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Despite their early stage of development, some important discoveries have been made for prevention of cancer. Of these, low-dose aspirin stands out as having the largest potential impact on the population at large. If aspirin has had earlier recommendations from professional bodies against using it in the general population based on some risks of gastrointestinal and cerebral bleeding, these recommendations now need to be updated in view of the much larger benefits seen for cancer prevention than for cardiovascular disease1.
The IARC Handbooks of Cancer Prevention cover cancer-preventive agents, including among others vitamin A, carotenoids, and retinoids, preventive actions (e.g. use of sunscreens, absence of excess body, fatness, physical activity, and consumption of fruit and vegetables) but also non-steroidal anti-inflammatory drugs including aspirin.
Among the factors that contribute to prevent cancer incidence, the World Cancer Report 2020 (WCR 2020) highlights specifically a series of observations that regular use of aspirin and other non-steroidal anti-inflammatory drugs has a major effect on the reduction of various tumour types2.
There is indeed now, says the WRC 2020, overwhelming evidence that aspirin has a major effect in particular on three common gastrointestinal cancer types – colorectal, stomach and oesophageal cancer (30% each and up to 50%, of oesophageal squamous cell carcinoma and oesophageal adenocarcinoma) – and potentially provides small reductions in three other major cancer types: lung, breast, and prostate cancer. This with smaller and less certain reductions for breast, prostate, and lung cancer (5–15%)3.
Globally, long-term use of about 10 years of aspirin was estimated to reduce overall cancer incidence by about 9% in men and 7% in women, and overall cancer mortality by 13% in men and 9% in women. Such a degree of significance in a prevention effect deserved thus to be more specifically analysed and highlighted. Although data are less extensive for women, men have a higher incidence of the cancer types for which the incidence is reduced by aspirin use, leading to greater absolute reductions4.
Further, the additional preventive benefits of use of aspirin associated with high-dose proton-pump inhibitors, and with statins for other cancer types and for cardiovascular disease, makes that these drugs may be good candidates for chemoprevention in groups at high risk5.
However, questions still remain about aspirin’s optimal dose, duration, efficacy, safety, and impact on different sub-types of specific cancers, and more research is needed.
Long-term regular aspirin use would contribute to a reduction of about one third in colorectal cancer incidence and mortality6. There is indeed some evidence that aspirin and cyclooxygenase 2 (COX-2) inhibitors may reduce recurrence of adenomas and incidence of advanced adenomas in individuals at an increased risk of colorectal cancer.
In individuals at average risk, use of aspirin (daily or alternate-day dose, ≥ 75 mg) appeared to reduce colorectal cancer incidence and mortality, after a latency of about 10 years, with a small reduction in all-cause mortality within 10 years of initiating use. In a recent network meta-analysis, low-dose aspirin appeared to be as effective as gFOBT or sigmoidoscopyin reducing colorectal cancer incidence and mortality, and more effective for cancers located in the proximal colon7.
For oesophageal cancer and stomach cancer, beneficial effects of a similar size have been observed.
A review of epidemiological data performed by a working group in 2015 suggested that aspirin and statins may provide some protective effect against pancreatic cancer, whereas non-aspirin non-steroidal anti-inflammatory drugs do not appear to have an effect on risk8.
Regular use (usually defined as at least once per week – of aspirin and, potentially, other NSAIDs has also been associated with a reduced risk of endometrial cancer among obese women; little effect was seen for normal-weight women. It is less clear whether any association is restricted to standard-dose aspirin or whether use of low-dose formulations may also confer a benefit. An effect is plausible because both aspirin and other NSAIDs inhibit cyclooxygenase (COX) activity, leading to a reduction in prostaglandin levels, and COX inhibitors also downregulate aromatase activity in breast cancer cell lines9.
For prostate cancer, widespread use of low-dose aspirin for 10 years between ages 50 and 65 years could have a major impact on cancer incidence and mortality while for lung cancer, breast cancer, smaller and less convincing reductions of 5–15% have recently also been found.
Emerging evidence suggests that very frequent use of aspirin (≥ 6 days per week) would be associated with modest reductions in risk of ovarian cancer in both pooled case–control and prospective studies. However, the effects of long-term aspirin use (i.e.≥ 10 years) and use of other analgesics (e.g. acetaminophen) and differential effects by histotype are not well described and additional studies are required to weigh potential risks and benefits and to delineate target populations.
There appears to be little or no effect on other major cancer sites10.
The relative impact of aspirin use appears to be similar between the sexes, but the overall effects are greater for men because these cancer types are relatively more common in men. The impact on cancer mortality appears to be larger than that for incidence, suggesting an anti-metastatic effect as well as a separate effect on incidence. The mechanisms that mediate these effects are currently not established, and trials are under way to examine aspirin as an adjuvant treatment for individuals with colorectal, stomach, oesophageal, breast, and prostate cancer.
Aspirin has had earlier recommendations from professional bodies against using it in the general population. However, those recommendations were based on comparing cardiovascular benefits with risks of bleeding, Gastrointestinal and cerebral bleeding are indeed the most important harms associated with aspirin use, and their risk and fatality rate increase with age. These recommendations now need to be updated in view of the much larger benefits seen for cancer prevention than for cardiovascular disease . These benefits have only been reported more recently, largely because they were not apparent until after 3–5 years of aspirin use.
Actually, aspirin/NSAIDs increase gastrointestinal bleeding by ~50%, mostly in initial period after starting treatment and haemorrhagic stroke by 35%, but with larger reduction in occlusive stokes and net decrease in incidence, but increase in fatal events12.
Nevertheless, when the reduction in risk of cancer and cardiovascular disease and the risk of excess bleeding are all considered in the general population aged 50–65 years, use of prophylactic aspirin is likely to be beneficial.
The benefit–risk ratio is highly favourable for the general population, both men and women, and is about 5:1 for serious events and at least 7:1 for deaths. The United States Preventive Services Task Force currently supports the use of aspirin for those at increased risk of cardiovascular disease or colorectal cancer.
Meanwhile, markers that identify individuals most likely to benefit would enable treatment to be more focused, and this is a current research priority.
The effects of daily use of aspirin on cancer incidence are not apparent until at least 3 years after the start of use, with a relative reduction in incidence after that time for all cancers of about 24%. From randomized trials and observational data, aspirin use lowers risk of sporadic colorectal cancer only after about a decade from onset of use13.
Some benefits however appear to be sustained for several years after treatment cessation in long-term users.
Potential chemoprevention of colorectal cancer mediated by aspirin and related drugs is not necessarily an exception.
The impact of aspirin use on cancer mortality appears to be larger than that for incidence, suggesting an anti-metastatic effect as well as a separate effect on incidence14. Although the mechanisms that mediate these effects are currently not established, the role of inflammation as a crucial mediator of colorectal cancer is well established, and the use of non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen has been found to significantly reduce the risk of colorectal cancer in some patient populations. Prostaglandins are also particularly significant in view of the protective effect of aspirin on several human tumour types.
Many gene variants that interact with environmental agents have been identified. In a genome-wide association study [GWAS] of gene × environment interactions published by the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO)15 and cited in the WCR 2020, a lower risk of colorectal cancer was associated with the use of aspirin and/or non-steroidal NSAIDs and this association differed according to genetic variation on chromosomes 12 and 15. Meanwhile, such potential chemoprevention of colorectal cancer mediated by aspirin and related drugs is not necessarily an exception.
Relative reductions in cancer incidence appear to be similar in men and women although data are less extensive for women and men have a higher incidence of the cancer types for which the incidence is reduced by aspirin use, leading to greater absolute reductions.
Trials are under way to examine aspirin as an adjuvant treatment for individuals with colorectal, stomach, oesophageal, breast, and prostate cancer16.
Data on other non-steroidal anti-inflammatory drugs, such as ibuprofen, sulindac, or celecoxib, are less extensive but there are no trials with long-term follow-up, except for studies of colorectal adenomas but observational studies have found similar overall effects on cancer incidence.
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Reference document : The World Cancer Report 2020 : Cancer Research for Cancer Prevention  1 See WRC Report 2020, p. 528 2 See summary & Conclusions p. 527 3 See summary & table p. 523 4 See p. 526 5 See p. 330 6 See p. 27 7 See p. 352 8 See p. 372 9 See p. 407 10 See p. 415 & 418 11 See p. 528 12 See p. 524 13 See p. 94 14 See p. 523 15 www.ncbi.nlm.nih.gov/pmc/articles/PMC4382867/ 16 See p. 523 |
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