Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials

Abstract

Observational data suggest that lower folate status is associated with an increased risk of colorectal neoplasia, implying that folate may be useful as a chemopreventive agent. We conducted a combined analysis of three large randomized trials of folic acid supplementation for the prevention of metachronous adenomas in patients with an adenoma history. Participants included 2,632 men and women who had a history of adenomas randomized to either 0.5 or 1.0 mg/day of folic acid or placebo and who had a follow-up endoscopy 6 to 42 months after randomization [mean = 30.6 (standard deviation = 8.1) months]. We used random-effects meta-analysis to estimate risk ratios (RRs) and 95% confidence intervals (CIs). The RR comparing folic acid versus placebo was 0.98 (95% CI = 0.82-1.17) for all adenomas and 1.06 (95% CI = 0.81-1.39) for advanced lesions. Folic acid was associated with a nonsignificant decreased risk of any adenoma among subjects in the lowest quartile of baseline plasma folate (≤ 11 nmol/L) and no effect among individuals in the highest quartile (> 29 nmol/L, p for trend = 0.17). There was a nonsignificant trend of decreasing risk of any adenoma associated with folic acid supplements with increasing alcohol intake. During the early follow-up reported here, more deaths occurred in the placebo group than in the folic acid group (1.7% vs. 0.5%, p = 0.002). In conclusion, after up to 3.5 years of folic acid use, there is no clear decrease or increase in the occurrence of new adenomas in patients with a history of adenoma.

Figure 1

Random-effects meta-analysis comparing folic acid versus placebo after a follow-up of 42 months. Estimates are unadjusted. Tests for heterogeneity are as follows: For any adenoma, Q=3.34 (P=0.19) and I²=70.0. For advanced lesion, Q=2.04 (P=0.36) and I²=2.0. AFPPS, Aspirin/Folate Polyp Prevention Study; NHS/HPFS, Nurses’ Health Study/Health Professional Follow-up Study; ukCAP, United Kingdom Colorectal Adenoma Prevention.

Figure 2

Random-effects meta-analysis comparing folic acid versus placebo for the endpoints of 3 or more adenomas, adenomas greater than or equal to 1 cm in estimated diameter and location in the colorectum. Estimates are unadjusted. Tests for heterogeneity are as follows: For >=3 adenomas, Q=0.99 (P=0.61) and I²=0.0; adenomas >= 1cm, Q=2.30 (P=0.32) and I²=13.0; rectal adenoma Q=2.19 (P=0.33) and I²=8.7; distal adenoma Q=5.32 (P=0.70) and I²=62.4 proximal adenoma Q=3.09 (P=0.21) and I²=35.3. Proximal adenomas include those in the transverse colon, hepatic flexure, ascending colon and cecum; distal adenomas include those in the sigmoid colon, descending colon and splenic flexure. AFPPS, Aspirin/Folate Polyp Prevention Study; NHS/HPFS, Nurses’ Health Study/Health Professional Follow-up Study; ukCAP, United Kingdom Colorectal Adenoma Prevention.

Figure 3

Random-effects meta-analysis comparing folic versus placebo by subgroups (all exams) for any adenoma. Estimates are unadjusted. P values are from tests for heterogeneity between groups for categorical variables (sex, family history of colorectal cancer, number of adenomas at baseline, advanced lesion at baseline, and aspirin treatment) and tests for trend for ordinal variables (age, BMI, smoking status, alcohol, dietary folate and plasma folate). Analysis of aspirin treatment group was restricted to the AFPPS and ukCAP trials and the analysis of plasma folate was restricted to the AFPPS and NHS/HPFS trials. AFPPS, Aspirin/Folate Polyp Prevention Study; NHS/HPFS, Nurses’ Health Study/Health Professional Follow-up Study; ukCAP, United Kingdom Colorectal Adenoma Prevention.

Figure 4

Random-effects meta-analysis comparing folic acid versus placebo by subgroups (all exams) for advanced adenoma. Estimates are unadjusted. P values are from tests for heterogeneity between groups for categorical variables (sex, family history of colorectal cancer, number of adenomas at baseline, advanced lesion at baseline, and aspirin treatment) and tests for trend for ordinal variables (age, BMI, smoking status, alcohol, dietary folate and plasma folate). Analysis of aspirin treatment group was restricted to the AFPPS and ukCAP trials and the analysis of plasma folate was restricted to the AFPPS and NHS/HPFS trials. AFPPS, Aspirin/Folate Polyp Prevention Study; NHS/HPFS, Nurses’ Health Study/Health Professional Follow-up Study; ukCAP, United Kingdom Colorectal Adenoma Prevention.