Aspirin decrease colon cancer review

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Cheers, Al.

New Engl J Mws. 348:879-880 March 6, 2003

Aspirin and the Prevention of Colorectal Cancer

F. Imperiale, M.D.

Awareness of the substantial morbidity and mortality attributable to colorectal

cancer has

focused attention on early detection and prevention through screening and on

other

strategies such as chemoprevention. Among several agents under evaluation,

aspirin

appears to have the inside track. Could aspirin reduce the burden of disease

associated

with the second-leading cause of cancer-related death in the United States?

A protective effect of aspirin is biologically plausible. Aspirin works in part

through the

inhibition of cyclooxygenase-2, an enzyme that is found in colorectal cancer

tissue.

Epidemiologic studies have shown a consistent 40 to 50 percent reduction in the

risk of

colorectal neoplasia, despite differences in the design of the studies, the

populations

studied, patterns of aspirin use, and outcomes. In randomized trials involving

patients with

familial polyposis, sulindac and celecoxib have reduced the number and size of

adenomatous polyps. However, the only randomized trial of aspirin found no

reduction in

the incidence of colorectal cancer either during the 5-year study period or up

to 12 years

after the study began.

It is unlikely that there will be a definitive clinical trial of aspirin or

nonsteroidal

antiinflammatory drugs for the primary or secondary chemoprevention of

colorectal cancer

in which colorectal cancer is the outcome, because a large sample and long-term

follow-up

would be needed. However, given the belief that the development of most

colorectal

cancers follows a sequence leading from adenoma to carcinoma, a clinical trial

in which

aspirin reduced the rate of recurrence of adenomas might make a compelling case

for its

effectiveness. The results of two such trials are reported in this issue of the

Journal.

In the study by Sandler and colleagues (pages 883–890), 635 patients who were

cured of colorectal cancer were randomly

assigned to receive 325 mg of enteric-coated aspirin or placebo daily. The trial

was terminated after a median duration of

treatment of 31 months because one or more adenomas were discovered in 17

percent of the patients in the aspirin group and

27 percent of those in the placebo group. Although the number of adenomas was

lower among the patients in the aspirin group,

the mean size of the adenomas did not differ significantly between groups, nor

did the proportions of patients with advanced

adenomas. The hazard ratio for detection of a new polyp in the aspirin group as

compared with the placebo group was 0.64,

indicating that aspirin delayed the development of adenomas. Adverse effects

were infrequent, and the rates were similar in the

two groups.

In the study by Baron and colleagues (pages 891–899), 1121 patients who had

recently had adenomas removed were

randomly assigned to placebo, to 81 mg of aspirin daily, or to 325 mg of aspirin

daily. After a mean duration of treatment of 33

months, advanced neoplasms were found in 12.9 percent of the patients in the

placebo group, 7.7 percent of those in the

81-mg group, and 10.7 percent of those in the 325-mg group. The rate of

recurrence of adenomas was significantly lower in the

group taking lower-dose aspirin than in the placebo group, but for unclear

reasons, the larger dose of aspirin did not significantly

reduce the rate of recurrence. Stroke and serious bleeding were more frequent in

the aspirin groups than in the placebo group,

but the differences were not statistically significant.

These trials indicate that aspirin reduces the risk of recurrent adenomas among

persons with a history of colorectal cancer or

adenomas. Does this mean that aspirin should now be recommended for secondary

chemoprevention in persons with a history

of colorectal neoplasia or for primary chemoprevention in the 90 percent of

persons 50 years of age or older who are

considered to be at average risk for colorectal cancer? This question requires

consideration of the clinical importance of the

outcomes, the duration of treatment, and the magnitude of the protective — and

harmful — effects of aspirin (see Table).

The numbers of persons who would need to be treated in order to prevent any

adenomas and to prevent advanced adenomas

suggest that there is a moderate-sized benefit, but the fact that most adenomas

do not progress to cancer makes these surrogate

outcomes less important in terms of prevention. These outcomes are used in

clinical trials because they occur earlier and more

frequently than does early-stage colorectal cancer — not because they are

necessarily clinically important. Given that

endoscopic surveillance for recurrent neoplasia would result in the detection

and removal of most or all neoplasms anyway, the

true clinical benefit — avoidance or delay of polypectomy for 1 of every 10 or

19 persons treated with aspirin — would seem

to be small.

And what about the adverse effects of aspirin? Among patients with a history of

colorectal adenomas or colorectal cancer, the

number of recurrent adenomas prevented by aspirin use would be much higher than

the number of episodes of bleeding it would

cause (see Table). However, the cumulative clinical importance of episodes of

bleeding probably exceeds that of the surrogate

neoplasm-related outcomes, especially when the effect of surveillance is taken

into account.

If aspirin were used for primary prophylaxis against colorectal cancer in adults

at average risk, the lower base-line risk of

neoplasia would mean that more people would need to be treated for a period of

10 to 20 years or longer (see Table). The

cumulative risk of major adverse effects most likely outweighs any benefit in

the prevention of colorectal cancer, particularly

when prevention due to screening is considered. With the same side-effects

profile, the benefit of aspirin in coronary artery

disease is arguably much greater, yet the U.S. Preventive Services Task Force

does not recommend aspirin unless the five-year

risk of coronary artery disease is 3 percent or higher. Cost-effectiveness

analyses that have evaluated aspirin for primary

chemoprevention indicate that it saves fewer lives at higher costs than does

screening for colorectal cancer by any method and

is not beneficial among persons at average risk who follow screening

recommendations.

Although aspirin may be of some benefit in preventing colorectal cancer, it

cannot yet be recommended for this indication and is

not a substitute for screening and surveillance. Nevertheless, the

well-conducted trials reported in this issue of the Journal

provide proof of the principle that aspirin moderately reduces the risk of

recurrent colorectal neoplasia and provide support for

the assumptions and probabilities that have been used in published analyses of

cost effectiveness. Determination of whether

aspirin has a role in preventing colorectal cancer must await the results of

clinical trials designed to determine whether it can be

used to decrease the required frequency or intensity of screening or

surveillance.