1. Risk Modifying Factors For Prostate & Other Cancers: Diet, Lifestyle and Sunshine! William B. Grant, Ph.D. SUNARC, San Francisco www.sunarc.org wgrant@sunarc.org Presented to Prostate Awareness Foundation, San Francisco, March 6, 2006

2. Outline 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

3. 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

4. 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

5. 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.

6. 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

7. My Ecologic Studies My first epidemiologic study, in 1997, identified the main dietary risk-modifying factors for Alzheimers 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.

8. Prostate Cancer Mortality Rates, Aged 65-74, 1985, Dietary Supply Data, 1970 CountryProstate Mortality Animal Energy Vegetable Protein FishMilk Protein Onions Korea412163320.319 Japan22427371564.328 Greece53631563216.036 Italy78633552412.419 USA1031057332121.422 Sweden131976396124.410

9. Prostate Cancer Risk Factors Milk protein (casein) Meat Fat Metabolic syndrome PSA testing Smoking Alcohol consumption Genetics

10. 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, Im convinced that casein is the culprit in milk.

11. 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].

12. 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).

13. 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.

14. 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)

15. 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 long- chain n-3 fatty acids may also retard prostate cancer progression. (U.S.)

16. 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

17. 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.

18. 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.

19. 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.

20. Smoking Smoking leads to an increase in free radicals such as hydrogen peroxide (H 2 O 2 ) H 2 O 2 can damage DNA. H 2 O 2 -DNA damage has been linked to increase risk of developing prostate cancer. However, lung cancer often kills before prostate cancer does.

21. 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).

22. 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 Alzheimers disease, and implicated in lung cancer.

23. Prostate Cancer Risk-Reduction Factors Vegetable protein, Phytoestrogens Allium family vegetables (onions, garlic, etc.) Tomatoes Cruciferous vegetables Vitamin D Selenium Fish Calcium, magnesium Folate Vitamin E Resveratrol Exercise

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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.

32. 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

36. 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.

37. 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.

38. 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)

39. 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 low- alcohol intake versus low-folate and high- alcohol intake was 0.46 (95% CI, 0.29- 0.75). (Italy)

40. 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.

41. 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.

42. 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, 0.82- 1.59) 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.

43. 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.

44. 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.

45. 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.

46. 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

47. Summary In general, animal products are related to prostate cancer risk while vegetable products are associated with prostate cancer risk reduction.

48. 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

49. 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.

50. Ornish – Low Fat, Vegan Diet 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. Thirty- nine 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. Dunn-Emke SRWeidner GPettengill EBMarlin ROChi COrnish DM 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.

51. Ornishs 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

52. 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.

53. Ornish: Diet, PSA 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.

54. Ornish Quality of Life Study 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. jennifer.daubenmier@pmri.org 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.Daubenmier JJWeidner GMarlin RCrutchfield LDunn-Emke SChi CGao BCarroll P Ornish D 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.

55. 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 early- stage 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.

56. 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.

57. Is Man a Vegetarian? AttributePlant EatersManAnimal Eaters JawFlush with faceFlushPointed, hinged Facial musclesWell developed Reduced Oral cavitySmall Large TeethCutting, grinding Grasping, piercing, tear SalivaCarbohydrate digesting enzymes No enzymes ChewingExtensive None

58. Man, Vegetarian - 2 AttributePlant EatersManAnimal Eaters Stomach size<30% GI tract21-27% GI tract60-70% GI tract Stomach pH4-5 with food <1 with food Colon functionAbsorb food Absorb water, salt Small intestine10-12+ x body length 10-11 x body length 3-6 x body length LiverCannot detoxify vitamin A Can detoxify vitamin A NailsFlattened Sharp claws

59. 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.

60. 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