Celecoxib (Celebrex) for Cancer Prevention

Cancer is a process in which a sequence of genetic changes gradually transforms a cell from normal to cancerous. The goal of cancer prevention is to intervene at an early point to stop or reverse that process. Chemoprevention, the use of pharmacologic interventions to stop the progression of normal cells to cancer cells, is an important tool for reaching that goal. The National Cancer Institute's (NCI) Division of Cancer Prevention is collaborating with Searle (now a part of Pharmacia Corp.,) and Pfizer Inc., to study the drug celecoxib (Celebrex™) for the prevention of several pre-cancerous and cancerous conditions. Celecoxib was approved by the U.S. Food and Drug Administration (FDA) on December 23, 1999, as an adjunct to usual care for patients with familial adenomatous polyposis (FAP), a hereditary form of colorectal cancer.

People with FAP develop hundreds to thousands of polyps throughout their colon and rectum, beginning in adolescence. Left untreated, nearly all patients develop colorectal cancer by their 40s and 50s. The primary treatment of FAP is surgical removal of most or all of the colon and rectum with subsequent surveillance of any remaining colorectal segment. About one in 10,000 people has FAP.

In an NCI-sponsored trial, celecoxib helped reduce the recurrence of colon polyps (which may be precursor lesions of colorectal cancer) in patients with FAP. The study was conducted at The University of Texas M. D. Anderson Cancer Center, and at St. Mark's Hospital in London. Dr. Gideon Steinbach, an assistant professor in the Department of Gastrointestinal Medicine and Nutrition at M. D. Anderson, was the principal investigator. Results of this trial were published in the New England Journal of Medicine June 29, 2000. Further studies of celecoxib in FAP patients will be conducted to assess its effect on the development of cancer.

Celecoxib was FDA-approved for the treatment of both osteoarthritis and adult rheumatoid arthritis in December 1998 and inhibits an enzyme known as cyclo-oxygenase-2 (COX-2). Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen, block COX-1 and COX-2 enzymes; COX-1 is necessary for healthy mucosal tissues and COX-2 is typically induced in inflammation and pre-cancerous tissues, such as polyps. Inhibition of COX-1 may be the cause of medical problems, like stomach bleeding, that occur when NSAIDS are taken regularly for long periods of time.

Epidemiologic studies have shown that people who regularly take NSAIDS to treat conditions such as arthritis have lower rates of colorectal polyps, colorectal cancer and colorectal cancer deaths. Based on these promising epidemiologic data as well as animal models treated with COX inhibitors and human pathologic samples showing high levels of COX-2 expression in cancerous tissues, NCI is supporting studies of the use of several COX inhibitors, including the following studies with celecoxib:

• Sporadic polyps, which occur in people without a known genetic predisposition to colon cancer, are the focus of a trial headed by researchers at Brigham and Women's Hospital in Boston. Several centers across the U.S. will enroll people in this study in which participants who had polyps surgically removed will be randomized to take one of two doses of celecoxib or a placebo to see if the drug reduces the recurrence of polyps. Studies to identify biological markers of the progression from healthy tissue to polyps to cancer also are under investigation as part of this trial. More than 50 centers in the U.S. and the United Kingdom are currently enrolling patients.
• Hereditary nonpolyposis colon cancer syndrome, or HNPCC, is a medical condition in which people are at an increased risk for early onset colorectal cancer and cancer at other sites (uterus, ovaries, stomach, urinary tract, small bowel, and bile duct). About 75% to 80% of persons with HNPCC develop colon cancer. HNPCC is associated with changes in any of five genes involved in DNA mismatch repair. In an ongoing study of people who have this syndrome, patients are being treated with one of two doses of celecoxib to evaluate its effects on a number of cellular and molecular biomarkers in normal-appearing rectal mucosa. Dr. Patrick Lynch, associate professor in M. D. Anderson's Department of Gastrointestinal Medicine and Nutrition, Dr. Henry Lynch, at Creighton University, and Dr. Ilan Kirsch, at NCI, are principal investigators.
• Barrett's esophagus is a condition caused by acid reflux into the lower esophagus in which cells that would normally line the esophagus are replaced by cells that resemble the lining of the intestine. People with Barrett's esophagus may be at an increased risk of developing esophageal cancer. Celecoxib is being compared to placebo in a phase II trial of people with this condition to see if the drug regresses the pre-cancerous tissue. A researcher at the Johns Hopkins University in Baltimore is heading the trial, which is open at Hopkins and at three other academic locations.
• Bladder dysplasia is a pre-cancerous condition that often leads to bladder cancer. It is most often found when a person with urinary symptoms is checked for cancer. Dr. Anita Sabichi, assistant professor of clinical cancer prevention at M. D. Anderson, is heading a trial of celecoxib vs. placebo for people diagnosed with superficial bladder dysplasia or bladder cancer who are at high risk for recurrence. The subsequent incidence of bladder dysplasia or bladder cancer will be assessed in addition to a variety of mechanistic biomarkers. This trial is open at M. D. Anderson and will open at several other U.S. centers.
• Actinic keratoses, which appear as rough, red or brown, scaly patches on the skin, is a pre-cancerous condition that can lead to squamous cell skin cancer. A study of oral celecoxib in people with this condition is under way at the University of Alabama at Birmingham and will open at four other locations later this year. Participants will receive either celecoxib or a placebo and the incidence of actinic keratoses will be measured, in addition to selected mechanistic biomarkers.
• Familial adenomatous polyposis (FAP). A clinical trial is planned for patients with FAP where celecoxib will be used in combination with another chemopreventive agent. The trial will take place at M. D. Anderson under the leadership of Dr. Frank Sinicrope, chairman ad interim of M. D. Anderson's Department of Gastrointestinal Medicine and Nutrition.

For more information on specific cancer prevention clinical trials, visit NCI's Cancernet website or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Cancer Institute (NCI) provided this information. If you have further questions about colorectal cancer, call the NCI's Cancer Information Service at 1-800-4-CANCER. If you have further questions about specific M. D. Anderson programs and services related to colorectal cancer, call The M. D. Anderson Information Line at 1-800-392-1611, option "3."