NSAIDS help reduce colorectal adenoma risk

SAN DIEGO — Data from two phase-3 trials suggested promising results for the prevention of colorectal cancer using nonsteroidal antiinflammatory drugs. Both trials were presented at the 2008 Annual Meeting of the American Association for Cancer Research.

The first study was conducted by researchers at the cancer center at the University of California, Irvine. The researchers examined the use of difluoromethylornithine (DFMO) in combination with sulindac for the prevention of colorectal adenomas. Data from the double blind, placebo-controlled trial indicated that this combination reduced the risk for recurrent colorectal adenomas by 95% with little toxicity.

“Combination chemoprevention of DFMO and sulindac can reduce colon adenoma polyp recurrence substantially,” said Frank Meyskens, MD, director of the center. “This combination can prevent a major precursor to colorectal cancer with little toxicity. This landmark study now opens the door to further clinical research.”

Meyskens and colleagues enrolled 375 patients who had a history of at least one colorectal polyp within the previous five years. Patients were randomly assigned to receive 500 mg DFMO plus 150 mg sulindac or placebo. Baseline characteristics were well balanced for age, sex, ethnicity and BMI. Follow-up was three years.

Data indicated a significant reduction of adenoma polyps on this combination treatment. Overall, researchers found a 70% reduction in the risk of recurrent adenoma in patients in the treatment group compared with patients treated with placebo. They found a 92% reduction in risk for advanced adenomas and a 95% reduction in risk for multiple adenomas (see chart on cover). The reduction rate was so significant that the trial was stopped early.

An analysis of adverse events and toxicity indicated no difference between the treatment and placebo groups.

NSAIDs in cancer prevention

Monica Bertagnolli, MD, chief, division of surgical oncology at the Brigham and Women’s Hospital presented the results of the second phase-3 study. The Adenoma Prevention with Celecoxib (APC) trial was conducted to evaluate the use of NSAIDs for cancer prevention.

“We found that celecoxib (Celebrex, GD Searle) is an effective agent for colorectal adenoma chemoprevention with persistent efficacy during five years after a three-year initial treatment,” Bertagnolli said. “However, it must be used with caution due to patient risk for cardiovascular toxicity.”

Bertagnolli and colleagues assigned 2,035 patients to receive 200 mg twice-daily celecoxib (400 mg total); 400 mg twice-daily celecoxib (800 mg total); or placebo. Patients were followed for three years; about one-third of patients were followed for an additional two-year off-treatment study to evaluate safety and efficacy.

At three years, patients assigned high-dose 400-mg celecoxib had a 29% reduction in incidence of adenoma. Patients assigned 800 mg had a 38% reduction. Even greater reductions were seen among patients with advanced adenomas (see chart). At five years, two years after cessation of medication, the rate of advanced adenoma was reduced by 41% at the 400-mg dose and by 26% at the 800-mg dose. “Overall, there was no increase in benefit seen for the higher dose,” Bertagnolli said.

Cardiovascular events were more common in patients assigned celecoxib; however, the researchers found that this risk was only elevated in patients who had baseline cardiovascular risk. – by Leah Lawrence

Editor's note: Dr. Bertagnolli received research funding and honoraria from Pfizer Inc.

These are two of the most active and important clinical trials in colorectal cancer prevention and even two of the most important trials in all of cancer prevention. The APC trial results have presented promising and provocative five-year results that involved about one-third of the previously reported trial population. As far as adverse events are concerned, cardiovascular risk of patients assigned celecoxib was related to baseline cardiovascular risk. The activity of sulindac and DFMO was also striking. There was no statistically significant clinical cardiovascular toxicity, and it validates the concept of combination chemoprevention proposed by Sporn (Nature. 1980;287:107-108). Serious cardiovascular adverse events were 8.4% in the combination group and 4.9% in the placebo group; though not statistically significant, this trend was worrisome. It could have been due to a higher baseline cardiovascular risk but in the end deserves further study.

– Scott Lippman, MD

Chair, Thoracic/Head and Neck Medical Oncology
The University of Texas M.D. Anderson Cancer Center

For more information:

• Bertagnolli M. #LB-141.
• Meyskens F. #LB-142. Both presented at: 2008 Annual Meeting of the American Association for Cancer Research; April 12-16, 2008; San Diego.