Colorectal cancer continues as the second leading cause of cancer death in the United States with 53,000 deaths in 1993. There is continuing controversy concerning the potential role of dietary fiber in the prevention of colon cancer. The results of animal studies, human epidemiologic studies, and mechanisms of action evaluations strongly suggest an inverse relationship between wheat bran fiber intake and colon adenoma and cancer incidence. Furthermore, high intakes of wheat bran fiber in both experimental carcinogenesis animal models and human metabolic epidemiology studies has been associated with significant reductions in fecal secondary bile acids, especially deoxycholic acid which is a well documented colon tumor promoting agent. Results of two relatively small, randomized Phase III intervention studies have been published. De Cosse et al. found that fiber supplementation in excess of 11 gm/day reduced the incidence of polyp recurrence in their study of 58 patients with familial adenomatous polyposis. A preliminary analysis of a study by Macrae and MacLennan in 400 patients with resected adenomatous polyps suggested that wheat bran fiber supplementation is associated with a significant reduction in recurrent adenoma size and degree of dysplasia. In our previous study of wheat bran fiber and calcium supplementation in 100 patients with resected colonic polyps we found high dose wheat bran fiber (13.5 gm/d) significantly reduced fecal total, primary, and secondary (including deoxycholic acid) bile acid concentrations and excretion rates at 9 months of supplementation as compared to baseline and 3 month levels. Our current, double-blind, placebo controlled Phase III cancer control study has been designed to measure the effects of wheat bran fiber supplementation (13.5 gm/d vs 2.0 gm/d X 3 years) on adenoma recurrence (at the year one and three year colonoscopies), epithelial cell proliferation (as measured by proliferating cell nuclear antigen or PCNA Labeling Index), fecal and plasma bile acid concentrations, and protein kinase C isotype expression and enzyme activity. To date more than 1550 patients with a history of a resected adenomatous polyp (within three months of diagnosis and consent) have been accrued and 1250 patients have been randomized to one of the two arms. Patient accrual is ongoing until Fall 1994 to achieve 950 fully evaluable patients who will undergo the year three colonoscopy while on-study. Rectal mucosal biopsy samples have been obtained from a 25% subset of randomized patients at baseline, and will be repeated at one, two, and three years of follow-up for PCNA LI and PKC isotype expression and enzyme activity. The wheat bran fiber supplements have been well tolerated with excellent patient compliance although non-cereal eaters have proven difficult study participants. This Project Protocol outlines the background, significance, aims, procedures, and progress of our Phase III wheat bran fiber trial in patients with resected adenomatous polyps.
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