Folate-Depleted Diet Compared With Folate-Supplemented Diet in Preventing Colorectal Cancer in Patients at High Risk for Colorectal Cancer

Phase I Clinical Study of Folate

RATIONALE: Chemoprevention therapy is the use of certain agents to try to prevent the development of cancer. The use of folic acid may be effective in preventing colorectal cancer. Eating a diet rich in folic acid may prevent the development of colorectal cancer.

PURPOSE: This randomized phase I trial is studying how well a folate-depleted diet works compared to a folate-supplemented diet in preventing colorectal cancer in patients who are at high risk for developing colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Dietary supplement: dietary intervention; Dietary supplement: folic acid

Detailed Description

OBJECTIVES:

Primary

• Analyze the effects of a folate-depleted vs a folate-supplemented diet on folate-related DNA endpoints (e.g., genomic and gene-specific DNA methylation and DNA strand breaks) in rectal epithelial cells in patients at high risk for colorectal neoplasia.
• Analyze the effects of these dietary interventions on folate-related DNA endpoints (e.g., genomic and gene-specific DNA methylation, DNA strand breaks, and uracil incorporation into DNA) in blood mononuclear cells in these patients.

Secondary

• Analyze the effects of these dietary interventions on the patterns of differential gene expression in rectal epithelial cells and blood mononuclear cells in these patients.

OUTLINE: This is a randomized, single-blind study.

• Run-in period: Patients are placed on an average folate-containing diet for 56 days.

• Randomization: After completion of the run-in period, patients are randomized to 1 of 2 arms.

  • Arm I (folate depleted diet): Patients are placed on a low-folate diet for 84 days. Patients receive oral folic acid supplementation once daily on days 57-84.
  • Arm II (folate supplemented diet): Patients continue on an average folate-containing diet for an additional 56 days. Patients receive oral folic acid supplementation once daily on days 1-56.

Patients are followed at 4 weeks.

PROJECTED ACCRUAL: A total of 20 patients (10 per arm) will be accrued for this study within 2.5 years.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 72 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Healthy persons at increased risk for colorectal neoplasia due to 1 of the following reasons:

  • Personal history of colorectal adenomatous polyps
  • Family history of colorectal adenoma or adenocarcinoma
• No history of multiple family members with colorectal neoplasia that is suggestive of dominant hereditary neoplasia

PATIENT CHARACTERISTICS:

Age

• 40 to 72

Performance status

• Ambulatory

Life expectancy

• At least 6 months

Hematopoietic

• No excessive bleeding or coagulation disorder

Hepatic

• ALT or AST ≤ 2 times upper limit of normal
• No unexplained elevated alkaline phosphatase

Renal

• Creatinine ≤ 2.0 mg/dL

Cardiovascular

• Homocysteine concentration ≤ 17um/L
• No sustained blood pressure > 150/95 mm Hg for 3 consecutive readings

Other

• Vitamin B_12 ≥ 250 pg/mL
• Folate level ≤ 20 mg/dL
• HIV negative
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 4 weeks after study participation
• No intestinal malabsorption or inflammatory bowel disease
• No prior malignancy except nonmelanoma skin cancer
• No calcium metabolism abnormalities or predisposing conditions, such as hyperparathyroidism
• No untreated hyperthyroidism
• No untreated insulin-requiring diabetes mellitus
• No daily alcohol intake > 2 ½ shot glasses of whiskey or three 8 ounce glasses of beer or wine
• No other serious illness that might limit life expectancy to < 6 months

PRIOR CONCURRENT THERAPY:

Biologic therapy

• None

Chemotherapy

• None

Endocrine therapy

• No concurrent hormone replacement therapy, including oral, transplanted, or injected contraceptives
• Concurrent thyroid hormone replacement is allowed as long as the patient is euthyroid for 3 months

Radiotherapy

• None

Surgery

• No prior gastrointestinal surgery, including gastrectomy or small or large bowel resections

  • Prior appendectomy or surgery of the esophagus allowed

Other

• More than 3 months since regular ingestion of ≥ 650 mg per day of aspirin (≥ 2 tablets of 325 mg regular strength OR > 1 tablet of 500 mg extra strength aspirin)
• More than 3 months since regular daily ingestion of nonsteroidal anti-inflammatory drugs
• At least 1 month since vitamin, mineral, or herbal supplementation
• No other concurrent vitamin, mineral, or herbal supplementation
• No concurrent anticoagulants
• No concurrent sterol-binding resins (i.e., cholestyramine)
• No other concurrent investigational drugs or medications that might alter rectal mucosal proliferation, folate metabolism, or renal/hepatic impairment
• No concurrent weight control medications
• No concurrent supplemental folate preparations containing > 400 mcg of folic acid per day

• No concurrent lipid-lowering medications

  • The following concurrent statin drugs are allowed provided patient has been taking a stable dose for ≥ 1 month:

    • Atorvastatin 10 or 20 mg/day
    • Fluvastatin 20 or 40 mg/day
    • Lovastatin 10 or 20 mg/day
    • Pravastatin 10 or 20 mg/day
    • Simvastatin 5 or 10 mg/day

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
•Analyze the effects of a folate-depleted vs a folate-supplemented diet on folate-related DNA endpoints	pre and post treatment

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: James Marshall, PhD, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start: September 1, 2004
• Primary Completion (Actual): February 1, 2007
• Study Completion (Actual): March 1, 2008

Study Registration Dates

• First Submitted: November 9, 2004
• First Submitted That Met QC Criteria: November 8, 2004
• First Posted (Estimate): November 9, 2004

Study Record Updates

• Last Update Posted (Estimate): January 13, 2014
• Last Update Submitted That Met QC Criteria: January 10, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: rectal cancer; colon cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Hematinics; Folic Acid
• Other Study ID Numbers: CDR0000393455; P30CA016056 (U.S. NIH Grant/Contract); RUH-PHO-0514-0404; RPCI-EPR-20703; AECM-0401022E; NEMCH-6060