Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial.
Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (> or =3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade > or =3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.
Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California, USA. flmeyske@uci.edu
Frank L
FL
Meyskens
Christine E
CE
McLaren
Daniel
D
Pelot
Sharon
S
Fujikawa-Brooks
Philip M
PM
Carpenter
Ernest
E
Hawk
Gary
G
Kelloff
Michael J
MJ
Lawson
Jayashri
J
Kidao
John
J
McCracken
C Gregory
CG
Albers
Dennis J
DJ
Ahnen
D Kim
DK
Turgeon
Steven
S
Goldschmid
Peter
P
Lance
Curt H
CH
Hagedorn
Daniel L
DL
Gillen
Eugene W
EW
Gerner
D000236:Adenoma / Q000175:diagnosis / Q000517:prevention & control*; D000328:Adult; D000368:Aged; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000517:prevention & control*; D004311:Double-Blind Method; D000518:Eflornithine / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D013467:Sulindac / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D010919:Placebos; D013467:Sulindac; D000518:Eflornithine