PHOENIX, ArizonaDrugs that inhibit cyclooxygenase-2 (COX-2) are
the hottest thing in arthritis care this year and may have a role to
play in combating colorectal cancer, according to a study presented
at the American College of Gastroenterology 64th Annual Scientific
Gideon Steinbach, MD, PhD, principal investigator of the study,
reported that the COX-2 inhibitor celecoxib (Celebrex) significantly
reduced the number of precancerous colon polyps in patients with
familial adenomatous polyposis (FAP) and caused regression of already
formed polyps. Dr. Steinbach is associate internist in the Division
of Cancer Prevention, The University of Texas M.D. Anderson Cancer
People who have FAP develop hundreds of polyps, and many of these
inevitably pro-gress to colorectal cancer unless surgically removed.
Drugs that prevent the development of these polyps in FAP patients
are thought to be strong candidates for preventing colorectal cancer
in people at risk for less aggressive, more commonplace forms of the
disease, Dr. Steinbach said. A successful protective agent could have
major public health effects, since colorectal cancer is the third
most common cancer in both men and women in most Western countries.
Background on COX-2
Nonsteroidal anti-inflammatory drugs (NSAIDs) are inhibitors of the
cyclooxy-genase enzyme, the key enzyme in the metabolism of
arachidonic acid to prostaglandins and thromboxanes. Recently it was
discovered that the cyclooxygenase enzyme includes two isoforms:
COX-1 and COX-2.
COX-1 is constitutively expressed in most tissues where it
contributes to physiologic functions, Dr. Steinbach said. Its
inhibition by NSAIDs has been associated with the common toxicities
of these agents, including gastric ulceration and bleeding. COX-2 is
an inducible enzyme that is induced in response to cytokines and
growth factors at sites of inflammation and in some tumors, including
colon adenomas and colon cancer.
Epidemiologic studies have shown that people who have taken NSAIDs
for prolonged periods of time have a lower than expected rate of
colorectal adenomas and carcinomas.
Extensive laboratory studies indicate that the tumor preventive
effects of NSAIDs are mediated, at least in part, by the inhibition
of COX-2, Dr. Steinbach said in an interview. Oshima et
al have shown that COX-2 gene knockout significantly inhibits polyp
formation in a mouse model of FAP. COX-2 inhibition by celecoxib also
inhibits tumor formation in a mouse model of FAP.
Dr. Steinbach noted that the NSAID sulindac has been widely used in
patients with FAP, along with surgical removal. Giardello et al (N
Engl J Med 328:1313, 1993) reported that sulindac reduced polyp
number by 44% and polyp size by 35% of pretreatment values in
patients with FAP.
In a recent study, COX-2 expression in tumor epithelial cells was
reported to be related to lymph node metastasis, more advanced Dukes
staging, and poorer outcome for patients with colorectal cancer
(Sheehan et al: JAMA 282:1254, 1999).
The discovery of COX-2 and its expression in tumors raised the
possibility that COX-2 could be effectively targeted for the purpose
of tumor prevention without the toxicities associated with
traditional NSAIDs, Dr. Steinbach said. The Celecoxib in
FAP Study was based on the research described above. It is the first
study of the effect of COX-2 inhibition on a human tumor.
This randomized, double-blind, placebo-controlled trial enrolled 77
patients with FAP. The colon was intact in 25 patients, while 52 had
had a subtotal colectomy. Patients were randomized 1:2:2 to placebo
(15 patients), celecoxib 100 mg twice daily (32 patients), or
celecoxib 400 mg twice daily (30 patients) for 6 months; 72 patients
completed the study.
Outcome measures were the number and size (greater than 2 mm) of
colorectal polyps in predefined areas of the colon and rectum at
baseline examination and at 6- month follow-up.
This was monitored by videoendoscopy oriented by a small tattoo
placed in the rectum of each patient. Videoendoscopy records were
scored by blinded reviewers as worse, same, or better than at baseline.
Dr. Steinbach reported that use of celecoxib 400 mg twice daily
significantly reduced the number of polyps by 28% and that 53% of
patients on this celecoxib dose had a reduction of better than 25% in
number of polyps.
In contrast, only one patient on placebo had a reduction in number of
polyps, and the reduction was only 7%. Blinded physician review of
endoscopies confirmed the benefit across the entire colorectum (P =
Mean polyp size decreased by 4.9% in the higher-dose celecoxib group
and by 0.7% in the placebo group (P = .055). Celecoxib also reduced
the overall colorectal polyp burden, defined as the sum of polyp
diameters in the monitored regions. Total polyp burden was reduced by
30.7% in the celecoxib 400 mg twice daily group (P = .001).
There was a consistent improvement in the celecoxib 400 mg
twice daily group, as well as in the celecoxib 100 mg twice daily
group, suggesting a dose-response relationship, Dr. Steinbach
The findings support the role of COX-2 in colon tumor growth and the
prospect that COX-2 inhibition may serve as a mechanism for colon
tumor prevention, Dr. Steinbach concluded. He said that a next step
could be to study whether COX-2 inhibition prevents polyp recurrence
in patients with sporadic colon tumors.