| FAP |
| Considering Celebrex to Lower Cancer Risk in People With FAP |
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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.
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What
Is Celebrex?
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| 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?
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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.
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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.
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Celebrex
Trial Results
| Treatment
Group |
Reduction
in the number of polyps |
| Placebo |
5%
|
| 200
mg per day |
12% |
| 800
mg per day |
28%
|
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Note:
|
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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 |
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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?
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| 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
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- 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
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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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 top
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References
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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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