Colorectal polyps: aspirin, COXIBs, and NSAIDs

Colorectal adenoma and aspirin
Familial adenomatous polyposis (FAP) and coxibs
Familial adenomatous polyposis (FAP) and sulindac
Comment

Colorectal polyps can occur in people with a history of colorectal cancer, or because they have familial adenomatous polyposis. For both there is laboratory work suggesting that NSAIDs decrease tumours and tumour activity. There is also abundant observational information showing that frequent use of NSAIDs or aspirin is associated with reduced incidence of some cancers.

The next step then is to move from observation to treatment trials. Here the occurrence of frequent colorectal polyps as precursors of later cancers is an ideal early surrogate marker of success. The details of the trials are in Table 1.

Table 1: Trials of aspirin, COXIBs, and sulindac in colorectal adenomas and familial polyposis

Reference	Design	Patients	Treatment	Benefits	Adverse events
Colorectal adenomas: aspirin
Sandler et al. NEJM 2003 348: 883-890	Randomised, double-blind comparison of aspirin or placebo for a median of 31 months	Colonoscopy for polyp removal within four months, and with colon or rectal cancer with curative surgery. Exclusion was familial polyposis	Aspirin 325 mg daily (N=317) Placebo (N=318)	Median time to first colonoscopy: Aspirin 16 months Placebo 11 months Significantly lower number of adenomas detected with aspirin, with 17% with at least one adenoma with aspirin and 27% with placebo	Adverse events appeared low in number and approximately the same in each group. Death rates similar in both groups
Baron et al. NEJM 2003 348: 891-899	Randomised, double-blind comparison of two doses of aspirin or placebo for a median of 33 months	One or more colorectal adenomas removed within three months, history of at least two confirmed adenomas, or adenoma of at least 1 cm removed in prior 16 months	Aspirin 325 mg daily (N=372) Aspirin 81 mg daily (N=377) Placebo (N=372)	Incidence of one or more adenomas was 47% with placebo, 38% with 81 mg aspirin and 45% with 325 mg aspirin. Bare statistical benefit for lower dose aspirin.	Increased incidence of cardiovascular events (MI, stroke, and revascularisation; 1.3% MI or stroke with aspirin, 0.3% with placebo) with higher dose aspirin than placebo (relative risk about 3). No differences in bleeding, hospital admission, or other cancer incidence.
Benamouzig et al. Gastroenterology 2003 125: 328-336	Randomised, double-blind comparison of two doses of aspirin or placebo for 48 months	At least 3 adenomas irrespective of size, or one confirmed adenoma measuring at least 6 mm diameter. Exclusion included familial polyposis, bowel resection	Lysine acetylsalicylic acid160 mg or 300 mg daily (N=140), or placebo (N=132)	At one-year colonoscopy, at least one adenoma in 38/126 (30%) with aspirin and 46/112 (41%) with placebo. Significant difference for larger adenomas and high grade dysplasia, and total adenomas, though on small numbers	Adverse events were not reported
Familial polyposis: coxibs
Steinbach et al. NEJM 2000 342: 1946-1952	Randomised, double-blind comparison of celecoxib or placebo for 6 months	Patients with FAP with five or more polyps 2 mm or more in diameter. Exclusion included colectomy within 12 months or anticipated within 8 months, use of NSAIDs or aspirin	Celecoxib 100 mg twice daily (N=32) Celecoxib 400 mg twice daily (N=30) Placebo (N=15)	Higher dose of celecoxib had significant decrease in number of polyps and polyp burden (by about 30%)	No difference in common adverse events. Two patients withdrawn with higher dose of celecoxib (allergic reaction and dyspepsia)
Higuchi et al. Clin Cancer Res 2003 9: 4756-4760	Randomised, double-blind comparison of rofecoxib or placebo for 9 months	Patients with FAP with colorectal polyps.	Rofecoxib 25 mg daily (N=10) Placebo (N=11)	Decrease of number of polyps with rofecoxib (7%) versus increase (3%) with placebo, and significant reduction in polyp size (17%) with rofecoxib	No difference in adverse event rates
Familial polyposis: sulindac
Labayle et al. Gastroenterol 1991 101: 653-659	Randomised, double-blind comparison of sulindac or placebo for 4 months in each phase of a crossover trial	Patients with FAP with colorectal polyps.	Sulindac 300 mg daily (N=10) Placebo (N=10) One non-compliant patient withdrawn	Sulindac had complete or almost complete regression in 9/9 patients, while with placebo there was an increase in 5, no change in 2, and relative decrease in 2	Not mentioned
Nugent et al. Br J Surg 1993 80: 1618-1619	Randomised comparison over six months	Patients with FAP with colorectal and duodenal polyps who had undergone prophylactic colectomy and with advanced duodenal polyposis	Sulindac Placebo	In 14 patients with rectal polyps, significant polyp regression was seen with sulindac compared with placebo	Not mentioned
Giardello et al. NEJM 1993 328: 1313-1316	Randomised, double-blind comparison of sulindac or placebo for 9 months	Patients with FAP with colorectal polyps, with 18/22 having undergone colectomy	Sulindac 300 mg daily (N=11) Placebo (N=11)	Number and diameter of polyps were 44% and 35% for sulindac. No patient had complete resolution of polyps	No adverse events were noted with sulindac
Ladenheim et al. Gastroenterol 1995 108: 1083-1087	Randomised, double-blind comparison of sulindac or placebo for 4 months	Patients with FAP with colorectal polyps.	Sulindac 300 mg daily (N=22) Placebo (N=22)	No clinically significant regression of sporadic colonic polyps	With sulindac four withdrawals with heartburn (2), anaemia, and urosepsis
Giardello et al. NEJM 2002 346: 1054-1059	Randomised, double-blind comparison of sulindac or placebo for 48 months	Patients had a disease causing mutation in the APC gene but no endoscopically identifiable colorectal adenomatous polyps and no history of surgery. Age 8 years or older (range 8-25 years)	Sulindac 150 or 300 mg daily (N=21) Placebo (N=20)	Four years of treatment did not affect the number or size of adenomas developed	No difference in adverse events. One withdrawal because of neutropoenia

Colorectal adenoma and aspirin

Three trials have examined the efficacy of aspirin versus placebo following colorectal cancer operations, or polyp removal, but with adenomas. These trials were generally large, with about 1,800 patients in total. Trials were properly randomised and double-blinded, and aspirin doses were generally 325 mg daily or less. They were also of long duration, between 30 and 48 months (though for this longer trial there is just a report at one year).

Two of the trials had an absolute reduction in people with at least one adenoma of 10%, while the other showed no difference (Table 1). Overall there was a significant reduction in patients having at least one adenoma with a relative risk of 0.83 (95% CI 0.73 to 0.95). The number needed to treat with 150 to 325 mg aspirin for one to three years for one patient to be free of adenomas was 16 (9 to 56).

One trial had an increased incidence of cardiovascular adverse events with aspirin, with a 1.3% incidence of heart attack and stroke compared with 0.3% with placebo.

Familial adenomatous polyposis (FAP) and coxibs

Two trials investigated the effect of coxibs on colorectal polyps in patients with FAP (Table 1) over six to nine months. They were randomised and double blind, but small. One showed a large 30% decrease in polyp number and burden with celecoxib 800 mg daily, while there was less effect in a tiny trial with rofecoxib 25 mg daily.

Familial adenomatous polyposis (FAP) and sulindac

Four small randomised trials have investigated sulindac (usually 300 mg daily) in FAP and its effect on colorectal polyps. All were very small (about 90 patients total), and of four to nine months duration. Three of the four showed a decrease in polyps, while one found no effect. A further trial in young FAP patients who had not developed colorectal adenomatous polyps showed no effect of sulindac on their development over four years.

Comment

Overwhelming evidence for the effect of aspirin, coxib, or NSAID on adenomatous polyp development is lacking. Most of the trials were well done, but most were also small, and there were conflicting results, from excellent to no effect. In FAP, having results in only 90 patients with sulindac trials and 60 in celecoxib trials does not give confidence that we know very much about treatment effects. Longer and larger trials would be needed to do that.

The best evidence, in terms of numbers, for aspirin in colorectal adenomas of non-familial origin, showed that there was a slight overall effect in 1,617 patients. Statistical significance was achieved, but barely, and the size of the effect was small, though any effect is welcome.

That aspirin is associated with excess strokes and possibly increased risk of myocardial infarction in people at low cardiovascular risk is known. Bandolier 105 reported a review looking at the evidence. The overall picture is obscured by types of study, levels of risk, confounding, and small numbers of events.

This does not help when trying to make decisions about treating colorectal polyps. The jury is still waiting for evidence.