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A UA researcher and others announced today that a specific drug combination has been shown to reduce the risk of a precursor to colon cancer by up to 95 percent.

By University Communications
April 14, 2008

An experimental drug combination tested by a University of Arizona researcher and others has been found to reduce the risk of recurrent colorectal polyps, a precursor to colon cancer, by up to 95 percent with minimal toxicity.

Participants in the study were given a combination of a low dosage of the targeted agent difluoromethylornithine, or DFMO, and sulindac, a non-steroidal anti-inflammatory drug, known as NSAID.

“Combination chemoprevention with DFMO and sulindac can substantially reduce colon polyp recurrence, especially those polyps associated with the greatest risk of colorectal cancer,” said Dr. Eugene W. Gerner, director of the Arizona Cancer Center’s Gastrointestinal Cancer Program and the National Cancer Institute-funded Specialized Program of Research Excellence, known as SPORE, in Gastrointestinal Cancers at The University of Arizona College of Medicine. Gerner is also a member of the UA’s BIO5 Institute.

Gerner and Dr. Frank Meyskens, director of the Chao Family Cancer Center at the University of California at Irvine, announced their research results today at the annual meeting of the American Association for Cancer Research, known as AACR, in San Diego. The research results also were published online this week in the inaugural issue of the AACR’s new journal, Cancer Prevention Research.

“The spectacular clinical results reported by Meyskens and colleagues in the lead article of this very first issue of this new AACR journal on cancer prevention represent a landmark advance in efforts to stop the current worldwide epidemic of cancer deaths,” said Michael B. Sporn, professor of pharmacology and toxicology at Dartmouth Medical School.

In earlier studies, the research team had established a safe and well-tolerated dose of DFMO, a specific inhibitor polyamine synthesis, which was 1/50th of what typically would 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.

“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. DFMO is a targeted agent that represents a new treatment paradigm,” said Meyskens.

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 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 1 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 significant difference between the treatment and placebo groups. There was no significant difference in side effects requiring an overnight hospitalization, gastrointestinal side effects, cardiovascular side effects, or hearing loss between the two groups.

“Recent studies have provided proof of principle that chemoprevention of colorectal cancer through the use of natural or synthetic agents to prevent or suppress the progression of precursor lesions (colorectal adenomas) is possible, but positive effects have been modest and have been associated with unacceptable toxicities,” said Dr. Robert S. Bresalier, professor of medicine and distinguished professor in gastrointestinal oncology for the University of Texas MD Anderson Cancer Center.

“Dr. Meyskens and his colleagues have employed sound biological principles and a methodical approach to demonstrate that a very substantial reduction in new adenoma formation in at-risk individuals is possible without substantial risk using DFMO and sulindac,” Bresalier said. “I look forward to seeing the results of additional long-term trials with these agents.”

“Our research was funded by several grants, including the GI SPORE sponsored by the National Cancer Institute. We are very gratified that our study has produced such promising results,” Gerner said.

The Arizona Cancer Center is one of only five institutions nationwide to receive a GI SPORE; the others include Harvard, Johns Hopkins, the University of North Carolina, and Vanderbilt University. Originally funded in 2002, the GI SPORE is the largest new grant awarded to the UA College of Medicine in the past 10 years. It was renewed in 2007 for another five years and funded at $12 million.