Is ursodeoxycholic acid effective for the prevention of colorectal adenoma recurrence?
- Sinicrope, Frank
SYNOPSIS
BACKGROUND
In rodent studies, ursodeoxycholic acid (UDCA) markedly reduces the development of carcinogen-induced colonic adenomas and carcinomas.
OBJECTIVES
To assess the ability of UDCA to prevent the recurrence of sporadic colorectal adenomas in humans.
DESIGN AND INTERVENTION
This phase III, double-blind, multicenter, placebo-controlled trial enrolled patients who had undergone the removal of at least one colorectal adenoma that was ≥3 mm in diameter within the previous 6 months. Eligible patients were required to have all colon polyps removed, excluding diminutive (<3 mm) rectal sessile polyps. Following a 4-week placebo run-in period, participants were randomized to treatment with either a daily dose of UDCA (Novartis, East Hanover, NJ) 8-10 mg/kg or placebo for 3 years, or until follow-up colonoscopy was performed (within 6 months of study completion). Adenoma recurrence was defined as the occurrence of at least one new colorectal adenoma or adenocarcinoma >6 months after the initial qualifying colonoscopy. Endoscopic surgical resection, and histopathology reports taken during follow-up were used to determine adenoma recurrence. High-grade dysplasia was identified by central pathology review. Adverse events were recorded every 3-4 months. In those patients who consented, a 72 hr stool sample was collected at baseline and at the end of the study to measure the concentration of bile acids.
OUTCOME MEASURES
The primary endpoint was recurrence of adenoma. Secondary endpoints included recurrence of advanced adenoma (defined as >10 mm, any villous histology, or high-grade dysplasia), polyp location, fecal bile-acid concentration, and incidence of adverse events.
RESULTS
A total of 1,285 patients were randomized to treatment with UDCA or placebo: 661 patients and 624 patients, respectively. Of these patients, 1,192 (92.8%) underwent at least one colorectal evaluation ≥6 months postrandomization and were included in the final analysis; 613 patients from the UDCA group and 579 from the placebo group. The adenoma recurrence rate was reduced in the UDCA group compared with the placebo group but did not reach statistical significance (recurrence ratio 0.88, 95% CI 0.73-1.05, P = 0.15). Recurrence of adenomas with high-grade dysplasia was significantly reduced in patients receiving treatment with UDCA compared with placebo (adjusted odds ratio 0.61, 95% CI 0.39-0.96, P = 0.03). Adenoma size, villous histology, and location did not differ significantly between treatment groups. The amount of deoxycholic acid (DCA) in the feces was significantly reduced in patients receiving UDCA treatment compared with placebo (median ratio of DCA to total bile acids was 0.33 and 0.51 in the UDCA and placebo groups, respectively; P < 0.001). The incidence of diarrhea (all grades) was significantly increased in patients receiving UDCA compared with placebo (69 patients [10.55%] versus 40 patients [6.41%]; P = 0.01).
CONCLUSION
UDCA treatment was associated with a statistically nonsignificant reduction in colorectal adenoma recurrence. Recurrence of adenomas with high-grade dysplasia was, however, significantly reduced by treatment with UDCA.