Chemoprevention for Colon Cancer: Dream or Reality?

Wouldnt it be nice to take a pill or dietary supplement and prevent colorectal cancer (CRC)? This is easier said than done, but we are making progress.

CRC is the second leading cause of cancer death in industrialized nations, accounting for 10 percent of the total cancer burden with an individual lifetime risk of approximately 6 percent in the U.S. While the highest impact form of prevention is CRC screening, the development of effective, inexpensive and safe chemopreventive agents would be of great benefit. Chemoprevention of colon cancer through the use of agents to prevent or suppress the progression of precursor lesions is a concept that is finding growing acceptance. Initial enthusiasm was based on epidemiology, animal trials, small clinical trials using biomarkers and trials in high-risk groups. The results of prospective, randomized trials relevant to the general (average-risk) population have in many cases been less impressive or definitive, but a number of recent trials have provided evidence that chemoprevention of colorectal neoplasia may become a reality. What is acceptable in terms of safety will depend on the risk for cancer development in a given population, the magnitude of risk reduction (preferably measured in reduced mortality) and the toxicity of a given agent.

For chemoprevention to become a reality, we need not only an effective agent, but one which can be used safely for long periods of time in healthy people. Minimal or no toxicity is acceptable when an agent is used in a population at average risk of colon cancer; it is a matter of balancing benefit versus risk. This lesson was learned when it was proposed that cyclooxygenase-2 (COX- 2) inhibitors would make ideal agents for chemoprevention of CRC. After all, these agents had proved to have less GI toxicity than standard NSAIDs. Given biological plausibility, preclinical in vitro and animal data, and data on the regression of adenoma in patients with familial adenomatous polyposis, three randomized trials were undertaken to examine the effect of COX-2 Wouldnt it be nice to take a pill or dietary supplement and prevent colorectal cancer (CRC)? This is easier said than done, but we are making progress. Robert S. Bresalier, MD Professor of Medicine Resoft Distinguished Professor in GI Oncology The University of Texas MD Anderson Cancer Center No disclosures to report 27 selective inhibitors on formation of new adenomas in patients with a history of sporadic adenomas. While these studies demonstrated significant reductions in new adenoma formation associated with use of these agents (up to 66 percent reduction in the number of patients developing advanced adenomas), they were also associated with a two-fold increased risk of cardiovascular events, such as myocardial infarctions and stroke. This increased cardiovascular risk led to one of the largest drug recalls in history.

Dietary chemoprevention has a strong appeal. There is convincing evidence that lifestyle and dietary risk factors are associated with increased or decreased risk of colon cancer, and lay public do not often consider dietary supplements as taking a drug. Unfortunately the scientific evidence for dietary chemoprevention seems softer than for other preventable causes of disease. Where epidemiologic evidence often seems strong, randomized clinical trials have been disappointing. High-fiber diets are associated with a reduced incidence of CRC in many epidemiologic studies, yet well-designed randomized trials have been negative. Folate has been protective against CRC in epidemiologic and preclinical trials, yet a large prospective randomized trial failed to demonstrate a protective effect of folate supplementation on recurrence of adenoma compared with placebo. It also suggested that folate supplementation in people with prior adenomas actually might increase adenoma risk. Even the protective effect of calcium has recently been called into question. These results do not mean that these agents are not protective, but point out the difficulty in carrying out and interpreting such studies. Nutritional epidemiology benefits from precision of measurement but there are often confounding variables and interactions, while intervention trials take place in a limited window and are often unable to examine dose-response.

All, however, is not doom and gloom. The most promising results and lessons for CRC prevention and risk versus benefit come from trials using aspirin. Case-control and cohort studies suggest that the risk for adenoma and carcinoma may be reduced 40 to 50 percent among long-term aspirin users compared with controls. In four large randomized trials of aspirin used for primary and secondary prevention of cardiovascular disease (a benefit of aspirin), aspirin reduced the 20-year risk of colon cancer by 24 percent and mortality by 35 percent. At least four prospective adenoma prevention trials now provide compelling evidence that aspirin use reduces the risk of colorectal adenoma in people with a history of adenoma or carcinoma. Molecular epidemiology in aspirin users has also taught us that preventive agents interact with genetic variation, and are not equally effective across the population. Regular use of aspirin appears to reduce the risk of colon cancers that express COX-2, but not the risk of those with weak or absent COX-2 expression. Likewise, CRC survival appears to be increased in aspirin users whose tumors contain PI3 kinase mutations but not in those without mutations. Thus, molecular epidemiology might be used to improve benefit versus risk. Despite this compelling data it is unclear what the benefit to risk is for long-term aspirin use in low-cancer-risk populations, and what the optimal aspirin dose (81 mg versus 325 mg) should be. Aspirin is associated with a two-to-six-fold increase in GI bleeding and intracranial hemorrhage, but complications of aspirin occur early and may be over-attributed (half of the bleeds may have occurred without aspirin).


It is the question of benefit versus risk that remains to be answered.


So are we making progress? I would argue that the answer is yes. Clearly, effective agents for chemoprevention of colon cancer exist. Proof of principle has evolved to proof in this regard. It is the question of benefit versus risk that remains to be answered. I would submit that we can, even now, tailor use of a given agent based on the ratio of benefit to risk. We might choose to use aspirin, for example, in those with a history of colon cancer, advanced or recurrent adenoma or a family history of CRC, especially in those with high cardiovascular risk (reduced by aspirin) and low GI bleeding risk. . The U.S. Preventive Services Task Force (USPSTF) is now considering recommending the use of low-dose aspirin for primary prevention of cardiovascular diseases and colorectal cancer in adults 50 to 59 years who have a 10 percent or greater 10-year cardiovascular disease risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin for at least 10 years. Consideration of the risk to benefit ratio for other age groups is emphasized in a draft statement from the USPSTF. Studies of cardiovascular risk associated with COX-2 inhibition have also demonstrated who is at high- or lowrisk for complications associated with an otherwise effective chemoprevention agent. We also need to look forward to other agents and combinations of agents (a large trial of aspirin and n-3 polyunsaturated fatty acids derived from fish oil is currently under way in the United Kingdom), revisit nutritional prevention and reduce risk factors for CRC that we can control such as obesity, lack of physical activity and tobacco use.

Will chemoprevention replace colon cancer screening? Almost assuredly not. Successful chemoprevention, however, could supplement the benefit of screening by targeting missed lesions, addressing the development of interval lesions, decreasing the number of adenomas that need to be removed at future colonoscopy, and slowing the growth of early cancers.

Dr. Bresalier has no conflicts to disclose.

References

1.Rothwell, PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow up of five randomized trials. The Lancet, 2010.376:1741-50.
2.Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352:1092-102.
3. Chan AT, Arber N, Burn J, et al. Aspirin in the chemoprevention of colorectal neoplasia: An overview. Cancer Prev Res 2012; 5:164-78.
4.Liao X, Lochhead P, Nishihara R. et al. Aspirin use, tumor PI3KCA mutation, and colorectalcancer survival. N Engl J Med 2012; 367: 1596-606.
5.Baron JA, Barry EL, Mott AA, Rees JR, Sandler RS, Bresalier RS, Robertson DA, Rothstein R, Summers RW. A clinical trial of calcium and vitamin D for the prevention of colorectal adenomas. N Engl J Med 2015; 373:1519-1530.
6.Chubak J, Kamieni A, Buist DSM, Anderson ML, Whitlock EP. Aspirin use for the preventionof colorectal cancer:a n updated systematic evidence review for the U.S. Preventive Services Task Force [internet]. Agency for Healthcare Research and Quality (US); 2015 Sep. Report No:15-05228-EF-1.

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