Results from a phase III clinical trial indicate that low doses of two chemopreventive agents, an anti-inflammatory and an experimental compound, are highly effective at preventing the recurrence of the lesions that are often precursors to colorectal cancer.

Trial results presented yesterday at the American Association for Cancer Research (AACR) annual meeting in San Diego, CA, showed that, compared with participants in the placebo arm, those treated with a combination of the investigational compound difluoromethylornithine (DFMO) and the anti-inflammatory agent sulindac had their risk of colon polyp recurrence reduced by 70 percent. More important, the results showed that the treatment was most effective in preventing the recurrence of the highest-risk polyps, advanced adenomas, demonstrating a 92 percent reduction.

"This is the most positive trial in chemoprevention in the last 20 years," says the trial's lead investigator Dr. Frank L. Meyskens from the Chao Family Comprehensive Cancer Center at the University of California, Irvine. "It should raise great hope that we'll be able to use chemoprevention in appropriate at-risk groups."

The trial was stopped early, following a recommendation by its Data Safety Monitoring Board, because the trial's primary goals had been met. Although 375 patients were randomly assigned to the placebo or intervention arms, the final analysis was based on data from 267 patients for whom the most complete information was available. All patients in the trial had previously had colorectal adenomas (3 mm or larger) removed, and the study treatment lasted for 36 months.

"This is a phase III study that demonstrates a lot of potential for this drug combination to decrease cancer risk," says Dr. Eva Szabo from NCI's Division of Cancer Prevention.

Data on cancer incidence are not yet available from the trial. "However," Dr. Szabo continues, "we understand the biology of polyp progression to colon cancer quite well." Given the decrease in adenoma recurrence seen in the study, there is a very strong likelihood of a true cancer prevention effect, she notes.

Originally developed by a French pharmaceutical company, DFMO inhibits a cell's synthesis of molecules called polyamines by blocking the function of an enzyme known as ornithine decarboxylase.

Based on data from laboratory and animal model studies, explains Dr. Meyskens - who, along with Dr. Eugene Gerner from the Arizona Cancer Center, has been studying DFMO since the early 1980s - the combination of DFMO and sulindac makes sense for cancer prevention.

"They affect two different pathways, both of which drive proliferation," he says.

Sulindac was an early member of the class of drugs known as nonsteroidal anti-inflammatory drugs, or NSAIDs. That same class also includes celecoxib (Celebrex), a COX-2 inhibitor that has had mixed results in other large adenoma recurrence prevention trials. It decreased adenoma recurrence but also increased the risk of serious cardiac events.

However, Dr. Meyskens cautions, "I don't think our study has gone on long enough to know whether sulindac has cardiovascular effects." There was an increase in cardio-vascular events, but it was not statistically significant.

The trial was launched only after two smaller "dose de-escalation" studies were done to identify the lowest effective dose of DFMO that could provide a clinical benefit. The dose used in this prevention trial is one-fiftieth of the dose used in the earlier treatment trials.

Based on earlier studies, some concerns do exist about DFMO-related toxicities, namely hearing loss. More patients in the DFMO/sulindac arm did experience minor reductions in hearing, as measured on audiograms. Participants who experienced hearing loss, mostly older participants, generally weren't aware of it.

"Across the entire group, the difference in hearing loss between treatment and placebo was approximately 2 decibels," he says. "That's [the sound of] rubbing your fingers together."

Dr. Meyskens' group is working with NCI to design larger phase III trials, including one in patients who have been treated for low-grade colorectal cancer. Currently, DFMO is not manufactured by any pharmaceutical company, so the team is also searching for industry partners to continue moving it through additional clinical trials and, they hope, regulatory approval.

"We hope these data will generate a lot of interest," Dr. Meyskens says.

—Carmen Phillips