Chemoprevention of Colorectal Neoplasia: The Potential for Personalized Medicine
2008; Elsevier BV; Volume: 134; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2008.02.012
ISSN1528-0012
Autores Tópico(s)Estrogen and related hormone effects
ResumoCRC development is a multi-step process that spans 10 to 15 years, thereby providing an opportunity for early detection and even prevention. The poor survival rate of advanced CRC has prompted the emphasis on prevention of this disease. CRC screening and removal of adenomas is an effective intervention, and is the cornerstone of prevention. However, screening efforts have had limited impact due to less than optimal compliance with guidelines. Chemoprevention involves the long-term use of a variety of oral agents that can delay, prevent or even reverse the development of adenomas in the large bowel, thus interfering with the multi-step progessing from adenoma to carcinoma. This effect is of particular importance to individuals with a hereditary prediposition to colorectal neoplasia and to those who are especially susceptile to the environmental causes of CRC. NSAIDs have drawn the most attention as chemoprevention agents. Sulindac and celecoxib are effective in promoting poly regression in high risk individuals with Familial Adenomatous Polyposis (FAP). In the more common sporadic setting the APROVe (refecoxib), APC and PreSAP (Celecoxib) trials have shown a significant reduction in adenoma recurrence but important concerns exist regarding cardiovascular toxicity associated with selective COX-2 inhibitors. These landmark studies are very important, as they provide a proof of concept that we can prevent high risk adenomas that can lead to CRC development. The ideal chemopreventive agent remains to be discovered with great emphasis on need not to harm. Possibly, combinations of agents will maximize effectiveness while limiting drug toxicity. Finally, personalized approaches will include the ability to predict risk and toxicity. CRC development is a multi-step process that spans 10 to 15 years, thereby providing an opportunity for early detection and even prevention. The poor survival rate of advanced CRC has prompted the emphasis on prevention of this disease. CRC screening and removal of adenomas is an effective intervention, and is the cornerstone of prevention. However, screening efforts have had limited impact due to less than optimal compliance with guidelines. Chemoprevention involves the long-term use of a variety of oral agents that can delay, prevent or even reverse the development of adenomas in the large bowel, thus interfering with the multi-step progessing from adenoma to carcinoma. This effect is of particular importance to individuals with a hereditary prediposition to colorectal neoplasia and to those who are especially susceptile to the environmental causes of CRC. NSAIDs have drawn the most attention as chemoprevention agents. Sulindac and celecoxib are effective in promoting poly regression in high risk individuals with Familial Adenomatous Polyposis (FAP). In the more common sporadic setting the APROVe (refecoxib), APC and PreSAP (Celecoxib) trials have shown a significant reduction in adenoma recurrence but important concerns exist regarding cardiovascular toxicity associated with selective COX-2 inhibitors. These landmark studies are very important, as they provide a proof of concept that we can prevent high risk adenomas that can lead to CRC development. The ideal chemopreventive agent remains to be discovered with great emphasis on need not to harm. Possibly, combinations of agents will maximize effectiveness while limiting drug toxicity. Finally, personalized approaches will include the ability to predict risk and toxicity. Colorectal cancer (CRC) is the second leading cause of cancer-related death in men (after lung cancer) and third in women (behind lung and breast cancers) in the United States.1Jemal A. Siegel R. Ward E. et al.Cancer statistics 2007.CA Cancer J Clin. 2006; 57: 43-66Crossref Scopus (5526) Google Scholar In recent years, the incidence and mortality of CRC have decreased slightly.1Jemal A. Siegel R. Ward E. et al.Cancer statistics 2007.CA Cancer J Clin. 2006; 57: 43-66Crossref Scopus (5526) Google Scholar It is not clear whether this decrease is due to lifestyle modifications, improvement in therapy, and/or a consequence of wider implementation of screening. Prevention of CRC is especially important because it is such a widely prevalent disease associated with considerable morbidity and mortality. Furthermore, CRC has a natural history of evolution from normal mucosa to adenoma to overt cancer that spans on average 10–20 years, thereby providing a window of opportunity for effective intervention and prevention. Chemoprevention interferes with the process of carcinogenesis by targeting key molecular pathways and is a recent approach to prevention of colorectal neoplasia. CRC screening is the cornerstone of prevention; however, it has limited efficacy due to low compliance with screening guidelines. Prevention of CRC by colonoscopic polypectomy is an effective intervention but is not yet available widely even in developed countries.2Seeff L.C. Shapiro J.A. Nadel M.R. Are we doing enough to screen for colorectal cancer? Findings from the 1999 Behavioral Risk Factor Surveillance System.J Fam Pract. 2002; 51: 761-766PubMed Google Scholar Early detection of CRC is not an adequate enough objective and as the emphasis of screening shifts toward precancerous adenomas, these lesions become important targets for primary prevention methods. Chemoprevention involves the long-term use of a variety of oral agents that can delay, prevent, or even reverse the development of adenomas in the large bowel and interferes with the multistep progression from adenoma to carcinoma. Chemoprevention is of particular importance to individuals with a hereditary predisposition to colorectal neoplasia and to those who are especially susceptible to the environmental triggers of CRC. The scientific basis of chemoprevention has evolved over the past 2 decades and represents a potential approach to reducing the incidence of and mortality from cancer.3Hong W.K. Lippman S.M. Itri L.M. et al.Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck.N Engl J Med. 1990; 323: 795-801Crossref PubMed Google Scholar, 4King M.C. Wieand S. Hale K. et al.Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.JAMA. 2001; 286: 2251-2256Crossref PubMed Google Scholar, 5Cuzick J. Forbes J. Edwards R. et al.First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial.Lancet. 2002; 360: 817-824Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar The ideal chemopreventive agent should fulfill the following criteria: (1) the drug must be effective; (2) it should have a convenient dosing schedule, ideally not more than once a day; (3) it should have minimal side effects or an acceptable safety profile in high-risk populations; (4) it should be easily administered; and (5) it should be inexpensive. Whenever we administer any agent to a patient, and in particular when we are treating healthy individuals, we must assess carefully the risk/benefit ratio (Figure 1). We wish to emphasize that the profile of safety and efficacy for any given drug varies significantly and depends on the severity of the disease and the tolerance of the individuals receiving the specific drug. Recent preclinical and clinical trials have provided data on the potential benefit of a number of micronutrients, minerals, and drugs in the chemoprevention setting.6Gill S. Sinicrope F.A. Colorectal cancer prevention: is an ounce of prevention worth a pound of cure?.Semin Oncol. 2005; 32: 24-34Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Some agents have been found to reduce the risk of adenoma/cancer growth or recurrence. At the same time, other studies have failed to show this protective effect, and some of these agents may be associated with some toxicity.7Bjelakovic G. Nikolova D. Antioxidant supplements for prevention of gastrointestinal cancers; a systematic analysis.Lancet. 2004; 364: 1219-1228Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar Cyclooxygenase (COX) is probably the most common therapeutic drug target in human history. Inhibitors of this enzyme have been used extensively and widely. Research in this area has been dominated by investigations of the 2 COX enzymes, COX-1 and COX-2, and the therapeutic market has been revolutionized by the development of drugs targeted selectively against COX-2. The hypothesis that nonsteroidal anti-inflammatory drugs (NSAIDs) might inhibit the occurrence or growth of CRC arose in the mid-1970s. Bennett and Del Tacca8Bennett A. Del Tacca M. Proceedings: prostaglandins in human colonic carcinoma.Gut. 1975; 16: 409Crossref PubMed Google Scholar and Jaffe9Jaffe B.M. Prostaglandins and cancer: an update.Prostaglandins. 1974; 6: 453-461Crossref PubMed Google Scholar reported that the concentration of prostaglandin E2 was higher in CRC than in the surrounding normal mucosa. Supportive evidence for the role of aspirin and NSAIDs in the prevention of CRC has been derived from more than 200 well-conducted, randomized, placebo-controlled animal studies, in which the administration of various NSAIDs consistently resulted in fewer tumors per animal and fewer animals with tumors, thereby clearly showing a preventive effect on carcinogen-induced colorectal tumorigenesis in rodents.10Rao C.V. Rivenson A. Simi B. et al.Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent.Cancer Res. 1995; 55: 1464-1472PubMed Google Scholar, 11Rao C.V. Reddy B.S. NSAIDs and chemoprevention.Curr Cancer Drug Targets. 2004; 4: 29-42Crossref PubMed Scopus (135) Google Scholar These findings were also supported by studies in genetically manipulated CRC rodent models12Oshima M. Murai N. Kargman S. et al.Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor.Cancer Res. 2001; 61: 1733-1740PubMed Google Scholar that reported a reduction in number and size of colorectal neoplasms in animals treated with NSAIDs. Intervention studies in patients with familial adenomatous polyposis have established that NSAIDs exert their effects on human colonic adenoma formation.13Waddell W.R. Loughry R.W. Sulindac for polyposis of the colon.J Surg Oncol. 1983; 24: 83-87Crossref PubMed Google Scholar Epidemiologic observations and population-based studies also showed that long-term use of aspirin and other NSAIDs reduced the risk of CRC (see reviews9Jaffe B.M. Prostaglandins and cancer: an update.Prostaglandins. 1974; 6: 453-461Crossref PubMed Google Scholar, 10Rao C.V. Rivenson A. Simi B. et al.Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent.Cancer Res. 1995; 55: 1464-1472PubMed Google Scholar, 11Rao C.V. Reddy B.S. NSAIDs and chemoprevention.Curr Cancer Drug Targets. 2004; 4: 29-42Crossref PubMed Scopus (135) Google Scholar, 12Oshima M. Murai N. Kargman S. et al.Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor.Cancer Res. 2001; 61: 1733-1740PubMed Google Scholar, 13Waddell W.R. Loughry R.W. Sulindac for polyposis of the colon.J Surg Oncol. 1983; 24: 83-87Crossref PubMed Google Scholar, 14Dubé C. Rostom A. Lewin G. et al.U.S. Preventive Services Task ForceThe use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force.Ann Intern Med. 2007; 146: 365-375Crossref PubMed Google Scholar, 15Bertagnolli M.M. Chemoprevention of colorectal cancer with cyclooxygenase-2 inhibitors: two steps forward, one step back.Lancet Oncol. 2007; 8: 439-443Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 16Arber N. Do NSAIDs prevent colorectal cancer?.Can J Gastroenterol. 2000; 14: 299-307PubMed Google Scholar). The protective effect of NSAIDs has been underscored in 57 of 59 epidemiologic studies, which showed prevention of adenoma recurrence, inhibition of CRC incidence, and even a lower mortality rate in both women and men (Figure 2). This protective effect depends on the dose and type of the drug but more importantly is directly related to the duration of exposure.15Bertagnolli M.M. Chemoprevention of colorectal cancer with cyclooxygenase-2 inhibitors: two steps forward, one step back.Lancet Oncol. 2007; 8: 439-443Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 17Flossmann E. Rothwell P.M. British Doctors Aspirin Trial and the UK-TIA Aspirin Trial Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomized and observational studies.Lancet. 2007; 369: 1603-1613Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 18U.S. Preventive Services Task ForceRoutine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: U.S. Preventive Services Task Force recommendation statement.Ann Intern Med. 2007; 146: 361-364Crossref PubMed Google Scholar, 19Kune G.A. Kune S. Watson L.F. Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study.Cancer Res. 1988; 48: 4399-4404PubMed Google Scholar, 20Giovannucci E. Egan M.K. Hunter D.J. et al.Aspirin and the risk of colorectal cancer in women.N Engl J Med. 2005; 333: 609-614Crossref Scopus (861) Google Scholar 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 potential prevention of cancer. Aspirin has been investigated extensively in the chemoprevention of colorectal adenomas and cancer, based in part on its inhibition of COX-1 and COX-2 enzymes, both of which are important mediators of prostaglandin production. To understand the dilemma of whether or not to use aspirin as a CRC chemopreventive agent, we need to assess the effectiveness of aspirin on prevention or regression of colorectal adenomas and cancer and then estimate whether the expected health benefits of the use of aspirin exceed its expected negative health consequences. The first population-based case-control study was reported by Kune et al.19Kune G.A. Kune S. Watson L.F. Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study.Cancer Res. 1988; 48: 4399-4404PubMed Google Scholar They showed a relative risk (RR) of 0.53% for CRC among regular aspirin users compared with nonaspirin consumers. The Nurses' Health Study was initiated in 1976 and included more than 120,000 nurses aged 30–55 years. From 1984 to 1992, 331 new cases of CRC, during 551,651 person-years of follow-up, were identified. Women who consistently took 2 or more aspirin tablets per week had no appreciable reduction in the risk of CRC as compared with nonusers up to 9 years (RR, 0.84; 95% confidence interval [CI], 0.55–1.28). There was a statistically significant reduction after 20 years of consistent use of aspirin (RR, 0.56; 95% CI, 0.36–0.90). The maximal reduction in risk was observed among women who took 4–6 tablets per week; higher doses had a similar apparent benefit.20Giovannucci E. Egan M.K. Hunter D.J. et al.Aspirin and the risk of colorectal cancer in women.N Engl J Med. 2005; 333: 609-614Crossref Scopus (861) Google Scholar In the observational Health Professionals Study of 50,000 individuals, regular aspirin use of more than twice a week was associated with a 32% (95% CI, 0.52–0.92) reduction in mortality from CRC.21Giovannucci E. Rimm E.B. Stampfer M.J. et al.Aspirin use and risk for colorectal cancer and adenoma in male health professionals.Ann Intern Med. 1994; 121: 241-246Crossref PubMed Google Scholar Chan et al22Chan A.T. Giovannucci E.L. Meyerhardt J.A. et al.Aspirin dose and duration of use and risk of colorectal cancer in men.Gastroenterology. 2008; 134: 21-28Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar evaluated CRC risk in a follow-up study (Health Professionals Follow-Up Study) over 18 years with 975 documented CRC cases. It was confirmed that prolonged aspirin use substantially reduces the risk of developing CRC. The effect was dose related, increasing from a RR of 0.94 (95% CI, 0.75–1.18) for men who used 0.5–1.5 standard aspirin (325 mg) per week compared with those who denied any aspirin use to a RR of 0.30 (95% CI, 0.11–0.81) for those using >14 aspirin per week as compared with nonusers. Significant reduction in risk of CRC required at least 6–10 years of aspirin use. The dosage of aspirin required for CRC chemoprevention in the Health Professionals Follow-Up Study was much higher than the lowest aspirin dose (81 mg) and treatment period (3 years) required for reducing adenoma recurrence. At the same time, this dosage (325 mg) causes significant rates of gastrointestinal and other toxicities.22Chan A.T. Giovannucci E.L. Meyerhardt J.A. et al.Aspirin dose and duration of use and risk of colorectal cancer in men.Gastroenterology. 2008; 134: 21-28Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Recently, Jacobs et al23Jacobs E.J. Thun M.J. Bain E.B. et al.A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence.J Natl Cancer Inst. 2007; 99: 608-615Crossref PubMed Scopus (171) Google Scholar examined the associations between long-term daily use of aspirin (325 mg/day) and overall incidence of cancer among 69,810 men and 76,303 women participating in the Cancer Prevention Study II Nutrition Cohort. Aspirin use was reported at enrollment and updated every 2 years. Daily use of aspirin for more than 5 years was associated with lower incidence of CRC (RR, 0.68; 95% CI, 0.52–0.90). On the other hand, 2 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 (RR, 0.97; 95% CI, 0.77–1.24).24Cook N.R. Lee I.M. Gaziano J.M. et al.Low-dose aspirin in the primary prevention of cancer The Women's Health Study: a randomized controlled trial.JAMA. 2005; 294: 47-55Crossref PubMed Scopus (462) Google Scholar The Physicians' Health Study was designed primarily to evaluate the effects 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.25Gann P.H. Manson J.E. Glynn R.J. et al.Low-dose aspirin and incidence of colorectal tumors in a randomized trial.J Natl Cancer Inst. 1993; 85: 1220-1224Crossref PubMed Scopus (302) Google Scholar After 5 years of aspirin therapy, there was no change in the incidence of CRC or adenomatous polyps (nonsignificant odds ratio of 1.15 [95% CI, 0.80–1.65] for CRC and 0.86 [95% CI, 0.68–1.10] for adenomas) between the treatment and the placebo groups.25Gann P.H. Manson J.E. Glynn R.J. et al.Low-dose aspirin and incidence of colorectal tumors in a randomized trial.J Natl Cancer Inst. 1993; 85: 1220-1224Crossref PubMed Scopus (302) Google Scholar Randomized trials of short-term duration (up to 4–5 years) have provided compelling evidence of an inverse relationship between aspirin and colorectal neoplasia. Nonetheless, prospective data on long-term risk of CRC according to dose or duration of therapy remain limited. Similarly, the British Doctors Aspirin Trial26Peto R. Gray R. Collins R. et al.Randomized trial of prophylactic daily aspirin in British male doctors.BMJ. 1988; 296: 313-316Crossref PubMed Google Scholar and the UK-TIA Aspirin Trial27Farrell B. Godwin J. Richards S. et al.The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results.J Neurol Neurosurg Psychiatry. 1991; 54: 1044-1054Crossref PubMed Scopus (6) Google Scholar failed to show a protective effect of aspirin. However, Flossmann and Rothwell17Flossmann E. Rothwell P.M. British Doctors Aspirin Trial and the UK-TIA Aspirin Trial Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomized and observational studies.Lancet. 2007; 369: 1603-1613Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar studied the long-term effect of aspirin in these 2 trials with reliable posttrial follow-up for more than 20 years. They also performed a systematic review of all relevant observational studies and concluded that the use of >300 mg/day of aspirin for at least 5 years in the randomized controlled trial was effective in primary prevention of CRC, with a latency period of about 10 years. These studies were, however, unable to circumvent confounders, such as intermittent and variable dosing, use of other NSAIDs, and risk-modifying drugs. Four randomized controlled trials in patients with previous adenoma or CRC have shown significant efficacy in preventing polyp recurrence at daily dosages of 81–325 mg/day of aspirin. Aspirin (325 mg/day) or placebo was prescribed to more than 600 patients with a recent history of CRC. A statistically significant reduction in the incidence of colorectal adenomas was found in the treatment arm during a planned interim analysis (17% vs 27%).28Sandler R.S. Halabi S. Baron J.A. et al.A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.N Engl J Med. 2003; 348: 883-890Crossref PubMed Scopus (756) Google Scholar Baron et al29Baron J.A. Cole B.F. Sandler R.S. et al.A randomized trial of aspirin to prevent colorectal adenomas.N Engl J Med. 2003; 348: 891-899Crossref PubMed Scopus (952) Google Scholar observed that a statistically significant reduction in the recurrence of adenomas was associated with use of 81- and 325-mg dosages of aspirin (17% and 4%, respectively). It was statistically significant only for the lower dosage. 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 (eg, reduction rates of 41% and 17%, respectively). Benamouzig et al30Benamouzig R. Deyra J. Martin A. et al.Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial.Gastroenterology. 2003; 125: 328-336Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar randomized 272 patients with a history of adenoma to receive lysine acetylsalicylate (a form of aspirin) 300 mg, 150 mg, or placebo once a day. Both dosages were effective in reducing polyp recurrence at 1 year in 27% (95% CI, 0.52–1.04). A lesser effect was seen at 4 years, and the lower (160 mg/d) dose was more effective.31Benamouzig R. Deyra J. Martin A. et al.Daily soluble aspirin and prevention of colorectal adenoma recurrence: four years results of the APACC trial.Gastroenterology. 2006; 130 (A101): 689Google Scholar In the UK-CAP trial, 945 patients, within 6 months of polypectomy, were randomized to receive aspirin (300 mg daily) and folic acid (0.5 mg daily). Of those randomized, more than 90% underwent a surveillance colonoscopy 3 years later. Patients receiving aspirin had a 21% reduction in the recurrence of adenoma. The likelihood of recurrence of advanced adenoma was substantially higher (37%).32Logan R.F.A. Grainge M.J. Shepherd V.C. et al.UK-CAP Trial GroupAspirin and folic acid for the prevention of recurrent colorectal adenomas.Gastroenterology. 2008; 134: 29-38Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar The available data would suggest that for chemoprevention, aspirin would need to be ingested in doses greater than used for cardiovascular prevention and for a duration of more than 10 years.17Flossmann E. Rothwell P.M. British Doctors Aspirin Trial and the UK-TIA Aspirin Trial Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomized and observational studies.Lancet. 2007; 369: 1603-1613Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 20Giovannucci E. Egan M.K. Hunter D.J. et al.Aspirin and the risk of colorectal cancer in women.N Engl J Med. 2005; 333: 609-614Crossref Scopus (861) Google Scholar Therefore, the potential benefit of aspirin needs to be carefully weighed against its potential adverse effects. Additional information is required to clarify the optimal dose, starting age, and duration of aspirin use. Aspirin, however, also decreases fatal cardiovascular events in people with known vascular disease by one sixth and vascular death by 25%.33Devine M.E. Rands G. Does aspirin affect outcome in vascular dementia? A retrospective case-notes analysis.Int J Geriatr Psychiatry. 2003; 18: 425-431Crossref PubMed Scopus (9) Google Scholar, 34Lauer M.S. Clinical practice Aspirin for primary prevention of coronary events.N Engl J Med. 2002; 346: 1468-1474Crossref PubMed Scopus (140) Google Scholar, 35Hayden M. Pignone M. Phillips C. et al.Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force.Ann Intern Med. 2002; 136: 161-172Crossref PubMed Google Scholar Perhaps it may also prevent dementia,33Devine M.E. Rands G. Does aspirin affect outcome in vascular dementia? A retrospective case-notes analysis.Int J Geriatr Psychiatry. 2003; 18: 425-431Crossref PubMed Scopus (9) Google Scholar so it should be carefully evaluated in those likely to receive the greatest benefit. Unfortunately, those at the highest risk for gastrointestinal complications and hemorrhagic stroke may be those most likely to benefit from the chemopreventive effects. If no risk was associated with ingestion of aspirin, then even with uncertainty about the reduction in the incidence and mortality of colorectal adenomas or CRC, the use of aspirin is preferred to its avoidance. The estimated rates of serious complications in patients taking aspirin are 1.4 per 10,000 person-years in patients younger than 65 years of age and 28–40 per 10,000 person-years in older patients with cerebrovascular disease.34Lauer M.S. Clinical practice Aspirin for primary prevention of coronary events.N Engl J Med. 2002; 346: 1468-1474Crossref PubMed Scopus (140) Google Scholar, 35Hayden M. Pignone M. Phillips C. et al.Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force.Ann Intern Med. 2002; 136: 161-172Crossref PubMed Google Scholar, 36Ridker P.M. Cook N.R. Lee I.-M. et al.A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.N Engl J Med. 2005; 352: 1293-1304Crossref PubMed Scopus (1212) Google Scholar Patients with an annual risk for coronary heart disease of ≥1.5% should consider taking aspirin to prevent cardiovascular mortality.36Ridker P.M. Cook N.R. Lee I.-M. et al.A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.N Engl J Med. 2005; 352: 1293-1304Crossref PubMed Scopus (1212) Google Scholar These patients may also benefit from a decrease in the incidence of colorectal adenomas and CRC mortality. It is also confirmed that patients with a low risk of coronary heart disease (less than 0.7% per year) should not take aspirin to prevent cardiovascular events. Aspirin consumption in patients with a moderate annual risk of coronary heart disease (0.7%–1.4%) is optional and depends on patient preferences and attitudes toward risk.36Ridker P.M. Cook N.R. Lee I.-M. et al.A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.N Engl J Med. 2005; 352: 1293-1304Crossref PubMed Scopus (1212) Google Scholar Aspirin should not be prescribed in subjects at low risk for both ischemic heart disease and CRC. Subjects with no family history of CRC who have had normal findings on colonoscopy can be regarded as at low risk for CRC. The use of aspirin and nonspecific NSAIDs is associated with gastrointestinal and renal toxicity caused by the inhibition of COX-1. In 1997, 107,000 hospitalizations and 16,500 deaths in the United States alone were attributable to NSAIDs and aspirin consumption.37Wolfe M.M. Lichtenstein D.R. Singh G. Gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.N Engl J Med. 1999; 340: 1888-1899Crossref PubMed Scopus (1538) Google Scholar When aspirin is given with a proton pump inhibitor, however, especially after Helicobacter pylori eradication, the risk of bleeding complications following aspirin or NSAID use is decreased dramatically (by 50%–90%).38Pilotto A. Franceschi M. Longoa M.G. et al.Helicobacter pylori infection and the prevention of peptic ulcer with proton pump inhibitors in elderly subjects taking low-dose aspirin.Dig Liver Dis. 2004; 36: 666-670Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Although chemoprevention of CRC is already possible, drugs that have more acceptable side effect profiles than the currently available aspirin and NSAIDs are required. COX-2 is an inducible enzyme that is overexpressed in sites of inflammation and neoplasia. Genetic evidence supports the role of COX-2 in the development of intestinal neoplasia.39Oshima M. Dinchuk J.E. Kargman S.L. et al.Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2).Cell. 1996; 87: 803-809Abstract Full Text Full Text PDF PubMed Scopus (2042) Google Scholar Furthermore, COX-2 is overexpressed in 40%–50% of adenomas and in 85% of CRC.40Eberhart C.E. Coffey R.J. Radhika A. et al.Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas.Gastroenterology. 1994; 107: 1183-1188Abstract PubMed Google Scholar The benefits of the chemopreventive effects of NSAIDs
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