A MERICAN A SSOCIATION FOR
T HE STUDY OF LIVER D I S E ASES
EDITORIALS | HEPATOLOGY, VOL. 64, NO. 3, 2016
Cholangiocarcinoma Risk Factors
and the Potential Role of Aspirin
SEE ARTICLE ON PAGE 785
C
holangiocarcinoma (CC) is the second most
common primary hepatobiliary cancer. Its
classification is based on anatomical location:
intrahepatic CC (ICC) originates within the liver, and
extrahepatic CC (ECC) originates in the extrahepatic
bile ducts. Epidemiological reports have demonstrated
an increasing incidence of CC, with annual percentage
changes of 2.3% and 0.14% for ICC and ECC, respec-
tively, between 1973 and 2012.(1) Defined risk factors
include primary sclerosing cholangitis, hepatolithiasis,
cirrhosis, and hepatitis infection. Other possible risk
factors include smoking, diabetes, gallstones, and bili-
ary cysts. Although these risk factors are associated
with a subset of patients, the majority of cases are spo-
radic. Most epidemiological studies have focused on
factors associated with heightened cancer risk; how-
ever, there has been increased interest in identifying
factors associated with cancer prevention. To this end,
Choi et al.(2) report a large hospital-based case-control
study of 2395 cases that examined whether aspirin use
Abbreviations: CC, cholangiocarcinoma; COX-2, cyclooxygenase 2;
ECC, extrahepatic cholangiocarcinoma; GI, gastrointestinal; ICC,
intrahepatic cholangiocarcinoma; NSAID, nonsteroidal anti-
inflammatory drug; USPSTF, US Preventive Services Task Force.
Received April 11, 2016; accepted April 19, 2016.
Copyright V C 2016 by the American Association for the Study of
Liver Diseases.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep.28613
Potential conflict of interest: Nothing to report.
ADDRESS CORRESPONDENCE AND
REPRINT REQUESTS TO:
Timothy M. Pawlik, M.D., M.P.H., Ph.D., F.A.C.S.
Division of Surgical Oncology
John L. Cameron Professor of Alimentary Surgery
Department of Surgery
Johns Hopkins Hospital
600 N. Wolfe Street
Blalock 688
Baltimore, MD 21287
E-mail: tpawlik1@jhmi.edu
708
was protective against CC. Of note, the association of
aspirin use and the incidence of cancer has been the
object of extensive previous epidemiologic studies, sug-
gesting that long-term aspirin use is associated with a
modest but significantly reduced risk for overall and
gastrointestinal (GI) tract cancers.(3)
The proposed mechanism for the biological activity of
nonsteroidal anti-inflammatory drugs (NSAIDs) against
cancer includes inhibition of the cyclooxygenase 2
(COX-2) enzyme.(4) Specifically, overexpression of
COX-2 has been demonstrated in CC cells.(5) Several
previous studies have investigated the role of NSAIDs
and CC. In one study that used the General Practice
Registration Database, which represents about 5 million
people in the UK, NSAIDs were reported not to be
associated with a decreased incidence of CC; however,
the specific effect of aspirin was not reported.(6) Con-
versely, in a separate case control study, aspirin use was
reported to be associated with a nonsignificant reduction
in the odds of developing all bile duct cancers.(7) Several
papers examining the association of aspirin use and the
incidence of cancer have been based on data from
randomized controlled trials that were investigating aspi-
rin use for non-cancer-related reasons. For example,
Rothwell et al.(8) used individual patient data from
randomized trials comparing daily aspirin use versus no
aspirin use to determine the effect of aspirin on cancer
death risk for GI and non-GI cancers. In this study, the
authors reported on 25,570 patients and noted that aspi-
rin reduced death due to cancer by about 20%. Recently,
Cao et al.(3) analyzed two large prospective cohort studies
in the United States that included 135,965 health care
professionals who underwent follow-up for as long as 32
years. The authors concluded that the benefit of aspirin
on the prevention of GI cancers was associated with the
use of aspirin for a minimum of 6 years. As result of
these findings, in 2015 the US Preventive Services Task
Force (USPSTF) recommended the use of aspirin to
prevent colorectal cancer among certain subgroups of
adults with specific cardiovascular risk profiles and, cur-
rently, aspirin is the first pharmacologic agent to be
endorsed by the USPSTF for chemoprevention of a can-
cer in a population without a high risk of developing
cancer.(3)

HEPATOLOGY, Vol. 64, No. 3, 2016
Choi et al. used a large single institution dataset that
included roughly 2000 patients from a more than 14-
year time span. Using a case-control study design, the
authors analyzed the protective effect of aspirin among
patients with an assortment of CC types (ICC, hilar
CC, and distal CC). Specifically, the authors matched
CC patients with patients selected from the Mayo
Clinic Biobank in a 2:1 manner based on age, sex,
race, and residence. Not surprisingly, the authors
reported an increased risk of CC associated with risk
factors such as primary sclerosing cholangitis and dia-
betes. Of more interest, there was also a significant
inverse association of aspirin use with all CC subtypes,
with adjusted odds ratios of 0.35 (95% confidence
interval [CI], 0.29-0.42), 0.34 (95% CI, 0.27-0.42),
and 0.29 (95% CI, 0.19-0.44) for ICC, perihilar CC,
and distal CC, respectively (all P < 0.001). This effect
of aspirin use on the decreased long-term incidence of
CC was consistent with many previous reports that
have examined other cancers.(9) In a large systematic
review, Algra and Rothwell(9) compared the effects of
regular aspirin use from observational versus random-
ized trials. Whereas the protective effect of aspirin was
similar to that reported by Choi et al., the magnitude
of the effect was somewhat less. Specifically, in many
past observational and randomized trials, estimates of
the effect of aspirin were associated with a 20%-40%
reduction in cancer risk.(3) The authors highlighted
how estimations of effect size were likely dependent on
appropriately detailed recording and analysis of aspirin
use. In light of this, one potential shortcoming of the
study by Choi et al. was the reliance on electronic
medical records to delineate aspirin users from nonas-
pirin users, as well as identification of duration and
dose of therapy. Although such data were available in
the medical records, accurate quantification of medica-
tion dosing and duration can be problematic.(9) To this
point, more than one-half of cases did not have avail-
able information on the duration of aspirin usage.
Information on other concurrent medications being
taken by patients was also limited. Such missing data
may have impacted data analyses and subsequent causal
inferences. For example, Chaiteerakij et al. previously
reported that treatment with metformin was associated
with a 60% reduction of CC in diabetic patients. Lack
of adjustment for metformin or other chemopreventive
medications in the aspirin and nonaspirin groups may
have unknowingly impacted the results. Finally, the
study probably suffered from some residual confound-
ing, because patients who were daily aspirin users likely
had a different medical profile than their matched con-
15273350, 2016, 3, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.28613, Wiley Online Library on [03/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BAGANTE, GAMBLIN, AND PAWLIK
trols (e.g., patients were healthier if they were taking
aspirin for prophylaxis but less healthy if they were tak-
ing it for therapeutic purposes). Although matching
can mitigate some of the differences between the two
groups, undoubtedly some residual bias remained. Fur-
thermore, the “biobank”-derived control patients were
individuals who had been followed at the Mayo Clinic
for a prolonged period and thus were likely different
from the general population.
Despite these limitations, the data by Choi et al.
contribute to the growing body of data that support a
chemopreventive role for aspirin use. Aspirin use is not
without its own set of potential complications. Low-
dose aspirin therapy has been associated with GI side
effects, which can range from dyspepsia and gastro-
duodenal erosions to symptomatic or complicated
ulcers resulting in an annual incidence of upper GI
bleeding of 0.6% and an increased relative risk of
2.6.(10) In addition, the use of enteric-coated or buf-
fered preparations do not necessarily reduce the risk of
GI complications.(10) As such, further work is needed
to characterize patient populations in which the bene-
fits of routine aspirin use outweigh the risks, especially
for a cancers that have a low baseline incidence (such
as CC). Choi et al. are to be congratulated on their
work, which adds to an already abundant literature on
the topic of aspirin and cancer prevention. However,
the retrospective design of the study, as well as the rel-
ative lack of detailed data on dosing, duration of use,
and concomitant other medications, do not allow for
definitive evidence to support routine recommenda-
tions for daily aspirin use. In an era of individualized
medicine, future prospective trials should aim to iden-
tify those subsets of patients who might benefit the
most from aspirin usage, as well as further delineate
the underlying mechanism of action related to this
potential chemopreventative approach.
Fabio Bagante, M.D.1,2
T. Clark Gamblin, M.D.3
Timothy M. Pawlik, M.D., M.P.H., Ph.D., F.A.C.S.1
1
Division of Surgical Oncology
Department of Surgery
Johns Hopkins Hospital, Baltimore, MD
2
Department of Surgery
University of Verona
Verona, Italy
3
Department of Surgery
Medical College of Wisconsin
Milwaukee, WI
709

BAGANTE, GAMBLIN, AND PAWLIK
REFERENCES
1) Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in
cholangiocarcinoma incidence in the U.S.: intrahepatic disease on
the rise. Oncologist 2016. pii: theoncologist.2015-0446.
2) Choi J, Ghoz HM, Peeraphatdit T, Baichoo E, Addissie BD,
Harmsen WS, et al. Aspirin-use and the risk of cholangiocarci-
noma. HEPATOLOGY 2016;64:785-796.
3) Cao Y, Nishihara R, Wu K, Wang M, Ogino S, Willett WC, et al.
Population-wide impact of long-term use of aspirin and the risk for
cancer. JAMA Oncol 2016. doi: 10.1001/jamaoncol.2015.6396.
4) Thun MJ, Jacobs EJ, Patrono C. The role of aspirin in cancer
prevention. Nat Rev Clin Oncol 2012;9:259-267.
5) Han C, Leng J, Demetris AJ, Wu T. Cyclooxygenase-2 promotes
human cholangiocarcinoma growth: evidence for cyclooxygenase-2-
independent mechanism in celecoxib-mediated induction of
p21waf1/cip1 and p27kip1 and cell cycle arrest. Cancer Res 2004;
64:1369-1376.
710
15273350, 2016, 3, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.28613, Wiley Online Library on [03/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HEPATOLOGY, September 2016
6) Grainge MJ, West J, Solaymani-Dodaran M, Aithal GP, Card
TR. The antecedents of biliary cancer: a primary care case-
control study in the United Kingdom. Br J Cancer 2009;100:
178-180.
7) Liu E, Sakoda LC, Gao YT, Rashid A, Shen MC, Wang BS,
et al. Aspirin use and risk of biliary tract cancer: a population-
based study in Shanghai, China. Cancer Epidemiol Biomarkers
Prev 2005;14:1315-1318.
8) Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP,
Meade TW. Effect of daily aspirin on long-term risk of death
due to cancer: analysis of individual patient data from rando-
mised trials. Lancet 2011;377:31-41.
9) Algra AM, Rothwell PM. Effects of regular aspirin on long-
term cancer incidence and metastasis: a systematic comparison of
evidence from observational studies versus randomised trials.
Lancet Oncol 2012;13:518-527.
10) Hsu PI, Tsai TJ. Epidemiology of upper gastrointestinal damage
associated with low-dose aspirin. Curr Pharm Des 2015;21:
5049-5055.