Downloaded from gut.bmj.com on September 30, 2014 - Published by group.bmj.com
Gut Online First, published on May 12, 2014 as 10.1136/gutjnl-2014-306780 Commentary
Is aspirin for colorectal cancer prevention on the prime time yet? Joseph JY Sung Aspirin is the most widely studied drug for chemoprevention of colorectal cancer but there are limitations. First the riskbenefit issue has not been fully addressed. What is the risk of bleeding associated with prescribing aspirin to asymptomatic individuals versus the benefit of cancer protection one can obtain from this treatment? Second, the optimal dosing, frequency and duration of aspirin usage in average-risk subjects (ie, patients with non-cardiovascular disease and patients with non-familial polyposis) have not been settled. Third, the potential ethnic difference has not been studied. Up to now, almost all studies were conducted in the Western population. Would Asians be responding to the treatment equally well? There are new and important data to support the use of aspirin in preventing colorectal cancer (CRC). Rothwell et al recently published their long-term data in 20-year follow-up studies giving strong support to the use of low-dose aspirin (75– 300 mg daily) in cancer prevention.1 2 These data which pool from five important randomised studies examine the effects of primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA trial, Dutch TIA trial) included over 14 000 patients with a median follow-up of more than 18 years. The longterm use of aspirin resulted in significant reduction of colon cancer incidence by 76% and mortality by 65%, without a significant reduction in rectal cancers. It was also reported that the benefit of aspirin is not just confined to CRC. Reduction in other malignancies, especially adenocarcinoma in the oesophagus, stomach, pancreas, lung and even prostate, has also been suggested. Although these data seem compelling, it should be pointed out that most of them are secondary analyses of cardiovascular prevention trials and not originally designed to examine cancer incidence and mortality. On the other hand, two randomised trials (Physician Health Study3 and Women’s Health Study4) designed to determine the effects of alternate-day dose of Correspondence to Professor Joseph JY Sung, Department of Medicine & Therapeutics, Chinese University of Hong Kong, Hong Kong 852, China; [email protected]
aspirin have disappointingly failed to demonstrate the benefit of cancer reduction. Some argue that this may be related to the insufficiency of alternate-day dosing, others doubt that the relatively short period of follow-up may not be enough. However, in a recent update of long-term follow-up of Women’s Health Study, alternate-day aspirin has been reported to prevent cancer but also induced more GI bleeding.5 In most of these studies, however, risks of GI complications associated with prophylactic aspirin use have been assessed as a secondary outcome. If the value of aspirin in cancer prevention is still disputed, what about preventing adenoma recurrence after polypectomy? Studies on adenoma prevention by aspirin are less controversial. There are at least four placebo-controlled, randomised trials examining the effects of aspirin in nearly 3000 patients with either a history of colorectal adenoma or previous CRC. While in each individual study, there are variations in outcome of cancer reduction using a daily dose of 81–325 mg aspirin,6 the pooled data have demonstrated a significant reduction in risk of colorectal adenoma by 17% and advanced colorectal adenoma by 28%.7 Again, the majority of subjects in these studies are Caucasians and the risk of GI bleeding is not assessed. In this study, Ishikawa et al demonstrated that low-dose, enteric-coated aspirin reduced adenoma and carcinoma recurrence in an Asian population.8 This study is unique in several ways: that it recruits only Asian ( Japanese) subjects, that it is a double-blinded placebocontrolled randomised study and that it uses enteric-coated aspirin instead of plain aspirin. The sample size is relatively small, with around 150 patients in each treatment arm, and the follow-up period of 2 years is relatively short. The number of adenomas, their morphological appearance ( polypoid vs flat adenoma), their distribution ( proximal vs distal colon), their histological type (tubular vs villous) are not mentioned and hence the proportion of advanced adenoma or invasive carcinoma not known. The numbers of invasive carcinoma and high-grade dysplasia between the two treatment groups were almost identical. Nevertheless, the authors reported a modest reduction in colorectal
tumour recurrence after adjustment for confounders such as sex, age and the number of recurrent tumours. All recurrent adenomas were tubular, and no villous adenoma was found. There was no adverse event reported in these two groups of patients, neither cardiovascular events nor GI bleeding. While this is an interesting study with its Asian favour, there are several points that one needs to take note of. First, it has been known that the chemopreventive effects of aspirin requires probably 7– 10 years before one can see the reduction of incidence of CRC.2 Even for adenoma reduction, it might take about 3 years before one can see the effects.6 It would be intriguing to continue the treatment and report a longer follow-up in this important study. Second, there was absence of cardiovascular event and GI adversity in this report. Enteric-coated aspirin has not been proven to be safer for the GI tract than plain aspirin.9 As aspirin at doses above 30 mg per day increases the bleeding risk by inhibiting cyclo-oxygenase 1 activity and thromboxane A, and dosage levels of 75–325 mg per day approximately double the risk of major GI bleeding from aspirin treatment,10 11 a complete lack of GI bleeding in this report could be a missed diagnosis of mild bleeding only detected by routine checking of faecal occult blood and haemoglobin levels, or short duration of follow-up. The relatively young age of patients in this study population can be another reason for the lack of GI toxicity. Colorectal cancer is rising at an alarming rate in Asia12 Screening and endoscopic polypectomy is undoubtedly the most commonly accepted method of preventing this malignant disease. The Asia Pacific Working Group on Colorectal Cancer has published their Consensus statements emphasising the importance of preventing colorectal cancers, yet chemoprevention has not been mentioned.13 That is because, up to now, chemoprevention still has its limitations. This study suggests that low-dose aspirin can prevent recurrence of adenomas in Asians, as much as it is in Westerners. It would be nice to see reduction of colorectal cancer after using aspirin in Asian populations as this is the ultimate target. There is, so far, no study comparing screening and colonoscopic polypectomy versus prophylactic aspirin in the prevention of colorectal cancer. Wouldn’t that be interesting? For now, I don’t think we can recommend aspirin for colorectal cancer prevention just yet. Competing interests None.
Sung JJY. GutArticle Month 2014 Vol 0 No(or 0 their employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence. 1 Copyright author
Downloaded from gut.bmj.com on September 30, 2014 - Published by group.bmj.com
Commentary Provenance and peer review Commissioned; externally peer reviewed. To cite Sung JJY. Gut Published Online First: [please include Day Month Year] doi:10.1136/gutjnl-2014306780 Received 7 February 2014 Revised 15 April 2014 Accepted 17 April 2014
2
3
4
5
▸ http://dx.doi.org/10.1136/gutjnl-2013-305827 Gut 2014;0:1–2. doi:10.1136/gutjnl-2014-306780
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REFERENCES
7
1
2
Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012;379:1602–12.
8
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 randomised trials. Lancet 2010;376:1741–50. Steering Committee of the Physician’s Health Study Research Group. Final report on the aspirin component of the ongoing Physician’s Health Study. N Engl J Med 1989;321:129–35. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293–304. Cook NR, Lee IM, Zhlang SM, et al. Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 2013;159:77–85. Chan AT, Arber N, Burn J. Aspirin in the chemoprevention of colorectal neoplasia: an overview. Cancer Prev Res 2012;5:164–78. Cole BF, Logan RF, Halabi S, et al. Aspirin for the chemoprevention of colorectal adenomas: Meta-analysis of the randomized trials. J Natl Cancer Inst 2009;101:256–66. Ishikawa H, Mutoh M, Suzuki S, et al. The preventive effects of low-dose enteric-coated aspirin
9
10
11
12
13
tablets on the development of colorectal tumours in Asian patients: a randomised trial. Gut Published Online First: 31 Jan 2014. doi:10.1136/gutjnl-2013305827 Kelly JP, Kaufman DW, Jurgelon JM, et al. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996;348:1413–16. Lanas A, Wu P, Medin J, et al. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol 2011;9:762–8. Patrono C, García Rodríguez LA, Landolfi R, et al. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005;353: 2373–83. Sung JJ, Lau JY, Goh KL, et al. Asia Pacific Working Group on Colorectal Cancer. Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol 2005;6:871–6. Sung JJ, Lau JY, Young GP, et al. Asia Pacific Working Group on Colorectal Cancer. Asia Pacific consensus recommendations for colorectal cancer screening. Gut 2008;57:1166–76.
Sung JJY. Gut Month 2014 Vol 0 No 0
Downloaded from gut.bmj.com on September 30, 2014 - Published by group.bmj.com
Is aspirin for colorectal cancer prevention on the prime time yet? Joseph JY Sung Gut published online May 12, 2014
doi: 10.1136/gutjnl-2014-306780
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/05/12/gutjnl-2014-306780.full.html
These include:
References
This article cites 12 articles, 3 of which can be accessed free at: http://gut.bmj.com/content/early/2014/05/12/gutjnl-2014-306780.full.html#ref-list-1
P
Gut Online First, published on May 12, 2014 as 10.1136/gutjnl-2014-306780 Commentary
Is aspirin for colorectal cancer prevention on the prime time yet? Joseph JY Sung Aspirin is the most widely studied drug for chemoprevention of colorectal cancer but there are limitations. First the riskbenefit issue has not been fully addressed. What is the risk of bleeding associated with prescribing aspirin to asymptomatic individuals versus the benefit of cancer protection one can obtain from this treatment? Second, the optimal dosing, frequency and duration of aspirin usage in average-risk subjects (ie, patients with non-cardiovascular disease and patients with non-familial polyposis) have not been settled. Third, the potential ethnic difference has not been studied. Up to now, almost all studies were conducted in the Western population. Would Asians be responding to the treatment equally well? There are new and important data to support the use of aspirin in preventing colorectal cancer (CRC). Rothwell et al recently published their long-term data in 20-year follow-up studies giving strong support to the use of low-dose aspirin (75– 300 mg daily) in cancer prevention.1 2 These data which pool from five important randomised studies examine the effects of primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA trial, Dutch TIA trial) included over 14 000 patients with a median follow-up of more than 18 years. The longterm use of aspirin resulted in significant reduction of colon cancer incidence by 76% and mortality by 65%, without a significant reduction in rectal cancers. It was also reported that the benefit of aspirin is not just confined to CRC. Reduction in other malignancies, especially adenocarcinoma in the oesophagus, stomach, pancreas, lung and even prostate, has also been suggested. Although these data seem compelling, it should be pointed out that most of them are secondary analyses of cardiovascular prevention trials and not originally designed to examine cancer incidence and mortality. On the other hand, two randomised trials (Physician Health Study3 and Women’s Health Study4) designed to determine the effects of alternate-day dose of Correspondence to Professor Joseph JY Sung, Department of Medicine & Therapeutics, Chinese University of Hong Kong, Hong Kong 852, China; [email protected]
aspirin have disappointingly failed to demonstrate the benefit of cancer reduction. Some argue that this may be related to the insufficiency of alternate-day dosing, others doubt that the relatively short period of follow-up may not be enough. However, in a recent update of long-term follow-up of Women’s Health Study, alternate-day aspirin has been reported to prevent cancer but also induced more GI bleeding.5 In most of these studies, however, risks of GI complications associated with prophylactic aspirin use have been assessed as a secondary outcome. If the value of aspirin in cancer prevention is still disputed, what about preventing adenoma recurrence after polypectomy? Studies on adenoma prevention by aspirin are less controversial. There are at least four placebo-controlled, randomised trials examining the effects of aspirin in nearly 3000 patients with either a history of colorectal adenoma or previous CRC. While in each individual study, there are variations in outcome of cancer reduction using a daily dose of 81–325 mg aspirin,6 the pooled data have demonstrated a significant reduction in risk of colorectal adenoma by 17% and advanced colorectal adenoma by 28%.7 Again, the majority of subjects in these studies are Caucasians and the risk of GI bleeding is not assessed. In this study, Ishikawa et al demonstrated that low-dose, enteric-coated aspirin reduced adenoma and carcinoma recurrence in an Asian population.8 This study is unique in several ways: that it recruits only Asian ( Japanese) subjects, that it is a double-blinded placebocontrolled randomised study and that it uses enteric-coated aspirin instead of plain aspirin. The sample size is relatively small, with around 150 patients in each treatment arm, and the follow-up period of 2 years is relatively short. The number of adenomas, their morphological appearance ( polypoid vs flat adenoma), their distribution ( proximal vs distal colon), their histological type (tubular vs villous) are not mentioned and hence the proportion of advanced adenoma or invasive carcinoma not known. The numbers of invasive carcinoma and high-grade dysplasia between the two treatment groups were almost identical. Nevertheless, the authors reported a modest reduction in colorectal
tumour recurrence after adjustment for confounders such as sex, age and the number of recurrent tumours. All recurrent adenomas were tubular, and no villous adenoma was found. There was no adverse event reported in these two groups of patients, neither cardiovascular events nor GI bleeding. While this is an interesting study with its Asian favour, there are several points that one needs to take note of. First, it has been known that the chemopreventive effects of aspirin requires probably 7– 10 years before one can see the reduction of incidence of CRC.2 Even for adenoma reduction, it might take about 3 years before one can see the effects.6 It would be intriguing to continue the treatment and report a longer follow-up in this important study. Second, there was absence of cardiovascular event and GI adversity in this report. Enteric-coated aspirin has not been proven to be safer for the GI tract than plain aspirin.9 As aspirin at doses above 30 mg per day increases the bleeding risk by inhibiting cyclo-oxygenase 1 activity and thromboxane A, and dosage levels of 75–325 mg per day approximately double the risk of major GI bleeding from aspirin treatment,10 11 a complete lack of GI bleeding in this report could be a missed diagnosis of mild bleeding only detected by routine checking of faecal occult blood and haemoglobin levels, or short duration of follow-up. The relatively young age of patients in this study population can be another reason for the lack of GI toxicity. Colorectal cancer is rising at an alarming rate in Asia12 Screening and endoscopic polypectomy is undoubtedly the most commonly accepted method of preventing this malignant disease. The Asia Pacific Working Group on Colorectal Cancer has published their Consensus statements emphasising the importance of preventing colorectal cancers, yet chemoprevention has not been mentioned.13 That is because, up to now, chemoprevention still has its limitations. This study suggests that low-dose aspirin can prevent recurrence of adenomas in Asians, as much as it is in Westerners. It would be nice to see reduction of colorectal cancer after using aspirin in Asian populations as this is the ultimate target. There is, so far, no study comparing screening and colonoscopic polypectomy versus prophylactic aspirin in the prevention of colorectal cancer. Wouldn’t that be interesting? For now, I don’t think we can recommend aspirin for colorectal cancer prevention just yet. Competing interests None.
Sung JJY. GutArticle Month 2014 Vol 0 No(or 0 their employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence. 1 Copyright author
Downloaded from gut.bmj.com on September 30, 2014 - Published by group.bmj.com
Commentary Provenance and peer review Commissioned; externally peer reviewed. To cite Sung JJY. Gut Published Online First: [please include Day Month Year] doi:10.1136/gutjnl-2014306780 Received 7 February 2014 Revised 15 April 2014 Accepted 17 April 2014
2
3
4
5
▸ http://dx.doi.org/10.1136/gutjnl-2013-305827 Gut 2014;0:1–2. doi:10.1136/gutjnl-2014-306780
6
REFERENCES
7
1
2
Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012;379:1602–12.
8
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 randomised trials. Lancet 2010;376:1741–50. Steering Committee of the Physician’s Health Study Research Group. Final report on the aspirin component of the ongoing Physician’s Health Study. N Engl J Med 1989;321:129–35. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293–304. Cook NR, Lee IM, Zhlang SM, et al. Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 2013;159:77–85. Chan AT, Arber N, Burn J. Aspirin in the chemoprevention of colorectal neoplasia: an overview. Cancer Prev Res 2012;5:164–78. Cole BF, Logan RF, Halabi S, et al. Aspirin for the chemoprevention of colorectal adenomas: Meta-analysis of the randomized trials. J Natl Cancer Inst 2009;101:256–66. Ishikawa H, Mutoh M, Suzuki S, et al. The preventive effects of low-dose enteric-coated aspirin
9
10
11
12
13
tablets on the development of colorectal tumours in Asian patients: a randomised trial. Gut Published Online First: 31 Jan 2014. doi:10.1136/gutjnl-2013305827 Kelly JP, Kaufman DW, Jurgelon JM, et al. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996;348:1413–16. Lanas A, Wu P, Medin J, et al. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol 2011;9:762–8. Patrono C, García Rodríguez LA, Landolfi R, et al. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005;353: 2373–83. Sung JJ, Lau JY, Goh KL, et al. Asia Pacific Working Group on Colorectal Cancer. Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol 2005;6:871–6. Sung JJ, Lau JY, Young GP, et al. Asia Pacific Working Group on Colorectal Cancer. Asia Pacific consensus recommendations for colorectal cancer screening. Gut 2008;57:1166–76.
Sung JJY. Gut Month 2014 Vol 0 No 0
Downloaded from gut.bmj.com on September 30, 2014 - Published by group.bmj.com
Is aspirin for colorectal cancer prevention on the prime time yet? Joseph JY Sung Gut published online May 12, 2014
doi: 10.1136/gutjnl-2014-306780
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/05/12/gutjnl-2014-306780.full.html
These include:
References
This article cites 12 articles, 3 of which can be accessed free at: http://gut.bmj.com/content/early/2014/05/12/gutjnl-2014-306780.full.html#ref-list-1
P
