EB, Han M et al. Cigarette smoking
and prostate cancer recurrence after prostatectomy. J Natl Cancer Inst 2011; 103:
8358.
65 Pantarotto J, Malone S, Dahrouge S, Gallant V, Eapen L et al. Smoking is associated
with worse outcomes in patients with prostate cancer treated by radical radiotherapy.
BJU Int 2007; 99: 5649.
66 Oefelein MG, Resnick MI. Association of tobacco use with hormone refractory disease
and survival of patients with prostate cancer. J Urol 2004; 171 (6 Pt 1): 22814.
67 Kenfield SA, Stampfer MJ, Chan JM, Giovannucci E. Smoking and prostate cancer
survival and recurrence. JAMA 2011; 305: 254855.
68 Meydani M. Vitamin E. Lancet 1995; 345: 1705.
69 Meydani SN, Hayek MG. Vitamin E and aging immune response. Clin Geriatr Med
1995; 11: 56776.
70 Gunawardena K, Murray DK, Meikle AW. Vitamin E and other antioxidants inhibit
human prostate cancer cells through apoptosis. Prostate 2000; 44: 28795.
71 Ripoll EA, Rama BN, Webber MM. Vitamin E enhances the chemotherapeutic effects
of adriamycin on human prostatic carcinoma cells in vitro. J Urol 1986; 136: 52931.
72 The effect of vitamin E and beta carotene on the incidence of lung cancer and other
cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention
Study Group. N Engl J Med 1994; 330: 102935.
73 Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK et al. Prostate cancer and
supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in
a controlled trial. J Natl Cancer Inst 1998; 90: 4406.

Lifestyle, dietary factors in the prevention of lethal PCa

KM Wilson et al
373
74 Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S et al. Nutrition intervention trials in
Linxian, China: supplementation with specific vitamin/mineral combinations,
cancer incidence, and disease-specific mortality in the general population. J Natl
Cancer Inst 1993; 85: 148392.
75 Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM et al. Effect of selenium
and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E
Cancer Prevention Trial (SELECT). JAMA 2009; 301: 3951.
76 Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS et al. Vitamin E and the
risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
JAMA 2011; 306: 154956.
77 Gaziano JM, Glynn RJ, Christen WG, Kurth T, Belanger C et al. Vitamins E and C in the
prevention of prostate and total cancer in men: the Physicians Health Study II
randomized controlled trial. JAMA 2009; 301: 5262.
78 Peters U, Littman AJ, Kristal AR, Patterson RE, Potter JD et al. Vitamin E and selenium
supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study
cohort. Cancer Causes Control 2008; 19: 7587.
79 Eichholzer M, Stahelin HB, Gey KF, Ludin E, Bernasconi F. Prediction of male cancer
mortality by plasma levels of interacting vitamins: 17-year follow-up of the prospective
Basel study. Int J Cancer 1996; 66: 14550.
80 Kirsh VA, Hayes RB, Mayne ST, Chatterjee N, Subar AF et al. Supplemental and
dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk.
J Natl Cancer Inst 2006; 98: 24554.
81 Chan JM, Stampfer MJ, Ma J, Rimm EB, Willett WC et al. Supplemental vitamin E
intake and prostate cancer risk in a large cohort of men in the United States. Cancer
Epidemiol Biomarkers Prev 1999; 8: 8939.
82 Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM et al. Lower prostate cancer risk in
men with elevated plasma lycopene levels: results of a prospective analysis. Cancer
Res 1999; 59: 122530.
83 Combs GF Jr, Combs SB. The nutritional biochemistry of selenium. Annu Rev Nutr
1984; 4: 25780.
84 Menter DG, Sabichi AL, Lippman SM. Selenium effects on prostate cell growth.
Cancer Epidemiol Biomarkers Prev 2000; 9: 117182.
85 Redman C, Scott JA, Baines AT, Basye JL, Clark LC et al. Inhibitory effect of
selenomethionine on the growth of three selected human tumor cell lines. Cancer
Lett 1998; 125: 10310.
86 Rayman MP. The importance of selenium to human health. Lancet 2000; 356: 233
41.
87 Neve J. Human selenium supplementation as assessed by changes in blood selenium
concentration and glutathione peroxidase activity. J Trace Elem Med Biol 1995; 9:
6573.
88 Duffield-Lillico AJ, Dalkin BL, Reid ME, Turnbull BW, Slate E et al. Selenium
supplementation, baseline plasma selenium status and incidence of prostate
cancer: an analysis of the complete treatment period of the Nutritional Prevention
of Cancer Trial. BJU Int 2003; 91: 60812.
89 Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK et al. Effects of selenium
supplementation for cancer prevention in patients with carcinoma of the skin. A
randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA
1996; 276: 195763.
90 Li H, Stampfer MJ, Giovannucci EL, Morris JS, Willett WC, et al. A prospective study of
plasma selenium levels and prostate cancer risk. J Natl Cancer Inst 2004; 96: 696703.
91 Yoshizawa K, Willett WC, Morris SJ, Stampfer MJ, Spiegelman D et al. Study of
prediagnostic selenium level in toenails and the risk of advanced prostate cancer.
J Natl Cancer Inst 1998; 90: 121924.
92 Brooks JD, Metter EJ, Chan DW, Sokoll LJ, Landis P et al. Plasma selenium level
before diagnosis and the risk of prostate cancer development. J Urol 2001; 166:
20348.
93 Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A et al. Association between
alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer.
J Natl Cancer Inst 2000; 92: 201823.
94 Nomura AM, Lee J, Stemmermann GN, Combs GF Jr. Serum selenium and subsequent
risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2000; 9: 8837.
95 van den Brandt PA, Zeegers MP, Bode P, Goldbohm RA. Toenail selenium levels and
the subsequent risk of prostate cancer: a prospective cohort study. Cancer Epidemiol
Biomarkers Prev 2003; 12: 86671.
96 Goodman GE, Schaffer S, Bankson DD, Hughes MP, Omenn GS et al. Predictors of
serum selenium in cigarette smokers and the lack of association with lung and prostate
cancer risk. Cancer Epidemiol Biomarkers Prev 2001; 10: 106976.
97 Hartman TJ, Albanes D, Pietinen P, Hartman AM, Rautalahti M et al. The association
between baseline vitamin E, selenium, and prostate cancer in the alpha-tocopherol,
beta-carotene cancer prevention study. Cancer Epidemiol Biomarkers Prev 1998; 7:
33540.
98 Peters U, Takata Y. Selenium and the prevention of prostate and colorectal cancer. Mol
Nutr Food Res 2008; 52: 126172.
99 Fleshner NE, Kapusta L, Donnelly B, Tanguay S, Chin J et al. Progression from highgrade prostatic intraepithelial neoplasia to cancer: a randomized trial of combination
vitamin-E, soy, and selenium. J Clin Oncol 2011; 29: 238690.
100 Marshall JR, Tangen CM, Sakr WA, Wood DP Jr, Berry DL et al. Phase III Trial of
Selenium to Prevent Prostate Cancer in Men with High-grade Prostatic
Intraepithelial Neoplasia: SWOG S9917. Cancer Prev Res (Phila) 2011; 4: 17619.
101 Etminan M, Takkouche B, Caamano-Isorna F. The role of tomato products and
lycopene in the prevention of prostate cancer: a meta-analysis of observational
studies. Cancer Epidemiol Biomarkers Prev 2004; 13: 3405.

102 Maiani G, Caston MJ, Catasta G, Toti E, Cambrodon IG et al. Carotenoids: actual
knowledge on food sources, intakes, stability and bioavailability and their protective
role in humans. Mol Nutr Food Res 2009; 53 Suppl 2: S194218.
103 Wu K, Erdman JW Jr, Schwartz SJ, Platz EA, Leitzmann M et al. Plasma and dietary
carotenoids, and the risk of prostate cancer: a nested casecontrol study. Cancer
Epidemiol Biomarkers Prev 2004; 13: 2609.
104 Beilby J, Ambrosini GL, Rossi E, de Klerk NH, Musk AW. Serum levels of folate,
lycopene, beta-carotene, retinol and vitamin E and prostate cancer risk. Eur J Clin
Nutr 2010; 64: 12358.
105 Karppi J, Kurl S, Nurmi T, Rissanen TH, Pukkala E et al. Serum lycopene and the risk
of cancer: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study. Ann
Epidemiol 2009; 19: 5128.
106 Peters U, Leitzmann MF, Chatterjee N, Wang Y, Albanes et al. Serum lycopene, other
carotenoids, and prostate cancer risk: a nested casecontrol study in the prostate,
lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers
Prev 2007; 16: 9628.
107 Kristal AR, Till C, Platz EA, Song X, King IB et al. Serum lycopene concentration and
prostate cancer risk: results from the Prostate Cancer Prevention Trial. Cancer
Epidemiol Biomarkers Prev 2011; 20: 63846.
108 Key TJ, Appleby PN, Allen NE, Travis RC, Roddam AW et al. Plasma carotenoids,
retinol, and tocopherols and the risk of prostate cancer in the European Prospective
Investigation into Cancer and Nutrition study. Am J Clin Nutr 2007; 86: 67281.
109 Giovannucci E. Commentary: serum lycopene and prostate cancer progression: a reconsideration of findings from the prostate cancer prevention trial. Cancer Causes
Control 2011; 22: 10559.
110 Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC. A prospective study of
tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst 2002; 94:
3918.
111 Gao X, LaValley MP, Tucker KL. Prospective studies of dairy product and calcium intakes
and prostate cancer risk: a meta-analysis. J Natl Cancer Inst 2005; 97: 176877.
112 Giovannucci E, Liu Y, Stampfer MJ, Willett WC. A prospective study of calcium intake
and incident and fatal prostate cancer. Cancer Epidemiol Biomarkers Prev 2006; 15:
20310.
113 Tseng M, Breslow RA, Graubard BI, Ziegler RG. Dairy, calcium, and vitamin D intakes
and prostate cancer risk in the National Health and Nutrition Examination
Epidemiologic Follow-up Study cohort. Am J Clin Nutr 2005; 81: 114754.
114 Rowland GW, Schwartz GG, John EM, Ingles SA. Calcium intake and prostate cancer
among African Americans: effect modification by vitamin D receptor calcium
absorption genotype. J Bone Miner Res; e-pub ahead of print 1 September 2011;
doi: 10.1002/jbmr.505.
115 Skinner HG, Schwartz GG. Serum calcium and incident and fatal prostate cancer in
the National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers
Prev 2008; 17: 23025.
116 Skinner HG, Schwartz GG. A prospective study of total and ionized serum calcium and
fatal prostate cancer. Cancer Epidemiol Biomarkers Prev 2009; 18: 5758.
117 Halthur C, Johansson AL, Almquist M, Malm J, Gronberg H et al. Serum calcium and
the risk of prostate cancer. Cancer Causes Control 2009; 20: 120514.
118 Allen NE, Key TJ, Appleby PN, Travis RC, Roddam AW et al. Animal foods, protein,
calcium and prostate cancer risk: the European Prospective Investigation into Cancer
and Nutrition. Br J Cancer 2008; 98: 157481.
119 Rohrmann S, Platz EA, Kavanaugh CJ, Thuita L, Hoffman SC et al. Meat and dairy
consumption and subsequent risk of prostate cancer in a US cohort study. Cancer
Causes Control 2007; 18: 4150.
120 Park Y, Mitrou PN, Kipnis V, Hollenbeck A, Schatzkin A et al. Calcium, dairy foods, and
risk of incident and fatal prostate cancer: the NIH-AARP Diet and Health Study. Am J
Epidemiol 2007; 166: 12709.
121 Koh KA, Sesso HD, Paffenbarger RS Jr, Lee M. Dairy products, calcium and prostate
cancer risk. Br J Cancer 2006; 95: 15825.
122 Butler LM, Wong AS, Koh WP, Wang R, Yuan JM et al. Calcium intake increases risk of
prostate cancer among Singapore Chinese. Cancer Res 2010; 70: 49418.
123 Ali MM, Vaidya V. Vitamin D and cancer. J Cancer Res Ther 2007; 3: 22530.
124 Giovannucci E, Pollak M, Liu Y, Platz EA, Majeed N et al. Nutritional predictors of
insulin-like growth factor I and their relationships to cancer in men. Cancer Epidemiol
Biomarkers Prev 2003; 12: 849.
125 Chan JM, Stampfer MJ, Ma J, Gann P, Gaziano JM et al. Insulin-like growth factor-I
(IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer.
J Natl Cancer Inst 2002; 94: 1099106.
126 Giovannucci E. Dietary influences of 1,25(OH)2 vitamin D in relation to prostate
cancer: a hypothesis. Cancer Causes Control 1998; 9: 56782.
127 Chan JM, Giovannucci E, Andersson SO, Yuen J, Adami HO et al. Dairy products,
calcium, phosphorous, vitamin D, and risk of prostate cancer (Sweden). Cancer
Causes Control 1998; 9: 55966.
128 Chan JM, Pietinen P, Virtanen M, Malila N, Tangrea J et al. Diet and prostate cancer
risk in a cohort of smokers, with a specific focus on calcium and phosphorus (Finland).
Cancer Causes Control 2000; 11: 85967.
129 Kristal AR, Cohen JH, Qu P, Stanford JL. Associations of energy, fat, calcium, and vitamin
D with prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2002; 11: 71925.
130 Corder EH, Guess HA, Hulka BS, Friedman GD, Sadler M et al. Vitamin D and prostate
cancer: a prediagnostic study with stored sera. Cancer Epidemiol Biomarkers Prev
1993; 2: 46772.
131 Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Prostate cancer and
prediagnostic levels of serum vitamin D metabolites (Maryland, United States).
Cancer Causes Control 1995; 6: 2359.

Asian Journal of Andrology

Lifestyle, dietary factors in the prevention of lethal PCa

KM Wilson et al
374
132 Gann PH, Ma J, Hennekens CH, Hollis BW, Haddad JG et al. Circulating vitamin D
metabolites in relation to subsequent development of prostate cancer. Cancer
Epidemiol Biomarkers Prev 1996; 5: 1216.
133 Nomura AM, Stemmermann GN, Lee J, Kolonel LN, Chen TC et al. Serum vitamin D
metabolite levels and the subsequent development of prostate cancer (Hawaii, United
States). Cancer Causes Control 1998; 9: 42532.
134 Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and
prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control
2000; 11: 84752.
135 Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E et al. Both high and low
levels of blood vitamin D are associated with a higher prostate cancer risk: a
longitudinal, nested case-control study in the Nordic countries. Int J Cancer 2004;
108: 1048.
136 Platz EA, Leitzmann MF, Hollis BW, Willett WC, Giovannucci E. Plasma 1,25dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer. Cancer
Causes Control 2004; 15: 25565.
137 Jacobs ET, Giuliano AR, Martnez ME, Hollis BW, Reid ME et al. Plasma levels of 25hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer. J Steroid
Biochem Mol Biol 2004; 8990: 5337.
138 Albanes D, Mondul AM, Yu K, Parisi D, Horst RL et al. Serum 25-hydroxy vitamin D and
prostate cancer risk in a large nested case-control study. Cancer Epidemiol
Biomarkers Prev 2011; 20: 185060.
139 Chen L, Davey Smith G, Evans DM, Cox A, Lawlor DA et al. Genetic variants in the
vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings
from the prostate testing for cancer and treatment study and a systematic review.
Cancer Epidemiol Biomarkers Prev 2009; 18: 287481.
140 Holt SK, Kwon EM, Koopmeiners JS, Lin DW, Feng Z et al. Vitamin D pathway gene
variants and prostate cancer prognosis. Prostate 2010; 70: 144860.

Asian Journal of Andrology

141 Hendrickson WK, Flavin R, Kasperzyk JL, Fiorentino M, Fang F et al. Vitamin D
receptor protein expression in tumor tissue and prostate cancer progression. J Clin
Oncol 2011; 29: 237885.
142 Fang F, Kasperzyk JL, Shui I, Hendrickson W, Hollis BW et al. Prediagnostic plasma
vitamin D metabolites and mortality among patients with prostate cancer. PLoS ONE
2011; 6: e18625.
143 Tunnicliffe JM, Shearer J. Coffee, glucose homeostasis, and insulin resistance:
physiological mechanisms and mediators. Appl Physiol Nutr Metab 2008; 33: 1290300.
144 Svilaas A, Sakhi AK, Andersen LF, Svilaas T, Strom EC, et al. Intakes of antioxidants in
coffee, wine, and vegetables are correlated with plasma carotenoids in humans. J Nutr
2004; 134: 5627.
145 Pulido R, Hernandez-Garcia M, Saura-Calixto F. Contribution of beverages to the
intake of lipophilic and hydrophilic antioxidants in the Spanish diet. Eur J Clin Nutr
2003; 57: 127582.
146 Svartberg J, Midtby M, Bonaa KH, Sundsfjord J, Joakimsen RM, et al. The associations
of age, lifestyle factors and chronic disease with testosterone in men: the Troms
study. Eur J Endocrinol 2003; 149: 14552.
147 Hsieh CC, Signorello LB, Lipworth L, Lagiou P, Mantzoros CS, et al. Predictors of sex
hormone levels among the elderly: a study in Greece. J Clin Epidemiol 1998;51:83741.
148 Phillips RL, Snowdon DA. Association of meat and coffee use with cancers of the large
bowel, breast, and prostate among Seventh-Day Adventists: preliminary results.
Cancer Res 1983; 43 (5 suppl): 2403s8s.
149 Hsing AW, McLaughlin JK, Schuman LM, Bjelke E, Gridley G, et al. Diet, tobacco use,
and fatal prostate cancer: results from the Lutheran Brotherhood Cohort Study. Cancer
Res 1990; 50: 683640.
150 Wilson KM, Kasperzyk JL, Rider JR, Kenfield S, van Dam RM, et al. Coffee
consumption and prostate cancer risk and progression in the Health Professionals
Follow-up Study. J Natl Cancer Inst. 2011; 103: 87684.