Transcript Epidemiological evidence for a role of UV

How to Reduce Risk of Death after
Diagnosis of Prostate Cancer
A presentation on
March 6, 2014
by William B. Grant, Ph.D.
Sunlight, Nutrition, and Health Research Center
San Francisco, California
www.sunarc.org
Disclosure
I am pleased to acknowledge funding from
these organizations:
 Bio-Tech-Pharmacal (www.Bio-Tech-Pharm.com)
(Fayetteville, AR)
 Sunlight Research Forum (Veldhoven)
Outline
Risk factors for prostate cancer incidence
Steps to take to reduce risk of death from
prostate cancer
Diet: advanced glycation end products
Vitamin D
UVB, vitamin D and cancer
Selected vitamin D-sensitive diseases
Recommended actions
NEJM on watchful waiting vs. prostatectomy
Risk-Modifying Factors for Prostate
Cancer Incidence
Diet
Exercise
UVB and vitamin D
A very-low-fat vegan diet increases
intake of protective dietary factors
 There is increasing evidence that dietary factors in
plant-based diets are important in the prevention of
chronic disease. This study examined protective (eg,
antioxidant vitamins, carotenoids, and fiber) and
pathogenic (eg, saturated fatty acids and cholesterol)
dietary factors in a very-low-fat vegan diet. Ninety-three
early-stage prostate cancer patients participated in a
randomized controlled trial and were assigned to a
very-low-fat (10% fat) vegan diet supplemented with
soy protein and lifestyle changes or to usual care.
Three-day food records were collected at baseline
(n=42 intervention, n=43 control) and after 1 year (n=37
in each group).
and decreases intake of pathogenic
dietary factors.
 Analyses of changes in dietary intake of macronutrients, vitamins,
minerals, carotenoids, and isoflavones from baseline to 1 year
showed significantly increased intake of most protective dietary
factors (eg, fiber increased from a mean of 31 to 59 g/day,
lycopene increased from 8,693 to 34,464 mug/day) and
significantly decreased intake of most pathogenic dietary factors
(eg, saturated fatty acids decreased from 20 to 5 g/day, cholesterol
decreased from 200 to 10 mg/day) in the intervention group
compared to controls. These results suggest that a very-low-fat
vegan diet can be useful in increasing intake of protective nutrients
and phytochemicals and minimizing intake of dietary factors
implicated in several chronic diseases.
 Dewell A, Weidner G, Sumner MD, Chi CS, Ornish D. J
Am Diet Assoc. 2008 Feb;108(2):347-56.
Changes in prostate gene expression in men
undergoing an intensive nutrition and lifestyle
intervention
Pathway analysis identified significant
modulation of biological processes that have
critical roles in tumorigenesis, including protein
metabolism and modification, intracellular
protein traffic, and protein phosphorylation (all
P < 0.05). Intensive nutrition and lifestyle
changes may modulate gene expression in the
prostate.
 Ornish D, Magbanua MJ, Weidner G, et al. Proc Natl Acad Sci U S
A. 2008 Jun 17;105(24):8369-74.
Mediterranean Diet
A higher Med-Diet score was not associated
with risk of advanced PCa or disease
progression. Greater adherence to the MedDiet after diagnosis of nonmetastatic PCa was
associated with lower overall mortality.
 Kenfield SA, Dupre N, Richman EL, Stampfer MJ, Chan JM,
Giovannucci EL. Mediterranean Diet and Prostate Cancer Risk and
Mortality in the Health Professionals Follow-up Study. Eur Urol.
2013 Aug 13.
Omega-6 to Omega-3 PUFA Ratio
 A low omega-6 to omega-3 PUFA ratio can delay the progression
of cells toward castration-resistance by suppressing pathways
involved in prostate cancer progression, such as the
Akt/mTOR/NFκB axis. It also suppresses the expression of cyclin
D1, and activation of caspase-3 and annexin V staining shows
induction of proapoptotic events. Taken together, our data
demonstrates that maintaining a low omega-6 to omega-3 fatty
acids ratio can enhance efficacy of hormone ablation therapy.
 Apte SA, Cavazos DA, Whelan KA, Degraffenried LA. A low
dietary ratio of omega-6 to omega-3 Fatty acids may delay
progression of prostate cancer. Nutr Cancer. 2013;65(4):55662.
Milk and Prostate Cancer
 The intake of total dairy products was associated with increased
PCa incidence [HR = 1.12 (95% CI: 0.93, 1.35); >2.5 servings/d vs.
≤0.5 servings/d]. Skim/low-fat milk intake was positively associated
with risk of low-grade, early stage, and screen-detected cancers,
whereas whole milk intake was associated only with fatal PCa [HR
= 1.49 (95% CI: 0.97, 2.28); ≥237 mL/d (1 serving/d) vs. rarely
consumed]. In the survival analysis, whole milk intake remained
associated with risk of progression to fatal disease after diagnosis
[HR = 2.17 (95% CI: 1.34, 3.51)]. In this prospective cohort, higher
intake of skim/low-fat milk was associated with a greater risk of
nonaggressive PCa.
 Song Y, Chavarro JE, Cao Y, Qiu W, Mucci L, Sesso HD, Stampfer MJ,
Giovannucci E, Pollak M, Liu S, Ma J. Whole milk intake is associated with
prostate cancer-specific mortality among U.S. male physicians. J Nutr.
2013 Feb;143(2):189-96.
Diet and Physical Activity
A total of 43 records were included in this review. Evidence from
observational studies suggests that a low-fat, high-fibre diet might
be protective against cancer recurrence and progression.
However, there is a paucity of RCTs substantiating this. There is
more support for physical activity, with a dose response for better
outcomes. When synthesized with findings from the World Cancer
Research Fund review of RCTs investigating the effect of diet and
physical activity interventions on cancer survival, evidence
suggests that the mechanism of benefit from diet and physical
activity pertains to body weight, with excess body weight being a
risk factor, which is modifiable through lifestyle.
 Davies NJ, Batehup L, Thomas R. The role of diet and physical activity in
breast, colorectal, and prostate cancer survivorship: a review of the
literature. Br J Cancer. 2011 Nov 8;105 Suppl 1:S52-73.
Eggs and Poultry
 Men who consumed 2.5 or more eggs per week had an 81%
increased risk of lethal prostate cancer compared with men who
consumed less than 0.5 eggs per week (HR: 1.81; 95% CI: 1.132.89; P(trend): 0.01). In the case-only survival analysis, we
observed 123 events during 19,354 person-years. There were
suggestive, but not statistically significant, positive associations
between postdiagnostic poultry (HR ≥ 3.5 vs. <1.5 servings per
week: 1.69; 95% CI: 0.96-2.99; P(trend): 0.07) and postdiagnostic
processed red meat (HR ≥ 3 vs. <0.5 servings per week: 1.45;
95% CI: 0.73-2.87; P(trend): 0.08) and risk of progression of
localized prostate cancer to lethal disease.
 Richman EL, Kenfield SA, Stampfer MJ, Giovannucci EL, Chan JM. Egg,
red meat, and poultry intake and risk of lethal prostate cancer in the
prostate-specific antigen-era: incidence and survival. Cancer Prev Res
(Phila). 2011 Dec;4(12):2110-21.
Advanced Glycation End Products
AGEs are formed both outside and inside the
body. Specifically, they stem from glycation
reaction, which refers to the addition of a
carbohydrate to a protein without the
involvement of an enzyme.
Inside the body, Glucose can bind with proteins
in a process called glycation, making cells
stiffer, less pliable and more subject to damage
and premature aging.
AGEs – from Cooking
Outside the body, AGEs can be formed by
heating (for example, cooking).
The total state of oxidative and peroxidative
stress on the healthy body, with the AGErelated damage to it,is proportional to the
dietary intake of exogenous (preformed) AGEs
and the consumption of sugars with a
propensity towards glycation such as fructose
and galactose.
AGE Levels of Various Foods- High
Frankfurter, broiled, 11,270 kU/100 kg
Olive oil, 10,040 kU/100 g
Chicken, deep fried, 9,700 kU/100 g
Peanut butter, 7,517 kU/100 g
 Beef cooked at high temperature, 7,000 kU/100 g
Aged cheese, 5,000 kU/100 g
Shrimp, fried, 4,328 kU/100 g
(100 g is approximately 3.4 ounces)
AGE Levels of Various Foods- Low
Chicken, boiled with lemon, 957 kU/100 g
Canned pink salmon, 917 kU/100 g
Liverwurst, 633 kU/100 g
Vegetables, grilled, 226 kU/100 g
Eggs, scrambled, 67 to 243 kU/100 g
Beans, red kidney, canned, 191 kU/100g
Bread, 23 to 150 kU/100 g
Rice, 9 kU/100g
Milk, whole, 5 kU/100 g
To Lower AGE Values in Cooking
Marinate meat in vinegar for an hour (low pH
reduces AGEs during cooking)
Boil meat and fish rather than broiling or frying
(lower temperature and water also retards
formation of AGEs)
Eat more grains and vegetables
Source of AGE Data
Uribarri J, Woodruff S, Goodman S, Cai W,
Chen X, Pyzik R, Yong A, Striker GE, Vlassara
H. Advanced glycation end products in foods
and a practical guide to their reduction in the
diet. J Am Diet Assoc. 2010 Jun;110(6):91116.e12.
Low AGEs Reduce the Risk of:
Reduced risk of diabetes mellitus,
cardiovascular disease, Alzheimer’s disease.
It is not clear that they play an important role in
cancer in general or prostate cancer in
particular.
 Cai W, Uribarri J, Zhu L, Chen X, Swamy S, Zhao Z, Grosjean F,
Simonaro C, Kuchel GA, Schnaider-Beeri M, Woodward M, Striker
GE, Vlassara H. Oral glycotoxins are a modifiable cause of
dementia and the metabolic syndrome in mice and humans. Proc
Natl Acad Sci U S A. 2014 Feb 24. [Epub ahead of print]
Vitamin D
Increasing serum 25-hydroxyvitamin D
[25(OH)D] concentration is one way to improve
overall health.
>40 ng/ml to 60 or 70 ng/ml seems to be
optimal.
To reach this level takes 2000-5000 IU/d
vitamin D3 (cholecalciferol).
Ecological Studies of UVB,
Vitamin D, Cancer
The first epidemiological study hypothesizing
that solar UVB, through production of vitamin D,
reduced the risk of cancer was published in
1980.
The brothers Cedric Garland and Frank
Garland, then at Johns Hopkins School of
Public Health, looked at the map of colon
cancer mortality rates in the U.S. and saw a link
to solar radiation.
300
300
350
350
Colon cancer mortality rates,
males, 1970-94; dashed lines:
Index of annual solar radiation
300
350
300
350
400
400
450
500
500
450
Higher UVB in the west
is due to higher surface
elevation and thinner
stratospheric ozone layer
19 Vitamin D-Sensitive Cancers
 Vitamin D-sensitive cancers with strong support from
several ecological studies after accounting for other
factors:
 Gastrointestinal: colon, esophageal, gallbladder,
gastric, pancreatic, rectal
 Urinary: bladder, kidney; Male: prostate
 Female: breast, cervical, endometrial, ovarian,
vulvar
 Blood: Hodgkin’s and non-Hodgkin’s lymphoma,
leukemia
 Miscellaneous: brain, lung, melanoma
Vitamin D and Prostate Cancer
Solar UVB irradiance early in life and
throughout life is associated with reduced risk
of prostate cancer.
Serum 25(OH)D levels out to 27 years prior to
diagnosis of prostate cancer are not correlated
with incidence of prostate cancer.
However, those with lower serum 25(OH)D
levels are at greater risk of more aggressive
prostate cancer.
Prostate Cancer Mortality Rates
Vitamin D Supplementation for
Prostate Cancer
Marshall DT, Savage SJ, Garrett-Mayer E,
Keane TE, Hollis BW, Horst RL, Ambrose LH,
Kindy MS, Gattoni-Celli S. Vitamin D3
supplementation at 4000 international units per
day for one year results in a decrease of
positive cores at repeat biopsy in 55% of
subjects with low-risk prostate cancer under
active surveillance. J Clin Endocrinol Metab.
2012 Jul;97(7):2315-24.
Vitamin D and Aggressive Prostate
Cancer
 There was evidence that men deficient in vitamin D had
a 2-fold increased risk of advanced versus localized
cancer (OR for deficient vs. adequate total
25(OH)D=2.33, 95% CI: 1.26, 4.28) and high-grade
versus low-grade cancer (OR for deficient vs. adequate
total 25(OH)D=1.78, 95% CI: 1.15, 2.77). There was no
evidence of a linear association between total 25(OH)D
and prostate cancer (p=0.44) or of an increased risk of
prostate cancer with high and low vitamin D levels.
 Gilbert et al. Int J Cancer. 2012 Sep 1;131(5):1187-96.
Vitamin D Mechanisms for Cancer
The primary mechanisms whereby vitamin D
reduces the risk of cancer are well known and
include effects on cellular differentiation,
proliferation and survival, modulation of growth
factor actions, anti-inflammatory effects,
inhibition of angiogenesis, and inhibition of
invasion and metastasis.
 Krishnan AV, Feldman D. Vitamin D and prostate cancer. Ch. 86 in
Vitamin D, Third Edit. Feldman D, Pike JW, Adams JS (eds). 2011,
1675-709.
100 Vitamin D Sensitive Diseases
Cancers – at least 20 types
Heart disease, both coronary and congestive
heart disease, and stroke
Diabetes, type 1 and 2
Infectious diseases – bacterial and viral
Autoimmune disease: multiple sclerosis
Bone diseases, fractures
Neurological diseases, especially of brain
An estimate of the global reduction
in mortality rates
 This study is based on interpretation of the journal
literature relating to the effects of solar ultraviolet-B
(UVB) and vitamin D in reducing the risk of disease and
estimates of the serum 25(OH)D level-disease risk
relations for cancer, cardiovascular disease (CVD) and
respiratory infections. The vitamin D-sensitive diseases
that account for more than half of global mortality rates
are CVD, cancer, respiratory infections, respiratory
diseases, tuberculosis and diabetes mellitus.
 Increasing serum 25(OH)D levels from 54 to 110 nmol/l
would reduce the vitamin D-sensitive disease mortality
rate by an estimated 15%, resulting in 2-year increase
in life expectancy.
Cardiovascular disease incidence vs.
25(OH)D level
Source
Grant WB. An estimate of the global reduction
in mortality rates through doubling vitamin D
levels. Eur J Clin Nutr. 2011 Sep;65(9):101626.
Suggested Action Items
 Measure serum 25(OH)D levels.
 The rule of thumb is each 1000 IU/d of vitamin D3
increases serum 25(OH)D level by 6-10 ng/ml;
however, there is considerable variability.
 An inexpensive source of vitamin D is www.Bio-TechPharm.com (Fayetteville, Arkansas) ($30 for 100 ea
50,000 IU capsules, water soluble vitamin D3 for the
general public). They supply research grade vitamin D
for intervention studies.
 Spread the word.
Conclusion
There is enough evidence now to conclude that
2000-4000 IU/day of vitamin D from oral intake
or production from UVB, leading to serum
25(OH)D levels of at least 40 ng/ml, can
significantly reduce the burden of breast and
many other types of cancer, other chronic and
infectious diseases, adverse pregnancy
outcomes, and increase healthy and total life
expectancy.
NEJM Paper on WW or Prostatectomy
 Radical Prostatectomy or Watchful Waiting in Early
Prostate Cancer
 Anna Bill-Axelson, M.D., Ph.D., Lars Holmberg, M.D.,
Ph.D., Hans Garmo, Ph.D., Jennifer R. Rider, Sc.D.,
Kimmo Taari, M.D., Ph.D., Christer Busch, M.D., Ph.D.,
Stig Nordling, M.D., Ph.D., Michael Häggman, M.D.,
Ph.D., Swen-Olof Andersson, M.D., Ph.D., Anders
Spångberg, M.D., Ph.D., Ove Andrén, M.D., Ph.D., Juni
Palmgren, Ph.D., Gunnar Steineck, M.D., Ph.D., HansOlov Adami, M.D., Ph.D., and Jan-Erik Johansson,
M.D., Ph.D.
 N Engl J Med 2014; 370:932-942March 6, 2014DOI:
10.1056/NEJMoa1311593
NEJM Paper
 Background
 Radical prostatectomy reduces mortality among men
with localized prostate cancer; however, important
questions regarding long-term benefit remain.
 Methods
 Between 1989 and 1999, we randomly assigned 695 men with
early prostate cancer to watchful waiting or radical prostatectomy
and followed them through the end of 2012. The primary end
points in the Scandinavian Prostate Cancer Group Study Number
4 (SPCG-4) were death from any cause, death from prostate
cancer, and the risk of metastases. Secondary end points included
the initiation of androgen-deprivation therapy.
Results
 During 23.2 years of follow-up, 200 of 347 men in the surgery
group and 247 of the 348 men in the watchful-waiting group died.
Of the deaths, 63 in the surgery group and 99 in the watchfulwaiting group were due to prostate cancer; the relative risk was
0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the
absolute difference was 11.0 percentage points (95% CI, 4.5 to
17.5). The number needed to treat to prevent one death was 8.
One man died after surgery in the radical-prostatectomy group.
Androgen-deprivation therapy was used in fewer patients who
underwent prostatectomy (a difference of 25.0 percentage points;
95% CI, 17.7 to 32.3). The benefit of surgery with respect to death
from prostate cancer was largest in men younger than 65 years of
age (relative risk, 0.45) and in those with intermediate-risk prostate
cancer (relative risk, 0.38). However, radical prostatectomy was
associated with a reduced risk of metastases among older men
(relative risk, 0.68; P=0.04).
Conclusion
Extended follow-up confirmed a substantial
reduction in mortality after radical
prostatectomy; the number needed to treat to
prevent one death continued to decrease when
the treatment was modified according to age at
diagnosis and tumor risk. A large proportion of
long-term survivors in the watchful-waiting
group have not required any palliative
treatment. (Funded by the Swedish Cancer
Society and others.)
Additional Resources
http://www.grassrootshealth.net/
http://www.healthresearchforum.org.uk/
http://www.pubmed.gov/
http://www.sunarc.org/
http://www.vitamindcouncil.org/
http://www.vitamindwiki.com/VitaminDWiki
For a copy of this presentation,
[email protected]