HOUSTONHereditary cancer syndromes sometimes provide
researchers with an accelerated look at cancer pathogenesis and can
suggest novel approaches to cancer prevention, Patrick M. Lynch, JD,
MD, told an investigators workshop sponsored by the University
of Texas M. D. Anderson Cancer Center and Pharmacia Oncology. As an
example, Dr. Lynch cited the use of celecoxib (Celebrex), recently
approved by the Food and Drug Administration (FDA) as adjunctive
therapy to reduce the number of polyps developed by patients with
familial adenomatous polyposis (FAP).
Reducing the massive polyposis of patients with FAP may help postpone
colectomy and reduce the risk of developing colorectal cancer, noted
Dr. Lynch, who is associate professor of medicine in the Department
of Medical Oncology and Digestive Diseases at M. D. Anderson in Houston.
Dr. Lynch reported that studies with celecoxib built on a previous
randomized, placebo-controlled trial that had shown a dramatic
reduction in adenoma burden after 4 months of treatment with
sulindac (Clinoril). Previous epidemiologic studies of nonsteroidal
anti-inflammatory drugs (NSAIDs) and cancer had also shown a decrease
in the risk of colorectal cancer in patients on chronic NSAID therapy.
Cyclooxygenase-2 (COX-2) inhibitors are attractive candidates for
chemoprevention because they selectively block the inducible
COX-2-mediated arachidonic acid pathway that contributes to pain and
inflammation and also to oncogenesis, while leaving the COX-1 pathway
relatively intact for maintenance of gastroprotection and platelet
function. COX-2 is expressed in all stages of human colon
carcinogenesis, Dr. Lynch said.
double-blind, placebo-controlled trial that led to approval of
celecoxib for use in FAP included 81 patients randomized to placebo
or to celecoxib 100 mg BID or 400 mg BID for 6 months. (The
FDA-approved dose of celecoxib for anti-inflammatory use is 200 mg
BID.) The researchers used photos and videotapes of GI tract segments
marked by anatomic landmarks or by India ink tattoos to assess the
effects of therapy.
Adenoma burden (defined as the sum of polyp diameters) was reduced
14.6% by treatment with 100 mg of celecoxib BID (P = NS) and
30.7% by treatment with 400 mg BID (P = .001) (see Figure 1).
In one patient the reduction in disease burden was nearly 50% (see
Figure 2). Dr. Lynch said that intermediate endpoints such as the
number of aberrant crypts are also being evaluated.
Long-Term Benefits Unknown
Celecoxib is now FDA-approved as adjunctive therapy in FAP to
reduce the number of adenomatous colorectal polyps. Long-term
clinical benefit in reduction of the number of polyps is unknown, and
it is important to remember that celecoxib treatment is not a
substitute for indicated surgery in these patients, Dr. Lynch
said. Usual care and regular monitoring of FAP patients should
not be altered. We also do not yet know if the benefits will persist
after celecoxib is discontinued.
Celecoxib could also prevent disease recurrence in the rectum after
colectomy, and Dr. Lynch said that there is a strong
suggestion that some patients also had suppression of adenomas
in the duodenum following celecoxib treatment. Use of celecoxib
chemoprevention in carriers of the FAP gene prior to the onset of
disease will also be studied, as will long-term efficacy. A large
multicenter trial of celecoxib chemoprevention in individuals who
have had resected sporadic adenomas is expected.