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Colon Cancer Prevention News: Clinical Trial Update
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Submitted By: Information, News and Press Releases
Information courtesy National Cancer Institute (NCI) Source: www.cancer.gov
Updated: 04/02/2006
NCI Studies Using the COX-2 Inhibitor Celecoxib: Questions and Answers
Key Points
Celecoxib is a drug that blocks the production of the cyclooxygenase (COX) enzyme. COX enzymes are produced by the body in response to inflammation and by precancerous and cancerous tissues. Drugs that reduce pain and inflammation from many medical conditions inhibit both COX-1 and COX-2 enzymes.
The use of celecoxib in the Adenoma Prevention with Celecoxib (APC) Trial was suspended in December 2004 because analysis by an independent Data Safety and Monitoring Board showed that the risk of fatal and major non-fatal cardiovascular events (cardiovascular death, heart attack, stroke, or heart failure) was 2.5 times higher for participants taking the drug compared to those on a placebo.
NCI continues to investigate celecoxib in ongoing clinical trials due to strong epidemiologic, laboratory, animal and clinical data showing the importance of the COX pathway in cancer.
1. What are cyclooxygenase (COX) inhibitors?
Cyclooxygenase (COX) inhibitors are compounds that block the action of cyclooxygenase enzymes, which are produced in response to inflammation and by precancerous and cancerous tissues. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation from many medical conditions by inhibiting both of these enzymes (COX-1 and COX-2). NSAIDs that inhibit only COX-2 enzymes were created to allow people to have relief from pain and inflammation while avoiding certain medical problems, such as stomach bleeding, that can occur when NSAIDs are taken regularly for long periods of time.
2. What is celecoxib (CelebrexTM)?
Celecoxib (CelebrexTM) is a COX-2 inhibiting drug manufactured by Pfizer, Inc., New York. 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. Because scientific work suggested the potential for COX-2 inhibitors to prevent and treat cancer, the National Cancer Institute (NCI) formed agreements with Pfizer to study this drug for the prevention and treatment of a variety of cancers.
3. What is the Adenoma Prevention with Celecoxib (APC) Trial?
The APC Trial is a clinical trial to determine if the arthritis drug celecoxib, which inhibits the enzyme COX-2, reduces the occurrence of new adenomas (precancerous polyps) in the colon and rectum of people who have already had such a polyp removed. More than 2,000 men and women age 30 and older were randomly assigned to take either 200 mg of celecoxib twice a day, 400 mg of celecoxib twice a day, or a placebo twice a day for three years. More than 90 centers, located mainly in the United States, but also in the United Kingdom, Australia, and Canada, took part in the trial. The trial enrolled participants from late 1999 through February 2002. For more information about the APC Trial, go to http://www.cancer.gov/newscenter/pressreleases/APCQandA.
4. Why did NCI suspend the use of celecoxib in the Adenoma Prevention with Celecoxib (APC) Trial?
The use of celecoxib in the APC Trial was suspended on Dec. 17, 2004, because an initial analysis by an independent Data Safety and Monitoring Board (DSMB) showed that the risk of major fatal and non-fatal cardiovascular events (cardiovascular death, heart attack, stroke, or heart failure) was 2.5 times higher for participants taking the drug compared to those on a placebo. Investigators in the APC Trial immediately suspended study drug use, although the participants are under observation for the planned remainder of the trial.
5. What did full analysis of the cardiovascular events on the APC Trial show?
APC investigators published a full report of the analysis of cardiovascular events on the trial in the March 17, 2005, issue of the New England Journal of Medicine (posted online Feb. 15, 2005). In this analysis, celecoxib use for an average of almost three years was associated with a dose-related increased risk of serious cardiovascular events (cardiovascular death, heart attack, stroke, or heart failure). Compared to study participants taking the placebo, people taking 200 mg of celecoxib twice a day had more than 2.3 times the risk of these serious events, and those taking 400 mg of celecoxib twice a day had 3.4 times the risk of these serious events.
In the placebo group, 7 of 679 people (1 percent) had a serious cardiovascular event, including one death. In the group of people taking 200 mg of celecoxib twice a day, 16 of 685 people (2.3 percent) had a serious cardiovascular event, including three deaths. In participants taking 400 mg of celecoxib twice a day, 23 of 671 people (3.4 percent) had a serious cardiovascular event, including six deaths.
Participants in the APC Trial were allowed to take aspirin for cardiac protection (81 mg daily), but those who did had no different risk of serious cardiovascular events than those who did not take aspirin.
6. Why did celecoxib increase the risk of these serious cardiovascular events?
The reason for the increased risk is not clear. Researchers are working to understand the possible mechanisms so they may one day be able to determine which people are at risk for these serious cardiovascular events and which might be able to take the drug safely.
7. What did NCI do to notify patients on COX-2 inhibitor clinical trials about this risk for serious cardiovascular events?
NCI notified all of the principal investigators (PIs) of its sponsored trials involving COX-2 inhibitors about the increased cardiovascular risk seen in the APC Trial. The PIs were instructed to notify their institutional review boards (IRBs), data safety monitoring boards (DSMBs), and trial participants about this new information. NCI also required that the informed consent for these trials be revised to reflect this new information and that participants in the trials be re-consented (that is, asked to sign new consent forms with updated information about the risks and benefits of the trials).
8. What language was added to the informed consent for these trials?
NCI recommended the following language for the revised informed consent form: "Recently, an increased risk of heart attacks, strokes, and/or deaths resulting from heart or blood vessel disease has been reported among people taking celecoxib in clinical studies. Although the increased risk is two to three times greater than the risk of patients who did not take celecoxib, these serious adverse events are rare. Taking celecoxib may increase your risk of one of these events."
9. How many clinical trials were affected by this information? Were any trials closed?
As of December 2004, NCI had about 50 prevention and treatment clinical trials with celecoxib of varying sizes either open or in planning stages. The 26 prevention trials ranged in size from under 10 participants to more than 2,000 participants and were for the prevention of bladder, breast, cervical, colorectal, esophageal, head and neck, skin, lung, oral, and prostate cancers, as well as multiple myeloma. NCI collaborated with Pfizer on the majority of the large prevention trials. The 23 treatment trials were mostly small phase I or II clinical trials in cancers including pancreatic, breast, ovarian, non-small cell lung, and other solid tumors. The treatment trials included two randomized phase III clinical trials in women with breast cancer.
NCI did not close any trials, but required that the PIs notify their IRBs, DSMBs, and participants of the new information. In response to the new information, the PIs, IRBs, and DSMBs had to consider the risks and benefits of continuing each trial, including both ethical and practical issues. For instance, some trials were close to completion and the PIs chose not to continue the intervention and to move to analyze the data at that point. For many treatment trials, celecoxib was not the primary treatment being used nor was its effectiveness the primary objective of the trial; for these studies the celecoxib was discontinued. Other trials, in which the duration or dosage of celecoxib was short or low, continued as they were designed.
10. What other NCI-supported analyses are under way to better understand the potential risks of taking celecoxib?
A panel of NCI-sponsored investigators is assessing the cardiovascular and cerebrovascular (CCV) safety of celecoxib using data from six randomized, placebo-controlled trials testing celecoxib. Use of celecoxib was nearly complete, suspended, or dropped in all of these trials. By analyzing the CCV safety data from these studies (and using consistent definitions of these events), a clearer picture of the risk profile of celecoxib may emerge. Analysis is ongoing and completion is expected later in 2006.
This safety analysis includes data from:
Three trials sponsored by NCI
The Adenoma Prevention with Celecoxib Trial, a study of men and women with a prior colorectal adenoma
The SelCel trial, a study of men and women with a prior colorectal adenoma, and
The MA27 Breast Adjuvant Trial, a study of postmenopausal women with estrogen receptor-positive breast cancer
Two trials sponsored by other institutes at the National Institutes of Health
The National Institute on Aging's ADAPT trial, which includes men and women at risk for Alzheimer's disease, and
The National Eye Institute's Diabetic Retinopathy Trial of people with diabetes and diabetic macular edema
Pfizer-sponsored Pre-SAP trial of men and women with a prior colorectal adenoma.
11. Why is NCI studying COX inhibitors in cancer prevention and treatment?
More than a decade of epidemiologic research suggests that people who regularly take drugs that block COX enzymes have lower rates of certain precancers, cancers, and cancer-related deaths. The data are most consistent for colorectal cancer, but this reduction in risk is also seen for other cancers. Animal and laboratory studies using a variety of NSAIDs and COX-specific inhibitors show a decrease in cancer incidence with the use of these compounds. On a molecular level, studies have shown that the inhibition of the COX pathway changes the characteristics of cancer cells by reducing cell proliferation, increasing programmed cell death, reducing formation of blood vessels to feed cancer cells, and changing the body's immune response.
12. Should people continue to use celecoxib for pain relief?
The FDA has advice for consumers and physicians regarding pain relievers and celecoxib on its Web site, http://www.fda.gov.
Included in this information is:
Advice on the Safe Use of Over-the-Counter Pain Relievers (analgesics) and Fever Reducers (antipyretics), available at: http://www.fda.gov/cder/drug/analgesics/default.htm.
FDA Alert for Practitioners on Celecoxib (marketed as Celebrex), available at:
http://www.fda.gov/cder/drug/infopage/celebrex/celebrex-hcp.htm. And an information page on COX-2 Selective (includes Bextra, Celebrex, and Vioxx) and Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), available at:
http://www.fda.gov/cder/drug/infopage/COX2/default.htm
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