A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas.
OBJECTIVE
In human and animal studies, nonsteroidal anti-inflammatory drugs have been associated with a reduced risk of colorectal neoplasia. Although the underlying mechanisms are unknown, inhibition of cyclooxygenase (COX), particularly COX-2, is thought to play a role. We conducted a randomized, placebo-controlled, double-blind trial to assess whether use of the selective COX-2 inhibitor rofecoxib would reduce the risk of colorectal adenomas.


METHODS
We randomized 2587 subjects with a recent history of histologically confirmed adenomas to receive daily placebo or 25 mg rofecoxib. Randomization was stratified by baseline use of cardioprotective aspirin. Colonoscopic follow-up evaluation was planned for 1 and 3 years after randomization. The primary end point was all adenomas diagnosed during 3 years' treatment. In a modified intent-to-treat analysis, we computed the relative risk of any adenoma after randomization, using Mantel-Haenszel statistics stratified by low-dose aspirin use at baseline.


RESULTS
Adenoma recurrence was less frequent for rofecoxib subjects than for those randomized to placebo (41% vs 55%; P < .0001; relative risk [RR], 0.76; 95% confidence interval [CI], 0.69-0.83). Rofecoxib also conferred a reduction in risk of advanced adenomas (P < .01). The chemopreventive effect was more pronounced in the first year (RR, 0.65; 95% CI, 0.57-0.73) than in the subsequent 2 years (RR, 0.81; 95% CI, 0.71-0.93). As reported previously, rofecoxib was associated with increased risks of significant upper gastrointestinal events and serious thrombotic cardiovascular events.


CONCLUSIONS
In this randomized trial, rofecoxib significantly reduced the risk of colorectal adenomas, but also had serious toxicity.
Baron
John A
JA
Department of Medicine, the Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, New Hampshire, USA. John.A.Baron@Dartmouth.edu
Sandler
Robert S
RS
Bresalier
Robert S
RS
Quan
Hui
H
Riddell
Robert
R
Lanas
Angel
A
Bolognese
James A
JA
Oxenius
Bettina
B
Horgan
Kevin
K
Loftus
Susan
S
Morton
Dion G
DG
D000236:Adenoma / Q000473:pathology / Q000517:prevention & control*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018890:Chemoprevention / Q000379:methods; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000473:pathology / Q000517:prevention & control*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007783:Lactones / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013450:Sulfones / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors
D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib