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

Abstract

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.More than 50,000 people in the United States will die in 2007 from colorectal cancer. In the United States, cancer is the leading cause of death in people under age 74 years (1), and colorectal cancer is the second most common cause of cancer deaths after lung cancer (2). Colorectal cancer may be prevented by removal of precursor adenomas found during screening sigmoidoscopy or colonoscopy (3), although rates are variable and range from 30% to 90% depending highly on reimbursement policies (4, 5).Diet and inflammation have been associated with risk of colorectal cancer (6), and a series of clinical trials have been conducted to test the efficacy of individual dietary supplements or anti-inflammatory agents to prevent the incidence or recurrence of colon polyps (7-14). Unfortunately, these trials have not translated into significant changes in medical practice for prevention or management of colon cancer for a variety of reasons, including lack of efficacy, unacceptable toxicities, and the availability of competing strategies for risk reduction (15).Studies in rodent models have shown that combination chemoprevention strategies are often more effective than those using individual agents (16,17). Difluoromethylornithine (DFMO) has been identified as a potent inhibitor of intestinal and colon carcinogenesis in animal models, especially in combination with nonsteroidal anti-inflammatory drugs (18)(19)(20). DFMO and the n...

Evaluation of Difluoromethylornithine for the Chemoprevention of Barrett's Esophagus and Mucosal Dysplasia

“…A recent randomized trial showed that the combination of DFMO and the nonsteroidal anti-inflammatory drug (NSAID) sulindac was associated with a 70% reduction in the recurrence of sporadic colorectal adenomas (13). This study lends further support for the evaluation of DFMO as an inhibitor of epithelial carcinogenesis.…”

Update on Cancer Prevention Research in the United States and China: The 2009 China—U.S. Forum on Frontiers of Cancer Research

“…Unfortunately, the use of celecoxib has been associated with an increased risk of adverse cardiovascular effects (24). Notably, low doses of the antiinflammatory sulindac and an investigational compound difluoromethylornithine (DFMO) prevented colon polyp recurrence by 70% and the recurrence of advanced adenomas by 92% in a recent phase III trial (25). These results clearly demonstrate the idea of combination prevention or therapy or convergent prevention and therapy, which will be discussed later in this perspective.…”

Perspective: The big C — for Chemoprevention

“…The Food and Drug Administration still forbids the use of two experimental drugs in clinical prevention trials, in spite of the fact that there is overwhelming evidence that combinations can be much safer and more effective than single agents 7 . Further appreciation and understanding of the concept of 'risk' is also essential.…”