Kristal AR, Arnold KB, Neuhouser ML, Goodman P, Platz EA, Albanes D, Thompson IM. Diet, supplement use, and prostate cancer risk: results from the prostate cancer prevention trial. Am J Epidemiol. 2010;172(5):566-5770.
The Prostate Cancer Prevention Trial was a randomized, placebo-controlled trial that tested whether finasteride, a 5 alpha-reductase inhibitor, could reduce the 7-year period prevalence of prostate cancer. Beginning in 1993, 18,880 men aged ≥ 55 years in the United States and Canada with normal digital rectal examination (DRE) results; prostate-specific antigen (PSA) levels of 3 ng/mL or less; and no history of prostate cancer, severe lower urinary tract symptoms, or clinically significant coexisting conditions were randomized to receive finasteride (5 mg/day) or placebo. During the PCPT, men underwent DRE and PSA determination annually, and a prostate biopsy was recommended for participants with an abnormal DRE results or a PSA level (adjusted for the effect of finasteride) of 4.0 ng/mL or greater. At the final study visit in year 7 (2000–2003), all men not previously diagnosed with prostate cancer were offered a biopsy, which consisted of a minimum of 6 core samples collected under transrectal ultrasonographic guidance. Biopsies were reviewed for adenocarcinoma by both the pathologist at the local study site and a central pathology laboratory, with full concordance. Clinical stage was assigned locally, and tumors were graded centrally using the Gleason scoring system.
Of the 18,880 participants, 7,615 (40.3%) were excluded who did not have an end-of-study biopsy, including 1,225 men who died, 6,381 who were medically unable to have a biopsy or refused, and 9 who underwent prostatectomy for reasons other than cancer; this left 2,401 cases and 8,864 noncases. The researchers then excluded 173 cases diagnosed on or after the trial end date (June 24, 2003), 92 cases diagnosed 180 days or more after their planned end-of-study visit, and 140 cases who were missing Gleason scores. From the 10,860 men remaining for study, researchers further excluded 102 men who were missing data on body mass index, 770 men who were missing dietary data, and 429 men whose dietary information was judged to be unreliable because of a reported energy intake less than 800 kcal/day or greater than 5,000 kcal/day. Some men did not complete dietary questionnaires because practitioners at their clinical site chose not to participate in the dietary studies or because prostate cancer was diagnosed before the questionnaire was administered. This analysis was based on 1,703 cancer cases diagnosed in 9,559 men.
9,559 Canadian and American men
Study Parameters Assessed
Details regarding demographic and health-related characteristics were collected at baseline using self-administered questionnaires. Level of physical activity was assessed using a 6-item questionnaire. Height and weight were measured at the baseline clinic visit.
One year after randomization, participants completed a 15-page booklet containing 2 questionnaires on diet and the use of nutritional supplements. Diet was assessed using a food frequency questionnaire (FFQ) developed specifically for this population of older men. The FFQ consisted of questions on 99 foods and 9 beverages, plus 18 questions on food preparation and 2 questions on consumption of fruits and vegetables. On the questionnaire, participants reported: the usual number of pills taken per day for multivitamins and antioxidant mixtures; both the number of pills taken per day and the dose for beta carotene, vitamin C, vitamin E, calcium, and zinc; and whether they used stress-type multivitamins, vitamin D, fish oil, or selenium at least 3 times per week. Multivitamin use and supplemental intake of specific nutrients (the sum of single supplements plus multivitamins) were categorized as low (corresponding to no use or infrequent use of a supplement), moderate (corresponding to the amounts generally obtained from multivitamins), and high (corresponding to amounts that are generally only possible from using high-dose single supplements). Because data for fish oil, selenium, and vitamin D were available only on whether these supplements were used at least 3 times per week, fish oil was coded as 0 or 0.5 g of docosahexaenoic (DHA) plus eicosapentaenoic (EPA) fatty acids per day, selenium was coded as 0 or 200 μg/day, and vitamin D was coded as 0 or 10 μg/day. The vitamin D content of multivitamins is also 10 μg; thus, men who used both multivitamins and single vitamins were placed in the high-dose vitamin D category.
In an inter- and intramethod reliability study carried out among 150 randomly selected men, we compared nutrient intakes calculated from the initial FFQ, intakes from six 24-hour recalls administered over the following year, and intakes from an additional FFQ completed after all 24-hour recalls had been administered. Based on the 128 men who completed the study, correlations between the first FFQ and the 24-hour recalls (adjusted for energy and deattenuated for measurement error) were: total fat, 0.71; polyunsaturated fat, 0.66; monounsaturated fat, 0.66; saturated fat, 0.75; alcohol, 0.84; carbohydrate, 0.70; protein, 0.50; vitamin C, 0.62; lycopene, 0.58; beta carotene, 0.68; vitamin D, 0.57; EPA + DHA, 0.87; calcium, 0.62; and zinc, 0.51. Correlations between repeat FFQs were above 0.60 for all nutrients, with the exception of 0.54 for EPA + DHA.
- Cancer was found in 1,703/9,559 men, of whom 127 had high-grade disease (Gleason score 8 to 10).
- There was no evidence of any association between use of any specific nutrient and overall risk for prostate cancer.
- Risk for high-grade prostate cancer was associated with high intake of polyunsaturated fats.
- Dietary calcium was positively associated with a finding of low-grade prostate cancer.
- Conversely, dietary calcium was inversely associated with a finding of high-grade prostate cancer.
- Polyunsaturated fat intake was positively associated with risk of high-grade cancer. There was no evidence that diet or the use of supplements in common use for prostate cancer prevention (e.g., lycopene, long-chain n-3 fatty acids, vitamin D, vitamin E, selenium) significantly affected risk for prostate cancer.
Using a FFQ to assess the relationship of food/supplement use to disease has shown to have low validity.1 As demonstrated in studies of dietary fat and breast cancer risk, there is a distinct possibility that moderate or weak associations of diet with cancer risk cannot be detected using FFQs but can be detected using multiple-day food records.2
Lycopene is a major component of tomatoes and highly associated with benefits against prostate cancer. Supplementation of lycopene has had mixed results in the literature. It seems reasonable to obtain lycopene from food, which might provide additional synergistic value, rather than from supplements, which show inconsistent results in studies.3
This study does not clarify which type of vitamin E participants use. The study does, however, cite the SELECT trial, a large population trial that did not find reduced risks after supplementing with vitamin E, selenium, or both. It’s important to note that the type of vitamin E used in the SELECT trial was only alpha tocopherol. In high doses, alpha-tocopherol “kicks out” critically important gamma-tocopherol in the cells. While alpha-tocopherol inhibits the production of free radicals, it is the gamma-tocopherol form of vitamin E that are required to trap and neutralize free radicals. In a study published in the Proceedings of the National Academy of Sciences, researchers reported that it could be dangerous to take high levels of alpha-tocopherol vitamin E without also consuming gamma-tocopherol.4 The reason for this finding seems to be that too much alpha-tocopherol could deprive the cells of the gamma form of vitamin E that is needed to neutralize existing oxidizing agents such as the peroxynitrite radical, which can be especially damaging. In a study with 10,456 men conducted at Johns Hopkins School of Public Health, men who had the highest blood levels of gamma-tocopherol were 5 times less likely to get prostate cancer. In addition to the finding that higher levels of gamma-tocopherol significantly reduced prostate cancer risk, the study also showed that selenium and alpha-tocopherol also reduced prostate cancer incidence, but only when gamma-tocopherol levels were high.5
In terms of calcium consumption, it is unclear why dietary calcium was positively associated with a finding of low-grade prostate cancer but inversely associated with a finding of high-grade prostate cancer.
In terms of calcium consumption, it is unclear why dietary calcium was positively associated with a finding of low-grade prostate cancer but inversely associated with a finding of high-grade prostate cancer. It is not defined if those who consumed calcium supplementation also consumed any amount of vitamin D3. Calcium, at least in dairy, may increase risk of prostate cancer by suppressing concentrations of circulating 1,25-D.6 All in all, dairy seems to increase the overall risk of prostate cancer and should be avoided by prostate cancer patients or those with a family medical history of prostate cancer.7
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2. Bingham SA, Luben R, Welch A, Wareham N, Khaw KT, Day N. Are imprecise methods obscuring a relation between fat and breast cancer? Lancet. 2003;362(9379):212-214.
3. Giovannucci E. Tomato products, lycopene, and prostate cancer: a review of the epidemiological literature. J Nutr. 2005;135(8):2030S-20301S.
4. Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci U S A. 1997;94(7):3217-3222.
5. Helzlsouer KJ, Huang HY, Alberg AJ, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000;92(24):2018-2023.
6. Giovannucci E. Dietary influences of 1,25(OH)2 vitamin D in relation to prostate cancer: a hypothesis. Cancer Causes Control. 1998;9(6):567-582.
7. La Vecchia C, Negri E, D'Avanzo B, Franceschi S, Boyle P. Dairy products and the risk of prostatic cancer. Oncology.1991;48(5):406-410.