Rofecoxib significantly reduces the risk of recurrence of colorectal polyps

Data from the APPROVe trial shows rofecoxib effective in broad, at-risk population

Bethesda, MD (August 30, 2006) – The use of the cyclooxygenase-2 (COX-2) inhibitor rofecoxib (Vioxx®) reduces the risk of colorectal adenomas, according to data being published in Gastroenterology, the journal for the members of the American Gastroenterological Association (AGA). The study, "A Randomized Trial of Rofecoxib for the Chemoprevention of Colorectal Adenomas," is scheduled for publication in December, but was released on-line in August due to the significance of the findings. The manuscript can be found on-line at http://www.gastro.org/user-assets/Documents/13_Media/Randomized_Trial.pdf.

John Baron, MD, lead author of the paper and a professor at Dartmouth Medical School, has been studying chemoprevention of colorectal cancer for more than twenty years. "These are exciting findings," he said. "They show once again the potential for non-steroidal anti-inflammatory drugs, or NSAIDs, to interfere with the development of cancer in the colon and rectum."

Extensive data have suggested previously that aspirin and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) could reduce colon cancer risk. This study now demonstrates such an effect for a selective COX-2 inhibitor in a placebo-controlled randomized study. While previous randomized studies have shown that COX-2 inhibitors can lower the risk of adenoma in patients with a rare genetic syndrome called familial adenomatous polyposis (FAP), the effect in the broad population of people at risk for colorectal cancer has not been previously demonstrated. More commonly referred to as "polyps," adenomas are benign tumors that are precursors to colon cancer, and are commonly found in older adults in the United States and worldwide.

The APPROVe (Adenomatous Polyp Prevention on Vioxx) study was a randomized, placebo-controlled, double-blind trial funded by Merck Research Laboratories. Study results showed that 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 (p<0.01). The benefit 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.

About the Study The study included 2,587 evaluable patients with a recent history of confirmed colorectal polyps followed at 108 sites in the United States and abroad. After removal of all polyps, patients were randomized to receive either placebo or 25 mg rofecoxib (the average daily recommended dose) on a daily basis. The primary endpoint was all polyps 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 colonoscopy at year four.

Patients treated with rofecoxib experienced more serious adverse events, including significant upper gastrointestinal events and, as reported previously, increased risks of thrombotic cardiovascular events (Bresalier et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. NEJM 2005; 352:1092-102). Dr. Baron 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 said.

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 alter pathways that lead to cancer.

"Colorectal cancer is the second leading cause of cancer death in the United States, so it is important to aggressively research and develop potential chemopreventive agents to help patients who are at the highest risk of developing the disease," according to Anil K. Rustgi, MD, editor of Gastroenterology and Chief of Gastroenterology at the University of Pennsylvania School of Medicine. "It is important to not hold onto this information until December so the results of this study can be added to the body of knowledge about cancer prevention that could potentially help physicians care for their patients."

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About Colorectal Cancer
Colorectal cancer is the third most common cancer in men and women and the second leading cause of cancer death. However it is one of the most easily prevented cancers, and has a relatively good prognosis when diagnosed and treated early. An individual's risk of colon cancer increases with age, therefore, all men and women should undergo a baseline colonoscopy at age 50, then again at the recommendation of their gastroenterologist. Eighty to 90 million Americans (approximately 25 percent of the US population) are considered at risk because of age or other factors, and more women over the age of 75 die from colorectal cancer than from breast cancer.

About the AGA Institute
The American Gastroenterological Association (AGA) is dedicated to the mission of advancing the science and practice of gastroenterology. Founded in 1897, the AGA is one of the oldest medical-specialty societies in the United States. Comprised of two non-profit organizations--the AGA and the AGA Institute--our more than 15,000 members include physicians and scientists who research, diagnose and treat disorders of the gastrointestinal tract and liver. The AGA, a 501(c6) organization, administers all membership and public policy activities, while the AGA Institute, a 501(c3) organization, runs the organization's practice, research and educational programs. On a monthly basis, the AGA Institute publishes two highly respected journals, Gastroenterology and Clinical Gastroenterology and Hepatology. The organization's annual meeting is Digestive Disease Week®, which is held each May and is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. For more information, please visit www.gastro.org.

About Gastroenterology
Gastroenterology, the official journal of the AGA Institute, is the most prominent journal in the subspecialty and is in the top one percent of indexed medical journals internationally. The journal publishes clinical and basic science studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition. The journal is abstracted and indexed in Biological Abstracts, CABS, Chemical Abstracts, Current Contents, Excerpta Medica, Index Medicus, Nutrition Abstracts and Science Citation Index. For more information, visit www.gastrojournal.org.

About Clinical Gastroenterology and Hepatology
The mission of Clinical Gastroenterology and Hepatology is to provide readers with a broad spectrum of themes in clinical gastroenterology and hepatology. This monthly peer-reviewed journal includes original articles as well as scholarly reviews, with the goal that all articles published will be immediately relevant to the practice of gastroenterology and hepatology. For more information, visit www.cghjournal.org.


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