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Are we ready to recommend aspirin for cancer prevention?
In The Lancet, Peter Rothwell and colleagues1 report The fact that low-dose aspirin reduces the risk of additional data supporting the hope that daily aspirin sporadic colorectal adenomas within a few years, but can ward off a panoply of cancers. Aspirin’s role in requires 5 years for an eff ect on invasive cancer and reducing risk of vascular events is well established, cancer death, suggests that at least some of aspirin’s although which risk factor profi les derive net benefi t chemopreventive eff remain controversial.2 The strongest proof of aspirin’s carcinogenesis.4 However, in some trials using high-antineoplastic eff ect has been in colorectal tumours. dose aspirin a reduction in cancer death emerged within Several epidemiological studies,3 randomised controlled only 2–3 years after randomisation. This suggests the trials of colon polyp recurrence,4 and randomised trials in possibility that aspirin might also have an eff ect on the patients with hereditary colorectal cancer syndromes5,6 growth and spread of established tumours as well as have shown that aspirin reduces incidence of colorectal their initiation. To address this hypothesis, Rothwell Published Online
neoplasia. In long-term follow-up of participants in fi ve and colleagues collected further detail regarding DOI:10.1016/S0140-
randomised trials of cardiovascular prevention, Rothwell the clinical presentation and outcome of patients 6736(11)61654-1
and colleagues previously reported that daily aspirin at diagnosed with cancers in fi ve of the vascular prevention See Online/Articles
any dose reduced risk of colorectal cancer by 24% and of trials from the UK. In their companion study,9 also in 6736(11)61720-0 andassociated mortality by 35% after a delay of 8–10 years.7 The Lancet, the benefi t of aspirin allocation reduced the DOI:10.1016/S0140- A chemopreventive benefi t of aspirin for other cancer risk of cancer with distant metastasis, particularly for See Online/Articles Lancet Oncol
sites was far less certain until Rothwell and colleagues’ adenocarcinomas. A similar association between aspirin DOI:10.1016/S1470- earlier pooled analysis of individual patient data from and lower risk of cancer with distant metastases but not eight randomised trials of cardiovascular prevention.8 regional spread was observed in the few case-control Daily aspirin use at any dose was associated with a studies that specifi cally examined cancer risk by extent 21% reduced risk of cancer death during the trials, of disease, in Annemijn Algra and Rothwell’s systematic with benefi t only apparent after 5 years,8 and reduced review of observational studies in The Lancet Oncology.10 mortality due to several cancers during post-trial Furthermore, within the fi ve trials from the UK, follow-up to 20 years. This fi nding was the fi rst among patients who presented with localised disease, convincing evidence that aspirin might prevent death individuals assigned aspirin had a lower risk of from several cancers, thereby widening its potential developing metastases over subsequent follow-up, population-wide eff ect.
particularly if they continued treatment after diagnosis.9 Rothwell and colleagues have now included an An especially pronounced risk reduction was evident in additional 43 randomised trials of daily aspirin of patients with colorectal cancer, which is consistent with any treatment duration for the primary or secondary previous observational studies that showed a lower risk prevention of vascular disease.1 Aspirin, irrespective of of colorectal-cancer-specifi c mortality associated with dose, signifi cantly reduced risk of non-vascular death aspirin use after diagnosis.11by 12% and of cancer death by 15%, with benefi t seen Although these results are compelling, they have within 3 years for high doses (≥300 mg/day) and after some limitations. First, these analyses do not include 5 years for low doses (<300 mg/day). Benefi t on fatal the largest randomised trials in primary prevention: the plus non-fatal cancers emerged after 3 years across Women’s Health Study (WHS) of 39 876 women treated several body sites. In 12 primary prevention trials, aspirin with alternate-day 100 mg aspirin over 10 years and the again reduced non-vascular death by 12%, but not Physicians’ Health Study (PHS) of 22 071 men treated vascular death, leading to a non-signifi cant eff ect on all- with alternate-day 325 mg aspirin over 5 years. After cause mortality. Finally, in six primary prevention trials, 10–12 years of follow-up, aspirin was not associated low-dose aspirin reduced risk of incident cancer by 12%. with reduced risk of colorectal cancer12,13 or overall cancer By contrast, aspirin reduced risk of major vascular events incidence or mortality.12 In the present report, these and increased risk of major extracranial bleeds, but only trials were excluded because of possible diff erences within the fi rst 3 years of follow-up. in the biological eff ect of alternate-day rather than Published online March 21, 2012 DOI:10.1016/S0140-6736(11)61654-1
daily aspirin. Such diff erences, although plausible, are endpoint, should be weighed against their possible far from conclusively established. Second, analyses of limitations regarding the dose or frequency of aspirin cancer incidence were confi ned to six randomised trials used. Also, despite a convincing case that the vascular of low-dose aspirin in primary prevention, although and anticancer benefi ts of aspirin outweigh the harms including the available secondary prevention trials of of major extracranial bleeding, these analyses do not cardiovascular disease would be less selective. Third, account for less serious adverse eff ects on quality of because these studies were designed to examine life, such as less severe bleeding. Additionally, although cardiovascular endpoints, information was not obtained doses as low as 75 mg/day seem suffi about cancer screening or surveillance. Thus, the prevention across several trials, data directly comparing potential for earlier diagnosis and removal of either doses within a single trial are inadequate. In fact, the precancerous precursors (eg, polyps) or cancers due limited data presented in Rothwell and colleagues’ to aspirin-associated bleeding or anaemia remains an study suggest an earlier reduction in cancer deaths with alternative explanation. Last, some analyses were limited higher doses than with lower doses (potentially related by the quality of available data. Some estimates pooled to an eff ect on prevalent tumours). Nonetheless, as we individual-level data with published results. Moreover, await data from additional trials (NCT01038583 and in analyses of cancer incidence, fatal outcome data for NCT00501059) and longer-term follow-up of the WHS some randomised trials were combined with incidence and PHS, Rothwell and colleagues’ impressive collection data from others.
of data moves us another step closer to broadening These caveats notwithstanding, Rothwell and recommendations for aspirin use. Moreover, future colleagues show quite convincingly that aspirin seems evidence-based guidelines for aspirin prophylaxis can no to reduce cancer incidence and death across diff erent longer consider the use of aspirin for the prevention of subgroups and cancer sites, with an apparent delayed vascular disease in isolation from cancer prevention.2,3eff ect. Additionally, aspirin’s known benefi ts in vascular disease and known toxic eff ects in causing major Andrew T Chan, *Nancy R Cookbleeding emerged in the short term, but diminished Division of Gastroenterology, Massachusetts General Hospital and over time. Thus, for most individuals, the risk-benefi t Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA (ATC); and Division of calculus of aspirin seems to favour aspirin’s long-term Preventive Medicine, Brigham and Women’s Hospital, Harvard anticancer benefi t. These fi ndings are consistent with Medical School, Boston, MA 02215, USA (NRC)observational fi ndings and our understanding of the ncook@rics.bwh.harvard.edustepwise progression of carcinogenesis.14,15 As we await NRC is an investigator for the Women’s Health Study. ATC has served as a the results of randomised studies of aspirin for the consultant to Bayer HealthCare and Millennium Pharmaceuticals. NRC declares that she has no confl icts of interest. adjuvant treatment of colorectal cancer, the fi ndings 1 Rothwell PM, Price JF, Fowkes FGR, et al. Short-term eff ects of daily aspirin also suggest that patients with a history of colorectal on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefi ts in 51 randomised controlled trials. Lancet 2012; cancer might represent a subgroup of individuals for published online March 21. DOI:10.1016/S0140-6736(11)61720-0.
whom, along with those with hereditary colon cancer 2 US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: US Preventive Services Task Force recommendation (Lynch syndrome),6 the risk of death from cancer might statement. Ann Intern Med 2009; 150: 396–404.
ciently high to warrant consideration of aspirin 3 US Preventive Services Task Force. Routine aspirin or nonsteroidal anti- infl ammatory drugs for the primary prevention of colorectal cancer: US therapy in the context of an individualised assessment Preventive Services Task Force recommendation statement. Ann Intern Med
2007; 146: 361–64.
Cole BF, Logan RF, Halabi S, et al. Aspirin for the chemoprevention of Do these data now allow a defi nitive conclusion colorectal adenomas: meta-analysis of the randomized trials. J Natl Cancer Inst
2009; 101: 256–66.
about population-based recommendations regarding 5 Burn J, Bishop DT, Chapman PD, et al. A randomized placebo-controlled routine use of aspirin for cancer prevention? Perhaps prevention trial of aspirin and/or resistant starch in young people with
familial adenomatous polyposis. Cancer Prev Res (Phila) 2011; 4: 655–65.
not, since the WHS and PHS remain signifi cant 6 Burn J, Gerdes A, Macrae F, et al, on behalf of the CAPP2 Investigators. counterbalancing trials that have not shown a cancer Long-term eff ect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. benefi t with alternate-day aspirin up to 10–12 years. Lancet 2011; 378: 2081–87.
Rothwell PM, Wilson M, Elwin CE, et al. Long-term eff ect of aspirin on The lower propensity for bias in the WHS and PHS, colorectal cancer incidence and mortality: 20-year follow-up of fi ve as randomised trials with cancer as a prespecifi ed randomised trials. Lancet 2010; 376: 1741–50. Published online March 21, 2012 DOI:10.1016/S0140-6736(11)61654-1
Rothwell PM, Fowkes FG, Belch JFF, Ogawa H, Warlow CP, Meade TW. 12 Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary Eff ect of daily aspirin on long-term risk of death due to cancer: analysis of prevention of cancer: the Women’s Health Study: a randomized controlled individual patient data from randomised trials. Lancet 2011; 377: 31–41.
trial. JAMA 2005; 294: 47–55.
Rothwell PM, Wilson M, Price JF, Belch JFF, Meade TW, Mehta Z. Eff ect of 13 Sturmer T, Glynn RJ, Lee IM, Manson JE, Buring JE, Hennekens CH. daily aspirin on risk of cancer metastasis: a study of incident cancers during Aspirin use and colorectal cancer: post-trial follow-up data from the randomised controlled trials. Lancet 2012; published online March 21. Physicians’ Health Study. Ann Intern Med 1998; 128: 713–20.
14 Chan AT, Manson JE, Feskanich D, Stampfer MJ, Colditz GA, Fuchs CS. 10 Algra AM, Rothwell PM. Eff ects of regular aspirin on long-term cancer Long-term aspirin use and mortality in women. Arch Intern Med 2007; incidence and metastasis: a systematic comparison of evidence from 167: 562–72.
observational studies versus randomised trials. Lancet Oncology 2012; 15 Huang ES, Strate LL, Ho WW, Lee SS, Chan AT. Long-term use of aspirin published online March 21. DOI:10.1016/S1470-2045(12)70112-2.
and the risk of gastrointestinal bleeding. Am J Med 2011; 124: 426–33.
11 Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of 16 Chan AT, Arber N, Burn J, et al. Aspirin in the chemoprevention of colorectal colorectal cancer. JAMA 2009; 302: 649–58.
neoplasia: an overview. Cancer Prev Res 2012; 5: 164–78. Published online March 21, 2012 DOI:10.1016/S0140-6736(11)61654-1


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