The combination of low-dose difluoromethylornithine and sulindac reduced the risk for recurrent colorectal adenomas so dramatically that a phase III trial was stopped early, according to a presentation at the annual meeting of the American Association for Cancer Research.

Difluoromethylornithine is a targeted agent, whereas sulindac is a non-steroidal anti-inflammatory drug.

"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, MD, 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 difluoromethylornithine that was 2 percent of what would typically be used to treat advanced cancers. The current trial was designed to test the combination of reduced-dose difluoromethylornithine with sulindac.

In the current phase III trial, researchers enrolled 375 patients with a history of at least one colorectal polyp in the previous five years. Patients were randomized to a combination of 500 mg difluoromethylornithine daily and 150 mg sulindac or to placebo.

At three years, the risk of a recurrent adenoma from 41.1 percent for placebo and 12.3 percent with combination treatment, a 70 percent reduction for the active treatment arm. When researchers measured advanced adenomas only, the rate was 8.5 percent with placebo compared with 0.7 percent with treatment, a 92 percent reduction.

For adenomas larger than one centimeter, the rate was 7 percent with placebo compared with 0.7 percent with treatment, a 90 percent reduction. Among patients who had previously had more than one adenoma, the rate of subsequent adenomas was 13.2 percent with placebo compared with 0.7 percent with treatment, 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.