Download Risk Modifying Factors For Prostate & Other Cancers: Diet

“Risk Modifying Factors For
Prostate & Other Cancers:
Diet, Lifestyle and Sunshine!”
William B. Grant, Ph.D.
SUNARC, San Francisco
www.sunarc.org
[email protected]
Presented to Prostate Awareness
Foundation, San Francisco,
March 6, 2006
Outline
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Epidemiology of prostate cancer
Prostate cancer risk factors
Prostate cancer risk reduction factors
Prostate cancer neutral factors
The Ornish program
Is man a vegetarian?
Useful resources
A Few Words About Cancer
• Cancer is thought to go through three
stages: initiation, progression, and
metastasis
• The progression stage can take 10-40
years before a tumor is discovered
• PSA testing can move detection ahead by
10 years
• Whatever affects progression can, very
likely, affect the tumor after detection
Epidemiology
• Epidemiology is the study of the rate of
diseases by populations or population
subgroups
• Epidemiologic data, along with other data,
can be used to determine the links to
environmental (and genetic) factors that
contribute to various diseases
Types of Ecologic Studies
• Cohort – a defined group of people is
followed for years, with exams and
questionnaires.
• Case-control – those with a disease
outcome (incidence, mortality, etc.) are
compared to those without that outcome.
• Ecologic – populations are defined
geographically, such as state or country,
and data are averaged accordingly.
Criteria for Causality
in a Biological System
• According to A.B. Hill [1965], causality in a
biological system can be assessed by:
– Strong associations
– Similar findings in different populations
– Ruling out confounding factors
– Identifing mechanisms
– Generally finding a linear dose-response
relationship
My Ecologic Studies
• My first epidemiologic study, in 1997, identified
the main dietary risk-modifying factors for
Alzheimer’s disease (total energy and fat (risk),
fish and cereals/grains (risk reduction)).
• Another study found animal products and
alcohol as risk factors for breast cancer, fish and
vitamin D as risk reduction factors.
• More recently, I identified UVB and vitamin D as
risk reduction factors for 17 types of cancer.
Prostate Cancer Mortality Rates, Aged
65-74, 1985, Dietary Supply Data, 1970
Country
Prostate
Mortality
Animal
Energy
Vegetable
Fish
Protein
Milk
Protein
Onions
Korea
4
121
63
32
0.3
19
Japan
22
427
37
156
4.3
28
Greece
53
631
56
32
16.0
36
Italy
78
633
55
24
12.4
19
USA
103
1057
33
21
21.4
22
Sweden
131
976
39
61
24.4
10
Prostate Cancer Risk Factors
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Milk protein (casein)
Meat
Fat
Metabolic syndrome
PSA testing
Smoking
Alcohol consumption
Genetics
Milk Protein (Casein)
• Milk has been identified as a risk factor in
many epidemiologic studies, including
cohort and ecologic.
• Many rat studies found that casein was a
tumor risk factor while soy protein was not.
• There is confusion in the literature due to
confounding with calcium, vitamin D.
• However, considering all the findings, I’m
convinced that casein is the culprit in milk.
Meat
• Several cohort studies have found meat and
meat mutagens (from overcooking) to be
associated with prostate cancer risk.
• High-temperature cooked meat contains
heterocyclic amines.
• More than 10 g/d of very well done meat,
compared with no consumption, was associated
with a 1.4-fold increased risk of prostate cancer
[95% confidence interval (95% CI), 1.05-1.92].
Meat Consumption among Black and White
Men and Risk of Prostate Cancer
• Among Black men, total red meat intake
(processed plus unprocessed red meat) was
associated with higher risk of prostate cancer
(RR, 2.0; 95% CI, 1.0-4.2 for highest versus
lowest quartile).
• This increase in risk was mainly due to risk
associated with consumption of cooked
processed meats (sausages, bacon, and hot
dogs; RR, 2.7; 95% CI, 1.3-5.3 for highest
versus lowest quartile).
Dietary Fat
• Arachidonic acid gives rise to
prostaglandin E2, which can stimulate
cancer growth through a variety of
mechanisms.
• Dietary sources rich in preformed
arachidonic acid include eggs and lean
meats, such as poultry, organ meats and
fish.
Dietary Fat –
Epidemiologic Studies
• Even though not statistically significant,
oil/fat consumption showed an elevated
risk (OR 1.7, 95%CI 0.9-3.3) for those who
consumed more than 2 kg of oil/fat per
month compared to those who consumed
less than 1 kg. (India)
• Margarine intake was positively associated
with prostate cancer 1.3, 95% CI 1.0-1.7).
(Australia)
Dietary Fat
• Although studies of prostate cancer are
less advanced, the indication is that a high
fat intake promotes the likelihood of
metastasis.
• Further research is required to establish
the roles of the various classes of fatty
acids but it does appear that the longchain n-3 fatty acids may also retard
prostate cancer progression. (U.S.)
Obesity
• Obesity likely contributes to prostate
cancer risk through a number of ways:
– Reduced availability of vitamin D
– Generation of Adipokines
– Increased levels of leptin
Leptin
• It is produced in adipose (fat) tissue.
• Its main function is to regulate energy
homeostasis under conditions of restricted
energy availability.
• However, it also stimulates growth,
migration, and invasion of cancer cells and
leads to formation of blood vessels around
tumors.
Metabolic Syndrome
• Additionally, metabolic syndrome, which
includes disturbed glucose metabolism
and insulin resistance, may also be
associated with prostate carcinogenesis.
• Adipokines, defined as biologically active
polypeptides produced by adipose tissue,
have been linked with a number of
carcinogenic mechanisms.
PSA Testing
• The jury seems to still be out on the usefulness
of PSA testing on prostate cancer mortality
rates.
• What is very interesting is that after introduction
of PSA testing in the U.S., incidence rates
doubled from the expected 120 cases/100k/year
for 1991 to 240 cases, mortality rates increased
by 22% over the expected 32 deaths/100k/year
before falling to 31 deaths/100k/year in 2001.
• Perhaps PSA testing a decade ago led to
aggressive treatment, with some treatment
leading to increased risk of death.
Smoking
• Smoking leads to an increase in free
radicals such as hydrogen peroxide (H2O2)
• H2O2 can damage DNA.
• H2O2-DNA damage has been linked to
increase risk of developing prostate
cancer.
• However, lung cancer often kills before
prostate cancer does.
Alcohol Consumption
• Only weak relations are found between alcohol
consumption and prostate cancer risk, with
several studies finding reduced risk.
• The Harvard Physicians’ Health Professionals
cohort study found a slight increased risk with
moderate drinking; risk was greatest among
men who consumed an average of > or = 105
g/week but who drank on only 1-2 days per
week (HR = 1.64, 95% CI: 1.13, 2.38).
Genetics
• Genetics plays a role in prostate cancer
risk, although the role is not well known.
• One factor may be the “thrifty gene” APOE
epsilon4, which increases fat storage and
is found at elevated levels among Africans,
Indians, Polynesians, and Inuit.
• It has been strongly linked to Alzheimer’s
disease, and implicated in lung cancer.
Prostate Cancer
Risk-Reduction Factors
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Vegetable protein,
Phytoestrogens
Allium family vegetables (onions, garlic, etc.)
Tomatoes
Cruciferous vegetables
Vitamin D
Selenium
Fish
Calcium, magnesium
Folate
Vitamin E
Resveratrol
Exercise
Vegetable Protein
• Rat studies find that soy protein does not cause
prostate cancer in rats, but casein does; the
authors failed to conclude that casein was a
carcinogen, but it follows logically.
• Ecologic study results find vegetable protein
associated with decreased risk of prostate
cancer mortality rates.
• Certain soy proteins, common in the Asian diet,
have been shown to inhibit prostate cancer cell
growth.
Phytoestrogens
• Phytoestrogens include mainly isoflavones
(IF), coumestans, and lignans. These
compounds are known to be present in
fruits, vegetables, and whole grains
commonly consumed by humans. IF are
found in legumes--mainly soybeans.
• Phytoestrogens have been shown to have
beneficial effects in fighting cancer.
Allium Family Vegetables
• Allium family vegetables include onions, garlic,
leeks, scallions, etc.
• Organosulfur compounds are the biologically
active components of allium vegetables, and
also give them the characteristic odor and flavor.
• There is increasing evidence that allium
derivatives from garlic have significant
antiproliferative actions on human cancers.
Allium Vegetable Study
• A study in Shanghai found that men in the
highest of three intake categories of total allium
vegetables (>10.0 g/day) had a statistically
significantly lower risk (odds ratio [OR] = 0.51,
95% confidence interval [CI] = 0.34 to 0.76) of
prostate cancer than those in the lowest
category (<2.2 g/day).
• The reduced risk of prostate cancer associated
with allium vegetables was independent of body
size, intake of other foods, and total calorie
intake and was more pronounced for men with
localized than with advanced prostate cancer.
Tomatoes
• Cooked tomatoes, more than fresh tomatoes,
have been found associated with prostate
cancer risk reduction.
• The active ingredient may be lycopene, as
reported in a number of studies.
• However, lycopene supplements are not
recommended since it is not clear that lycopene
is the active ingredient of tomatoes, and whole
foods are better sources of nutrients than are
supplements in general.
Cruciferous Vegetables
• Epidemiological and dietary studies have
revealed an association between high
dietary intake of cruciferous vegetables
and decreased prostate cancer risk.
• The mechanisms are well known.
Canadian Results
• A decreasing, statistically significant association was
found with increasing intakes of green vegetables (OR =
0.54, 95% CI = 0.40-0.71 for 4th quartile), tomatoes (OR
= 0.64, 95% CI = 0.45-0.91), beans/lentils/nuts (OR =
0.69, 95% CI = 0.53-0.91), and cruciferous vegetables
(OR = 0.69, 95% CI = 0.52-0.91 for 3rd quartile).
• Higher intakes of fruit were associated with higher ORs
(OR = 1.51, 95% CI = 1.14-2.01 for 4th quartile), an
effect that was seen for total fruit and citrus fruit, as well
as for all other noncitrus fruits.
• Among the grains, refined-grain bread intake was
associated with a decrease in risk (OR = 0.65 for 4th
quartile), whereas whole-grain breakfast cereals were
associated with a higher risk for prostate cancer.
Vitamin D
• Ecologic studies first suggested that solar
UVB, through production of vitamin D,
could reduce the risk of prostate cancer.
• The mechanisms for vitamin D acting to
reduce cancer risk are well known, and
they seem to oppose the cancer risk
mechanisms from prostaglandins2 formed
from arachidonic acid.
Vitamin D Mechanisms
• Increases cell differentiation
• Suppresses growth stimulatory signals and
amplifies growth inhibitory signals, leading to
induction of cell death/apoptosis (death in a
benign manner rather than a disruptive manner)
• Suppresses genes responsible for enhancing
cellular proliferation
• Modulates immune responsiveness
• May reduce blood vessel formation around
tumors
• Reduces metastasis
511-SEER,trends
42
40
HI, Pros, D, 5-yr
UT, Pros, D, 5-yr
IA, Pros, D, 5-yr
CT, Prostate, D, 5-yr
38
36
34
32
30
28
1975
1980
1985
Year (9)
1990
1995
Selenium (Se)
• The evidence for Se as a cancer preventive
agent includes that from geographic, animal,
prospective and intervention studies.
• There is some evidence that Se may affect not
only cancer risk but also progression and
metastasis.
• Evidence showing an association between Se,
reduction of DNA damage and oxidative stress.
Fish
• Some fish, especially cold water ocean
fish, are good sources of omega-3 fatty
acids, vitamin D, and selenium.
• However, please note that fish are a
source of animal protein, mercury, other
toxins and carcinogens, and fish stocks
are being reduced globally.
Calcium, Magnesium
• The adjusted odds ratios for prostate cancer death for
those with higher magnesium levels in their drinking
water, as compared to the lowest tertile, were 0.73 (95%
CI = 0.51-1.03) and 0.64 (95% CI = 0.43-0.96),
respectively. (Taiwan)
• The adjusted odd ratios for the relationship between
calcium levels in drinking water and prostate cancer
were not statistically significant. (Taiwan)
• In this randomized controlled clinical trial, there was no
increase in prostate cancer risk associated with calcium
supplementation and some suggestion of a protective
effect. (USA)
Folate
• The OR of prostate cancer was 0.66 (95%
CI, 0.51-0.85) for the highest versus the
lowest quintile of folate intake. (Italy)
• The combined OR for high-folate and lowalcohol intake versus low-folate and highalcohol intake was 0.46 (95% CI, 0.290.75). (Italy)
Sources of Folate
• Good sources include fruit, vegetables, grains,
and beans.
• After fortification of bread in the U.S. (1998), the
category "bread, rolls, and crackers" became the
single largest contributor of total folate to the
American diet, contributing 15.6% of total intake.
• Mean serum folate concentration increased
more than two-fold (136%), from 11.4 nmol/L to
26.9 nmol/L.
Vitamin E, Other Antioxidants
• Small molecule dietary antioxidants include
ascorbic acid, Vitamin E, glutathione, various
polyphenols and carotenoids.
• Note that mixed tocopherols are the best form of
vitamin E
• Increased bleeding, especially when vitamin E is
combined with a potent platelet aggregation
inhibitor, has to be considered a side effect of its
mechanism of action.
Vitamin E, Harvard Study
• Men consuming at least 100 IU of supplemental vitamin
E daily had multivariate RRs of 1.07 (95% confidence
interval [CI], 0.95-1.20) for total and 1.14 (95% CI, 0.821.59) for metastatic or fatal prostate cancer compared
with those consuming none. Current use, dosage, and
total duration of use of specific vitamin E supplements or
multivitamins were not associated with risk.
• However, among current smokers and recent
quitters, those who consumed at least 100 IU of
supplemental vitamin E per day had a RR of 0.44 (95%
CI, 0.18-1.07) for metastatic or fatal prostate cancer
compared with nonusers.
Antioxidants in Red Wine
(and Grape Juice)
• Each additional glass of red wine consumed per
week showed a statistically significant 6%
decrease in relative risk (OR = 0.94; 95% CI =
0.90-0.98).
• This is likely due to resveratrol, a polyphenol in
red wine, possesses many pharmacological
activities including cardioprotection,
chemoprevention, anti-tumor effects, and
nuclear factor-kappa B (NF-kappaB) inactivation.
Exercise
• For total prostate cancer, no association was
observed for total, vigorous, and nonvigorous
physical activity. (Harvard cohort study)
• In men 65 years or older, we observed a lower
risk in the highest category of vigorous activity
for advanced (0.33; 95% confidence interval,
0.17-0.62, for more than 29 vs 0 metabolic
equivalent hours) and for fatal (relative risk,
0.26; 95% confidence interval, 0.11-0.66)
prostate cancer.
• No associations were observed in younger men.
My Ecologic Study Results for
Prostate Cancer
• In 1999, I reported that milk was an
important risk factor for prostate cancer
and that tomatoes were associated with
risk reduction.
• In 2004, I reported that animal products
were associated with risk, onions with
reduced risk.
Latest Results
• In my latest study, using prostate cancer
mortality rates for men aged 65-74 years in 37
countries in 1984-6 vs. dietary factors for 1970, I
found, in this order:
– Vegetable protein – risk reduction
– Decreasing latitude (index of vitamin D) – risk
reduction
– Milk protein – risk
– Fish – risk reduction
– Onions – risk reduction
Summary
• In general, animal products are related to
prostate cancer risk while vegetable
products are associated with prostate
cancer risk reduction.
George Orwell, Animal Farm
• George Orwell said: 'four legs good, two
legs bad.'
• The results presented here for prostate
cancer risk are consistent with:
– Two or four legs, bad
– Fins, good and bad
– Roots and shoots, good
Putting These Findings
into Practice
• The results presented here can be
combined into guidelines for diet and
lifestyle
• This has been done by several people
including
– Dean Ornish, M.D.
– John McDougall, M.D.
– Neal Barnard, M.D.
Ornish – Low Fat, Vegan Diet
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J Am Diet Assoc. 2005 Sep;105(9):1442-6.
Nutrient adequacy of a very low-fat vegan diet.
Dunn-Emke SR, Weidner G, Pettengill EB, Marlin RO, Chi C, Ornish DM.
Preventive Medicine Research Institute, Sausalito, CA, USA.
This study assessed the nutrient adequacy of a very low-fat vegan diet. Thirtynine men (mean age=65 years) with early stage prostate cancer who chose the
"watchful waiting" approach to disease management, were instructed by a registered
dietitian and a chef on following a very low-fat (10%) vegan diet with the addition of a
fortified soy protein powdered beverage. Three-day food diaries, excluding vitamin
and mineral supplements, were analyzed and nutrient values were compared against
Dietary Reference Intakes (DRI). Mean dietary intake met the recommended DRIs.
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On the basis of the Adequate Intake standard, a less than adequate intake was
observed for vitamin D. This demonstrates that a very low-fat vegan diet with
comprehensive nutrition education emphasizing nutrient-fortified plant foods is
nutritionally adequate, with the exception of vitamin D. Vitamin D supplementation,
especially for those with limited sun exposure, can help assure nutritional
adequacy.
Ornish’s Exact Recommendations:
• A vegan diet, predominantly fruits, vegetables, whole grains
(complex carbohydrates), legumes and soy products (tofu plus 58
gm of a fortified soy protein powdered beverage) – low in simple
carbohydrates and with approximately 10% of calories from fat
• Fish oil (3 gm daily)
• Vitamin E (400 IU daily), selenium (200 mcg daily) and vitamin C (2
gm daily)
• Moderate aerobic exercise (walking 30 minutes 6 days weekly)
• Stress management techniques (gentle yoga based stretching,
breathing, meditation,
imagery and progressive relaxation for a
total of 60 minutes daily)
• A 1-hour support group once weekly to enhance adherence to the
intervention
Comment by John McDougall, M.D.
• McDougall Note: For other health reasons I do not
recommend soy concentrates, vitamin E, and fish
oil. Explanations found in my newsletter archives.
• Comment: “Why continue throwing gasoline on a
fire?” Research accumulated over the past 50 years
clearly shows that the rich Western diet is at the
foundation of the cause of prostate cancer. Dairy
products, red meat, and all kinds of fats and oils have
been the focus of research pointing to practical means
for the cause and prevention of this potentially fatal
disease. Therefore, you would expect your doctor to be
recommending, with great enthusiasm, a healthy diet for
people who already have prostate cancer.
Ornish: Diet, PSA
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Intensive lifestyle changes may affect the progression of prostate
cancer by Dean Ornish in the September 2005 issue of The Journal of
Urology found, “Intensive lifestyle changes may affect the progression of
early, low grade prostate cancer in men.” A total of 93 men with elevated
PSA levels (4 to 10 ng/ml), with a Gleason score of less than 7, and who
had not undergone conventional treatments, were split into two groups. For
one year, one group followed a low-fat vegan diet and the other continued
with the American diet (control group). Because of a rise in PSA levels or
signs of disease progression, 6 in the control group eventually underwent
conventional therapy (surgery, radiation, chemotherapy) – none in the
vegan diet group required further treatment. PSA decreased 4% in the
vegan diet group and rose 6% in the control American-diet group.
Serum (a part of the blood) was taken from the patients and used to grow
prostate cancer cells in the laboratory. The serum from those on the
vegan diet inhibited growth of these cells 8 times more effectively than
did the serum from those on the American diet. The stricter the patients
followed the low-fat vegan diet the better the results with PSA and cancer
cell growth inhibition.
Ornish Quality of Life Study
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Urology. 2006 Jan;67(1):125-30. Lifestyle and health-related quality of life of men with
prostate cancer managed with active surveillance.
Daubenmier JJ, Weidner G, Marlin R, Crutchfield L, Dunn-Emke S, Chi C, Gao B, Carroll P,
Ornish D. Preventive Medicine Research Institute, Sausalito, California 94965, USA.
[email protected]
OBJECTIVES: To assess the impact of lifestyle on health-related quality of
life (HR-QOL), perceived stress, and self-reported sexual function in men
with early-stage prostate cancer electing active surveillance.
METHODS: A total of 44 intervention and 49 usual-care control participants
were enrolled in a randomized clinical trial examining the effects of lifestyle
changes on prostate cancer progression. The intervention consisted of a
low-fat, vegan diet, exercise, and stress management. Participants
completed the Medical Outcomes Study Short Form-36 Health Status
Survey (a measure of mental and physical HR-QOL), the Perceived Stress
Scale, the Sexual Function subscale of the University of California, Los
Angeles, Prostate Cancer Index, and measures of lifestyle behaviors (to
yield an overall lifestyle index) at baseline and 12 months. The data were
analyzed using analysis of variance for repeated measures. The
relationship between lifestyle and QOL was also analyzed using multiple
linear regression analyses.
Ornish Study (continued)
• RESULTS: Intervention participants had significantly improved their
lifestyle compared with controls at 12 months. The quality-of-life
scores were high across groups and time points. However, a
healthier lifestyle was related to better QOL at baseline.
Participants in both groups who reported a healthier lifestyle
also reported better mental and physical HR-QOL and sexual
function. Furthermore, participants whose lifestyle improved over
time showed enhanced physical HR-QOL and decreased perceived
stress.
• CONCLUSIONS: Men who choose active surveillance for earlystage prostate cancer are able to make comprehensive lifestyle
changes. Although the average QOL was already high in this
sample, individuals who improved their lifestyle enhanced their QOL
further.
Neutral Factors
• Saw palmetto – latest study found no effect.
• The role of NSAIDs is unclear, and the long-term
toxicity and risk of GI bleeding associated with
NSAIDs may limit their usefulness.
• Although finasteride has decreased overall
prostate cancer occurrence, the risk of invasive
tumors may outweigh the benefit of this agent.
Is Man a Vegetarian?
Attribute
Plant Eaters
Man
Animal
Eaters
Jaw
Flush with face
Flush
Pointed, hinged
Facial muscles
Well developed
Well
developed
Reduced
Oral cavity
Small
Small
Large
Teeth
Cutting, grinding
Cutting,
grinding
Grasping,
piercing, tear
Saliva
Carbohydrate
digesting
enzymes
Carbohydrate
digesting
enzymes
No enzymes
Chewing
Extensive
Extensive
None
Man, Vegetarian - 2
Attribute
Plant Eaters
Man
Animal
Eaters
Stomach size
<30% GI tract
21-27% GI tract
60-70% GI tract
Stomach pH
4-5 with food
4-5 with food
<1 with food
Colon function
Absorb food
Absorb food
Absorb water,
salt
Small intestine
10-12+ x body
length
10-11 x body
length
3-6 x body
length
Liver
Cannot detoxify
vitamin A
Cannot detoxify
vitamin A
Can detoxify
vitamin A
Nails
Flattened
Flattened
Sharp claws
Summary and Conclusion
• Prostate cancer risk is strongly tied to diet and
lifestyle.
• Progression of prostate cancer can be controlled
by diet and lifestyle to a much greater extent
than the American health care system admits.
• A low-fat, plant-based diet, coupled with vitamin
D and selected vitamin and mineral
supplements, should be very effective.
Additional Information on
Plant-Based Diets
• T. Colin Campbell, Ph.D. The China Study,
BenBella Books, 2005
• John McDougall, M.D., Santa Rosa
www.drmcdougall.com
• Neal Barnard, M.D., Physicians
Committee for Responsible Medicine
www.pcrm.org
• San Francisco Vegetarian Society
www.sfvs.org