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FAP
  Considering Celebrex to Lower Cancer Risk in People With FAP

By Frances Pu, PhD

Reviewed by Miriam Komaromy, MD



Celebrex™ (celecoxib) recently became the only drug federally approved for reducing the number of polyps in patients withfamilial adenomatous polyposis (FAP), a hereditary colon cancer syndrome in which people develop hundreds or thousands of colon polyps. While this is an important advance in FAP treatment, some key points must be kept in mind. First, Celebrex is approved only as add-on therapy and does not replace standard care. Second, although polyps are generally a precursor to colon cancer, it is not known whether reducing the number of polyps will actually reduce the likelihood of developing colon cancer.

 

 
 
 

What Is Celebrex?

Celebrex is a drug that reduces inflammation. It is one of a class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin or ibuprofen that were originally approved for treatment of arthritis. NSAIDs work by blocking certain enzymes that cause inflammation, called cyclooxygenases. While most NSAIDs block more than one cyclooxygenase enzyme (called Cox-1 and Cox-2), the drug Celebrex is very specific in blocking only one of them (Cox-2). This is important, because it is thought that some of the negative gastrointestinal side effects of other NSAIDs (such as abdominal pain and gastrointestinal bleeding) result from their blocking Cox-1 activity. Since Celebrex only blocks COX-2, it makes sense to think that it might not cause these side-effects. However, because far fewer people have been exposed to Celebrex than traditional NSAIDs, this reduction in gastrointestinal side effects is far from proven.
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Why Was Celebrex Approved as A Supplemental Treatment for FAP?

Approval of this drug should be greeted with cautious optimism. Celebrex is approved as an additional treatment for patients with FAP. It is not meant to replace colon removal surgery or regular cancer screenings. The FDA approved Celebrex based mostly on data from one study, which is summarized below.

 

People in the study:

  • Celebrex was tested in 77 people with FAP for the ability to reduce the number of intestinal polyps.
  • 52 participants had already had their colons surgically removed, but had not had their rectum removed, and so were still at risk for forming polyps and cancers of the rectum.
  • 25 participants had intact colons.
  • Roughly a dozen patients had attenuated FAP.

How the study was done:

Polyps were counted before and after six months of treatment. Participants received one of the following:
  • Placebo (an inactive pill that looked just like Celebrex)
  • 200 mg of Celebrex per day
  • 800 mg of Celebrex per day
Participants and their doctors were not told which type of treatment they were receiving until the study was finished. This type of study is called a randomized, double-blind study.

Results:

  • On average, participants taking the highest dose of Celebrex (800mg per day) had a twenty-eight percent reduction in the number of polyps
  • This was significantly better than the approximately five percent reduction seen among participants taking placebo.
  • The most frequent side effects were diarrhea, abdominal pain, and indigestion.
Celebrex Trial Results
Treatment Group Reduction in the number of polyps
Placebo 5%
200 mg per day 12%
800 mg per day 28%

 

Note:


What would these results mean if an "average" participant started the trial with 100 polyps?

Reduction in the number of polyps Number of polyps an "average" participant would have after treatment
5% 95
12% 88
28% 72

Unknowns related to this trial:

  • Whether a twenty-eight percent reduction in polyps translates into a reduced need for colon screening
  • Whether a twenty-eight percent reduction in polyps translates into any reduction in cancer risk
  • Whether Celebrex prevents polyp formation in children with FAP
  • Whether Celebrex is safe or effective in the long term

Factors about this trial to keep in mind:

  • The number of participants, all adults and mainly Caucasian, was quite small when compared to the thousands of patients involved in the arthritis clinical trials for Celebrex. This means that there were too few patients followed for too short a time to draw any conclusions about Celebrex's effect on the development of cancer in FAP patients, or to make broad assumptions about side effects.
  • The participants who received 800 mg of Celebrex daily (the group with the best results) were significantly younger than the participants in either of the other treatment groups.
  • Not all participants had the same results. Almost half of those taking 800mg of Celebrex per day had less than a twenty-five percent reduction in the number of polyps.

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How Does Celebrex Reduce the Number of Polyps?

Celebrex blocks an enzyme (Cox-2) that may cause cells to be more responsive to signals that tell cells to grow, and less responsive to signals that tell cells to die (in the extreme state, this leads to cancer). Increased Cox-2 activity is associated with FAP, Hereditary Non-Polyposis Colorectal Cancer (HNPCC), sporadic colon cancer, and a number of other cancers. Cox-2 may also help tumor cells grow blood vessels that provide them with nutrients as well as a path to spread. By blocking the Cox-2 enzyme, it is thought that Celebrex helps to prevent the excessive cell growth that leads to polyp formation and then cancer.

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Practical Implications

  • Celebrex has not been proven to prevent or reduce the occurrence of cancer in FAP patients. (In fact, there is a recent report of one FAP patient who developed colon cancer just a few months into treatment with Clinoril — generic name sulindac — a drug very similar to Celebrex.)
  • It is crucial that regular or standard care for FAP not be delayed or avoided when taking Celebrex, which has not been shown to reduce cancer risk.
  • Celebrex should only be used as a secondary therapy to suppress polyps in FAP patients with residual rectum after colectomy (surgical removal of the colon) or in patients with an intact colon awaiting colectomy.
  • Health insurance providers may require pre-approval to provide coverage for Celebrex at the most effective dosage used to reduce polyp formation in FAP patients.
  • Celebrex has not been tested in people younger than 18 years of age and has not been tested for the prevention of polyp formation in children with FAP who have yet to develop polyps.

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Future Implications

The approval of Celebrex for supplemental treatment of FAP offers hope that in the future, scientists may be able to develop a drug that can completely prevent polyps. If such a drug were to exist, it might also benefit people with other hereditary colon cancer syndromes, such as hereditary nonpolyposis colorectal cancer (HNPCC). In fact, a study is currently underway at the M.D. Anderson Cancer Center in Texas to investigate whether Celebrex will have any benefit for patients with this syndrome. A positive result in this trial would offer HNPCC patients the same hope for a future therapy that FAP patients now enjoy.

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Related News
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References

G.D. Searle & Co. (1999). U.S. Prescribing Information for Celebrex. http://www.celebrex.com/prescribing/index.htm

Hawk, E. et al. (1999). Chemoprevention in hereditary colorectal cancer syndromes. Cancer 86: 2551-2563.

Jones, M.K. et al. (1999). Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nature Medicine 5: 1418.

Patterson, S. (1999). "FDA Approves Use of Celebrex as Adjunctive Therapy for Familial Adenomatous Polyposis. Hereditary Colon Cancer Newsletter. http://www.mdacc.tmc.edu/~hcc/winter99/approved.htm

Smyrk, T, Thorson, AG and Lynch, HT. (1995). Rectal cancer after prolonged sulindac chemoprevention. Cancer. 75(4):936-8.

Steinbach, G. et al. (2000). The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. The New England Journal of Medicine 342:1946-1952.

 

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