Transcript Study Design

The Effect of Celecoxib, a
Cyclooxegenase-2 Inhibitor, In
Familial Adenematous Polyposis
Gideon Steinbach, M.D., Ph. D., Patrick Lynch,
M.D., J.D., Robin K.S. Phillips, M.B., B.S., Marina
H. Wallace, M.B., B.S., Ernest Hawk, M.D.,
M.P.H., Gary B. Gordon, M.D., Ph.D., Naoki
Wakabayashi, M.D., Ph.D., Brian Saunders, M.D.,
Yu Shien, Ph.D., Takashi Fujimara, M.D., Li-Kuo
Su, Ph.D., and Bernard Levin, M.D.
Why Familial Adenomatous
Polyposis?
• Human colon cancer develops from normal
mucosa to adenomatous polyps to carcinoma
• Patients with FAP as a result of germ-line
mutations in the Adenomatous Polyposis Coli
gene have a nearly 100 % risk of colon cancer
• Study of FAP may provide insight helpful for
sporadic adenomas that develop as a result of
mutations in the APC gene
Cyclooxegenase-2 and Colon
Cancer
Gupta, RA, and Dubois, RN. Colorectal Cancer
Prevention and Treatment by Inhibition of
Cyclooxegenase-2. Nature Reviews: Cancer. Oct.,
2001 (1): 11-23.
• Cox-2 derived prostoglandins
may interact with malignant
epithelial cells (cellautonomous) or surrounding
stromal cells (landscaping
effect)
• Cell-autonomous effects:
changes in key regulatory
genes that inhibit apoptosis
and enhance migration
• Landscaping effects: Cox-2
supports fibroblast
neurovascularization near
tumors
Sulindac and Rectal Adenomas
• Sulindac, a nonselective cyclooxeganase
inhibitor, caused regression in controlled
and uncontrolled studies
• Rapid recurrence observed after
discontinuing therapy (~3-4 mo)
• But, sulindac was found to inhibit normal
COX-1 activities, leading to gastric
ulceration
Study Design
•
•
•
•
Double-Blind Study
Placebo Controlled
Age Discrepancy?
Surgical Status?
90
80
70
60
50
40
30
20
10
0
East
West
North
1st 2nd 3rd 4th
Qtr Qtr Qtr Qtr
Celecoxib Efficacy
90
80
70
60
50
40
30
20
10
0
East
West
North
1st 2nd 3rd 4th
Qtr Qtr Qtr Qtr
• 400 mg Celecoxib
treatment 2x daily is most
effective in reducing total
number of polyps
• 400 mg Celecoxib
treatment 2x daily was
most effective in reducing
total polyp burden
(average sum of polyp
diameters)
• Regression in patients
given the Placebo?
Distribution of Polyp Regression
• Patients receiving Celecoxib treatment (100 or 400
mg) show definite bias towards reduction in
number of polyps
• Large outlyer population in these groups?
Change in Colorectal Polyposis
• Patients receiving 400 mg of
Celecoxib 2x daily show
improvement in all areas of
colon
• Patients receiving 100 mg of
Celecoxib 2x daily show
trend towards improvement
in rectum, ascending colon,
and cecum
• Are these two areas the first
targets of cox-2 inhibitormediated polyp regression?
Is the mechanism different
for different dosages?
Side Effects?
• Most common adverse events reported were
diarrhea and abdominal pain
• Incidence of each event was similar among
all groups: diarrhea (placebo, 13%, 400mg
2x daily, 13 %, and 100 mg 2x daily, 19%)
and abdominal pain (placebo, 13%, 400mg
2x daily, 3 %, and 100 mg 2x daily, 7%)
Is This Really Cox-2 Inhibition?
•
•
•
•
•
High Doses of NSAIDs (50-1000 um) can induce apoptosis in vitro
independently of COX-2 (or COX-1) by:
Inhibition of IKKBeta Kinase
Decreasing the levels of anti-apoptosis protein BCL-X
Overexpressing pro-apoptitic (?) Peroxisome Proliferator Activated Receptor
What is bioavailable in Celecoxib Treatment?
What Now?
• Study the role of COX-2 inhibition in
prevention of adenoma development in preclinical FAP adolescents
• Study the role of COX-2 inhibition in the
prevention of colorectal tumors in persons
with sporadic adenomatous polyps
Can COX-2 Inhibitors Prevent
Polyp Formation?
Giardello, FM, et. Al. Primary Chemoprevention of Familial Adenomatous Polyposis with Sulindac. N Eng J Med
2002 (346): 1054-9.
• Clinical trials in 2002 with Sulindac (non-specific COX inhibtion) in 41
young patients with FAP genotype who were phenotypically unaffected
• Prostoglandin production in the mucosa was lower than in the placebo
group
• However, “standard doses of sulindac did not prevent the development
of adenomas in subjects with FAP” (NEJM, 2002; 346:1054-9)
Treatment Issues
• COX-2 inhibition of development of
sporadic colon cancer?
• Inhibition of Microsatellite unstable
tumorigenesis
• Treatment of colorectal cancer in the
context of Inflammatory Bowel Disease?
The End!