High-Dose Folic Acid in Preventing Colorectal Cancer in Patients Who Have Had Polyps Surgically Removed

OBJECTIVES: I. Determine whether high-dose folic acid decreases global DNA hypomethylation,
as well as other intermediary markers, in normal-appearing colonic epithelium of patients
with colonic adenomas. II. Determine whether a decrease in global DNA hypomethylation and
other intermediary markers can be induced safely and whether these effects persist after
folic acid is discontinued in these patients. III. Confirm pilot data that indicates patients
with adenomas have widespread DNA hypomethylation of the colorectal mucosa compared to
controls. IV. Evaluate the effect of folic acid on the clinical course and rate of recurrence
of adenomatous polyps in these patients. V. Study a control group of patients with no history
of neoplastic, hyperplastic, or inflammatory colorectal lesions.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients
are stratified according to participating center and age (50-70 vs 30-49 and over 70).
Patients with adenomatous polyps at least 10 mm at colonoscopy are randomized to 1 of 2
treatment arms. Patients found to have no neoplastic, hyperplastic, or inflammatory polyps at
colonoscopy are assigned to a control (untreated) group and complete laboratory studies and a
baseline food frequency questionnaire only. Arm I: Patients receive folic acid daily. Arm II:
Patients receive placebo daily. Treatment continues in both arms for 1 year in the absence of
unacceptable toxicity or disease progression. Patients are followed at 1 year.

PROJECTED ACCRUAL: A total of 80 patients (30 per arm and 20 for the control group) will be
accrued for this study within 24 months.

DISEASE CHARACTERISTICS: Colonic adenoma(s) of at least 10 mm completely resected within 18
months prior to randomization or suspected adenomatous polyp(s) Colonoscopy with submission
of at least 7 rectosigmoid biopsies required at entry No benign hyperplastic polyps or
polyps less than 10 mm to be eligible for treatment No polyposis coli (i.e., more than 100
polyps in colon) No history of invasive colorectal cancer

PATIENT CHARACTERISTICS: Age: 21 and over Performance status: ECOG 0-2 Life expectancy: Not
specified Hematopoietic: Platelet count greater than 100,000/mm3 Hemoglobin greater than 10
g/dL No untreated pernicious anemia Hepatic: Bilirubin less than 2 mg/dL ALT less than 2
times normal Alkaline phosphatase less than 2 times normal PT normal Renal: Not specified
Gastrointestinal: No intestinal malabsorption No inflammatory bowel disease Other: No
seizure within the past year No poor medical risk No other malignancy within past 5 years
except basal cell cancer, superficial skin cancer, or carcinoma in situ of the cervix No
vitamin B12 deficiency (less than 200 pg/mL) Not pregnant or nursing Fertile patients must
use effective barrier contraception

PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No concurrent
methotrexate Endocrine therapy: Not specified Radiotherapy: Not specified Surgery: See
Disease Characteristics No prior small bowel resection Other: No concurrent anticonvulsants
No concurrent drugs that markedly interfere with folate absorption or metabolism (e.g.,
sulfasalazine and phenytoin) No concurrent vitamins during and for 2 years after beginning
of study