Current Colorectal Cancer Reports

, Volume 9, Issue 1, pp 1–8

Tipping the Balance: Benefits and Risks of Aspirin in Chemoprevention of Colorectal Cancer

Prevention and Early Detection (N Arber, Section Editor)
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Abstract

Convincing evidence now exists to support a clear role for aspirin in the chemoprevention of gastrointestinal malignancies, in particular colorectal cancer. Although much of the data comes from large-scale epidemiological studies, recent randomised controlled trials have added statistically robust evidence to corroborate a beneficial effect of aspirin in the paradigm of chemoprevention, providing a promising avenue for further research into its long-term benefits in this context. The current evidence favours low-dose aspirin: 75-300 mg for 10 years or more in patients at high risk of colorectal cancer is optimal. These putative benefits must be viewed in the light of aspirin’s well-established myriad of side effects, including gastrointestinal and intracerebral haemorrhage. The complex risk–benefit profile of aspirin in general and specific populations is considered in this review.

Keywords

Colorectal cancer Chemoprevention Aspirin 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010;19:1893–907.PubMedCrossRefGoogle Scholar
  2. 2.
    Thun MJ, DeLancey JO, Center MM, Jemal A, Ward EM. The global burden of cancer: priorities for prevention. Carcinogenesis. 2010;31(1):100–10.PubMedCrossRefGoogle Scholar
  3. 3.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.PubMedCrossRefGoogle Scholar
  4. 4.
    Thiagarajan P, Jankowski JA. Aspirin and NSAIDs; benefits and harms for the gut. Best Pract Res Clin Gastroenterol. 2012;26(2):197–206.PubMedCrossRefGoogle Scholar
  5. 5.
  6. 6.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v1.2. Cancer incidence and mortality worldwide: IARC CancerBase no. 10. Lyon: International Agency for Research on Cancer, 2010. Available via http://globocan.iarc.fr. Accessed 3 Oct 2012.
  7. 7.
    National Cancer Intelligence Unit. Colorectal survival by stage. Accessed 3 Oct 2012.Google Scholar
  8. 8.
    Rothwell PM, Wilson M, Elwin C-E, Norrving B, Algra A, Warlow CP, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Recent Results Cancer Res. 2012;191:121–42.CrossRefGoogle Scholar
  9. 9.
    Cuzick J, Otto F, Baron JA, Brown PH, Burn J, Greenwald P, et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 2009;10(5):501–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Flower RJ. Non-steroidal anti-inflammatory drugs: back to the future. Rheumatology (Oxford). 1999;38(8):693–6.CrossRefGoogle Scholar
  11. 11.
    Vainio H, Morgan G. Aspirin for the second hundred years: new uses for an old drug. Pharmacol Toxicol. 1997;81:151–2.PubMedCrossRefGoogle Scholar
  12. 12.
    Davies MK, Hollman A. Stamps in cardiology. Heart. 1999;81(5):458.PubMedGoogle Scholar
  13. 13.
    McKee SA, Sane DC, Deliargyris EN. Aspirin resistance in cardiovascular disease: a review of prevalence, mechanisms, and clinical significance. Thromb Haemost. 2002;88(5):711–5.PubMedGoogle Scholar
  14. 14.
    Born G, Patrono C. Antiplatelet drugs. Br J Pharmacol. 2006;147 Suppl 1:S241–51.PubMedGoogle Scholar
  15. 15.
    Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. The Lancet, vol. 2, no. 8607, pp. 349–360, 1988.Google Scholar
  16. 16.
    US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150(6):396–404.Google Scholar
  17. 17.
    Gasic GJ, Gasic TB, Stewart CC. Anti-metastatic effects associated with platelet reduction. Proc Natl Acad Sci USA. 1968;61:46–52.PubMedCrossRefGoogle Scholar
  18. 18.
    Bennett A, Del Tacca M, Stamford IF, Zebra T. Prostaglandins from tumours of human large bowel. Br J Cancer. 1977;35:881–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Thun MJ, Namboodiri MM, Heath CWJ. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med. 1991;325:1593–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Rosenberg L, Palmer JR, Zauber AG, Warshauer ME, Stolley PD, Shapiro S. A hypothesis: nonsteroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer. J Natl Cancer Inst. 1991;83(5):355–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Benamouzig R, Deyra J, Martin A, Girard B, Jullian E, Piednoir B, et al. Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial. Gastroenterology. 2003;125(2):328–36.PubMedCrossRefGoogle Scholar
  22. 22.
    Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003;348(10):891–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Jankowski J, Barr H, de Caestecker J, Watson P, Attwood S, Moayyedi P. Aspirin in the prevention of cancer. Lancet. 2011;377(9778):1649–50.PubMedCrossRefGoogle Scholar
  24. 24.
    Jankowski J, Barr H, Moayyedi P. Does aspirin really reduce the risk of colon cancer? Lancet. 2012;379(9826):1586–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Flossmann E, Rothwell PM, British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet. 2007;369(9573):1603–13.PubMedCrossRefGoogle Scholar
  26. 26.
    • Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376(9754):1741–50. The group demonstrated a reduction in long-term incidence of, and mortality from, colorectal cancer with aspirin therapy using data from RCTs. That low-dose aspirin is as effective as higher doses is of crucial importance in realising the paradigm of chemoprevention. However, the side effect profile was not complete at the time of publication..PubMedCrossRefGoogle Scholar
  27. 27.
    Moayyedi P, Jankowski JA. Does long term aspirin prevent cancer? BMJ. 2010;341:c7326. doi:10.1136/bmj.c7326.PubMedCrossRefGoogle Scholar
  28. 28.
    • Hassan C, Rex DK, Cooper GS, Zullo A, Launois R, Benamouzig R. Primary prevention of colorectal cancer with low-dose aspirin in combination with endoscopy: a cost-effectiveness analysis. Gut. 2012;61(8):1172–9. This was a cost-effectiveness analysis comparing addition of low-dose aspirin to conventional screening with colonoscopy or sigmoidoscopy in prevention of CRC. The group’s findings are of practical relevance to gastroenterologists and may influence practice..PubMedCrossRefGoogle Scholar
  29. 29.
    • Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 2012;13(5):518–27. This systematic review demonstrated that the long-term benefits of regular aspirin therapy extend to prevention of several cancers. One important finding was the reduction in risk of distant metastases..PubMedCrossRefGoogle Scholar
  30. 30.
    Liu T, Pemberton PA, Robertson AD. Three-state unfolding and self association of maspin, a tumor-suppressing serpin. J Biol Chem. 1999;274:29628–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Bhattacharyya M, Girish GV, Ghosh R, Chakraborty S, Sinha AK. Acetyl salicylic acid (aspirin) improves synthesis of maspin and lowers incidence of metastasis in breast cancer patients. Cancer Sci. 2010;101(10):2105–9. doi:10.1111/j.1349-7006.2010.01655.x.PubMedCrossRefGoogle Scholar
  32. 32.
    Hayden M, Pignone M, Phillips C, Mulrow C. 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(2):161–72.PubMedGoogle Scholar
  33. 33.
    US Preventive Services Task Force. Routine 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;146:361–4.Google Scholar
  34. 34.
    Jankowski JA, Hooper PA. Chemoprevention in Barrett’s esophagus: a pill a day? Gastrointest Endosc Clin N Am. 2011;21(1):155–70.PubMedCrossRefGoogle Scholar
  35. 35.
    Ranke C, Creutzig A, Luska G, Wagner HH, Galanski M, Bode-Böger S, et al. Dose-dependent side effects of acetylsalicylic acid therapy. Results of a prospective randomized clinical study in patients with peripheral arterial occlusive disease. Med Klin (Munich). 1993;88(10):571–6.Google Scholar
  36. 36.
    Lanas A, Scheiman J. Low-dose aspirin and upper gastrointestinal damage: epidemiology, prevention and treatment. Curr Med Res Opin. 2007;23(1):163–73.PubMedCrossRefGoogle Scholar
  37. 37.
    • Lanas A, Wu P, Medin J, Mills EJ. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol. 2011;9(9):762–768.e6. High-quality evidence from this recent meta-analysis demonstrates a statistically significant bleeding risk with low doses of aspirin therapy, which is partially mitigated by co-administration with PPI cover. This suggest a practical avenue for reducing gastrointestinal toxicity in high-risk individuals..PubMedCrossRefGoogle Scholar
  38. 38.
    Chan FK. Anti-platelet therapy and managing ulcer risk. J Gastroenterol Hepatol. 2012;27(2):195–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352:238–44.PubMedCrossRefGoogle Scholar
  40. 40.
    Chan AT, Arber N, Burn J, Chia WK, Elwood P, Hull MA, et al. Cancer Aspirin in the chemoprevention of colorectal neoplasia: an overview. Prev Res (Phila). 2012;5(2):164–78.CrossRefGoogle Scholar
  41. 41.
    He J, Whelton PK, Vu B, et al. Aspirin and risk of hemorrhagic stroke: a metaanalysis of randomized control trials. JAMA. 1998;280:1930–5.PubMedCrossRefGoogle Scholar
  42. 42.
    De Berardis G, Lucisano G, D'Ettorre A, Pellegrini F, Lepore V, Tognoni G, et al. Association of aspirin use with major bleeding in patients with and without diabetes. JAMA. 2012;307(21):2286–94.PubMedCrossRefGoogle Scholar
  43. 43.
    Saloheimo P, Ahonen M, Juvela S, Pyhtinen J, Savolainen ER, Hillbom M. Regular aspirin-use preceding the onset of primary intracerebral hemorrhage is an independent predictor for death. Stroke. 2006;37(1):129–33.PubMedCrossRefGoogle Scholar
  44. 44.
    Gorelick PB, Weisman SM. Risk of hemorrhagic stroke with aspirin use: an update. Stroke. 2005;36(8):1801–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Rainsbury JW, Molony NC. Clopidogrel versus low-dose aspirin as risk factors for epistaxis. Clin Otolaryngol. 2009;34(3):232–5.PubMedCrossRefGoogle Scholar
  46. 46.
    Saloheimo P, Juvela S, Hillbom M. Use of aspirin, epistaxis, and untreated hypertension as risk factors for primary intracerebral hemorrhage in middle-aged and elderly people. Stroke. 2001;32(2):399–404.PubMedCrossRefGoogle Scholar
  47. 47.
    Soyka MB, Rufibach K, Huber A, Holzmann D. Is severe epistaxis associated with acetylsalicylic acid intake? Laryngoscope. 2010;120(1):200–7.PubMedGoogle Scholar
  48. 48.
    Ward SA, Demos L, Workman B, McNeil JJ. Aspirin for primary prevention of cardiovascular events in the elderly: current status and future directions. Drugs Aging. 2012;29(4):251–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Suehiro T, Yakeishi Y, Sakai F, Matsuzaki K, Sanefuji K, Toyokawa T, et al. Gastrointestinal bleeding associated with antithrombotic therapy in the elderly in Japan. Hepatogastroenterology. 2012;59(115):774–7.PubMedGoogle Scholar
  50. 50.
    Caspi D, Lubart E, Graff E, Habot B, Yaron M, Segal R. The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients. Arthritis Rheum. 2000;43(1):103–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Sostres C, Lanas A. Gastrointestinal effects of aspirin. Nat Rev Gastroenterol Hepatol. 2011;8(7):385–94. doi:10.1038/nrgastro.2011.97.PubMedCrossRefGoogle Scholar
  52. 52.
    Gao R, Li X. Risk assessment and aspirin use in Asian and Western populations. Vasc Health Risk Manag. 2010;6:943–56.PubMedGoogle Scholar
  53. 53.
  54. 54.
    Teramoto T, Shimada K, Uchiyama S, Sugawara M, Goto Y, Yamada N, et al. Rationale, design, and baseline data of the Japanese Primary Prevention Project (JPPP)-a randomized, open-label, controlled trial of aspirin versus no aspirin in patients with multiple risk factors for vascular events. Am Heart J. 2010;159(3):361–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010;138(6):2044–58.PubMedCrossRefGoogle Scholar
  56. 56.
    Grover S, Stoffel EM, Mercado RC, Ford BM, Kohlman WK, Shannon KM, et al. Colorectal cancer risk perception on the basis of genetic test results in individuals at risk for Lynch syndrome. J Clin Oncol. 2009;27(24):3981–6.PubMedCrossRefGoogle Scholar
  57. 57.
    • Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378(9809):2081–7. This well-designed, randomised trial demonstrated a statistically significant beneficial role for aspirin in CRC prevention in individuals with a high lifetime risk of CRC. This supports calls for individuals with inherited predisposition to CRC to be offered aspirin prophylaxis as the benefits are likely to outweigh the risks in this population..PubMedCrossRefGoogle Scholar
  58. 58.
    Kirk R. Disease prevention: pain killer—cancer preventer. Nature Reviews Clinical Oncology. 2012;9:4.CrossRefGoogle Scholar
  59. 59.
    Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596–606.PubMedCrossRefGoogle Scholar
  60. 60.
    Bennett C, Vakil N, Bergman J, Harrison R, Odze R, Vieth M, et al. Consensus statements for management of Barrett's dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology. 2012;143(2):336–46.PubMedCrossRefGoogle Scholar
  61. 61.
    Sandler RS. Point/counterpoint: aspirin should not be promoted for colon cancer prevention: counterpoint. Cancer Epidemiol Biomarkers Prev. 2008;17(7):1562–3.PubMedCrossRefGoogle Scholar
  62. 62.
    Huang ES, Strate LL, Ho WW, Lee SS, Chan AT. Long-term use of aspirin and the risk of gastrointestinal bleeding. Am J Med. 2011;124(5):426–33.PubMedCrossRefGoogle Scholar
  63. 63.
    The Esophageal Adenocarcinoma Genetics Consortium, The Wellcome Trust Case Control Consortium 2, Su Z, Gay LJ, Strange A, Palles C, Band G, et al. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus. Nat Genet. 2012;44(10):1131–6. doi:10.1038/ng.2408.PubMedCrossRefGoogle Scholar
  64. 64.
    Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ. 2000;321:1183–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988;2(8607):349–60.Google Scholar
  66. 66.
    Cappelleri JC, Fiore LD, Brophy MT, Deykin D, Lau J. Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: a meta-analysis. Am Heart J. 1995;130(3 Pt 1):547–52.PubMedCrossRefGoogle Scholar
  67. 67.
    Hur C, Nishioka NS, Gazelle GS. Cost-effectiveness of aspirin chemoprevention for Barrett's esophagus. J Natl Cancer Inst. 2004;96(4):316–25.PubMedCrossRefGoogle Scholar
  68. 68.
    Roderick PJ, Wickes HC, Meade TW. The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials. Br J Clin Pharmacol. 1993;35:219–26.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of GastroenterologyQueens Medical CentreNottinghamUK
  2. 2.Digestive Disease CentreLeicesterUK
  3. 3.Department of OncologyUniversity of OxfordOxfordUK
  4. 4.Centre for Digestive DiseasesQueen Mary University of LondonLondonUK

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