Assessment of The Association of Non-Steroidal Anti Inflammatory Drugs

Usage with Colorectal Cancer as A Comprehensive Consideration To

Reduce The Risk of Colorectal Cancer Incidence: A Systematic Review of
Cohort Studies

Nadia K. Heryadi1, Michelle Imanuelly2, Michele Indrawan3, Johan Wibowo4, Jonathan J. Anurantha5

Abstract
(Introduction) Aspirin mechanisms include the modulation of cyclo-oxygenase-2 (COX-2),
the principle of an enzyme that produces pro-inflammatory prostaglandins, including
prostaglandin E2, which increases the proliferation of cells, promotes angiogenesis and
increases resistance to apoptosis. We are hoping to continue to aid people through small steps
using this systematic review and to prove our hypothesis on non-steroidal anti-inflammatory
drug medications, specifically aspirin, can reduce the risk of colorectal cancer. (Method) A
systematic review was conducted through a systematic analysis, such as the PICO method and
MeSH terminology. The inclusion criteria used in this systematic review are a cohort study,
NSAID specifically aspirin, colorectal incidence, and adult population. For the exclusion
criteria, we used meta-analysis, systematic review, literature review, cross-sectional studies,
animal studies, child population, and participants with a previous cancer diagnosis. (Result)
The search yielded five cohort studies. Through reviews, all studies showed that the use of
aspirin is associated with the reduction of colorectal cancer development. (Conclusion) To
conclude, aspirin can reduce the risk of colorectal cancer development.

Keywords: adult, cohort study, colorectal cancer, non-steroidal anti-inflammatory drugs,

prevention

Author information
Affiliations
Faculty of Medicine, Pelita Harapan University
Nadia K. Heryadi, Michelle Imanuelly

Corresponding author
Correspond to: Nadia K. Heryadi
Introduction
The world has been around for approximately 4.54 billion years with it, humanity
evolves along with diseases. Within, rise the people that dedicated themselves to medicine,
thus resulting in numerous medications to aid the ones in need. The sentinel account of a
hereditary colorectal family was by Dr. Aldred Warthin, who first suspected the disorder in the
family of an affected woman who subsequently died of endometrial cancer over 100 years ago.
He began to study their family or also known as Family G in 1895 and in the year 1913 he
published his first documentation report about a pattern of endometrial and gastrointestinal
cancers, particularly gastric and colon. This study marked the beginning of numerous updates
surrounding colorectal cancer. We are hoping to do the same, thus continuing to aid people
through small steps using this systematic review and to prove our hypothesis on non-steroidal
anti-inflammatory drugs medications, specifical aspirin, are able to reduce the risk of colorectal
cancer¹.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are an FDA approved class of drugs
purposely for the use of antipyretic, anti-inflammatory, and analgesic agents. NSAIDs are
typically divided into groups based on their chemical structure and selectivity, as the following:
acetylated salicylates (aspirin), non-acetylated salicylates (diflunisal, salsalate), propionic
acids (naproxen, ibuprofen, acetic acids (diclofenac, indomethacin), enolic acids (meloxicam,
piroxicam), anthranilic acids (meclofenamate, mefenamic acid), naphthylalanine
(nabumetone), and selective COX-2 inhibitors (celecoxib, etoricoxib). NSAIDs mechanism of
action is through inhibiting the enzyme cyclooxygenase (COX), this enzyme is required to
convert arachidonic acid into thromboxanes, prostaglandins and prostacyclins. There are two
cyclooxygenase isoenzymes, COX-1 and COX-2. COX-1 gets constitutively expressed in the
body and has a role in maintaining gastrointestinal mucosa lining, kidney function, and platelet
aggregation. COX-2 is not constitutively expressed in the body, instead, it is inducibly
expressed during an inflammatory response².
Cancer is a process where normal cells progressively turn or transform into malignancy,
this is known to arise as a consequence of damage to the genome³. This damage may come
from errors in DNA replication, chemical instability of certain DNA bases or attacks by free
radicals. DNA damage might also come from exogenous agents such as ionizing radiation, UV
radiation, and chemical carcinogens. The loss of epigenomic and genomic stability accelerates
the accumulations of mutations and epigenetic alteration in tumor suppressor genes and
oncogenes, also in the case of colorectal cancer, this event drives the malignant transformation
of colon cells through rounds of clonal expansion⁴. As a reminder, the hallmarks of cancer are
the following: avoiding immune destruction, evading growth suppressors, genome instability
and mutation, deregulating cellular energetics, enabling replicative immortality, tumor-
promoting inflammation, inducing angiogenesis, resisting cell death and lastly the activation
of invasion and metastasis.
Environmental and genetic factors-promoted of the acquisition of hallmark behaviors
of cancer are the causes of colorectal cancer in colon epithelial cells. The evolution of normal
epithelial cells in the colon to adenocarcinoma follows a predictable progression of histological
and concurrent epigenetic and genetic changes. Observation in the ‘classic’ colorectal cancer
formation model shows the vast majority of cancers arise from a polyp along with an aberrant
crypt opening and further evolves into an early adenoma with <1 cm in size, histologically
tubular or tubulovillous. This adenoma then progresses into an advanced adenoma, with >1 cm
in size and/or with villous histology before it finally progresses into or becoming colorectal
cancer. The process takes 10-15 years although may also progress much rapidly in certain
conditions or settings, for example in patients with Lynch Syndrome. There are two identified
discretion of normal colon to colorectal cancer sequences, the first one mentioned above as the
‘classic’ or traditional pathway. In the year of 2010, it was thought that only tubular and
tubulovillous adenomatous polyps were thought to be the only lesions that are capable of
progressing into cancer, at the same time another sequence was discovered, also called an
alternate pathway and it involves serrated polyps from molecular and histological events that
are identified to be distinct from tubular adenomas. The classification of polyps is divided into
three categories: hyperplastic polyps, sessile serrated adenomas, and traditional serrated
adenomas. Serrated polyps arise in the right colon, including the cecum, ascending colon and
transverse colon also has a form of epigenetic instability that is characterized by excessive
aberrant CpG island DNA methylation called the CpG Island Methylator Phenotype or CIMP.
However, polyps that arise in the left colon, including descending colon, sigmoid colon and
rectum, are typically microsatellite stable although it frequently carries mutations in KRAS.
The most common alterations seen in colorectal cancer include those in APC, catenin-beta1
(CTNNB1), KRAS, BRAF, SMAD4, transforming-growth factor-beta receptor 2 (TGFBR2),
TP53, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-alpha (PIK3CA), AT-
rich interactive domain 1A (ARID1A), SRY (sex-determining region Y) box 9 (SOX9), family
with sequence similarity 123B (FAM123B; also known as AMER1) and ERBB2, this promote
the tumorigenesis by perturbing the function of key signaling pathways, including the Wnt–β-
catenin, epidermal growth factor (EGF)-mitogen-activated protein kinase (MAPK),
phosphatidylinositol 3-kinase (PI3K) and TGF-β signaling pathways, or by affecting genes that
regulate central behaviors of cells such as DNA repair and proliferation. Colorectal cancer is
frequently initiated by alterations that affect the Wnt signaling pathway, and the ensuing
neoplastic cells then progress upon deregulation of other signaling pathways, including the
RAS–RAF–MAPK, TGF-β, and the PI3K–AKT pathways⁴.
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer,
is the third most commonly diagnosed cancer in the world. In males with cancer, CRC ranked
third in prevalence with 746000 cases which defined as 10% of the male population, following
after lung and prostate cancer. Among women with cancer, it is ranked second in prevalence
with up to 614000 cases or 9.2% total female population following after breast cancer. CRC
incidence and mortality show wide geographical variations across the world. CRC in different
countries are compared using age-standardized incidence rates (ASRis) and it is observed to be
the highest in Australia and New Zealand, with the lowest rates in Western Africa. Europe
shows huge variations in the ASRis among men, the highest incidences are observed in
Slovakia, Hungary and the Czech Republic, in contrast among women it is observed that
Norway, Denmark, and Holland show the highest incidences. As of 2016, the American Cancer
Society estimated 134490 of new CRC cases would emerge and be diagnosed in individuals
both male and female, following the death of 49190 individuals from CRC in the United States.
As for the Eastern Mediterranean Region, Israel (36 per 100000) is observed to have the highest
incidence of CRC, followed by Jordan (26 per 100000) and Kazakhstan (23 per 100000). It is
also shown that there is a high incidence of CRC in the Asian Pacific region with various data
among regions. The highest incidence is reported in South Korea (ASRis: 45 per 100000), the
high incidence is also observed in Singapore and Japan (ASRis: 34 and 32 per 100000,
respectively), but in other countries, for example, India, have much lower ASRis (6 per
100000). From the data that is shown, screening is recommended to reduce both incidence and
mortality although only some countries have established or implemented a nationally organized
screening program. Organized screening programs can be observed in most European
countries; however, it is not possible to be observed in countries such as Slovakia, Central
America, South America, the Middle East, and Africa. The lack of organized programs may be
due to limited resources or facilities for screening such as colonoscopy facilities⁵.
Limitations of screening and lack of facility to reduce both incidence and mortality have
given rise to cohort studies that purposely focus on the chemoprevention of colorectal cancer
with the usage of NSAIDs. These studies will be the base of our systematic review and thus
we hypothesize that NSAIDs will significantly reduce the risk of colorectal cancer in both
males and females.
NSAID, specifically aspirin, has the function to act primarily through specific
mechanisms, for example, antiplatelet effects, to inhibit the progression of cancer or
metastases. Aspirin may also influence additional mechanisms that are critical to early
tumorigenesis, explaining why there is a strong association of aspirin with a lower incidence
of gastrointestinal tract cancer. These mechanisms include modulation of COX-2, mentioning
the principle of the enzyme that produces pro-inflammatory prostaglandins, including
prostaglandin E2, which increases the proliferation of cells, promotes angiogenesis, and
increases resistance to apoptosis. Aspirin may also play a role in Wnt signaling, nuclear factor-
kB signaling, polyamine metabolism, and DNA repair, in addition, the colorectal cancer is
frequently initiated with the alterations that affect the Wnt-signaling pathway⁶.

Methods
For our systematic review, we used the data from several cohort studies published in
online journals specifically Pubmed. The cohort studies that we used were published within
2016-2017. The data were accessed on 12th of June 2020 using the following keywords or
terms : (“Colorectal Cancer” OR “CRC”) AND (“Nonsteroidal Anti-Inflammatory Drugs” OR
“NSAID” OR “Aspirin”) AND (“Prevention”) AND (“Adult”) AND (“Cohort” OR “Cohort
Study”). We limited our literature search to studies by only accessing data from NCBI and used
English as the primary language for the paper.
A systematic analysis, such as PICO method and MeSH terminology, was also used in
this study. For example, for the PICO method, we used “Adult” for the People or Population
(P). For the Intervention (I) we used “Nonsteroidal anti-inflammatory drug usage” or “Aspirin
usage”. For comparison (C) we compared the data from the participant who doesn’t consume
aspirin or as we called it “Control”. And for the Outcome (O) we used “Colorectal cancer
incidence”. The inclusion criteria used in this systematic review are a cohort study, NSAID
specifically aspirin, Colorectal incidence, Adult population. For the exclusion criteria, we used
Meta-analysis, Systematic review, Literature review, Cross-sectional studies, Animal studies,
Child population, and participants with a previous cancer diagnosis.
Afterward, the data were reviewed by 2 reviewers using a standardized form. Then each
paper was independently checked and assured by 3 other reviewers to reduce the risk of error.
The purpose of this study is to assess whether NSAID such as aspirin could be used to
significantly reduce the risk of cancer, for example, gastrointestinal (GI) tract cancer, especially
CRC. Based on our theory in the introduction, Our hypothesis for this study is to assess if the
usage of Non-Steroidal Anti Inflammatory Drugs such as aspirin can reduce the risk of having
Colorectal cancer.
Results
We used the PICO method and MeSH terminology and obtained 5 cohort studies that
will be analyzed and reviewed. The graph below shows the process of selection of the articles.

Figure. 1 Flow chart with pieces of information of different selection phases of the cohort studies
Authors Study Year Subject Result

Cao et al ⁶. Prospective 2016 Healthy US female Regular aspirin use

Cohort nurses aged 30-55 and was associated with
healthy US male reduced incidence or
health professionals overall cancer,
aged 40-75 especially CRC

Soriano et al ⁷. 3 Different 2016 3 Comparative cohort Low-dose aspirin was

cohort studies studies consist of associated with a
patients as new users significantly reduced
risk of CRC
of low dose aspirin,
non-aspirin users, new
users of paracetamol,
and users naive to
low-dose aspirin

Rodriguez et al ⁸. Cohort with 2017 Subjects aged 40-89 Users of low-dose

nested case consist of new-users aspirin had a
control and non-users of low- significantly reduced
analysis dose aspirin risk of CRC

Soriano et al ⁹. Comparative 2017 Individuals with no Low-dose aspirin

cohort CVD consist of new- initiation was
users and non-users associated with a
aspirin reduced incidence of
CRC

Vaughan et al ¹⁰. Cohort 2016 Iowa women aged 55-
69 with various
frequency, dose, and
duration of use for
aspirin
Aspirin use in elderly
women may provide
prophylactic benefit
to cancer incidents,
superiorly for CRC

Note :
CRC : Colorectal Cancer
CVD : Cardiovascular Disease
US : United States

Table 1.1 Summary of studies on the association between non-steroidal anti inflammatory drugs and colorectal
cancer
Discussion
A cohort study conducted by Cao et al., using 2 Large prospective cohort studies in the
United States (US) with a total of 135.965 participants consisting of 88.084 women and 47.881
men with the age ranged from 30-55 in 1976 enrollment and 40-75 years in 1986 enrollment.
The follow-up lasted until June 30, 2012, for the Nurses Health Study (NHS) cohort and
January 31, 2010, for the Health Professional Follow-up Study (HPFS) cohort. The data then
were accessed from September 15, 2014, to December 17, 2015. The follow-up rates in both
cohort studies have been greater than 90%. In the NHS the aspirin use was first used in 1980
and every 2 years after except in 1986 and for HPFS started in 1992 and also every 2 years
after, the participants then were asked how much aspirin they consumed per week. The
outcome of each study is to find out the incidence of cancer which was defined according to
the International Classification of Diseases, Ninth Revision. From 2 of the large prospective
cohort studies, the data shows a significant association between the use of aspirin and the risk
of cancer up to 19% for colon and rectum cancer, 15% lower risk for GI tract cancer, and 3%
lower risk for overall cancer for comparison. The benefits of aspirin compared to the risk of
CRC shows a dose-dependent association as will be shown in the following table. During the
first 5 Years, the author didn’t observe any significant reduction in the risk of cancer compared
with the non-regular user. However, after 5 years the data shows a progressive reduction in the
risk of cancer exclusively for the GI tract cancer as shown in table 2.1.1.

Table 2.1.1 Dose of Standard Aspirin and Risk for Cancer

Table 2.1.2 Data were obtained from the 1980-2012 Nurses’ Health Study and the 1986-2010 Health
Professionals Follow-up Study
 These studies suggested that regular aspirin use was associated with a lower risk for
overall cancer (RR, 0.97; 95% CI, 0.94-0.99), which was primarily owing to a lower incidence
of gastrointestinal tract cancers (RR, 0.85; 95% CI, 0.80-0.91), especially colorectal cancers
(RR, 0.81; 95% CI, 0.75-0.88). The benefit of aspirin on gastrointestinal tract cancers appeared
evident with the use of at least 0.5 to 1.5 standard aspirin tablets per week; the minimum
duration of regular use associated with a lower risk was 6 years. Among individuals older than
50 years, regular aspirin use could prevent 33 colorectal cancers per 100 000 person-years
(population-attributable risk (PAR), 17.0%) among those who had not undergone a lower
endoscopy and 18 colorectal cancers per 100 000 person-years (PAR, 8.5%) among those who
had. Regular aspirin use was not associated with the risk for breast, advanced prostate, or lung
cancer. The author suggested that aspirin may act primarily through specific mechanisms to
inhibit the progression of cancer or metastases. Additionally, the study also suggested that
aspirin may have an additional influence on the gastrointestinal tract including CRC. They
proposed that aspirin may influence additional mechanisms critical to early tumorigenesis such
as the modulation of COX-2 and play a role in Wnt signaling. The study has some limitations
as mentioned by the author such as that as an observational study the results are not as definitive
as a randomized clinical trial (RCT) designed study however the large, detailed prospective
cohort, and high follow-up rate make up for this limitation. In conclusion, Cao et al. suggest
that regular use of aspirin is associated with a reduced incidence of overall cancer, with more
substantial benefits for gastrointestinal cancer, notably CRC. They also suggest that aspirin
may be a potential low-cost alternative to endoscopic CRC screening in a limited resource
situation.

In a cohort study conducted by Soriano et al., using patient records from The Health
Improvement Network (THIN), they followed 3 different cohorts of patients that are varied by
their demographic and clinical characteristics to estimate the association between using low-
dose aspirin with CRC incidence.
First, it consisted of new-users and non-users of low-dose aspirin. Second, subsisted of new-
users of low-dose aspirin at the start of follow-up and new-users of paracetamol. The third
cohort involved naive users to low-dose aspirin.
Exclusions of the participants were if they had a prescription of low-dose aspirin or
diagnosis of cancer before the study entry. They were excluded in Study 2 if they had a
prescription of paracetamol monotherapy before the study entry, but it was not an exclusion
criterion in Studies 1 and 3. The characteristics of each study are shown in Table 2.2.1.

Table 2.2.1 Characteristics of study cohort(s) in each study design

 In Study 1 showed new users of low-dose aspirin were identified by their first low-dose
aspirin prescription as their start date. Each participant was matched to an individual who was
still free of low-dose aspirin at the start date by age, sex, and the number of Primary Care
Practitioner (PCP) visits in the previous year. In study 2, it comprised new users of paracetamol
as a neutral drug in the start date to minimize any bias arising from differences between users
and non-users of low-dose aspirin. This study chose paracetamol as a good comparison through
an assessment by the following criteria: i) it has no known effect on CRC, ii) it is not a proxy
of significant comorbidity, and iii) prevalence of use among the source population is
sufficiently common to sample form. In Study 3, they use all individuals in the source
population. Participants in each study were followed up from the beginning of the study until
the earliest of the following: Read code for CRC, record cancer other than CRC, age of 90
years, death or the end of the study period (31 December 2011 in Study 1 and 31 December
2012 in Studies 2 and 3). All studies were using a new-user study design in order to minimize
the bias present among prevalent users.
The incidence of CRC per 10,000 person-years was 16.74 (95% CI: 16.16–17.35),
16.34 (95% CI: 15.78–16.93) and 8.68 (95% CI: 8.53–8.83) in Studies 1, 2 and 3 respectively.
Incidence rates increased with age in both sexes and men were higher than women in all age
groups. In Studies 1 and 2, the mean age at the beginning was higher (64 years) than in Study
3 (53 years). Fewer comorbidities were shown in Study 3 that consisted of younger individuals.
They were less likely to be overweight, obesity, taking some medications, and had fewer PCP
visits than individuals in Studies 1 and 2. Patient characteristics of each study are shown in
table 2.2.2.

Table 2.2.2 Patient characteristics of study cohort(s) in each study design

 Current use of low-dose aspirin was associated with a significant reduction in risk of
CRC in each study design; RR 0.66 (95% CI: 0.60–0.73) in Study 1, 0.71 (95% CI: 0.63–0.80)
in Study 2 and 0.69 (95% CI: 0.64–0.74) in Study 3. Reduced risks of CRC were seen
throughout treatment duration, and no dose-response relationships were observed. Based on
three cohort studies, there was no association between paracetamol monotherapy usage and
CRC, RRs: 1.04 (95% CI: 0.91–1.19) in Study 1, 1.00 (95% CI: 0.88– 1.14) in Study 2 and
1.00 (95% CI: 0.93–1.09) in Study 3.
The results of the study cohort(s) support a 30% protective effect of low-dose aspirin
against CRC development. This effect was consistent across the studies with different study
designs, supporting previous findings. In each study design, the effective amount of low-dose
aspirin daily to reduce CRC incidence is 75 mg/day. The author did not observe any dose-
response relationships between low-dose aspirin and CRC. However, more than 90% of aspirin
use in three studies was at a dose of 75 mg/day.

According to the nested case control-analyzed cohort study that was conducted by
Rodriguez et al., with a source population of individuals aged 40 – 84 years old
demographically from the United Kingdom (UK) with the exact time from 1 January 2000 up
to 31 December of 2009. After the in-trial period, these individuals were then followed-up to a
maximum of 12 years to identify the incidence of CRC. This study also used the Duke’s staging
to hypothesize the strength of the association between low-dose aspirin and CRC.
Two cohort studies comparing new-users of low-dose aspirin (classified ‘as treated’)
with non-users of low-dose aspirins and were matched by age, sex, and precious primary care
practitioner visits. As a result, among those whose stages were recorded (N = 1421), about one
third or 34.9% were Dukes Stage D and a quarter or 26.0% were Dukes Stage C. The mean age
of these cases was 68 years old with 59% of them being male. Overall, 54% of the cases, after
5 years, were still alive and 87% were of Dukes A Stage cases and 78% of Dukes Stages B,
57% of Dukes Stages C, 9% of Dukes Stages D, and 57% as of the unknown stage.
Associations between the use of low-dose aspirin and CRC showed a decreased risk of
CRC with all aspirin doses evaluated which were – 75, 150 or 300 mg/day and current low-
dose aspirin users had a statistically significant decreased risk of CRC, up to 34% with the RR
0.66 (95% CI: 0.60-0.73). During treatment, it is observed that after the first year there was a
significant and constant 40% reduction. An association of low-dose aspirin usage with primary
cardiovascular disease (CVD) prevention also showed a 30% statistically significant reduced
risk of CRC and 40% reduced risk when used for secondary CVD prevention. Reduced risk of
CRC with low-dose aspirin was also observed in patients with or without GI antecedents, there
were no differences for both men and women (p for interaction = 0.27), age factor also did not
modify the protective effect of the aspirin (p for interaction = 0.24), in addition, it was also
seen for both fatal and non-fatal cases either in the colon or rectal. A significant decrease in
risks of CRC was observed for Dukes Stages B to D, as well as Dukes Stage A but with the
suggestion of substantial risk reduction after 5 years therapy as there was no reduction in risk
that was observed after 1 year of treatment. The rate ratio for the following Dukes Stages were
observed to be; RR 0.54 (95% CI 0.42-0.68) for Dukes Stage B, RR 0.71 (95% CI 0.56-0.91)
for Dukes Stage C, and RR 0.60 (95% CI 0.48-0.74) for Dukes Stage D and the RR was 0.68
(95% CI 0.60-0.78) for unknown cancer stage. Ratio rate for Dukes Stage A was 0.94 (95% CI
0.66-1.33) with no reduction in risk observed with less than 1 year of treatment although after
5 years therapy showed a ration rate 0.53 (95% CI 0.24-1.19; seven Dukes Stage A CRC cases
-alone had at least 5 years low-dose aspirin exposure). The data regarding the rate ratio of
Dukes Stages are shown in the figure. 2.
 Figure. 2 Association of rate ratio (95% CI) based on several category

Patients that started the treatment with low-dose aspirin showed a significant decrease
in risk up to 34% of developing CRC compared with those not taking low-dose aspirin.
Reduction in risk was also apparent or observed across all age groups, unrelated to dose,
gender, indication, CRC location or case-fatality status.

A study conducted by Soriano et al. which was done using THIN method in the UK.
THIN is a primary care database of anonymized patient electronic medical records, a method
using the representative of the UK population in the matter of age, sex and geographic
distribution and validated as a usage in pharmacoepidemiologic research. THIN also receives
data from PCP that recorded information prospectively as their routine patient care and sent
their data anonymously and is used for research projects, patient information will then be sent
or entered using Read codes or as free text. This cohort study was comprised with THIN
method consisted of individuals aged 40-84 years in between 1 January 2000 and 31 December
2009, these individuals should meet various eligible criteria; at least 2 years of registration with
PCP, at least 1 year since the beginning of their computerized prescription history and at least
one encounter visit recorded in the previous 3 years.
Two cohort studies consist of new users of low-dose aspirin (N = 170,336) and those
who were still free of low-dose aspirin, comprising the comparator cohort (N = 154,056).
Exclusions for these individuals were if they had a prescription for low dose aspirin or
diagnosis of cancer before the study entry and also individuals aged 70 years with fewer than
two PCP recorded consultations and follow up longer than 1 year. Each member from the low-
dose aspirin cohort were then matched with the members of the comparator cohort by age, sex,
calendar year and the number of PCP visits (0-1, 2-4, 5-9, 10-19 or ≥20 in the previous year)
then from both cohort individuals. The author then excluded individuals with recorded CVD
before the start date and left the eligibility for primary prevention of CVD. Exploration of
individuals’ medical records using automated computer algorithms in THIN that has Read
codes suggestive of CVD was used to help exclude the individuals.
Participants from both cohorts were then followed up from the index date to the earliest
of the following: record of cancer other than CRC, 90 years of age, Read code for CRC, death
or the end of the follow-up period (31 December 2011). Overall the incidence of CRC per
10,000 person-years was 14.90 (95% CI: 13.95 – 15.92) in the new users of low-dose aspirin
cohort and 18.15 (95% CI: 17.24 – 19.12) for the non-user comparator cohort and as observed,
both free of CVD from the index date. Details about the incidence of CRC can be seen in table
2.4.1.

Table 2.4.1 Incidence rate ratio of patient with colorectal cancer

Characteristics baseline of the cohort studies were observed by frequency distributions

for demographics, lifestyle factors, and healthcare use, also gender, age, and previous PCP
visits and also the distribution of smokers and alcohol consumption in both new users of low-
dose aspirin cohort and non-user comparator cohort. Observed low-dose aspirin cohort
individuals mean BMI was 28.6 kg/m² and obesity (BMI ≥ 30 kg/m²) was more frequent than
the comparator cohort. Higher prevalence of traditional risk factors such as hypertension, gout,
diabetes, deep vein thrombosis, pulmonary embolism, atrial fibrillation and heart failure can
also be observed in the low-dose aspirin cohort more than in the comparator cohort. Low-dose
aspirin cohort also showed the usage of at least one of the drugs such as antihypertensive
medications, stations, and oral antidiabetics was substantially higher, going up to 66.1% in
these individuals compared with the comparator cohort which only accounts for 38.1%.
Similarities of characteristics baseline that was observed between the new-users of low-dose
aspirin cohort and the comparator cohort were the distribution of current smokers and alcohol
consumption and also the frequency of gastrointestinal disorders such as dyspepsia,
uncomplicated and complicated peptic ulcer and gastro-oesophageal reflux disease.
Following the individuals in the low-dose aspirin cohort, a total of 885 incident cases
of CRC occurred over a mean follow-up of 5.43 years and 1445 cases occurred in the non-user
comparator cohort over a mean follow up of 5.17 years. Observation of low-dose aspirin
cohort’s incidence rate ratios showed significant reduction in risk of CRC when it is initiated
at either 60-69 years of age (IRR 0.80, 95% CI: 0.70–0.91) or 70-79 years of age (IRR 0.79,
95% CI: 0.69–0.91). Lower incidence rates of CRC were seen in the individuals of low-dose
aspirin cohort compared with the comparator cohort amongst the individuals with either 0-9 or
≥10 PCP visits in the year before the start date. The result of this study also showed that low-
dose aspirin is associated with the reduction of incidence rate of CRC in individuals with free
of CVD, but when initiated at the age of 60-79 years of age and also a possible case when given
to the individuals of the age of 40-59 years old, which occurs in both genders and across levels
of general health status and this health status was observed using the number of previous PCP
visits, but with the individuals without CVD aged 80-89 years old, initiation of low-dose aspirin
was not associated with the risk of CRC. This study has also provided an estimation of the
incidence of CRC in real-world users and non-users of low-dose aspirin without known CVD
and this includes individuals with gastrointestinal disorders who may have been excluded from
the RCTs. The prevalence of gastrointestinal disorders at the start of follow-up was also
noteworthy as it was similar between the study cohorts, which suggested that the cohorts had
the same level of baseline gastrointestinal risk.
Several strengths were found in this study such as an inclusion of a broad range of
patients, matching of two study cohorts, and high validity of recorded CRC diagnoses in THIN.
The use of ‘new-user’ design would remove the possibility of survivor bias that can be seen or
present by the inclusion of prevalent users. The overall characterization of the two study
cohorts has given a strong suggestion that the results of this study were unlikely to be affected
by any healthy user bias. Note that the low-dose aspirin cohort was not comparable with the
comparator cohort, as it can be observed that traditional CVD risk factors were more prevalent
among the low-dose aspirin cohort, an expected finding because these factors were the ones
that influence the prescribing of aspirin for CVD prophylactic purposes and there was no
evidence that cardiovascular profile is an independent risk factor of CRC, in addition,
differences on both cohorts would not be expected to have any noticeable effect on the results.
Potential for the changes in low-dose aspirin use during follow-up was also another limitation,
this change is an important factor to consider when making comparisons between studies.
Estimation of absolute CRC risk obtained within this study will help and guide the clinical
decisions regarding the use of low-dose aspirin in the real-world primary CVD prevention
setting.

To examine associations between aspirin usage and the incidence of aspirin-sensitive

cancers (cancers of colon, pancreas, breast, and ovaries), Vaughan et al. grouped 14,386
women over 70 years old (mean age 78.6 years, range 73-87) in the Iowa Women’s Health
Study (IWHS) into three different groups based on aspirin dosage taken in various frequency
and duration. Among the 14,386 participants, 30% (n=4,180) reported never using aspirin, 34%
(n=4,817) reported using low-dose aspirin (81 mg), and 36% (n=5,038) reported using regular-
dose (325 mg) or high-dose (650 mg) aspirin. Women were excluded as censored at the date
of last follow-up, death, or non-aspirin sensitive cancer diagnosis, whichever occurred first.
Two nested Cox proportional hazard models were used in this study, aiming to analyze the
association between each aspirin metric (frequency, dose, and duration) and incidence of
aspirin-sensitive cancers. Model 1 included only age as an adjusting covariate. Model 2
included age, BMI, smoking (as ever and never), and frequency of nonaspirin NSAIDs use. In
addition, aspirin dose per year and lifetime aspirin dose was also recorded and analyzed in this
analytical cohort study. Details containing data of patient characteristics can be seen in table
2.5.1.
 Table 2.5.1 Frequency of patients with numerous characteristic

Demographic characteristics were compared between groups (lifestyle, behaviors,

sociodemographic factors, medical histories, anthropomorphic measures) from follow-up in
2004 and it was found that low-dose aspirin users were substantially more likely to have a
higher diet quality score and report multivitamin use, a higher level of physical activity, and a
history of HRT (Hormone Replacement Therapy). Among women with aspirin consumption
history, the most frequent reason for reported use was for heart issues, headaches, and body
pains.
Compared to nonuse of aspirin; HRs (95 % CI) were 1.00 for reference, the HRs (95%
CI) for incidence of aspirin-sensitive-cancers were 0.87 (0.72-1.06) for regular to high doses
of aspirin use, proving a significant association between the dose of aspirin taken and cancer
incidence. In terms of frequency (compared to nonusers), lowest HRs (95 % CI) were recorded
at 0.87 (0.67-1.13) for aspirin use ≤1 time/week. For the duration, a number of 112 cancer cases
were found at 5-9 years of aspirin consumption; HRs (95 % CI) 0.88 (0.69-1.12), also recorded
as the lowest aspirin-sensitive-cancer incidence compared to non-users. For cumulative aspirin
use, HRs (95 % CI) was 0.87 (0.70-1.09) for > 60,000 mg of aspirin dose per year and 0.95
(0.75-1.19) for 95,000 < 280,000 mg or (0.75-1.21) for >280,000 mg of aspirin in their lifetime,
versus nonuse of aspirin.

Table 2.5.2 Amount of cancer cases and hazard ratio based of various aspirin metric

One of the limitations of this analysis is the potential of selection bias. The elderly
women who responded to the survey tended to be healthier than nonresponders. Thus, it is
possible that the women who were included in this study might benefit less from aspirin
compared to women with other potential systemic or cardiovascular disease who did not
respond to the survey.
Conclusion
The chemopreventive effect of aspirin has been proven effective in reducing the risk
ratio of aspirin-sensitive-cancers, primarily for colorectal cancer. This conclusion is confirmed
by findings of 5 recent reviews which shows a decreasing trend in colorectal cancer risk, where
participants in the experimental group were examined in various metrics of daily aspirin intake
including dose, frequency, and duration. Several findings suggest that aspirin use in aspirin-
sensitive-cancers prevention were dose-dependent and further studies with larger sample sizes
with more variety of interventions and longer follow-up time are needed to evaluate the
maximum potential of this chemopreventive agent. One of the limitations of this systematic
review is the low power to evaluate more specific studies focusing on population, specific
dosage, duration of aspirin intake and limitations in gathering studies from more resources.
Despite its advantages, we acknowledge that not every individual can benefit from aspirin for
its side effects such as gastrointestinal bleeding and other toxicity complications including
convulsions, anion gap metabolic acidosis, and acute renal failure.
Studying aspirin use in the prevention of cancers is a significant, safe, and efficient
strategy. Moreover, reducing cancer incidence with aspirin could lower costs and associated
comorbidities, which is particularly important in reducing future medical interventions to
enhance the quality of life.
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