Cyclooxygenase (COX) inhibitors tested in both prevention and treatment clinical trials

Nov 4 2004

Numerous compounds are examined by the National Cancer Institute (NCI) for their potential to prevent or treat cancer. One class of compounds, cyclooxygenase (COX) inhibitors, is currently being tested in both prevention and treatment clinical trials.

Epidemiologic studies have shown that people who regularly take non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen to treat conditions like arthritis, have lower rates of colorectal polyps, colorectal cancer, and death due to colorectal cancer. NSAIDs block cyclooxygenase enzymes, which are produced by the body when there is inflammation and are also produced by precancerous tissues. Inhibition of COX-2 may help treat and prevent cancer, while inhibition of COX-1 may induce certain medical problems, like stomach bleeding, that occur when NSAIDS are taken regularly for long periods of time.

Pharmaceutical companies have created NSAIDs that block only COX-2; one of them, celecoxib (CelebrexTM), manufactured by Pfizer, Inc., New York, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of both osteoarthritis and adult rheumatoid arthritis (diseases in which the joints are inflamed) in December 1998. Because over a decade of scientific work has suggested the potential of COX-2 inhibitors to prevent and treat cancer, the National Cancer Institute (NCI) has clinical trials under way to look at the efficacy and safety of these drugs.

NCI's Division of Cancer Prevention (DCP) began its studies with celecoxib with a trial in people with Familial Adenomatous Polyposis (FAP). Patients with FAP develop hundreds to thousands of precancerous polyps (adenomas) throughout the colon and rectum. Left untreated, nearly all FAP patients develop colorectal cancer by their 40s and 50s. The primary treatment for FAP is surgical removal of most or all of the colon and rectum with subsequent surveillance of any remaining colorectal segment. In an NCI-sponsored trial, celecoxib helped reduce the number of colon polyps in patients with FAP. The results of this study were published in the New England Journal of Medicine on June 29, 2000, and led to FDA-approval of celecoxib as an adjunctive drug (an accessory or auxiliary agent) that could be added to the standard of care in people with FAP.

As of October 2004, DCP sponsored 23 trials of varying sizes to test the potential of celecoxib to prevent cancer in a number of organ sites. These trials range in size from under 10 participants to more than 2,000 and aim to prevent bladder, breast, cervical, colorectal, esophageal, head and neck, skin, lung, oral, and prostate cancers, as well as multiple myeloma. The majority of these trials are in collaboration with Pfizer, Inc.

Additionally, to examine potential benefits of COX-2 inhibitors for the treatment of patients with cancer, NCI's Division of Cancer Treatment and Diagnosis (DCTD) is sponsoring almost 20 trials of varying sizes with celecoxib. The majority of these studies are small phase I or II clinical trials in cancers such as pancreatic, breast, ovarian, non-small cell lung, and solid tumors. DCTD also is sponsoring two ongoing randomized phase III clinical trials: the first trial compares, exemestane vs anastrozole, in postmenopausal women with estrogen receptor-positive primary breast cancer; the second trial compares several chemotherapy agents in node-negative breast cancer patients. Both phase III trials randomized women to either those taking celecoxib or not taking celecoxib, in addition to the agents mentioned above.

On September 30, 2004, the COX-2 inhibitor rofecoxib (VioxxTM) was removed from the market after a two-fold increased risk of cardiovascular toxicities was identified in people taking the drug for 18 months within a trial to prevent colon adenomas. The sponsor of the 2,600 person trial, Merck & Co., Inc. (New Jersey), sent a letter to physicians announcing the removal of the drug and explaining the action. NCI's Division of Cancer Prevention had planned to undertake a lung cancer prevention trial using rofecoxib, but has abandoned that plan following the withdrawl of rofecoxib.

On October 18, 2004, Pfizer, Inc. announced it will initiate a trial of celecoxib users that will last for two years. The study will examine inflammation and cardiovascular events in osteoarthritis patients at high risk for heart disease. It will be conducted at major universities and hospitals around the world and is expected to start early in 2005, enrolling 4,000 patients who have had a recent heart attack and who also have a history of osteoarthritis.

Based on the safety concerns reported in the rofecoxib trials, and the possibility that these concerns may extend to other COX-2 inhibitors such as celecoxib, NCI is rapidly reviewing data in both prevention and treatment trials. All of NCI's large trials have Data Safety and Monitoring Boards which regularly meet in person and review data on adverse events monthly. Cardiovascular experts have been added, where appropriate, to evaluate adverse cardiovascular events.