Vitamins E and C in the Prevention of Prostate and Total Cancer in Men

The Physicians' Health Study II Randomized Controlled Trial

Gaziano, J. Michael MD, MPH
Glynn, Robert J. ScD
Christen, William G. ScD
Kurth, Tobias MD, ScD
Belanger, Charlene MA
MacFadyen, Jean BA
Bubes, Vadim PhD
Manson, JoAnn E. MD, DrPH
Sesso, Howard D. ScD, MPH
Buring, Julie E. ScD

Divisions of Preventive Medicine (Drs Gaziano, Glynn, Christen, Kurth, Bubes, Manson, Sesso, and Buring and Mss Belanger and MacFadyen), Aging (Drs Gaziano, Kurth, Sesso, and Buring), and Cardiovascular Disease (Dr Gaziano), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System (Dr Gaziano), Boston; Department of Ambulatory Care and Prevention (Dr Buring), Harvard Medical School, Boston; and Departments of Epidemiology and Biostatistics (Drs Glynn, Kurth, Manson, and Sesso), Harvard School of Public Health, Boston.

Corresponding Author: J. Michael Gaziano, MD, MPH, Brigham and Women's Hospital, 1620 Tremont St, Boston, MA 02120 ([email protected]).

Published Online: December 9, 2008 (doi:10.1001/jama.2008.862).

Author Contributions: Dr Gaziano had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Gaziano and Dr Glynn contributed equally and are co–first authors of this article.

Study concept and design: Gaziano, Glynn, Belanger, Manson, Sesso, Buring.

Acquisition of data: Gaziano, Glynn, Kurth, Belanger, MacFadyen, Bubes, Manson, Sesso, Buring.

Analysis and interpretation of data: Gaziano, Glynn, Christen, Kurth, Bubes, Manson, Sesso, Buring.

Drafting of the manuscript: Gaziano, Glynn, Sesso, Buring.

Critical revision of the manuscript for important intellectual content: Gaziano, Glynn, Christen, Kurth, Belanger, MacFadyen, Bubes, Manson, Sesso, Buring.

Statistical analysis: Glynn, Bubes, Sesso.

Obtained funding: Gaziano, Sesso, Buring.

Administrative, technical, or material support: Gaziano, Kurth, Belanger, MacFadyen, Bubes, Manson, Sesso.

Study supervision: Gaziano, Kurth, Belanger, MacFadyen, Bubes, Manson, Sesso.

Financial Disclosures: Dr Gaziano reported receiving investigator-initiated research funding from the National Institutes of Health, the Veterans Administration, Veroscience, and Amgen; serving as a consultant or receiving honoraria from Bayer AG and Pfizer; and serving as an expert witness for Merck. Dr Glynn reported receiving investigator-initiated research funding from the National Institutes of Health, Bristol-Meyers Squibb, and AstraZeneca. Dr Christen reported receiving research funding support from the National Institutes of Health, Harvard University (Clinical Nutrition Research Center), and DSM Nutritional Products Inc (Roche). Dr Kurth reported receiving investigator-initiated research funding from Bayer AG, the National Institutes of Health, McNeil Consumer & Specialty Pharmaceuticals, Merck, and Wyeth Consumer Healthcare; being a consultant to i3 Drug Safety; and receiving honoraria from Genzyme for educational lectures and Organon for contributing to an expert panel. Dr Manson reported receiving investigator-initiated research funding from the National Institutes of Health and assistance with study pills and packaging from BASF and Cognis. Dr Sesso reported receiving investigator-initiated research funding from the National Institutes of Health, American Heart Association, American Cancer Society, California Strawberry Commission, Roche Vitamins Inc (now DSM Nutritional Products Inc), and Cambridge Theranostics Ltd. Dr Buring reported receiving study agents and packaging from Bayer Healthcare and the Natural Source Vitamin E Association, as well as research funding from the National Institutes of Health. No other authors reported financial disclosures.

Funding/Support: This work was supported by grants CA 97193, CA 34944, CA 40360, HL 26490, and HL 34595 from the National Institutes of Health (Bethesda, Maryland) and an investigator-initiated grant from BASF Corporation (Florham Park, New Jersey). Study agents and packaging were provided by BASF Corporation, Wyeth Pharmaceuticals (Madison, New Jersey), and DSM Nutritional Products Inc (formerly Roche Vitamins) (Parsippany, New Jersey).

Role of the Sponsor: BASF Corporation, Wyeth Pharmaceuticals, and DSM Nutritional Products Inc had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Data and Safety Monitoring Board: Voting members included Lawrence Cohen, Theodore Colton, I. Craig Henderson, Ross Prentice, and Nanette Wenger (chair); ex-officio members included Frederick Ferris, Peter Greenwald, Natalie Kurinij, Howard Parnes, Eleanor Schron, and Alan Zonderman.

Disclaimer: Dr Gaziano, a contributing editor for JAMA, was not involved in the editorial review of or decision to publish this article.

Additional Contributions: We are indebted to the 14 641 physician participants for their long-standing dedication and conscientious collaboration. We also acknowledge the long-term contributions of Charles Hennekens, MD, DrPH, Florida Atlantic University, to the Physicians' Health Study, and the exemplary contributions of the staff of the Physicians' Health Study at Brigham and Women's Hospital, under the leadership of Charlene Belanger: Kenneth Breen, Mary Breen, Mary G. Breen, Jose Carrion, Ivan Fitchorov, Natalya Gomelskaya, Beth Holman, Andrea Hrbek, Tony Laurinaitis, Chandra McCarthy, Geneva McNair, Leslie Power, Philomena Quinn, Harriet Samuelson, Miriam Schvartz, Fred Schwerin, Michelle Sheehey, Joanne Smith, Martin Van Denburgh, and Phyllis Johnson Wojciechowski. Finally, we are grateful for the efforts of the Physicians' Health Study Endpoint Committee, including Samuel Goldhaber, Carlos Kase, Meir Stampfer, and James Taylor, over the course of the Physicians' Health Study II. Each named individual was compensated for his or her contribution as part of the grant support.

JAMA: The Journal of the American Medical Association 301(1):p 52-62, January 7, 2009.

Context

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. 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.

Objective

To evaluate whether long-term vitamin E or C supplementation decreases risk of prostate and total cancer events among men.

Design, Setting, and Participants

The Physicians' Health Study II is a randomized, double-blind, placebo-controlled factorial trial of vitamins E and C that began in 1997 and continued until its scheduled completion on August 31, 2007. A total of 14 641 male physicians in the United States initially aged 50 years or older, including 1307 men with a history of prior cancer at randomization, were enrolled.

Intervention

Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily.

Main Outcome Measures

Prostate and total cancer.

Results

During a mean follow-up of 8.0 years, there were 1008 confirmed incident cases of prostate cancer and 1943 total cancers. Compared with placebo, vitamin E had no effect 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). There was also no significant effect of vitamin C on 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 had a significant effect on colorectal, lung, or other site-specific cancers. Adjustment for adherence and exclusion of the first 4 or 6 years of follow-up did not alter the results. Stratification by various cancer risk factors demonstrated no significant modification of the effect of vitamin E on prostate cancer risk or either agent on total cancer risk.

Conclusions

In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer. These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men.

Trial Registration

clinicaltrials.gov Identifier: NCT00270647

Published online December 9, 2008 (doi:10.1001/jama.2008.862).