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Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial

Authors' Affiliations: ¹ Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California; ² Arizona Cancer Center, University of Arizona, Tucson, Arizona; ³ Department of Veterans Affairs Long Beach Healthcare System, Long Beach, California; ⁴ Loma Linda University, Loma Linda, California; ⁵ University of Michigan, Ann Arbor, Michigan; ⁶ Denver Department of Veteran Affairs Medical Center and University of Colorado, Denver, Colorado; ⁷ Kaiser Permanente, Sacramento, California; ⁸ University of Kansas, Kansas City, Kansas; and ⁹ National Cancer Institute, Bethesda, Maryland

Requests for reprints: Frank L. Meyskens, Jr., UCI Cancer Center, Building 44, Route 81, 101 City Drive Cancer Center Orange CA 92668. Phone: 714-456-6310; Fax: 1-714-456-2240; E-mail: flmeyske{at}uci.edu.

Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade 3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.

Commentary

Clinical Prevention of Recurrence of Colorectal Adenomas by the Combination of Difluoromethylornithine and Sulindac: An Important Milestone

Michael B. Sporn and Waun Ki Hong
Cancer Prevention Research 2008 1: 9-11. [Full Text] [PDF]