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Research in Context Panel:
Evidence before this study: Preclinical data, epidemiological studies, and meta-analyses of randomised
data from cardiovascular trials support the hypothesis that aspirin could be an effective adjuvant cancer
therapy (Langley R, et al. Br J Cancer 2011;105(8):1107-13; Algra AM et al. Lancet Oncol 2012;13(5):518-
27 ). Globally, several phase III studies are ongoing to assess this, though debate continues about the
safety profile of aspirin particularly after radical therapy for gastrointestinal malignancies.
Added value of this study: The Add-Aspirin trial (encompassing 4 individually powered phase III studies in
gastro-oesophageal, colorectal, prostate and breast cancer) is the largest of the ongoing trials and
includes a pre-defined feasibility analysis to assess the acceptability of randomisation, tolerability and
toxicity based on an open label run-in phase prior to double- blind randomisation. The data show that
aspirin is well tolerated after radical cancer therapy, acceptable to patients, and there is no evidence to
suggest there is increased toxicity in the gastro-oesophageal cohort over other tumour-specific cohorts.
Implications of all the available evidence: Aspirin is a low cost generic drug with the potential to have a
large impact on cancer outcomes globally. Outcomes from gastro-oesophageal cancer remain poor and
there is an imperative to complete recruitment to the ongoing trials as quickly as possible. The rationale
and supporting evidence for evaluating aspirin as a potential anti-cancer therapy remains strong. More
generally, a run-in approach may be useful in adjuvant (or prevention) studies for reducing the risk of
non-adherence and participant attrition at a later date.
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TITLE PAGE
Aspirin as an Adjuvant Treatment for Cancer: Feasibility Results from the Add-
Aspirin Randomised Trial
Short Title: Add-Aspirin Trial: Feasibility & Early Toxicity
Nalinie Joharatnam1, Fay Cafferty2, Richard Hubner3, Daniel Swinson4, Sharmila Sothi5, Kamalnayan
Gupta6, Stephen Falk7, Kinnari Patel8, Nicola Warner9, Victoria Kunene10, Sam Rowley11, Komel Khabra12,
Tim Underwood13, Janusz Jankowski14, John Bridgewater15, Anne Crossley16, Verity Henson17, Lindy
Berkman18, Duncan Gilbert19, Howard Kynaston20, Alistair Ring21, David Cameron22, Farhat Din23, Janet
Graham24, Timothy Iveson25, Richard Adams26, Anne Thomas27, Richard Wilson28, C.S Pramesh29, Ruth
Langley30 on behalf of the Add-Aspirin Trial Management Group
Author Correspondence: Professor Ruth Langley, MRC Clinical Trials Unit, Institute of Clinical Trials &
Methodology, 90 High Holborn, London, WV1V 6LJ, UK. ruth.langley@ucl.ac.uk.
1) Nalinie Joharatnam MRCP, Clinical Research Fellow, MRC Clinical Trials Unit, University College London, UK
2) Fay Cafferty PhD, Senior Statistician and Project Lead, MRC Clinical Trials Unit, University College London, UK
3) Richard Hubner PhD, Consultant Medical Oncologist, The Christie Hospital, Manchester, UK
4) Daniel Swinson MD, Consultant Medical Oncologist, St James University Hospital, Leeds, UK
5) Sharmila Sothi MRCP, Consultant Clinical Oncologist, University Hospital Coventry and Warwickshire, UK
6) Kamalnayan Gupta FRCR, Consultant Clinical Oncologist, Worcestershire Royal Hospital, Worcester, UK
7) Stephen Falk MD, Consultant Clinical Oncologist, Bristol Haematology & Oncology Centre, Bristol, UK
8) Kinnari Patel DPhil, Consultant Medical Oncologist, Churchill Hospital, Oxford, UK
9) Nicola Warner BM, Consultant Clinical Oncologist, Stoke Mandeville Hospital, Aylesbury, UK
10) Victoria Kunene MSc, Consultant Clinical Oncologist, Manor Hospital, Walsall, UK
11) Sam Rowley, Statistician, MRC Clinical Trials Unit, UCL, UK
12) Komel Khabra MSc, Statistician, MRC Clinical Trials Unit, UCL, UK
13) Tim Underwood PhD, Professor of Gastrointestinal Surgery & MRC Clinical Scientist, University of Southampton,
Southampton, UK
14) Janusz Jankowski PhD, Professor of Gastroenterology, Royal College of Surgeons, Ireland; National Institute for Health
and Care Excellence, UK; Gastroenterology Unit, Morecambe Bay University Hospitals NHS Trust, UK
15) John Bridgewater PhD, Professor of Medical Oncology, University College Hospital London, UK
16) Anne Crossley, Research Nurse, St James University Hospital, Leeds, UK
17) Verity Henson, Research Nurse, Bristol Haematology and Oncology Cancer Centre, UK
18) Lindy Berkman MSc, Patient and Public Involvement Representative, NCRI Consumer Liaison Group, London, UK
19) Duncan Gilbert PhD, Consultant Clinical Oncologist, MRC Clinical Trials Unit at UCL, London, UK
20) Howard Kynaston MD, Professor of Urological Surgery, Cardiff University, Cardiff, UK
21) Alistair Ring FRCP, Consultant Medical Oncologist, Royal Marsden Hospital, London, UK
22) David Cameron MD, Professor & Chair of Oncology, Cancer Research UK Edinburgh Centre, MRC Institute of Genetics &
Molecular Medicine, Western General Hospital, Edinburgh
23) Farhat VN Din MD, Senior Lecturer and Honorary Consultant Colorectal Surgeon & CSO Clinical Scientist, Cancer
Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western
General Hospital, Edinburgh, UK
24) Janet Graham PhD, Consultant Medical Oncologist, Beatson West of Scotland Cancer Centre
25) Timothy Iveson MD, Consultant Medical Oncologist, Southampton General Hospital, UK
26) Richard Adams MD, Professor of Clinical Oncology, Velindre Cancer Centre, Wales, UK
27) Anne Thomas PhD, Professor of Medical Oncology, Leicester Royal Infirmary, Leicester, UK
28) Richard Wilson PhD, Professor in Cancer Medicine, University of Glasgow, Glasgow
29) CS Pramesh MS, Professor and Chief of Thoracic Surgery, Department of Surgical Oncology, Tata Memorial Hospital,
Mumbai, India.
30) Ruth Langley PhD, Professor of Oncology and Clinical Trials, MRC Clinical Trials Unit at UCL, London, UK
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ABSTRACT
Background: Pre-clinical, epidemiological and randomised data indicate aspirin prevents tumour
development and metastases leading to reduced cancer mortality, particularly for gastro-oesophageal and
colorectal cancer. Randomised trials evaluating aspirin use after primary radical therapy are ongoing. To
address concerns about toxicity particularly bleeding after radical treatment for gastro-oesophageal
cancer, a pre-planned feasibility analysis was incorporated into the ongoing Add-Aspirin trial.
Method: The Add-Aspirin protocol includes 4 phase III randomised-controlled trials evaluating the effect
of aspirin on recurrence/survival after radical therapy in 4 tumour cohorts: gastro-oesophageal (GO),
colorectal (CRC), breast and prostate. An open-label run-in phase (aspirin 100mg daily for 8 weeks)
precedes double-blind randomisation (1:1:1 aspirin 300mg: aspirin 100mg: matched placebo). A pre-
planned analysis of feasibility, including recruitment, adherence, and toxicity was performed. The trial is
registered with the International Standard Randomised Controlled Trials Number registry
(ISRCTN74358648), and remains open to recruitment.
Findings: After two years of recruitment (October 2015- October 2017), 3494 participants were registered
on the trial (gastro-oesophageal 115, colorectal 950, breast 1675, prostate 754) with end of run-in data
available for 2253. Adherence: 95% (2148/2253) took 6-7 tablets/week and 85% proceeded to
randomisation, with rates consistent across tumour cohorts. 0·6% (14/2253) reported grade 3 toxicity
during the run-in period, with no upper gastrointestinal bleeding (any grade) in the gastro-oesophageal
cohort. The most frequent grade 1/2 toxicity overall was dyspepsia in 6.5% (146/2253).
Interpretation: Aspirin is well-tolerated after radical cancer therapy though marked differences in
recruitment rates across the tumour cohorts within the Add-Aspirin trial were seen. Toxicity has been low
and there is no evidence of a difference in adherence, acceptance of randomisation or toxicity between
the cohorts. Aspirin offers a potential low cost and well tolerated therapy to improve gastrointestinal
cancer outcomes.
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Funding: Cancer Research UK, The National Institute for Health Research Health Technology Assessment
Programme and The MRC Clinical Trials Unit at UCL.
Keywords: aspirin; gastro-oesophageal cancer; colorectal cancer; toxicity
Abbreviations used in this paper: CI (confidence interval), CRT (chemoradiation), GI (gastrointestinal), GO
(gastro-oesophageal), GCP (good clinical practice), HR (hazard ratio), NHS (National Health Service),
NSAIDs (non-steroidal anti-inflammatory drugs), RCT (randomised controlled trial), RR (relative risk).
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Introduction
Globally, cancers arising from the oesophagus, stomach and colon account for approximately 20% of all
cancer mortality (1). Mean five year survival rates from gastro-oesophageal cancer are particularly poor
(15%) (2), attributed to the frequently advanced stage at presentation of the disease and the challenges
of treatment (3). These factors are compounded in low and middle income countries by the lack of access
to potentially curative therapies and treatment costs.
Pre-clinical and observational studies provide substantial evidence that aspirin may prevent or delay the
development of cancer and metastases (4, 5). Many observational studies have demonstrated an
association between aspirin use and a decreased risk of developing cancer (3, 6), particularly for gastro-
oesophageal and colorectal cancer (Table 1). For example, the relative risk (RR) of developing
oesophageal cancer in aspirin users compared to non-users is estimated to be 0·75, 95% confidence
interval (CI) 0·62-0·89 (7-9). Similar effects are seen for several other common cancers including gastric,
colorectal, pancreatic, ovarian, breast and prostate cancer. Most recently an epidemiological study of
63,605 patients who had received Helicobacter pylori eradication therapy reported a relative risk
reduction of 70% in the development of gastric cancer with aspirin use (HR 0·30, 95% CI 0·15-0·61) (10).
Meta-analyses of randomised-controlled trials (RCTs) designed to investigate the cardiovascular effects of
aspirin support the observations that aspirin reduces the risk of developing cancer. Long-term follow up of
approximately 77,000 trial participants demonstrates a reduced risk of fatal cancer in those allocated to
aspirin compared to placebo (11, 12). The greatest effects were seen in oesophageal and colorectal
cancer, with a reduction in the 20-year risk of death from oesophageal cancer of 58% (hazard ratio (HR)
0·42, 95% CI 0·25-0·71, p=0·001) and for colorectal cancer death (HR 0·60, 95% CI 0·45-0·81, p=0·0007)
(11, 13). Further analysis attributed the reduction in cancer mortality with aspirin to a reduction in the risk
of metastases both at presentation (HR 0·69, 95% CI 0·38-0·77, p=0·0007) and subsequently (HR 0·45, 95%
CI 0·28-0·72, p=0·0009).
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Substantiating the hypothesis that aspirin reduces the risk of metastases several non-randomised cohort
and population studies (also summarised in Table 1) demonstrate that aspirin use after a cancer diagnosis
reduces both cancer mortality and overall mortality compared to non-use. For example, a recent Dutch
population-based study of 13,000 patients with gastrointestinal cancer showed a marked reduction in
overall mortality of 48% (HR 0·52, 95% CI 0·44-0·63) in aspirin users post diagnosis compared to non-users
(14). Similarly, a study of more than 1700 patients in China who underwent surgical resection for gastro-
oesophageal cancer reported a five-year survival of 51·2% in those patients allocated to daily aspirin post-
operatively compared to only 41% on placebo (p=0·04) (15).
Based on these studies, several large, long-term randomised trials are underway to assess the benefit of
aspirin after radical cancer therapy. The largest and most comprehensive is the Add-Aspirin protocol
(ISRCTN74358648), which encompasses individually powered phase III trials in 4 common tumours gastro-
oesophageal, colorectal, breast and prostate cancer. A pre-planned feasibility analysis (after two years of
recruitment) was incorporated into the Add-Aspirin trial to assess recruitment, tolerability, and
adherence, and to address any concerns about toxicity, particularly gastrointestinal bleeding, on aspirin
after radical cancer therapy. We present this analysis for all tumour cohorts to provide reassurance about
the use of aspirin after radical cancer therapy.
Method:
Study Design and Participants: The Add-Aspirin protocol has been described in detail previously. In brief,
the main eligibility criteria, across the four tumour cohorts, include completion of a standard radical
potentially curable treatment schedule (which may include surgery +/- neoadjuvant or adjuvant
oncological management or primary chemoradiation (CRT)), with no evidence of residual disease or
metastases. Patients already receiving aspirin, other anti-coagulants or long-term non-steroidal anti-
inflammatory drugs are excluded. The gastro-oesophageal trial includes patients with histologically
confirmed adenocarcinoma or squamous cell carcinomas of the oesophagus, gastro-oesophageal junction
or stomach and the colorectal trial patients with adenocarcinomas stage II/III (and stage IV with
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completely resected liver metastases only). Participants (in all cohorts) are over the age of 16, with no
upper age limit, and have a performance status of 0-2. Exclusion criteria include evidence of
moderate/severe renal impairment (glomerular filtration rate (eGFR) <45ml/min/1.73m2), and liver
function tests greater than 1.5x the upper limit of normal. Participants with a history of active or previous
peptic ulceration or gastrointestinal bleeding within the last year, except where the cause of bleeding has
been surgically removed, are excluded. All participants provide fully informed written consent.
Randomisation and masking: Randomisation is via a central system at the coordinating trials unit,
accessible by phone to recruiting teams. Participants <75 years are randomised (1:1:1) to receive either
aspirin 100mg, aspirin 300mg or a matched placebo to be taken daily for at least five years. Those aged 75
years or older are randomised 2:1 to aspirin 100mg or matched placebo only, due to increased risks of
toxicity with higher doses and older age (16). For both age groups, allocation uses a minimisation
algorithm based on key prognostic factors (specific to tumour type and not listed here to protect the
integrity of the ongoing trial) and incorporating a random element. Use of matching placebos and
identical drug packs ensures that participants and investigators remain blind to treatment allocation.
Procedures: Participants are initially registered onto the run-in phase of the study and receive aspirin
100mg oral daily open-label for eight weeks. In the gastro-oesophageal cohort this can commence
between six and fourteen weeks after surgery, up to fourteen weeks after the final fraction of
radiotherapy, or up to eight weeks after the end of adjuvant chemotherapy, depending on which
treatment pathway has been undertaken; and in the colorectal cohort timelines are slightly shorter,
commencing six to twelve weeks after surgery and up to six weeks after the final fraction of adjuvant
radiotherapy or end of adjuvant chemotherapy. Participants in the breast cohort may receive endocrine
therapy and trastuzumab concomitant with trial participation where appropriate, and similarly androgen
deprivation therapy in the prostate cohort may be ongoing at the time of trial registration.
Dose reductions are not permitted in the run-in period; however time extensions are permitted if
inadequate adherence is felt to be a temporary phenomenon. On completion of the run-in period,
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adherence and tolerance of aspirin is assessed to determine suitability for subsequent randomisation.
Participants experiencing any aspirin-related severe toxicity (grade ≥3 CTCAEv4), or significant (grade 3 or
4) gastrointestinal bleed, active gastrointestinal ulceration, new or worsening tinnitus (≥ grade 2), macular
degeneration, intracranial bleeding or hypersensitivity to aspirin do not proceed to randomisation. Early
versions of the protocol considered any grade of gastrointestinal bleeding, rather than grade 3 or 4 only,
an aspirin related severe toxicity, with the newer version of the protocol commenced in December 2016
after 1,938 participants had already registered.
Outcomes: The primary outcome measure for the colorectal, breast and prostate cohorts is based on
disease recurrence and is overall survival for the gastro-oesophageal cohort. Secondary outcome
measures include adherence, toxicity, second malignancies and cardiovascular events. The overall
recruitment target for entry into the run-in phase is 11,000 participants from centres across the UK, India
and the Republic of Ireland, although at the time of the feasibility analysis only UK sites had commenced
recruitment.
Statistical Analysis: The current analysis was based on recruitment rates, toxicity and adherence at the
end of the run-in period, pre-planned two years after recruitment commenced. As a feasibility
assessment, there was no comparative hypothesis nor associated power calculation. Analyses consisted of
summary statistics (frequencies and percentages) based on data from the end of the run-in period
including the proportion of participants proceeding to randomisation; tabulation of reasons for non-
randomisation; participant reported adherence and aspirin-related toxicities (reported using CTCAE v4) by
grade and according to protocol requirements for treatment discontinuation. All participants for whom
the relevant data had been received at the time of analysis were included. Analyses were conducted using
Stata (StataCorp LLC, v.15).
The Add-Aspirin trial (ISRCTN74358648, EudraCT 2013-004398-28) is being conducted in compliance with
the Declaration of Helsinki 2008, the principles of Good Clinical Practice (GCP) and applicable national
regulatory legislation. The protocol was approved by the South Central – Oxford C research ethics
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committee and by local Research and Development departments at all participating UK centres; as well as
by local ethics committees at all participating Indian sites. All participants provided written informed
consent before registration. All authors had access to the study data and reviewed and approved the final
manuscript. The Add-Aspirin study is registered as an International Standard Randomised Controlled Trial
[ISRCTN74358648].
Role of the funding source:
The academic study sponsor, University College London (UCL), through the team at the MRC Clinical Trials
Unit at UCL, along with the multi-disciplinary Trial Management Group, had full responsibility for the
study design, the collection, analysis, interpretation of data, writing of the report, and in the decision to
submit the paper for publication. The trial statisticians (FHC, SR, KK) had full access to all the data in the
study and corresponding author had final responsibility for the decision to submit for publication, in
discussion with the independent data monitoring and trial steering committees.
Results:
Trial Recruitment: Recruitment commenced in October 2015 and, by October 2017, 3494 participants
were registered from 150 centres across the UK (sites across India and the Republic of Ireland had yet to
open to recruitment at the time of the feasibility analysis). The target registration rates were gastro-
oesophageal 2,350 in six years, colorectal 2,900 in three and a half years, breast 3,450 in three and a half
years and prostate 2,350 in five years. Overall recruitment was good with registration rates exceeding the
early estimated targets in the breast and prostate cohorts, but the gastro-oesophageal registrations in
particular were slower than expected. At the time of the feasibility analysis, 115 were registered to the
gastro-oesophageal cohort, 950 to the colorectal cohort, 1,675 to the breast cohort and 754 to the
prostate cohort, with an average accrual rate of 167 registrations a month [Table 2]. Figure 1 shows the
consort diagram for this analysis with end of run-in data available for 2253 participants at the time of the
analysis.
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Baseline Characteristics: Baseline characteristics of all participants from the breast, colorectal, gastro-
oesophageal and prostate cohorts were as expected [Table 3]. Median age was lowest in the breast
participants (52 years), and highest in the prostate participants receiving radical radiotherapy (71 years).
In the gastro-oesophageal cohort, participants were predominantly male (81%) and histology
adenocarcinoma in 82% (68/83), with only 18% (15/83) squamous cell carcinoma. Most participants in the
colorectal and gastro-oesophageal cohort were stage III (61% and 52% respectively). Most participants in
the breast, colorectal and gastro-oesophageal cohorts had received chemotherapy, either neo-adjuvant,
adjuvant or both. All gastro-oesophageal patients who have received radical surgery were mandated to
use a proton pump inhibitor (PPI) with trial treatment and at the time of registration 11% of the breast
cohort, 18% colorectal, 13% prostate and 69% of gastro-oesophageal patients were already prescribed
PPIs [Table 3].
Randomisation: The run-in period was still ongoing in 300/3494 participants at the time of the feasibility
analysis. Of those who had completed the run-in phase 2719/3194 (85%) had proceeded to
randomisation. This rate was similar across all the tumour-specific cohorts and close to the 90% rate
anticipated in the trial design. End of run-in data was available for 2253 participants (end-of run-in case
report forms are received within two to eight weeks of completing the run-in). The reasons for not
proceeding to randomisation were often multifactorial, with minor toxicity (grade 1-2) and/or patient
choice most frequent [Figure 1 and Table 4]. 69/83 (83%) of gastro-oesophageal participants registered
were treated with primary surgery. 60/69 (87%) received neoadjuvant and/ or adjuvant chemotherapy,
and 618/710 (87%) of the colorectal participants, with 30% of these still ongoing [Table 3]. Very few
participants (1%, 26/2253 with end of run-in data available) experienced toxicity requiring protocol-
mandated discontinuation of trial treatment. 2/26 were subsequently randomised after clinical review:
one case of grade 3 hypertension, as the elevated blood pressure returned to normal on subsequent
measurement; and one case of grade 2 tinnitus, which was deemed pre-existing and not felt to be related
to trial treatment. Within the gastro-oesophageal cohort, only two participants (3%) experienced toxicity
requiring discontinuation, one with grade 3 oesophageal pain and one grade 2 rectal bleed. The protocol
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has subsequently been amended to allow participants with minor bleeding or bruising (grade 1-2) during
the run-in period to continue in the trial, at the discretion of the investigator.
Adherence: Adherence was generally good with 95% (2148/2253) taking 6-7 tablets per week, similar
across the four cohorts (70/75, 93% of the gastro-oesophageal cohort; 578/602, 96% of the colorectal
cohort), assessed using patient self-reporting, review of used blister packs and diary cards.
Toxicity: 13/2253 (0·6%) reported grade 3 toxicities during the run-in period and no grade >3
gastrointestinal bleeds were reported [Table 5]. 26% (157/602) of colorectal participants were receiving
ongoing chemotherapy at the time of toxicity, and 17% of gastro-oesophageal. With the exception of the
one participant experiencing grade 3 oesophageal pain, no other grade >3 toxicity occurred in the gastro-
oesophageal cohort. The most frequent grade 1 or 2 toxicity reported during the run-in period across all
cohorts was dyspepsia (246/2253, 11%), with grade 1-2 bruising the second most frequent (211/2253,
9%). Only one (1/602, 0·2%) participant experienced a grade 1 upper gastrointestinal bleed in the
colorectal cohort, with no instances of upper gastrointestinal bleed of any grade in the gastro-
oesophageal cohort during the run-in period. 15/2253 (0.6%) of all participants experienced a grade 1-2
lower gastrointestinal bleed, only one of which were in the gastro-oesophageal cohort. There were no
grade 4 toxicities or treatment related deaths in any cohort.
Discussion:
The Add-Aspirin study is designed to assess the effect of aspirin on the prevention of metastases and
disease recurrence following radical cancer therapy in high risk individuals. The data presented show
aspirin is well tolerated after radical therapy including surgery or chemoradiation, acceptable to patients,
and there is no early evidence of increased toxicity in patients who received radical therapy for gastro-
oesophageal cancer compared to the other common solid tumours within the Add-Aspirin protocol.
The study has also demonstrated marked differences in recruitment rates across the 4 common cancers.
Some of this variance is not unexpected. Gastro-oesophageal cancer, for example, is less common in high
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income countries and fewer patients complete a radical treatment pathway. Shared risk factors with
cardiovascular disease, particularly smoking, mean more potential participants are already prescribed
aspirin and therefore ineligible for the study. However, the recruitment rates have been in line with
predictions for the breast and prostate cohorts but below the anticipated rates in the gastro-oesophageal
and colorectal cohorts, although the rationale for evaluating aspirin as a therapy to prevent recurrence is
strongest for these tumour types. Long-term data from randomised vascular trials demonstrate that the
greatest effect of aspirin in reducing cancer mortality was seen for gastrointestinal adenocarcinomas (20
year risk of gastrointestinal cancer death HR 0·46, 95% CI 0·27-0·77, with benefits greatest for
adenocarcinomas HR 0·66, 95% CI 0·56-0·77)(11).
Recently reported randomised trials further support the rationale that aspirin prevents tumour
development particularly in the gastrointestinal tract. In the phase III AspECT trial (NCT00357682) in
Barrett’s metaplasia, the combination of a high dose proton pump inhibitor with 300mg of aspirin was
demonstrated to significantly lengthen the time to event outcome, a composite of high grade dysplasia,
oesophageal adenocarcinoma and all-cause mortality (17). Only 1% (28/2557) of participants experienced
study-treatment-related grade 3-5 adverse events, of which only 0·6% (15/2557) were aspirin-related.
Similarly, the SeAfOod trial (ISRCTN05926847) has shown a decrease in the mean number of colorectal
adenomas per patient with allocation to aspirin (adjusted incidence rate ratio 0·78, 95% CI 0·68-0·90),
particularly in right sided and serrated adenomas, and there was no increased risk of gastrointestinal
adverse events in the aspirin group compared to placebo (18).
In 2016, the US Preventative Task Force recommended initiating low dose aspirin for the primary
prevention of cardiovascular disease (CVD) and colorectal cancer in adults aged 50 to 59 years who have a
10% or greater ten-year CVD risk, are not at increased risk for bleeding, and have a life expectancy of at
least ten years(19). Despite this, concerns about the use of aspirin for cancer chemoprevention and the
risk of serious bleeding continue (20). Aspirin does increase the risk of bleeding though the magnitude of
this effect is often over-estimated. The most extensive randomised data from the Antithrombotic Trialists’
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Collaboration meta-analysis encompassing ~95,000 individuals demonstrated only a very modest increase
in the risk of extracranial and major gastrointestinal bleeds from 0·07% per year to 0·1% per year on
aspirin compared to control, with a similar small difference in the risk of intracranial bleeds (control 0·03%
per year vs aspirin 0·04% per year, p=0·05) (21). No intracranial bleeds were reported during this
feasibility analysis. The vast majority of bleeding episodes (excluding intracranial bleeding) related to
aspirin resolve without sequelae (20), and in the vascular setting are generally considered to be
outweighed by the benefits gained from aspirin, namely the prevention of secondary CVD events. From a
population perspective, Cuzick et al have estimated that for every 100 men or women who start taking
aspirin at the age of 55, over a 20 year period, the benefits on cancer mortality will be greater than on
vascular mortality and outweigh the risks of serious bleeding (6).
Reluctance to prescribe aspirin for cancer prevention has been highlighted in a recent study of UK general
practitioners. Aspirin reduces the incidence of cancer in people with Lynch Syndrome and is
recommended in several clinical guidelines, including The National Institute for Health and Care
Excellence (NICE) (22). Despite this, a study of 1,007 UK general practitioners revealed that almost 20%
were unwilling to prescribe 300mg of aspirin daily despite a randomised trial demonstrating its cancer
preventative effects in Lynch Syndrome (23). More than 30% of respondents were uncomfortable
discussing the benefits and harms of aspirin with their patients, even with the recommendation from a
secondary care clinician (23). This reluctance might partly explain the lower recruitment rates seen in the
gastrointestinal cohorts of the Add-Aspirin study, particularly from physicians who treat patients with
gastrointestinal bleeding. Several strategies are incorporated into the trial design to mitigate the bleeding
risk on aspirin, including exclusion of individuals with a known increased risk of bleeding; randomising
participants over the age of 75 years to only 100mg of aspirin or placebo (and not the higher aspirin
dose), due to the increased risk of bleeding with both dose and age (16, 20); and use of a proton pump
inhibitor for patients who have undergone gastrectomy or oesophagectomy, and recommended in those
aged over 75 years (16). The data presented in this paper should provide further reassurance that the risk
to participants is low.
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Completing recruitment within the predicted timelines remains a challenge for many clinical trials.
Recruitment predictions from potential sites are used to advise trial recruitment projections, and sites
have been shown to over-estimate their predicted recruitment rates based on their maximum or best
possible, rather than mean monthly recruitment (24). When trials are slow to recruit, the relevance of the
clinical question or the acceptability of the randomisation is frequently cited as the reason. The Add-
Aspirin protocol challenges these assumptions as the clinical question is the same across the tumour
cohorts and there is no evidence that the randomisation is not acceptable to patients.
Recent results published from the ASPREE (ASPirin in Reducing Events in the Elderly) trial (NCT01038583),
which recruited more than 19,000 healthy participants mainly, >70 years old, who were randomly
allocated to aspirin 100mg daily or placebo, showed no difference in the primary outcome measure (a
composite of death, dementia and permanent physical disability)(25). Subgroup analyses reported an
increase in cancer mortality, subsequently attributed to an increase in the risk of incident metastatic
cancer but with no increase in incident cancers overall (26). Possible explanations for this observation
include an increase in bleeding from occult metastatic disease in this older cohort unmasking some
cancers at an earlier stage. The severity and consequences of bleeding with aspirin is known to increase
with age (16, 20). Follow up of the ASPREE trial is currently relatively short at 4.7 years, and longer term
follow-up may provide more clarification (25). Given the substantial body of previous data on the cancer
chemopreventative effects of aspirin, the subgroup analysis from the ASPREE trial has not undermined
the rationale for the Add-Aspirin trial or the other ongoing adjuvant aspirin studies internationally.
Opportunities for combining data from these trials will exist in the future.
To our knowledge, this is the most up-to-date and comprehensive data on the feasibility, toxicity and
tolerability of aspirin use in breast, colorectal, prostate and gastro-oesophageal cancers after potentially
curative therapy. One limitation to this study is that it is only relatively early data, but recent evidence
suggests that the risk of bleeding events on aspirin reduces with time, most frequently occurring in the
first few months of commencing treatment (16). As such, although only early data, it is likely to be a good
15
surrogate for the risk of future toxicity. More generally, since participants have all recently undergone
major treatment, a significant amount of the reported toxicity in this study may be due to previous or
ongoing other therapies. We also recognise that the measurements of adherence used are subject to
recall bias, however translational sub-studies currently underway will also objectively measure adherence
in this cohort of patients. Despite the challenging nature of radical therapy, particularly in the gastro-
oesophageal cohort where post-operative complication rates have been shown to be as high as 30% and
have a major detrimental impact on quality of life (27), this has not been reflected in the measured
adherence to trial treatment and, as a result, rates of progression from run-in to randomisation have been
close to the expected 90% in line with the other cohorts.
Conclusion
The rationale and supporting evidence for evaluating aspirin as a potential anti-cancer therapy is strong
and completion of clinical trials specifically designed to assess this hypothesis is the next required step.
Re-purposed medicines such as aspirin offer the potential for low cost therapies to improve cancer
outcomes. Evidence-based information about potential efficacy and toxicity is required to help physicians
conduct meaningful discussions with potential participants about trial participation.
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Supplementary Attachment:
Add-Aspirin protocol
Appendix – Table 1 and Table 4
Author Contributions:
RL is chief investigator. NJ and RL drafted the manuscript. RL conceived the study concept and design. NJ,
RH, DS, SS, KG, SF, KP, NW, VK, JG, TI, JB, AC, VH, DG, HK, AR, DC, TI, RA, AT, RW, CSP, RL collected data.
SR, FC and KK had access to the study data and contributed to the analysis and interpretation of the data.
All other authors reviewed and approved the final manuscript.
Acknowledgments:
The trial is being jointly funded by Cancer Research UK (grant number C471 /A15015), The National
Institute for Health Research Health Technology Assessment Programme (project number 12/01/38), The
MRC Clinical Trials Unit at UCL (MC_UU_12023/28). In India, the Sir Dorabji Tata Trust provides funding. In
the Republic of Ireland, Cancer Trials Ireland provide additional support. Bayer Pharmaceuticals AG is
providing aspirin and placebo.
We would like to thank the study participants and their families, site research staff, and members of the
wider Add-Aspirin trial management groups, trial steering committee and independent data monitoring
committee.
We would like to acknowledge in particular Professor Carlo Patrono, Professor Peter Rothwell and
Professor Sir John Burn who have provided specialist knowledge and expertise in the field of aspirin.
Declaration of Interest
The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the
Department of Health and Social Care
RL and the MRC Clinical Trials Unit at UCL report non-financial support from Bayer Pharma AG (supply of
trial drugs) during the conduct of the study. RL reports grants from CRUK and NIHR, and honorarium from
the Aspirin Foundation during the conduct of the study. JB reports personal fees from Astrazeneca,
personal fees from Roche, personal fees from Merck Serono, personal fees from BMS, grants and other
from Incyte, other from MSD, personal fees and other from Amgen, outside the submitted work; RW
reports other from Almac Discovery, personal fees from Servier, personal fees from Amgen, personal fees
from Clovis Oncology, personal fees from Halozyme, personal fees from BMS, personal fees from Karus
Therapeutics, personal fees from Roche, personal fees from AstraZeneca, personal fees from Pierre Fabre,
personal fees from CV6 Therapeutics, outside the submitted work; All other authors declare no
competing interests.
Author Correspondence: Professor Ruth Langley, MRC Clinical Trials Unit, Institute of Clinical Trials &
Methodology, 90 High Holborn, London, WV1V 6LJ, +44 (0)20 7670-4714. ruth.langley@ucl.ac.uk.
FHC, SR, KK had full access to all the data in the study; RL had final responsibility for the decision to submit
for publication in discussion with the (independent) trial oversight committees.
17
Data Sharing Statement: The Add-Aspirin trial data are held at MRC CTU at UCL, which encourages
optimal use of data by employing a controlled access approach to data sharing
(http://www.ctu.mrc.ac.uk/our_research/datasharing/). Requests for data can be made at any time and
can be initiated by contacting mrcctu.ctuenquiries@ucl.ac.uk or through the URL:
http://www.ctu.mrc.ac.uk/our_research/datasharing/application_process/. There is a formal application
process, whereby the request will undergo review by the trial team, as well as independent researchers,
to ensure that the proposed research is both ethical and has a strong scientific rationale. Data will not be
released if it would compromise the ongoing trial. The specific data and associated documents to be
shared will be dependent on the nature of the individual request and this will be documented in a formal
data sharing agreement.
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