Vitamin C and Vitamin E Supplement Use and Colorectal Cancer Mortality in a Large American Cancer Society Cohort Eric J. Jacobs, 1 Cari J. Connell, Alpa V. Patel, Ann Chao, Carmen Rodriguez, Jennifer Seymour, Marjorie L. McCullough, Eugenia E. Calle, and Michael J. Thun Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia 30329-4251 Abstract Some recent epidemiological studies have suggested that use of vitamin C or vitamin E supplements, both of which are important antioxidants, may substantially reduce the risk of colon or colorectal cancer. We examined the association between colorectal cancer mortality and use of individual vitamin C and E supplements in the American Cancer Society’s Cancer Prevention Study II cohort. We used proportional hazards modeling to estimate rate ratios among 711,891 men and women in the United States who completed a self-administered questionnaire at study enrollment in 1982, had no history of cancer, and were followed for mortality through 1996. During the 14 years of follow-up, 4404 deaths from colorectal cancer occurred. After adjustment for multiple colorectal cancer risk factors, regular use of vitamin C or E supplements, even long- term use, was not associated with colorectal cancer mortality. The combined-sex rate ratios were 0.89 [95% confidence interval (CI), 0.73–1.09] for 10 or more years of vitamin C use and 1.08 (95% CI, 0.85–1.38) for 10 or more years of vitamin E use. In subgroup analyses, use of vitamin C supplements for 10 or more years was associated with decreased risk of colorectal cancer mortality before age 65 years (rate ratio  0.48; 95% CI, 0.28 – 0.81) and decreased risk of rectal cancer mortality at any age (rate ratio  0.40; 95% CI, 0.20 – 0.80). Our results do not support a substantial effect of vitamin C or E supplement use on overall colorectal cancer mortality. Introduction Vitamin C and vitamin E, both important antioxidants, may reduce the risk of cancer by neutralizing reactive oxygen spe- cies or other free radicals that can damage DNA (1–3). With respect to colorectal cancer, vitamin C and E inhibit colorectal cancer in rodent models (4 – 6), and supplementation with vi- tamin C or E decreases fecal mutagenicity in humans (7). If vitamin C or E supplement use substantially reduces the risk of colorectal cancer, there could be important public health im- plications because vitamin supplements are relatively inexpen- sive and easy to use and because colorectal cancer is the third most common cause of cancer death in men and women in the United States (8). Only three prospective studies have exam- ined the association between colon or colorectal cancer and use of vitamin C or E supplements (9 –11). Some results from these prospective studies suggest a reduction in risk, particularly for vitamin E supplementation. However, none of these studies reported results by duration of vitamin supplement use. We therefore examined the association between colorectal cancer mortality and the use of individual vitamin C or E supplements, particularly long-term use, in a large prospective study of adults in the United States. This analysis focuses on vitamin C or E intake specifically from individual vitamin C or E supplements, rather than intake from diet, multivitamins, or from all sources combined. Most individual vitamin C or E supplements contain doses several times greater than those typically obtained from diet or multi- vitamins. Materials and Methods Study Cohort and Follow-Up. Subjects in this analysis were drawn from the 508,351 male participants and 676,306 female participants in CPS-II. 2 These participants were enrolled in 1982 by American Cancer Society volunteers in all 50 states of the United States, the District of Columbia, and Puerto Rico as described previously (12). Participants completed a four-page baseline self-administered questionnaire in 1982 that included information on demographic characteristics and various behav- ioral, environmental, occupational, and dietary factors. The median age at enrollment was 57 years for men and 56 years for women; no participants were younger than 30 years. The vital status of study participants was determined through December 31, 1996 using two approaches. American Cancer Society volunteers made personal inquiries in Septem- ber 1984, 1986, and 1988 to determine whether the participants they had enrolled were alive or dead and to record the date and place of all deaths. Reported deaths were verified by obtaining death certificates. Automated linkage using the National Death Index (13) extended follow-up of the entire cohort through December 31, 1996 and identified deaths among the 21,704 participants lost to follow-up between 1982 and 1988. At the completion of follow-up in December 1996, 237,452 partici- pants had died (20.0%), 944,313 were alive (79.7%), and 2,892 (0.2%) had follow-up truncated on September 1, 1988 because of insufficient data for National Death Index linkage. Death certificates or codes for cause of death were obtained for 98.6% Received 4/19/00; revised 10/12/00; accepted 10/17/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at Department of Epide- miology and Surveillance Research, American Cancer Society, National Home Office, 1599 Clifton Road NE, Atlanta, GA 30329-4251. 2 The abbreviations used are: CPS-II, Cancer Prevention Study II; RR, rate ratio; CI, confidence interval; BMI, body mass index; OR, odds ratio. 17 Vol. 10, 17–23, January 2001 Cancer Epidemiology, Biomarkers & Prevention on March 8, 2016. © 2001 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from