Cancer is a process in which a sequence of genetic alterations 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 studying the drug celecoxib (Celebrex™) for the prevention of cancer in people with precancerous conditions and in people at high risk for second cancers. Celecoxib inhibits the body's production of an enzyme known as cyclooxygenase-2 (COX-2), which helps control inflammation. In fact, celecoxib 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.
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 produced by the body when there is inflammation and is also produced by precancerous 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 celecoxib.
In all of the following studies of celecoxib, NCI is collaborating with Searle, Skokie, Ill., (now a part of Pharmacia Corp., Peapack, N.J.) and Pfizer Inc., New York, N.Y.
Familial Adenomatous Polyposis (FAP)
Beginning in adolescence, people with Familial Adenomatous Polyposis (FAP) develop hundreds to thousands of precancerous polyps throughout their colon and rectum. 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. It is estimated that about 1 in 10,000 people has FAP.
In an NCI-sponsored trial, celecoxib helped reduce the number of colon polyps that occurred in patients with FAP. The study was conducted at the University of Texas M. D. Anderson Cancer Center, Houston, and at St. Mark's Hospital in London (U.K.). Gideon Steinbach, M.D., at the University of Texas, was the principal investigator. Results of this trial were published in the New England Journal of Medicine on June 29, 2000.
Celecoxib was approved by the Food and Drug Administration (FDA) on Dec. 23, 1999, as an adjunct to usual care for patients with familial adenomatous polyposis (FAP) based on the results of this NCI-sponsored trial. To build on these data, NCI is planning two additional trials of celecoxib. One will look at use of the drug earlier in the progression of the disease and the other will compare celecoxib alone to celecoxib plus another prevention drug. When the protocols are finalized, they will be listed within the clinical trials information on NCI's web site (http://cancer.gov).
Sporadic polyps, which occur in people without a known genetic predisposition to colon cancer, are the focus of a phase III trial headed by Monica Bertagnolli, M.D., at Brigham and Women's Hospital in Boston. Centers across the United States are enrolling people into 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 are under investigation as part of this trial as well. More than 50 centers in the United States and the United Kingdom are currently enrolling patients.
Hereditary Nonpolyposis Colon Cancer
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, ovary, stomach, urinary tract, small bowel, and bile duct). About 75 to 80 percent of persons with HNPCC develop colon cancer.
In an ongoing phase I/II study of people who have this syndrome, people with HNPCC 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. Patrick Lynch, M.D., at the University of Texas M. D. Anderson Cancer Center, Henry Lynch, M.D., at Creighton University in Omaha, and Ilan Kirsch, M.D., at NCI, Bethesda, Md., 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 precancerous tissue. Arlene Forastiere, M.D., at the Johns Hopkins University in Baltimore, is heading the trial.
Bladder Dysplasia and Bladder Cancer
Bladder dysplasia is a precancerous condition that often leads to bladder cancer. It is most often found when a person with urinary symptoms is checked for cancer. Anita Sabichi, M.D., at the University of Texas M. D. Anderson Cancer Center, is heading a phase II/III 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 biomarkers. This trial is open at M. D. Anderson Cancer Center and several other U.S. centers.
Actinic Keratoses (Skin Cancer Prevention)
Actinic keratoses, which appear as rough, red or brown, scaly patches on the skin, is a precancerous condition that can lead to squamous cell skin cancer. A phase II/III study of oral celecoxib in people with this condition is headed by Craig Elmets, M.D., at the University of Alabama at Birmingham. The trial will open there and 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 biomarkers.