News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd
Release Date: December 9, 2008; Valid for credit through December 9, 2009
Physicians – maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians – up to 0.25 AAFP Prescribed credit(s) for physicians
December 9, 2008 — Neither vitamin E nor vitamin C reduces the risk for prostate cancer or total cancer, according to the results of a large, long-term, randomized trial of male physicians reported in the December 9 Early Release issue of the Journal of the American Medical Association.
“Many individuals take vitamins in the hopes of preventing chronic diseases such as cancer, and vitamins E and C are among the most common individual supplements,” write J. Michael Gaziano, MD, MPH, from the Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues from the Physicians’ Health Study II. “A large-scale randomized trial suggested that vitamin E may reduce risk of prostate cancer; however, few trials have been powered to address this relationship. No previous trial in men at usual risk has examined vitamin C alone in the prevention of cancer.”
The goal of this study was to evaluate whether long-term vitamin E or C supplementation decreases the risk for prostate cancer and total cancer events among men enrolled in the Physicians’ Health Study II.
This randomized, double-blind, placebo-controlled factorial trial of vitamins E and C began in 1997 and was completed as scheduled on August 31, 2007. Of 14,641 male physicians in the United States initially aged 50 years or older who enrolled, 1307 men had a history of cancer at randomization. Participants were randomly assigned to receive individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily or matching placebos. Primary endpoints were incidence of prostate cancer and of total cancer during a mean follow-up of 8.0 years.
During follow-up, there were 1008 confirmed incident cases of prostate cancer and 1943 total cancers. Vitamin E had no apparent effect vs placebo on the incidence of prostate cancer (active and placebo vitamin E groups, 9.1 and 9.5 events per 1000 person-years; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.85 – 1.09; P = .58) or total cancer (active and placebo vitamin E groups, 17.8 and 17.3 cases per 1000 person-years; HR, 1.04; 95% CI, 0.95 – 1.13; P = .41).
Vitamin C also had no apparent significant effect on the incidence of total cancer (active and placebo vitamin C groups, 17.6 and 17.5 events per 1000 person-years; HR, 1.01; 95% CI, 0.92 – 1.10; P = .86) or prostate cancer (active and placebo vitamin C groups, 9.4 and 9.2 cases per 1000 person-years; HR, 1.02; 95% CI, 0.90 – 1.15; P = .80).
Neither vitamin E nor vitamin C supplementation was significantly associated with colorectal, lung, or other site-specific cancers. Overall findings were not affected by adjustment for adherence and exclusion of the first 4 or 6 years of follow-up. Adjustment for various cancer risk factors did not show any significant change of the effect of vitamin E on prostate cancer risk or either agent on total cancer risk.
“In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer,” the study authors write. “These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men.”
Limitations of the study include lack of generalizability to less well-nourished populations, findings limited to 1 choice of dose for each agent, use of synthetic vitamin E, limited duration, and inability to determine the role of these agents in chemoprevention when taken with other micronutrients.
“It is reassuring that there was not a clear signal of harm for either agent,” the study authors conclude. “Results of the multivitamin arm of the PHS [Physicians’ Health Study] II will be forthcoming in several years.”
The National Institutes of Health and BASF Corporation supported this study. Study agents and packaging were provided by BASF Corporation, Wyeth Pharmaceuticals, and DSM Nutritional Products Inc. Dr. Graziano and 6 of the study authors have disclosed various financial relationships with the National Institutes of Health, the Veterans Administration, Veroscience, Amgen, Bayer AG, Pfizer, Merck. the National Institutes of Health, Bristol-Meyers Squibb, AstraZeneca, Harvard University (Clinical Nutrition Research Center), DSM Nutritional Products Inc (Roche). McNeil Consumer & Specialty Pharmaceuticals, Wyeth Consumer Healthcare, i3 Drug Safety, Genzyme, Organon, Cognis, American Heart Association, American Cancer Society, California Strawberry Commission, Cambridge Theranostics Ltd, and/or the Natural Source Vitamin E Association. The remaining study authors have disclosed no relevant financial relationships.
JAMA. Published online December 9, 2008.
Observational studies have indicated a possible reduction in the risk for certain cancers with vitamin C and vitamin E. Vitamin E has been observed to reduce the risk for prostate cancer, but studies have been short in duration, and longer studies are needed. Currently, more than half of US adults take vitamin supplements, and vitamins C and E are among the most popular vitamins taken.
This is a randomized, placebo-controlled, 2 x 2 x 2 x 2-factorial, double-blind, 8-year trial of physicians in the Physicians’ Health Study II to examine the risk for prostate cancer and other cancers associated with use of vitamins C and E.
- Included were healthy male physicians aged 50 years or older recruited via the American Medical Association, who completed a baseline questionnaire and met adherence guidelines of at least two thirds of placebo taken during a 12-week placebo run-in.
- Excluded were men with cancer (except nonmelanoma skin cancer).
- 14,641 physicians were enrolled and were randomly assigned to receive either vitamin E (400 IU) every other day (n = 3659) or vitamin C (500 mg of synthetic ascorbic acid) daily (n = 3673), both supplements (n = 3656), or placebo (n = 3653).
- Participants were sent monthly calendar packs containing vitamin or placebo every 6 months for the first year and annually thereafter.
- They were sent annual questionnaires asking about endpoints and adverse effects.
- Adherence was defined as taking at least two thirds of agents.
- At 4 years, adherence to vitamin E and placebo were 78% and 77%, respectively; at 8 years, adherence was 72% and 70%, respectively.
- For vitamin C and placebo, adherence at 4 years was 78% and 78%, respectively; at 8 years, it was 71% and 71%, respectively.
- The primary endpoint for vitamin E was total prostate cancer and total cancer.
- The primary endpoint for vitamin C was total cancer, and secondary endpoints were colorectal cancer and prostate cancer.
- Total cancer and cancer mortality were secondary endpoints for both.
- Cancers were determined by self-report questionnaire, letter, and telephone calls; medical records were examined.
- A National Death Index search was also conducted for participants with unknown vital status.
- Mean age was 64.3 years at baseline, and mean follow up was 8 years for a total of 117,711 person-years of follow-up.
- There were 1943 confirmed cases of total cancer and 1008 cases of prostate cancer.
- A total of 1661 men died during follow-up.
- In the vitamin E study, overall rates of prostate cancer were 9.1 and 9.5 per 1000 person-years for the active and placebo groups, respectively.
- The lack of effect of vitamin E did not vary for up to 10 years.
- Rates of total cancer were 17.8 and 17.3 per 1000 person-years, respectively, with no significant difference.
- Vitamin E did not reduce the incidence of any site-specific cancers including colorectal, bladder, or pancreatic cancer or total cancer mortality.
- For vitamin C, the rates of total cancer were 17.6 and 17.5 per 1000 person-years, respectively, with no difference.
- There was no difference in rates of prostate cancer (9.4 and 9.2 cases per 1000 person-years for vitamin C and placebo, respectively).
- There was no effect of vitamin C on colorectal, lung, bladder, or pancreatic cancer.
- There was no effect of vitamin C on total mortality rate.
- There was no effect of other factors, including cancer risk factors, on the effect of vitamins E or C on cancer risk.
- There were no significant effects of either vitamin C or E on minor bleeding, gastrointestinal tract symptoms, fatigue, drowsiness, skin, or other adverse effects.
- The authors concluded that neither vitamin C nor E supplementation reduced the risk for prostate cancer or total cancer and that there was no evidence for the use of these vitamins to prevent cancer in middle-aged men.
Pearls for Practice
- Vitamin E supplementation at 400 IU every other day for 8 years is not associated with a reduced risk for prostate cancer, other cancers, and total cancer mortality in middle-aged men.
- Vitamin C supplementation at 500 mg daily is not associated with a reduced risk for prostate cancer, other cancers, or total cancer mortality in middle-aged men.