Aspirin is Clinically Effective in Chemoprevention of Colorectal Neoplasia: Point Free

Colorectal cancer (CRC) prevention has become an important goal for health providers, physicians, and the general public. CRC is a highly prevalent disease that is associated with considerable mortality and morbidity rates, with >1,000,000 new cases and 500,000 deaths expected worldwide in 2006 (1). CRC has a natural history of transition from precursor to malignant lesion that spans 15 to 20 years on average, providing a window of opportunity for effective interventions and prevention. As promising as modern screening tests may be, they are relatively expensive, carry some risk, and require expertise. Most importantly, the level of patient willingness to accept screening is low in many countries, thereby limiting effectiveness.

Early detection of CRC is not an adequate enough objective. Surgery is still required, recurrence is possible, and anxiety persists. Recognition of the ability to prevent CRC by identifying and removing precancerous adenomas has led to a marked increase in the use of colonoscopy as a primary screening tool. As the emphasis of screening shifts toward precancerous adenomas, they have become attractive targets for primary prevention methods. Foremost among the agents currently being evaluated for their ability to reduce the recurrence rates of adenomas is aspirin. There is much evidence suggesting an inverse relationship between aspirin consumption, adenoma incidence, and CRC incidence and mortality.

Aspirin was first synthesized more than a century ago, and its benefits are still being discovered. They are, indeed, remarkable, ranging from relief of pain to prevention of cancer. Low-dose aspirin is now widely used for cardiovascular disease prevention, with several large cohort studies demonstrating its efficacy even at the low dose of 81 mg a day (1). Aspirin has been investigated extensively in the chemoprevention of colorectal adenomas and cancer, based in part on their inhibition of cyclooxygenase (COX)-1 and COX-2 enzymes, both of which are important mediators of prostaglandin production. To understand the dilemma whether or not to use aspirin as a chemopreventive agent for CRC, we need to assess the effect of aspirin on prevention or regression of colorectal adenomas and cancer, and then estimate whether the expected health benefit of the use of aspirin exceeds its expected negative health consequences.

The Nurses' Health Study was initiated in 1976 and included >120,000 nurses ages 30 to 55 years. Data on life-style, diet, and medications have been retrieved from self-administered questionnaires that had been modified over the years. Chan et al. (2) found a significantly lower rate of CRC among regular aspirin users (2 or more regular 325 mg tablets per week). The risk reduction was evident only after 5 years of exposure, with the protective effect being more significant after 10 years (Table 1). The dose of aspirin was important as well. Women consuming 2 to 5 regular aspirins per week experienced a modestly reduced relative risk (RR; 11%), whereas those who consumed at least 14 doses per week experienced the highest (32%) reduction in CRC incidence.

The mortality in the Nurses' Health Study was recently evaluated after a lapse of 24 years. Aspirin users had a 0.75 and 0.65 RR of cardiovascular and CRC death, respectively (3). Long-term use of >20 years further reduced the RR to 0.60.

In the observational health professionals' study on 50,000 individuals, regular aspirin use of more than twice a week was associated with a 32% reduction in mortality from CRC (4).

Jacobs et al. (5) recently examined the associations between long-term daily use of aspirin (325 mg/day) and overall cancer incidence among 69,810 men and 76,303 women participating in the Cancer Prevention Study II Nutrition Cohort. Aspirin use was reported at enrollment in 1992 to 1993 and updated in 1997, 1999, and 2001. Daily aspirin use for >5 years was associated with a lower incidence of CRC (RR, 0.68) among men and women combined.

Two large trials of aspirin in primary prevention showed no effect on the occurrence of CRC. The Women's Health Study randomized healthy women to low-dose aspirin versus placebo. An average of 10 years of follow-up failed to show a primary preventive effect of aspirin (6). The Physicians' Health Study was primarily designed to assess the effect of aspirin (325 mg every other day) on the risk of coronary artery disease and cancer in 22,071 male physicians in the United States (7). After 5 years of aspirin therapy, there was no change in the incidence of CRC or polyps (nonsignificant odds ratio of 1.15 for CRC and 0.86 for adenomas) between the treatment and the placebo groups.

The British Doctors Aspirin Trial (N = 5,139, two-thirds allocated 500 mg aspirin for 5 years, one-third allocated to open control; ref. 8) and the United Kingdom Transient Ischaemic Attack Aspirin Trial (N = 2,449, two-thirds allocated 300 mg or 1,200 mg aspirin for 1-7 years, one-third allocated to placebo control; ref. 9) failed to show a protective effect of aspirin. Flossmann et al. (10), however, studied the long-term effect of aspirin in these two randomized trials with reliable posttrial follow-up for >20 years. They also did a systematic review of all relevant observational studies and showed that the use of >300 mg aspirin per day for at least 5 years in the randomized control trials (RCT) was effective in primary prevention of CRC, with a latency period of about 10 years. These results were consistent with findings from their meta-analysis of the observational studies. These studies were, however, unable to circumvent confounders, such as intermittent and variable dosing, use of other nonsteroidal anti-inflammatory drugs and risk-modifying drugs.

Taken together, no clear message on optimal dosing has emerged from cohort studies thus far. It is, however, suggested that long-term follow-up is required from other randomized trials to establish the effects of lower or less frequent doses of aspirin on the incidence and mortality from CRC.

Three randomized controlled trials of patients with previous adenoma or CRC have shown significant efficacy in preventing polyp recurrence when given at daily doses of 81 to 325 mg/day of aspirin. These trials were not, however, entirely in agreement as to the lowest effective aspirin dose, and they were relatively short-term in duration, i.e., up to 3 years.

In the first trial, aspirin (325 mg qd) or placebo was prescribed to >600 patients with a recent history of CRC, and there was a significant reduction in the incidence of colorectal adenomas in the treatment arm during a planned interim analysis (17% versus 27%; ref. 11). Aspirin also delayed the onset of recurrent adenoma.

In the second trial, 81 mg or 325 mg of aspirin per day was compared with a placebo in patients with a history of one or more colorectal adenomas. A reduction in the recurrence of adenomas was associated with aspirin consumption (17% and 4%, respectively), although it was significant only for the lower dose (12). The 81-mg dose was associated with a 3.7% absolute risk reduction in the incidence of advanced adenomas (RR reduction, 41%; 95% confidence interval, 8-62%). Notably, protection against advanced adenomas (>1 cm, high-grade dysplasia, and villous histology) was more pronounced than the effect on risk of recurrence of any adenoma (e.g., reduction rates of 41% and 17%, respectively).

In the third trial, Benamouzig et al. (13) randomized 272 patients with a history of adenoma to receive lysine acetylsalicylate (a form of aspirin) 300 mg, 150 mg, or placebo daily. Colonoscopies were done at 1 and 4 years. Both dosages were effective in reducing polyp recurrence. A lesser effect at 4 years was seen, and the lower (160 mg/day) dose was surprisingly more effective (14). The benefit was greatest with the higher (300 mg/day) dose at 1 year (13, 14).

From the combined results of the above-cited trials, significantly fewer subjects in the low-dose aspirin group developed recurrent sporadic colorectal adenomas [RR, 0.77 (95% confidence interval, 0.61-0.96), NNT (number needed to treat), 12.5 (95% confidence interval, 7.7-25)] after 1 to 3 years (15).

If no risk had been shown to be associated with aspirin, it would follow that the argument in favor of its use is stronger than that of its avoidance, even with uncertainty about the reduction in the incidence of colorectal adenomas or CRC. However, aspirin is associated with some risk of serious adverse events (e.g., bleeding, and ulcer). The estimated rates of excess serious complications in patients taking aspirin are 1.4 per 10,000 person-years in patients younger than ages 65 and 28 years to 40 per 10,000 person-years in older patients with cerebrovascular disease. The estimated mortality rate with major aspirin-related complication is age-dependent and varies between 2% and 8% (16-18).

Patients with an annual risk for coronary heart disease of ≥1.5% should take aspirin to prevent cardiovascular mortality (18). These patients will also benefit from the decrease in the incidence of colorectal adenomas and CRC mortality. It is also confirmed that patients with a low risk for coronary heart disease (<0.7% per year) should not take aspirin to prevent cardiovascular events. Subjects who should take nonsteroidal anti-inflammatory drugs or celecoxib on a regular basis for a long period of time are those at very high risk for CRC (e.g., familial adenomatous polyposis). There are no data regarding the usefulness of aspirin in this setting. In the case of moderate risk for CRC (personal history of advanced adenoma or CRC) consumption of aspirin (81-324 mg) for a short term (1-3 years) can reduce polyp recurrence (11-14). It should be emphasized that aspirin should not replace regular surveillance colonoscopy; rather, it should be taken until the next scheduled colonoscopy. If a subject is polyp free, there is no need for further consumption of aspirin, as long as he or she continues to participate in a surveillance colonoscopy program on a regular basis. These recommendations are supported by the recent statement of the US Preventive Services Task Force regarding the use of aspirin for primary prevention of CRC (19). They conclude that aspirin use prevents adenoma recurrence and reduce the incidence of CRC, especially if taken for long term and in high dose. Because this approach is associated with possible adverse consequences, chemoprevention should be combined with a screening program.

Aspirin consumption in patients with a medium annual risk for coronary heart disease (0.7-1.4%) is subjective and depends on patients' preferences and their utility function and attitude toward risk (18). For them, aspirin consumption for cancer prevention can shift the balance in favor of prevention (cancer and heart disease) and the use of aspirin.

Aspirin should not be prescribed in subjects at low risk for both ischemic heart disease and CRC. Subjects with no family history of CRC and who have normal colonoscopy can be regarded as low risk for CRC (Table 2).

Primary prevention is recommended in the general population (age >50 years) who are not participating in a regular CRC screening program. Aspirin (∼500-1,000 mg per week) should be taken for at least 5 and most probably for >10 years. There are ample data that such an approach will significantly reduce CRC mortality, and will outweigh toxicity, especially in high risk populations.

These recommendations are summarized in Fig. 1.

All people may be born equal, but their genomes slightly differ. Ideally, modern medicine should be personalized by offering a specific therapy based on the molecular profile of an individual and the lesion that is involved. In such a setting, the mechanism by which aspirin affects CRC carcinogenesis is poorly understood. Aspirin inhibits COX-2, which promotes inflammation and cell proliferation, and is overexpressed in the majority of human CRC. If aspirin principally works via COX-2 inhibition, then its use should preferentially reduce the risk of tumors that overexpress COX-2. Indeed, Chan et al. (20) had recently reported that regular aspirin use reduced the risk of CRC in COX-2–expressing cancers but not in cancers with weak or absent COX-2 expression.

In conclusion, randomized trials have provided compelling evidence of a causal relationship between aspirin usage and colorectal neoplasia. Nonetheless, prospective data on long-term risk of CRC according to dose or duration of therapy remain limited. In all likelihood, long-term use of moderate aspirin dose in high-risk subjects can decrease the incidence and reduce the mortality from CRC.

Figure 2 clearly displays that aspirin can prevent adenoma formation, reduce the incidence of CRC, and decrease CRC mortality. Aspirin has a chemopreventive role in CRC prevention based on considerable observational data. The data consistently show that the rates of colorectal neoplasia are significantly lower in aspirin users than in nonusers.

The balance of risks and benefits does not make aspirin suitable for primary prevention in all average-risk populations. Rather, its use should be considered in several groups with an increased risk of CRC, in particular, CRC survivors, those with advanced adenomas and those with a strong family history of colorectal neoplasia. All of these subjects should be offered surveillance colonoscopy but with the increasing recognition of lesion miss rate; during colonoscopy, aspirin may be used to decrease this miss rate.

The public seems eager to consider primary prevention measures of heart attack and stroke by taking low-dose aspirin (16-18). Individuals are going to be much more enthusiastic because this cardiovascular prophylaxis may yield an incidental prevention of CRC as well. There is no doubt that aspirin has some toxicity. Nevertheless, if aspirin can truly prevent a multitude of common cancers (5), there might be clinical situations in which daily adult-strength of aspirin (325 mg) would be indicated among individuals at increased cancer risk whose cardiovascular risk profile already made them candidates for low-dose aspirin.

The information regarding the duration of treatment, the dose of aspirin, and the subgroups of the population that might benefit the most from aspirin prophylaxis is limited, particularly the long term follow-up of the RCT. Nevertheless, there is strong evidence to support aspirin use in patients at risk for CRC and/or coronary heart disease. In spite of the limited prospective data on long-term risk of CRC according to dose or duration of therapy remain limited, we suggest that a reduction in CRC risk mandates consistent, long-term use of aspirin at moderate to high doses.