Chemoprevention of colorectal cancer: a systematic review in rodents.
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References to Human Studies (Not in PubMed, or Multiple Links)
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Arber N., et al., Tel Aviv Sourasky Medical Ctr., Tel Aviv, Israel
Chemoprevention of colorectal adenomas with celecoxib in an international randomized, placebo-controlled, double-blind trial
Proc Amer Assoc Cancer Res 2006;47:[Abstract #CP4].
Reported by Rabiya Tuma, MedPage Today Staff Writer. Reviewed by Rubeen K. Israni, M.D., April 03, 2006.
The PreSAP (the international Prevention of Sporadic Adematous Polyps) trial included a similar group of patients at 107 centers in 32 countries. A total of 1,561 patients who had had an adenomatous polyp removed within 30 days were randomized to either 400 mg daily of Celebrex (n=933) or placebo (n=628) in a 3:2 ratio. Patients were stratified according to aspirin use and treatment center.
At year one, 88.7% of patients had a colonoscopy as did 79.2% at year three. At that point, 33.6% of patients in the active drug arm had developed new polyps compared to 49.3% in the placebo arm (HR=0.64, P<0.0001).
When patients in the PreSAP trial were stratified into lower and higher risk, defined as those with three or more adenomas at baseline, or an age of 60 or above and a parent with colorectal cancer, the team found an exaggerated benefit of drug. Approximately 70% of the subjects on placebo had new adenomas compared to approximately 50%, for a relative risk reduction of 33% (P=.0002).
Again, the researchers grouped adverse events into types for statistical analyses. Renal/hypertensive events occurred in 15.3% of placebo subjects compared to 20.7% of those on drug (p<0.01). The rate of gastrointestinal events was not significantly different between the groups, with 10.4% of placebo patients and 12.1% in the Celebrex arm.
All types of cardiovascular events occurred significantly more often in the Celebrex arm (7.5%) versus the control arm (4.8%, P<0.05). There were only 23 serious cardiac events in the 933 patients (2.5%) drug arm compared to 12 out of 628 (1.9%) in the placebo arm (HR=1.3, 95% CI 0.6-2.6). Again, however, there were a disproportionate number of these events in patients with a prior history, nine in the active drug arm out of 128 (7.0%) patients and three out of 70 (4.2%) in the placebo arm (HR=1.6, 95% CI, 0.4-6.1).
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Bertagnolli M.M., Craig J. Eagle, Ernest T. Hawk, and The Adenoma Prevention with Celecoxib (APC) Study
Celecoxib reduces sporadic colorectal adenomas: Results from the Adenoma Prevention with Celecoxib (APC) trial
Proc Amer Assoc Cancer Res 2006;47:[Abstract #CP3].
Cyclooxygenase-2 (Cox-2) has been implicated in the pathogenesis of colorectal cancer, and drugs that inhibit this enzyme reduce the occurrence of precursor colorectal adenomas both in animal models and in patients with familial adenomatous polyposis. These studies suggest that Cox-2 inhibitors also prevent sporadic colorectal neoplasia.
Methods We performed a randomized, double-blind trial of the selective Cox-2 inhibitor celecoxib for the prevention of colorectal adenomas. A total of 2035 patients were randomized to receive placebo (679 patients), 200 mg celecoxib (685 patients), or 400 mg celecoxib (671 patients), administered twice daily. The randomization was stratified for the use of low dose aspirin, which occurred in 31% of participants. A followup colonoscopy was performed at 1 year and 3 years after study randomization. We used the life-table extension of the Mantel-Haenszel test (Mantel-Cox) to compare the groups with respect to the risk of newly detected colorectal adenomas or colorectal cancers over 3 years. Study participants underwent safety assessments by telephone interviews performed at 2-month intervals. Complete medical histories and physical exams were also performed at baseline and after 1 and 3 years of study drug use. Safety analyses considered particular issues related to NSAID use, including gastrointestinal, renal, cardiovascular, and hemorrhagic events.
Results Follow-up colonoscopies were completed at year 1 for 89% of those randomized and at year 3 for 76% of those randomized. The incidence of one or more adenomas at either colonoscopy was 60.6% in subjects taking placebo, and was significantly reduced in patients taking celecoxib (P < 0.0001) in a dose-responsive manner. The respective relative risks of advanced neoplasms (adenomas ³ 1 cm diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer) were also significantly reduced in patients using celecoxib (P < 0.0001). Final safety analyses confirmed our earlier report of increased cardiovascular events in patients using celecoxib and provided data related to the effect of celecoxib upon gastrointestinal, renal, and bleeding risks in the study population.
Conclusions The APC Trial found that celecoxib significantly reduced formation of large intestinal adenomas at 1 and 3 years after polypectomy. Final safety analyses confirmed an increased risk of cardiovascular events among celecoxib users and provided data useful in estimating the overall benefit:risk ratio of celecoxib use for sporadic adenoma chemoprevention.
Brigham and Women's Hospital, Boston, MA, Pfizer, Inc., New York, NY, National Cancer Institute, Bethesda, MD
More detailed data reported by Rabiya Tuma, MedPage Today Staff Writer. Reviewed by Rubeen K. Israni, M.D., April 03, 2006.
Patients were evaluated with colonoscopies at one and three years, and 89% of study participants had the one year check-up, as did 76% at three years. Of those, 60.6% of placebo patients had new adenomas detected at one of those times. There was a significant reduction in the likelihood of adenoma detection in both Celebrex arms, (hazard ratio for 200-mg group = 0.67, HR for 400-mg group = 0.55, P<0.0001).
The results were even more exaggerated when only high risk adenomas, defined as greater than 1 cm, villous histology, high grade dysplasia, intramucosal carcinoma, or invasive carcinoma, were evaluated. In that group, 25% of the placebo patients developed new lesions while on study. The risk decreased significantly for both active drug arms (HR for 200 mg arm = 0.43, HR for 400 mg arm =0.34, P<0.001).
Because the number of adverse events was small in all arms of the trial, the researchers combined several related events together into larger categories for analysis. The grouping was done prior to unblinding and included renal/hypertensive events (n=234) and gastrointestinal ulceration and hemorrhage (n=435). There complications were not significantly different between arms, though there was a non-significant trend in the aspirin users for a dose-dependent increase in the number of ulcerations and hemorrhages with increasing Celebrex dose.
There were a total of 46 cardiovascular events in the trial, with seven in the placebo arm (1%) including one death; 16 (2.3%) in the 200-mg Celebrex arm, with three deaths, and 23 (3.4%) in the 400-mg arm with six deaths
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Cole BF, Baron JA, Sandler RS, Haile RH, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Byers T.
A randomized trial of folic acid to prevent colorectal adenomas
Proc AACR 2005; 46: [Abstract #4399] 96th Amer Assoc Cancer Res Annual Meeting April 16-20, 2005 Anaheim/Orange County, CA
Background: Laboratory and epidemiologic data suggest that folic acid supplementation has an antineoplastic effect in the large bowel. The Aspirin-Folate Polyp Prevention Study is a randomized, double-blind, factorial design trial of folic acid and aspirin supplementation as chemoprotective agents against colorectal adenomas. Findings regarding aspirin have been reported; we report here the folic acid results.
Methods: Subjects with a recent history of adenomas were randomly assigned to receive placebo (n=505) or 1 mg of folic acid (n=516) daily with or without aspirin. Follow-up colonoscopy was scheduled approximately three years after the qualifying endoscopy (1st follow-up interval), at which point aspirin supplementation was completed. Randomized supplementation with folic acid or placebo continued until the next surveillance exam (2nd follow-up interval) in subjects who re-consented after completing the 1st follow-up interval. The occurrence of one or more adenomas, adenoma multiplicity (number per subject), and the occurrence of advanced lesions (adenomas with any villous features, severe dysplasia, size of 1 cm or larger, or invasive cancer) were compared during follow up of the folic acid and placebo groups.
Results: Adherence to study medications and avoidance of folic-acid-containing vitamin supplements were excellent, with compliance rates varying over time between 87% and 96% of subjects. In the 1st follow-up interval, surveillance colonoscopies were performed in 987 subjects (97%). The incidence of one or more colorectal adenomas was 42% in placebo subjects and 44% in folic acid subjects (crude risk ratio [RR]: 1.04; 95% confidence interval [CI]: 0.90 to 1.20). The incidence of advanced lesions in the folic acid group was modestly higher than in placebo (9% vs. 12%; RR: 1.31; 95% CI: 0.90 to 1.89). 925 subjects consented to extended follow-up, with 729 continuing randomized treatment. With the end of funding for continued treatment, the trial was stopped October 1, 2004. Analysis of the 488 subjects who underwent colonoscopic follow-up in the 2nd interval showed RR's similar to those of the 1st follow-up interval. Subjects in the folic acid group tended to have greater adenoma multiplicity. In the subgroup that continued treatment in the 2nd follow-up interval, the mean (SD) number of adenomas per subject was 0.55 (0.89) in the placebo group and 0.79 (1.40) in the folic acid group (rate ratio: 1.44; 95% CI: 1.03 to 2.02). No other significant adverse effects of folic acid were detected.
Conclusions: Folic acid supplementation at 1 mg/day does not reduce the incidence of colorectal adenomas. There was weak evidence that folic acid increases the risk of multiple adenomas.
This trial was conducted by the Polyp Prevention Study Group and was supported by a grant from the National Cancer Institute (CA 59005). Folic acid and placebo tablets were supplied by Wyeth Pharmaceuticals.
- Low fat interventions (and subsequent caloric reduction)
Schatzkin 2000
McKeown-Eyssen 1994
MacLennan 1995
- Beta-carotene interventions
Greenberg 1994
MacLennan 1995
- Vitamin C and E interventions
Greenberg 1994
McKeown-Eyssen 1988
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Meyskens F.L.Jr., McLaren C.E., Pelot D. et al.
Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas:
A Randomized Placebo-Controlled, Double-Blind Trial
Cancer Prevention Research, 1, 32-38, 2008. - - - - - FREE FULL TEXT on CaPR AACR website
Published Online First on April 14, 2008 doi: 10.1158/1940-6207 CAPR-08-0042.
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 (.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 .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.
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Corpet DE & Taché S, 2002, Nutrition & Cancer - & - DE Corpet & F Pierre, 2003, Cancer Epidemiol. Biomarkers Prevention - http://www.inra.fr/reseau-nacre/sci-memb/corpet/indexan.html & Mirror site