Aug. 31, 2006 A researcher from Dartmouth reports the results of a clinical trial that shows that the cyclooxygenase-2 (COX-2) inhibitor rofecoxib (VIOXX®) reduces the risk of colorectal adenomas, or polyps. Polyps are benign tumors that are precursors to colon cancer, and they are often found in older adults.
The results of the study appeared online on August 30 at the American Gastroenterological Association website in advance of being published in the journal, Gastroenterology. Extensive data have suggested previously that aspirin and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) could reduce colon cancer risk, and this study now demonstrates a similar effect for VIOXX®.
"These are exciting findings," says Dr. John Baron, the lead author of the paper and a professor at Dartmouth Medical School, who has been studying chemoprevention of colorectal cancer for more than twenty years. "They show once again the potential for NSAIDs to interfere with the development of cancer in the colon and rectum."
This study, called the APPROVe (Adenomatous Polyp Prevention on VIOXX®) study, was a randomized, placebo-controlled, double-blind trial conducted by Merck Research Laboratories. The study involved 108 sites in the United States and abroad and followed 2,587 patients with a recent history of confirmed colorectal adenomas. After removal of all polyps, the subjects were randomized to receive daily placebo or 25 mg rofecoxib on a daily basis. The primary endpoint was to analyze all adenomas diagnosed during the three-year treatment period based upon colonoscopies conducted one year and three years after baseline.
In addition, an extension to the APPROVe study was conducted to assess recurrence of adenomas in the year following the end of the three years' treatment through a colonoscopy at year four. Previous randomized studies have also shown that COX-2 inhibitors can lower the risk of polyps in patients with a rare genetic syndrome called familial adenomatous polyposis (FAP), but this is the first to illustrate the effect in the broad population of people at risk for colorectal cancer.
Patients taking rofecoxib had a lower recurrence rate of adenomas than those taking placebo (41 percent vs 55 percent; p<0.0001; relative risk 0.76; 95 percent CI 0.69-0.83). Rofecoxib also reduced the risk of advanced adenomas, which are polyps that are more likely to become cancerous. The chemopreventive effect was larger in the first year (RR 0.65; 95 percent CI 0.57-0.73) than in the subsequent two years (RR = 0.81, 95 percent CI 0.71-0.93). In the year following three years' treatment, patients taking rofecoxib experienced a slightly increased risk of any adenoma, but not of advanced adenomas. However, over the entire length of the trial (three years of treatment and one year off drug), patients taking rofecoxib experienced a reduction of the risk of any adenoma.
Baron says that patients treated with rofecoxib experienced more serious adverse events, including significant upper gastrointestinal events and, as reported previously, increased risks of thrombotic cardiovascular events. But he does not believe that the side effects will derail the eventual development of effective chemoprevention.
"While the toxicity of the currently available COX-2 inhibitors may be problematic, the demonstration of efficacy certainly implies that other agents may be suitable for longer term use," he says.
Baron says that although it is not known how rofecoxib interferes with carcinogenesis, inhibition of COX-2 has been thought to play a role. Other mechanisms are possible, however, and scientists are actively seeking to understand exactly how non-steroidal anti-inflammatory drugs after pathways that lead to cancer.
Additional authors on the paper include Robert S. Sandler, Robert S. Bresalier, Hui Quan, Robert Riddell, Angel Lanas, James A. Bolognese, Bettina Oxenius, Kevin Horgan, Susan Loftus, and Dion G. Morton.
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