SAN DIEGO -- A combination of the targeted agent difluoromethylornithine (DFMO) at a low dose and sulindac, a non-steroidal anti-inflammatory drug (NSAID), reduces the risk of recurrent colorectal adenomas, an early sign of colon cancer, by up to 95 percent with less toxicity than with chemotherapy, researchers report.
“There is a great hope that we will be able to prevent colon cancer effectively using this method. We had not been able to do this before due to the high toxicity of available therapies. Difluoromethylornithine is a targeted agent that represents a new treatment paradigm,” said Frank Meyskens, M.D., director of the Cancer Center at the University of California at Irvine.
In earlier studies, Meyskens’s team had established a safe and well-tolerated dose of DFMO that was 1/50th of what would typically be used to treat advanced cancers. By combining this reduced dose of DFMO with sulindac researchers believed they could achieve a significant clinical effect with reduced toxicity.
For the current study, researchers enrolled 375 patients who had a history of at least one colorectal polyp within the previous five years. Patients were randomly assigned to either a combination of 500 mg of daily DFMO and 150 mg of the NSAID sulindac, or placebo. Patients were followed for three years to measure adenoma recurrence.
Overall, the combination treatment reduced the risk of a recurrent adenoma from 41.1 percent in the placebo group to 12.3 percent with treatment, a 70 percent reduction.
When researchers measured advanced adenomas only, the rate was 8.5 percent in the placebo group compared with 0.7 percent in the treatment group, a 92 percent reduction.
For adenomas larger than one centimeter, the rate was 7 percent in the placebo group compared with 0.7 percent in the treatment group, a 90 percent reduction. Among patients who had previously had more than one adenoma, the rate of subsequent adenomas was 13.2 percent in the placebo group compared with 0.7 percent in the treatment group, a 95 percent reduction.
The rate of reduction was so pronounced that the trial’s independent data and safety monitoring board stopped the trial early.
An analysis of side effects and toxicity found no difference between the treatment and placebo groups. There was no difference in side effects requiring an overnight hospitalization, gastrointestinal side effects, cardiovascular side effects, or hearing loss between the two groups.
“These are important findings, but they are not ready for prime time yet. What we have shown here is that there is value in testing these agents at lower doses and in combination to determine if we can achieve the same effect without the damaging side effects,” Meyskens said.
Marked efficacy of difluoromethylornithine plus sulindac in reducing recurrent colorectal adenomas in patients with prior adenomas: results of a randomized, placebo-controlled double-blind phase III trial: Abstract LB-142
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