Current issues of ACP Journal Club are published in Annals of Internal Medicine


Etiology

Long-term dietary folate was associated with a decreased risk for colon cancer in women

ACP J Club. 1999 Mar-April;130:51. doi:10.7326/ACPJC-1999-130-2-051


Source Citation

Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med. 1998 Oct 1;129:517-24.


Abstract

Question

Is folate intake from diet or dietary supplements associated with a decreased risk for colon cancer in women?

Design

Population-based cohort study of women in the Nurses' Health Study with 14-year follow-up.

Setting

United States.

Participants

88 756 female nurses who were 30 to 55 years of age in 1976. Exclusion criteria were cancer other than non-melanoma skin cancer, ulcerative colitis, familial polyposis syndrome, implausibly high or low scores for total energy intake, and missing questionnaire data.

Assessment of risk factors

Nurses completed mailed questionnaires at baseline and every 2 years thereafter. Food-frequency questionnaires included information on 61 foods and beverages and vitamin and mineral supplements. For analysis, nurses were divided into quartiles based on folate intake in 1980 (≤ 200, 201 to 300, 300 to 400, and > 400 µg/d), with the lowest level given the relative risk (RR) of 1.0. Baseline data also included information on age, weight, height, smoking history, physical activity, aspirin use, colonoscopy or sigmoidoscopy, and parental history of colorectal cancer. These variables were used for adjustment of data along with consumption of red meat, alcohol, and fiber and total energy intake.

Main outcome measures

Self-reported cases of colon or rectal cancer subsequently confirmed by blinded assessment of hospital records and pathology reports.

Main results

During follow-up, 655 cases of confirmed colorectal adenocarcinoma were reported (442 in the colon, 224 in the distal colon, 143 in the rectum, and 70 at undetermined sites). Women in the highest quartile of use had a decreased risk for colon cancer (RR 0.69, 95% CI 0.52 to 0.91). Adjustments of the data for combinations of baseline variables did not change this result substantially. Use of supplements containing > 100 µg of folic acid for ≥ 15 years was associated with a greater decrease in risk for all colon cancer (RR 0.21, CI 0.05 to 0.84); for proximal colon cancer (RR 0.16, CI 0.06 to 0.52); and for distal colon cancer (RR 0.37, CI 0.15 to 0.90).

Conclusions

Folate intake from diet or dietary supplements was associated with a decreased risk for colon cancer in women. Long-term use of folate-containing dietary supplements showed greater decreases in risk.

Source of funding: In part, National Institutes of Health.

For correspondence: Dr. E. Giovannucci, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USA. FAX 617-432-2435.


Commentary

Colon cancer occurs when a mucosal cell and progeny, which are gradually accumulating mutations in replication-control genes, finally achieve pernicious immortality. The basis for these mutations remains unclear, but most epidemiologic studies suggest that diets high in fats and low in fruits and vegetables favor carcinogenesis (1). Because fruits and vegetables are the primary source of folic acid, folate itself may prevent colon cancer. This does not mean that colon cancer arises from traditional folate deficiency. However, recognition of tissue-specific folate deficiency (2) and that vitamins and other compounds have the potential for additional biological effects at high doses (3) suggests that folate ingestion beyond recommended dietary allowances may indeed reduce the risk for colon cancer.

In the study by Giovannucci and colleagues, women with the highest levels of folate intake (levels that required vitamin supplementation) showed the lowest risk for cancer. Whether the same effect could have been achieved with dietary folate alone is not addressed, but it seems likely that the 1 L of raw chopped spinach or the 600 mL of boiled lima beans required to obtain the 400 µg of folate—issues of bioavailability aside—would be difficult to consume on a daily basis.

Although the other risk factors studied did not correlate with protection, previous work has suggested that vitamin E intake correlates inversely with the risk for colonic adenoma (4). It remains possible, therefore, that the combination of nutrients, rather than folate alone, is implicated in the decreased risk for colon cancer. These data probably pertain to men as well as women.

When the evidence is tantalizing, the disease dire, and the intervention inexpensive and safe as this study shows, I think multivitamin supplementation that includes folate should now be among the preventive measures physicians advocate, even as work elucidating the root cause of colon cancer continues.

Joseph M. Alcorn, MD
University of New MexicoPresbyterian/St. Joseph's HospitalsAlbuquerque, New Mexico, USA


References

1. Slattery ML, Boucher KM, Caan BJ, Potter JD, Ma KN. Eating patterns and risk of colon cancer. Am J Epidemiol. 1998;148:4-16.

2. Meenan J, O'Hallinan E, Scott J, Weir DG. Epithelial cell folate depletion occurs in neoplastic but not adjacent normal colon mucosa. Gastroenterology. 1997;112:1163-8.

3. Goodwin JS, Tangum MR. Battling quackery: attitudes about micronutrient supplements in American academic medicine. Arch Intern Med. 1998;158:187-91.

4. Tseng M, Murray SC, Kupper LL, Sandler RS. Micronutrients and the risk of colorectal adenomas. Am J Epidemiol. 1997;144:1005-14.