Download Accepted version - Queen Mary University of London

Role of Aspirin in Cancer Prevention.
Authors:
Mangesh A. Thorat, MBBS, MS, DNB; Jack Cuzick, PhD
Affiliations:
Dr. Mangesh A. Thorat
Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine
Queen Mary University of London
Charterhouse Square, London EC1M 6BQ
United Kingdom
Tel: +44 (0)20 7882 3546
Fax: +44 (0)20 7882 3890
Email: [email protected]
Prof. Jack Cuzick
Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine
Queen Mary University of London
Charterhouse Square, London EC1M 6BQ
United Kingdom
Tel: +44 (0)20 7882 3518
Fax: +44 (0)20 7882 3890
Email: [email protected]
Correspondence:
Prof. Jack Cuzick
Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine
Queen Mary University of London
Charterhouse Square, London EC1M 6BQ
United Kingdom
Tel: +44 (0)20 7882 3518
Fax: +44 (0)20 7882 3890
Email: [email protected]
Keywords: aspirin; prevention; cancer; cardiovascular disease; myocardial infarction; stroke; peptic
ulcer; gastrointestinal bleeding; benefit-harm; Helicobacter pylori
Word count: text-only 3166
References: 87
Abstract
Since its first synthesis in 1897, several medicinal roles and mechanisms of action of aspirin have
become apparent; latest among these being its role in cancer prevention and treatment. A large
body of evidence supports aspirin’s effect in reducing cancer incidence and cancer mortality, but
duration of use needs to be at least 5 years. The beneficial effects are particularly large for
colorectal, oesophageal and gastric cancers with apparently smaller reductions for breast, prostate
and lung cancer. The major harm is gastrointestinal bleeding, but serious sequelae are minimal at
ages < 70 years. It is very likely that use of prophylactic aspirin in the general population aged 50 70+ years will result in net overall benefit. Outstanding issues are whether standard dose
(~300mg/day) can lead to greater net benefits than low dose (75-100mg/day), the optimum duration
of use and appropriate ages for use in average risk individuals.
Introduction
Barks of Willow tree were used for medicinal purposes for thousands of years before medicinal
acetylsalicylic acid (ASA) was synthesised and labelled as Aspirin by Bayer AG in 1897 [1,2]. While
aspirin was extensively used for its analgesic, antipyretic and anti-inflammatory properties, the exact
mechanism of action was elucidated more than 70 years later by John Vane [3,4]. John Vane was
jointly awarded Nobel Prize in 1982 for his work on aspirin. Discovery of anti-platelet effects led to
increasing use of aspirin as an anti-thrombotic agent in prevention of cardiovascular diseases from
1980s [5]. Adding another dimension to its medicinal properties, cancer prevention and anti-cancer
effects of aspirin have only recently become apparent, almost hundred years after its launch [6].
We review the role of aspirin in cancer prevention in terms of mechanisms of action, general and
site-specific effects on cancer incidence, potential harms of aspirin use and overall balance of
benefits and harms. Role of aspirin in preventing deaths from cancer is also briefly discussed. We
also discuss methods for mitigation of harms of aspirin use and identify important research
questions.
Mechanisms of action
Aspirin has several different pharmacological effects. These range from anti-platelet action at low
doses to anti-inflammatory action at high doses. Apart from these effects, several new mechanisms
of action are still being discovered.
Anti-platelet action
Arachidonic acid is metabolised by Prostaglandin H Synthase (PGHS) or Cyclooxygenase (COX) to
synthesise prostanoids. Prostanoids are tissue-specific lipid compounds involved in signalling, and
these include Prostaglandin (PG) D2, E2, F2α, Thromboxane A2 (TXA2) and prostacyclin (PGI2). Two
major isoforms of PGHS have been identified, COX-1 and COX-2. COX-1 is constitutively expressed in
most tissues, while COX-2 is expressed in several tissues like vascular endothelium, brain and kidney.
COX-1 is the only isoform present in mature platelets and is involved in synthesis of TXA2, which has
a central role in platelet aggregation. COX-2 in the vascular endothelium, on the other hand, is
involved in PGI2 synthesis [7].
Aspirin irreversibly inactivates both COX-1 and COX-2. The level of inhibition of activity by aspirin is
dependent on drug availability in target tissue and recovery of COX activity through de novo enzyme
synthesis [8]. Mature platelets lack nuclei and therefore cannot synthesise COX-1 enzyme [8].
Platelets also pass through portal circulation where aspirin concentration is much higher than that in
systemic circulation [9]. Therefore, cardio-protective anti-platelet effects of aspirin appear at doses
as low as 30 mg per day where it has very transient and minimal effects on non-platelet targets.
Anti-inflammatory action
Aspirin is metabolised rapidly during its first-pass through liver and by plasma esterases resulting in a
very short half life of 15-20 minutes [9]. Therefore, in order to maintain a sustained inhibition of
COX-1 and COX-2 enzymes in nucleated cells, frequent dosing (3-4 times per day) of large doses
(around 2000 mg per day) is needed. Anti-inflammatory action of aspirin is thought to be mediated
through several mechanisms including sustained inhibition of prostanoid synthesis, inhibition of
protein kinase IkBkinase β (IKKβ) in the NF-kB pathway [10] and aspirin-triggered 15-epi-lipoxins
[11].
Analgesic action
Analgesic effects of aspirin are thought to be mediated through numerous mechanisms [12]. There
appears to be a dose-response relationship between aspirin dose and its analgesic effects [13].
Anti-cancer action
Evidence from randomised controlled trials (RCTs) [14-16] and observational studies [17-20] shows
that aspirin’s impact on mortality exceeds its effect on incidence (see below). This means that aspirin
not only has chemopreventive action but also prevents cancer progression and metastasis. The
mechanisms of action at play in these anti-cancer effects are however not clear yet. Various
hypotheses have been proposed, the most accepted among these proposes that anti-cancer action is
mediated through COX-2 inhibition [21,22]. Although supported by epidemiological data [23], this
hypothesis cannot explain clear anti-cancer effects seen at low doses of aspirin [14,15,24]. Several
other mechanisms like inhibition of NF-kB [23], induction of polyamine catabolism [25], inhibition of
mTOR signalling [26] and activation of AMP-activated protein kinase [26,27], effects on PI3-kinase
pathway [28] or its cross-talk with COX-2 [29,30] and induction of apoptosis through other pathways
[31,32] have been proposed. All these mechanisms however require higher drug concentrations than
those achieved by low-dose aspirin (< 100 mg/day) [33]. Anti-platelet action of aspirin may reduce
direct interaction of platelets with cancer cells and thus prevent metastasis [34,35]. Similarly, it may
prevent platelet-mediated COX-2 induction and downstream signalling at the site of intestinal
mucosal injury and thereby increase apoptosis, reduce proliferation and angiogenesis as proposed
by Thun and colleagues [36]. These two mechanisms based on anti-platelet action of aspirin, the
former resulting in prevention of cancer progression and the latter resulting in prevention of
carcinogenesis, are compatible with the anti-cancer effects seen at low doses of aspirin. The
relationship between aspirin dose and anti-cancer effect is unclear. While indirect comparisons of
RCTs show no clear indication of greater reduction in cancers [15] or adenomas [37] with increasing
dose, observational studies [38,39] have shown benefit above 300mg dose and reductions in
advanced adenomas were also greater with the higher dose [40]. RCT in high-risk individuals has also
shown benefit of large magnitude with higher doses of 600mg [41]. It is plausible that mechanisms
other than anti-platelet action are involved in aspirin’s anti-cancer effect when doses higher than
100mg per day are used.
Overall effects on cancer
Beneficial effect of aspirin in preventing colorectal cancer (CRC) and deaths due to CRC is now
beyond question [14,15,24,38,41-49]. Beneficial effects on two other gastrointestinal (GI) cancers,
viz. oesophageal and gastric cancers [24,42,43,47-49] and on lung [24,42,43,46], breast [24,42,43,4649] and prostate cancers [24,42,43,47,50] have also emerged over past several years [14,24,42,43].
There appears to be little or no effect on other major cancer sites including pancreatic, endometrial,
and hematopoietic tumours; even then overall cancer incidence and mortality is reduced
[14,24,44,47]. Thus, aspirin reduces incidence of and/or mortality from several cancers and
cardiovascular disease. Use of prophylactic aspirin in the general population for prevention of major
diseases and related deaths is likely to be beneficial, when its benefits on both, overall cancer and
cardiovascular disease are considered together and not just effects on CRC [51] or cardiovascular
disease [52] in isolation, as done by US Preventive Services Task Force (USPSTF) in the past [51,52].
Cancer Incidence
Analyses of data from RCTs showed that aspirin use at doses between 75 to 300 mg/d reduced
overall cancer incidence by 12% [14]. The magnitude of benefit was larger (19% reduction) when
scheduled treatment duration was 5 years or more. [14]. The beneficial effects only became
apparent after 3 years with a 24% reduction observed after 3 years of follow-up. Overall relative
reductions in cancer incidence were similar in men and women [14].
Cancer Mortality
The beneficial effects of aspirin on overall cancer mortality are of a larger magnitude than effects on
cancer incidence. Analyses of data from RCTs showed that reductions in cancer deaths became
apparent after 5 years and the beneficial effects lasted for over 20 years in the trials with long
follow-up [24]. Overall, aspirin reduced cancer deaths by 20%; the magnitude of benefit was larger
at 34% reduction seen after 5 years of follow-up. The magnitude of benefit was also larger with
longer duration of aspirin use, 31% reduction in mortality with scheduled treatment duration of 7.5
years or more [24]. Overall relative reductions were similar in men and women [24]. Data from RCTs
show that aspirin may have larger effect on adenocarcinomas than non-adenocarcinoma solid
tumours [14,24]. Evidence from epidemiological studies shows a reduction in recurrence in both
breast and colorectal cancers, trials are underway to examine aspirin as an adjuvant treatment (see
below).
Site-specific effects
Aspirin use results in reduction in the incidence and mortality of range of cancers in the gastrointestinal tract and cancers of breast, prostate and lung. The evidence is strongest for reduction in
CRC, followed by reductions in oesophageal and gastric cancers. The effects on breast, prostate and
lung cancers are smaller.
Colorectal cancer:
A very large body of evidence supports a reduction in colorectal cancer incidence and mortality as a
result of regular aspirin use [14,15,24,38,41-49]. Long-term follow-up of 3 trials of low-dose aspirin
(75-300 mg/d) use found a 25% reduction in the incidence of colorectal cancer [15]. The effects were
not apparent immediately and the reduction in incidence was 30% when the scheduled treatment
duration was 2.5 years or more and 38% when treatment duration was 5 years or more. Two trials,
the Women’s Health Study (WHS) [44] and the Physicians’ Health Study (PHS) [53] investigated
alternate day use (WHS 100mg alternate day, PHS 325mg alternate day). Of these, WHS has now
reported a 42% post-treatment reduction (RR 0.58; 95%CI 0.42-0.80) and an overall reduction of
20% [44]. PHS, however, has not shown any reduction in colorectal cancer [53,54]. The observed
benefit in WHS is noteworthy because majority of the women enrolled in the trial were younger
than 55 years.
Observational studies, collectively based on a much larger number of cases, have similarly reported a
27% reduction in CRC incidence; a 38% reduction seen in case-control studies and a 19% reduction in
cohort studies [42,43].
Larger benefits have been seen in individuals at high-risk of colorectal cancer [41]. CAPP2, a
randomised trial in Lynch syndrome carriers, reported a 63% reduction in CRC incidence among
those completing 2 years of 600 mg daily aspirin [41].
The effects of aspirin have also been seen in prevention of adenoma, a pre-malignant lesion of CRC.
A meta-analysis of 4 RCTs reported a 28% reduction in advanced adenomas within a short 33 month
follow-up [40].
The effect size of aspirin in preventing CRC mortality is greater than that for CRC incidence, with a
40% overall reduction was observed in meta-analyses of large number of trials [15,24]. The results of
observational studies are also consistent with this observation [46,48,49].
Oesophageal cancer:
Case-control studies have reported a 43% reduction in incidence of oesophageal cancer and cohort
studies have reported a 27% reduction [42,43]. The observed reductions in incidence are similar for
squamous cell oesophageal cancers (39%) and adenocarcinomas (36%) including gastric cardia [43].
A larger effect on oesophageal cancer mortality reduction has been observed; a 44% reduction in
cohort studies [48,49] and a 58% reduction after 5 years of follow up in randomised trials [24]. RCTs,
however, have suggested the effect of aspirin is primarily on adenocarcinomas [16,24].
Gastric cancer:
Case-control studies have reported a 39% reduction in gastric cancer incidence and cohort studies
have reported a 25% reduction in incidence [42,43]. While data on aspirin’s effect on gastric cancer
incidence are not available from RCTs, an overall 31% reduction (P= 0.11) in deaths has been
reported. The effect appeared mostly after 10 years of use, when a 58% reduction (P= 0.007) was
observed [24]. Cohort studies have also reported a 41% reduction in gastric cancer mortality [48,49].
Breast cancer:
A much smaller effect is seen on breast cancer. Case-control studies reported an 18% reduction in
breast cancer incidence, while the reduction observed in cohort studies was 8% [42,43]. However,
no effect on breast cancer incidence was seen in the WHS [55], results remain unchanged after a
longer 17.5 year follow-up [44]. A meta-analysis of observational studies and RCT found a 14%
reduction [56]. Similar small, 5% in case-control study [46] and 14% in cohort studies, non-significant
reduction in breast cancer mortality has also been observed [48,49]. A non-significant increase in
breast cancer mortality was seen in an overview of RCTs [42], however, this may be unreliable as the
number of events was very small (n = 23).
Prostate cancer:
Similar to breast cancer, the effect on prostate cancer is also small. Case-control studies reported an
14% reduction in prostate cancer incidence, while the reduction observed in cohort studies was 9%
[42,43], the effect was predominantly limited to high grade tumours. The effects on mortality are
slightly larger; a non-significant 19% reduction in mortality observed in the RCTs [24], and a nonsignificant 16% reduction in lethal prostate cancers (metastasis or death) observed in the Health
Professionals Follow-up study (HPFS) [50].
Lung cancer:
The evidence for aspirin’s effect on lung cancer is more variable but generally favourable. Casecontrol studies reported a 19% reduction in incidence of lung cancer, but no reduction was observed
in cohort studies [42,43]. The reduction in lung cancer mortality in RCTs was 29% while it was 12%
(non-significant) in case-control studies. Two [47,49] of three cohort studies did not observe any
reduction, while the third observed a 19% reduction [48].
Other cancers:
Among other cancers, there may be a small effect on pancreatic cancer but the evidence is variable
and less clear. Cohort studies reported a non-significant 4% reduction in incidence while the
reduction observed in case-control studies was 7% (non-significant) [42,43]. Although a nonsignificant 19% reduction in mortality in the RCTs was seen [24], the reduction in cohort studies was
only 3% (non-significant) [48,57]. A study of patients with mismatch repair defects [41] reported a
large reduction in endometrial cancer, but the effect in average-risk women is unknown. A
significant beneficial effect of aspirin has not been seen for any other cancer site
Aspirin as an adjuvant treatment
Detailed discussion of potential role of aspirin in cancer treatment [58] is outside the scope of this
paper; however, a brief note is necessary as it has a role in prevention of cancer deaths and it may
help us understand some of the multiple mechanisms of aspirin action. Observational studies in
breast cancer [19], and colorectal cancer [17,20,23] have reported that taking or continuing aspirin
after the diagnosis of cancer results in reduced metastasis and improved survival. Results of
translational work from the Nurses’ Health Study (NHS) and the HPFS show that this benefit is
pronounced and possibly limited to cancers with PIK3CA mutation [28]. Several trials are ongoing or
have been planned to investigate adjuvant role of aspirin in treatment of cancers; ASCOLT trial [59]
in CRC, Big A trial [60] in non-small cell lung cancer and ADD-Aspirin trial [58] in a range of cancers
including colorectal, gastro-oesophageal, breast and prostate cancer are notable examples.
Harms
The most important harms of aspirin are excess bleeding either intracranial (haemorrhagic stroke) or
gastrointestinal and peptic ulcers. Any increase in the risk of haemorrhagic stroke is compensated by
a larger reduction in ischaemic strokes. Hypertension is the major risk factor for haemorrhagic stroke
and these tend to occur mainly in individuals with inadequately treated hypertension [61]. Ensuring
adequate blood pressure control before start and during aspirin use can minimise this harm.
Several meta-analyses of RCTs and observational studies [62-67] have estimated that both low-dose
and standard dose aspirin results in a 1.5 to 1.7-fold increase in the risk of GI
bleeding/complications. However, majority of these episodes are minor events and are considerably
less severe as compared to the events prevented by aspirin, viz. cancer, myocardial infarction (MI)
and strokes. Therefore, only major bleeding episodes should be considered in any analysis of benefit
and harms; data from the Antithrombotic Trialists’ Collaboration (ATT) suggest that aspirin increases
such major bleeding events by 0.3 per 1000 per year [62]. Case-Fatality rates associated with GI
bleeding or peptic ulcer perforations are around 5% in those younger than 65 years [68-74];, fatality
rises sharply beyond 70 years [7].
Pre-existing GI pathology or presence of H. pylori infection are also major risk factors [75,76]. A
significant proportion of older individuals (50 years or more) are infected with H. pylori, even in the
developed world [77,78]. H. pylori eradication therapy is effective in preventing GI complications
[79,80]. Screening and eradication of H. pylori before starting aspirin may minimise its harms and
also improve cost-effectiveness of such strategy to prevent gastric cancer [81,82]. Diabetes,
smoking, and raised cholesterol are other risk factors for GI bleeding [62]. It is also important to note
that the excess risk of bleeding is high during first few months of aspirin use and it then tends to
approach normal risk [15,83]. Careful assessment of risk factors and monitoring for early bleeding
episodes and their timely treatment [84] may considerably mitigate aspirin-related harms.
Overall balance of benefits and harms
For every 1000 men aged between 50 and 84 years in the UK, 14 are diagnosed with cancer and 7
die due to cancer every year. The corresponding figures for women are 11 diagnoses and 5 deaths
[85]. GI cancers alone account for 20% of cancers (and cancer deaths) in men and 15% of cancers
(and cancer deaths) in women; whereas six cancers on which aspirin has a preventive effect account
for 60% of cancer diagnoses and 55% of cancer deaths in men and women alike. Therefore, even if
benefits of aspirin on cardiovascular diseases are ignored, aspirin use can result in prevention of
substantial number of cancers and cancer deaths. Aspirin-related major harms and fatalities, on the
other hand, are relatively infrequent and can be minimised further. Therefore, aspirin appears to be
a very effective cancer prevention agent which may also have a role in cancer treatment.
Research priorities
It is clear that aspirin needs to be used for a minimum of 5 years for preventive benefits to accrue
which then appear to continue for several years after the drug is stopped. The most appropriate
duration of drug use is however not clear. In order to minimise harms, it seems prudent to avoid
using aspirin after 70 years of age. Results of ASPREE trial [86,87] will shed light on relative merits of
aspirin use in elderly individuals age 65 years or more. While daily low-dose aspirin (< 100 mg/day) is
an effective cancer-preventive agent, evidence from adenoma prevention studies [40] and studies in
high-risk individuals [41] points to a possibility of larger effect sizes with standard (300-325 mg/day)
or higher doses (e.g. > 600 mg/day). Therefore, trials are needed to identify the dose of aspirin at
which net benefits (benefits minus harms) are greatest and adherence to drug use is maximum. The
role of H. pylori screening and eradication before starting aspirin to minimise GI harms merits
evaluation in a clinical trial; HEAT trial (ClinicalTrials.gov Identifier: NCT01506986) is addressing role
of this strategy in current aspirin users. Further research is needed to identify markers of high
bleeding risk, data and samples from participants of ongoing adjuvant aspirin trials may prove useful
in this work.
Conclusions
Evidence from a very large number of studies points to a key role of aspirin in cancer prevention.
Aspirin use results in a substantial reduction in cancer incidence and a larger reduction in cancer
mortality. The beneficial effects of aspirin appear to be mainly through its effects on colorectal,
oesophageal, gastric cancers with small effects on breast, prostate and lung cancers. Although
concerns regarding aspirin-related bleeding exist, majority of such events are minor. The potential
benefits of aspirin in terms of cancers and cancer deaths prevented are likely to be much larger than
bleeding events of comparable severity. For a drug synthesised in 19th century, aspirin may very well
emerge as the cancer preventive agent of 21st century.
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