How to Reduce Risk of Death after Diagnosis of Prostate Cancer

1. 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

2. Disclosure I am pleased to acknowledge funding from these organizations: • Bio-Tech-Pharmacal (www.Bio-Tech-Pharm.com) (Fayetteville, AR) • Sunlight Research Forum (Veldhoven)

3. 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

4. Risk-Modifying Factors for Prostate Cancer Incidence • Diet • Exercise • UVB and vitamin D

5. 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).

6. 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.

7. 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.

8. Mediterranean Diet • A higher Med-Diet score was not associated with risk of advanced PCa or disease progression. Greater adherence to the Med-Diet 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.

9. 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):556-62.

10. 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.

11. 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.

12. 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: 1.13-2.89; 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.

13. 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.

14. 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 AGE-related 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 fructoseand galactose.

15. 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)

16. 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

17. 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

18. 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):911-16.e12.

19. 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]

20. 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).

21. 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.

22. 300 300 350 350 300 350 300 350 400 400 450 500 500 450 Colon cancer mortality rates, males, 1970-94; dashed lines: Index of annual solar radiation

23. Higher UVB in the west is due to higher surface elevation and thinner stratospheric ozone layer

24. 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

25. 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.

26. Prostate Cancer Mortality Rates

27. 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.

28. 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.

29. 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.

30. 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

31. 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.

32. Cardiovascular disease incidence vs. 25(OH)D level

33. 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):1016-26.

34. 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-Tech-Pharm.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.

35. 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.

36. 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., Hans-Olov 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

37. 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.

38. 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 watchful-waiting 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).

39. 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.)

40. 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, wbgrant@infionline.net