Review

Journal of International Medical Research

2014, Vol. 42(1) 316
A review of the clinical ! The Author(s) 2013
Reprints and permissions:
diagnosis and therapy sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0300060513505488
of cholangiocarcinoma imr.sagepub.com

Denghua Yao1,2, Vamsi Krishna Kunam3 and

Xiao Li1,2

Abstract
Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy worldwide.
The incidence of intrahepatic CCA is increasing, whereas that of extrahepatic CCA is decreasing.
This review looks at the new advances that have been made in the management of CCA, based on a
PubMed and Science Citation Index search of results from randomized controlled trials, reviews,
and cohort, prospective and retrospective studies. Aggressive interventional approaches and new
histopathological techniques have been developed to make a histological diagnosis in patients with
high risk factors or suspected CCA. Resectability of the tumour can now be assessed using multiple
radiological imaging studies; the main prognostic factor after surgery is a histologically negative
resection margin. Biliary drainage and/or portal vein embolization may be performed before
extended radical resection, or liver transplantation may be undertaken in combination with
neoadjuvant chemotherapy or chemoradiotherapy. Though many advances have been made in the
management of CCA, the standard modality of treatment has not yet been established. This review
focuses on the clinical options for different stages of CCA.

Keywords
Cholangiocarcinoma, diagnosis, therapy, malignant biliary obstruction, photodynamic therapy,
review

Date received: 8 July 2013; accepted: 20 July 2013

Introduction
Cholangiocarcinoma (CCA) is a fatal cancer
of the biliary epithelium; it arises either
within the liver (intrahepatic cholangiocar-
cinoma; ICC) or in the extrahepatic bile
1
Department of Gastroenterology and Hepatology, West
China Hospital, Sichuan University, Chengdu, China
2
Department of Interventional Radiology, West China
Hospital, Sichuan University, Chengdu, China
3
Department of Radiology, Cleveland Clinic, Cleveland,
OH, USA
Corresponding author:
Professor Xiao Li, Department of Interventional Radiology
and Department of Gastroenterology and Hepatology,
West China Hospital, Sichuan University, 37 Guoxue Lane,
Chengdu 610041, Sichuan Province, China.
Email: simonlixiao@gmail.com
4 Journal of International Medical Research 42(1)
ducts (extrahepatic cholangiocarcinoma;
ECC). Globally, CCA is the second most
common primary hepatic malignancy, with
a reported incidence of one to two cases per
100 000 in the USA.1 Several epidemio-
logical studies have shown that the incidence
and mortality rates of ICC are increasing,
while those of ECC are falling.27
The exact aetiology of CCA is unknown.
There are several well-dened risk factors,
however, including primary sclerosing chol-
angitis, liver uke infestation, congenital
bropolycystic liver disease and intrahepatic
biliary stones.2,5,8,9 Other risk factors
include exposure to dioxin, Thorotrast or
nitrosamines.10
As there are no specic symptoms in early
malignant lesions, patients with CCA
mostly present in the advanced stages of
the disease, which contributes to its poor
prognosis. With the advent of new tech-
niques such as intraductal ultrasonography
and in situ hybridization for clinical screen-
ing in patients with high risk factors, early
detection of CCA has become feasible: this
can lead to successful surgical resection
of these lesions and an improved
outcome. In patients with advanced CCA,
margin-negative (R0) resection can be
achieved in increasing numbers of patients
using preoperative portal vein embolization
followed by extended radical resection or
neoadjuvant chemoradiotherapy, and then
organ transplantation, with an improved
prognosis. In patients with unresectable
CCA, new technologies such as photo-
dynamic therapy and endoscopic or percu-
taneous stent implantation have
signicantly improved quality of life and
survival time.
This review was based on literature
searches in PubMed and the Science
Citation Index using the following
search terms: cholangiocarcinoma and
diagnosis; aetiology; surgery; extended
surgery; liver transplantation; neo-
adjuvant chemoradiation; chemotherapy;
radiotherapy; palliative biliary drainage;
and photodynamic therapy. Results from
reviews, case reports, randomized controlled
trials, and cohort, prospective and retro-
spective studies for which the title and
abstract were available in English were
included. Studies with <10 patients were
excluded.
Diagnosis
The clinical features of CCA depend on the
stage and location of the tumour. As there
are no specic symptoms in the early stages
of CCA, most patients present at an
advanced stage. Patients with ECC usually
present with obstructive jaundice, whereas
those with ICC usually present with abdom-
inal pain. Common complaints include prur-
itus, weight loss, fever, and symptoms
related to biliary obstruction such as clay-
coloured stools and dark urine. Physical
signs include jaundice, hepatomegaly and a
right upper quadrant mass. Serum alkaline
phosphatase and bilirubin levels are elevated
if bile duct obstruction is present. No spe-
cic tumour markers have yet been identi-
ed in CCA. Although the sensitivity and
specicity of carcinoembryonic antigen and
cancer antigen 19-9 (CA19-9) are low, they
may be of value in predicting prognosis after
surgery or for screening of patients, espe-
cially in those with predisposing risk fac-
tors.11,12 Other markers may have clinical
signicance. Serum levels of matrix metallo-
proteinase-713 and tumour M2-PK14 have
been shown to have the potential to dier-
entiate CCA from benign biliary tract dis-
ease with more sensitivity and specicity
than CA19-9. In addition, an animal trial
reported that a novel CCA-associated
carbohydrate antigen may have potential
as a marker for the early diagnosis of
CCA.15 Zabron et al. conrmed that neu-
trophil gelatinase-associated lipocalin
(NGAL) was a potential biomarker to dis-
tinguish benign from malignant biliary
Yao et al.
obstruction.16 The development of modern
tissue pathological technology enabled some
new aspects of CCA to be studied.
Subrungruang et al. demonstrated upregu-
lation of seven genes (FXYD3, GPRC5A,
CEACAM5, MUC13, EPCAM, TMC5 and
EHF) and downregulation of three genes
(CPS1, TAT and ITIH1) in ICC. This
provided exon-level expression proles,
which might be useful for early diagnosis
of CCA.17 Shigehara et al. demonstrated
that some miRNAs (miR-9, miR-302c, miR-
199a-3p and miR-222) in human bile were
more highly expressed in biliary tract cancer
than in benign conditions, so miR-9 might
be helpful in the diagnosis and clinical
management of biliary tract cancer.18
Markers for the precise prediction of the
prognosis of CCA have been dicult to
identify. Recently, it has been shown that
single nucleotide polymorphisms (SNPs)
were able to predict the outcome of CCA
and the B-cell-lymphoma-2 (Bcl-2) 938C>
A polymorphism was associated with a
favourable clinical outcome.19
In patients with suspected CCA, transab-
dominal ultrasonography and other non-
invasive imaging should be performed to
conrm the diagnosis. Transabdominal
ultrasound is sensitive for visualizing the
bile ducts, conrming ductal dilatation and
ruling out choledocholithiasis. For precise
characterization of the neoplasm and plan-
ning further management, however,
other imaging modalities such as computed
tomography (CT), contrast-enhanced CT
(including three-dimensional reconstruc-
tion, three-phase CT and CT angiography),
cholangiography, positron emission tomog-
raphy (PET) and magnetic resonance ima-
ging (MRI), including magnetic resonance
cholangiopancreatography (MRCP), should
be carried out preoperatively.
Computed tomography and contrast-
enhanced CT can not only visualize the
local anatomical structures, measure the size
of the tumour and the extent of the bile duct
5
dilatation, and detect regional lymph node
enlargement, atrophy of the lobe and satel-
lite nodules, but also have the advantage of
being able to perform precise multidirec-
tional assessment of biliary and vascular
involvement, which helps in the accurate
prediction of resectability.2025 Similarly,
MRCP in combination with MRI is a reli-
able non-invasive diagnostic method for the
pre-therapeutic staging of CCA. Due to its
intrinsic high tissue contrast and multiplanar
ability, MRI with MRCP is capable of
examining all the structures involved, such
as bile ducts, vessels and hepatic paren-
chyma, and a precise preoperative assess-
ment of the tumour can therefore be
achieved.2629 There are no major dierences
between CT and MRI for preoperative
appraisal for patients with CCA,30 and
these imaging techniques play complemen-
tary roles in the process of clinical diagnosis
and preoperative assessment. PET using the
radiotracer [18F]uorodeoxyglucose has
become a useful staging technique for
many neoplasms. One study of 123 patients
with suspected and potentially operable
CCA demonstrated that PET-CT was more
accurate than CT in the diagnosis of regional
lymph node metastases (75.9% versus
60.9%, P 0.004) and distant metastases
(88.3% versus 78.7%, P 0.004), but had no
statistically signicant advantage over CT or
MRI/MRCP in detecting local lesions.31
Although the rapid development of ima-
ging technology and instrumentation has
enabled the accurate demonstration of
lesions, these imaging modalities are of
limited value in early CCA, when there are
small or even no changes in morphology. In
addition, dierentiating between benign and
malignant bile duct stricture is very dicult,
but this distinction is important in treatment
planning. These clinical problems can be
addressed by the use of cytology or tissue
biopsy via endoscopic retrograde cholangio-
pancreatography (ERCP), percutaneous
transhepatic cholangiography (PTC),
6 Journal of International Medical Research 42(1)
cholangioscopy or endoscopic ultrasonog-
raphy (EUS)-guided ne needle aspiration.
Due to its relative ease and safety, many
studies have suggested that cytology during
ERCP, despite its low sensitivity, remains a
good choice for the diagnosis of causes of
biliary stricture.3235 To improve the sensi-
tivity, further renements in technique and
procedure have been suggested. One study of
cytodiagnosis through ERCP showed that
intraductal aspiration had a signicantly
higher sensitivity (89% versus 78% for
adequate samples and 89% versus 37% for
all samples) and signicantly superior cellu-
lar adequacy (92.8% versus 35.7%) than
brushing in patients with suspected malig-
nant biliary stricture.36 In patients with
negative results on ERCP-guided bile duct
biopsy, biopsy sensitivity was improved by
the use of intraductal ultrasonography
(IDUS)-guided forceps during ERCP.37
Similarly, cytology or biopsy during PTC
has been shown to be eective and safe. In
the study of Jung et al.,38 patients with
obstructive jaundice underwent translum-
inal forceps biopsy during or after percutan-
eous transhepatic biliary drainage (PTBD),
with a sensitivity, specicity and accuracy of
78.4%, 100% and 79.2%, respectively, with-
out any major complications related to the
biopsy procedures. Other studies have also
demonstrated that biopsy during PTBD is a
safe procedure and can provide relatively
high accuracy in the diagnosis of malignant
biliary obstructions.39,40 Currently, there are
no signicant dierences in sensitivity and
complications between cytology/biopsy with
ERCP or PTC, but more attention should be
paid to the fact that catheter tract implant-
ation metastasis is not a rare complication
following PTBD in ECC.41,42 The study of
Kim et al.43 indicated that PTC in combin-
ation with IDUS was highly accurate for
assessing Bismuth type in patients with hilar
CCA, which may help in the identication of
an optimal surgical plan for the treatment of
hilar CCA, especially in Bismuth type III
and IV. IDUS images also have important
clinical signicance in the dierentiation of
malignant and benign lesions. Tamada
et al.37 reported that when IDUS images
showed a polypoid lesion, localized wall
thickening, intraductal sessile tumour or
sessile tumour outside of the bile duct, the
sensitivities of the biopsy were 80%, 50%,
92% and 53%, respectively, and that the
presence of sessile tumour (intraductal or
outside of the bile duct), tumour size
>10.0 mm and interrupted wall structure
on IDUS images could predict malignancy
in patients with a negative ERCP-guided bile
duct biopsy. In addition, a number of studies
have demonstrated the safety and high
accuracy, sensitivity and specicity of EUS
and EUS-guided ne needle aspiration in
patients with negative results after endo-
scopic brush cytology and biopsy.4348 These
results suggest that these techniques can play
a signicant role in planning further
management.
As patients with primary sclerosing chol-
angitis have a high risk of developing CCA,
attention should be paid to early detection
of malignant lesions in these patients.
Tumour serology combined with IDUS
and cross-sectional liver imaging and cytol-
ogy during ERCP/PTC have been shown to
be helpful for CCA screening and diagnosis
in patients with primary sclerosing cholan-
gitis.4951 Naitoh et al.52 reported that IDUS
ndings were useful for distinguishing
immunoglobulin G4-related sclerosing chol-
angitis from CCA. In addition, Huddleston
et al.53 described the use of UroVysionTM
uorescence in situ hybridization on bile
duct brushing for the detection of CCA in a
17-year-old boy with primary sclerosing
cholangitis.
Treatment
Resection
Surgical resection is the only potentially
curative approach currently available,
Yao et al.
although distant metastasis to the lung,
peritoneum or other organs is a contraindi-
cation for resection. Preoperative evaluation
of the future remnant liver volume and the
patients general condition is important in
deciding whether or not they are suitable for
surgery. The prognosis of patients with
CCA after surgery is generally poor, with a
reported 5-year survival rate in all patients
of <20%, improving to approximately 30%
in those with R0 resection; median survival
times were 15 and 28 months, respectively.54
Many studies have demonstrated that the
major independent prognostic factor after
surgery is R0 resection of the tumour.5457
To achieve R0 resection, hepatectomy and/
or pancreaticoduodenectomy is frequently
required. Local resection in combination
with caudate lobectomy for hilar CCA has
resulted in a greater number of patients with
R0 resection and has improved the long-
term prognosis.58 More aggressive resection
with trisegmentectomy or even semihepa-
tectomy has been used in some patients and
was associated with signicantly increased
survival.5960 However, the postoperative
mortality due to liver dysfunction is also
slightly higher with these more extensive
operations.5861 To reduce the risk of post-
operative liver dysfunction with semihepa-
tectomy or resection of more than 5060%
of the liver, some researchers have employed
preoperative ipsilateral portal vein
embolization, which can induce compensa-
tory hypertrophy of the future remnant
liver.6264 Some patients deemed not suitable
for surgery because of liver dysfunction or
severe cholangitis secondary to cholestasis
or bile duct obstruction may be able to
undergo surgical resection following pre-
operative biliary drainage.65
Other prognostic factors after R0 resec-
tion for CCA include lymph node metasta-
sis, perineural invasion and combined
vascular resection due to portal vein and/
or hepatic artery invasion.1,54,6668 In hilar
CCA, the invasion depth of the tumour
7
(5 mm versus <5 mm) has been reported to
be a better predictor of long-term outcome
than the American Joint Committee on
Cancer staging system.69 In patients with
ICC, the macroscopic histopathology has
been shown to be useful for predicting
survival after hepatectomy, with the mass-
forming plus periductal inltrating type
having a more unfavourable prognosis
than the mass-forming type.59
Liver transplantation
The use of liver transplantation is contro-
versial as CCA has a poor prognosis with
high recurrence rates. However, a study at
the Mayo Clinic in the USA found that after
liver transplantation with neoadjuvant che-
moradiation, the survival rate of patients
with localized, node-negative hilar CCA was
signicantly higher than that of patients
with resectable hilar CCA after R0 resection
(P 0.022);70 in addition, tumour recur-
rence was less frequent (13% versus 27%)
and occurred later (mean 40 months versus
21 months) after transplantation compared
with resection.70 Another retrospective
study demonstrated that orthotopic liver
transplant had a signicantly higher 5-year
tumour recurrence-free survival rate (33%)
than radical bile duct resection combined
with partial hepatectomy (0%) (P 0.05)
and orthotopic liver transplant combined
with neoadjuvant and adjuvant therapies
was associated with a better survival rate
(47%) than transplant alone (20%) or trans-
plant with adjuvant therapy (33%)
(P 0.03) in patients with intrahepatic or
hilar CCA.71 The strategy of combining
neoadjuvant chemotherapy and liver trans-
plantation may bring new hope to the
treatment of this dicult disease.
Palliative biliary drainage
As patients with CCA mostly present at an
advanced stage, many are unsuitable for
8 Journal of International Medical Research 42(1)
curative resection because of chronic duct
obstruction resulting in recurrent cholangitis
and liver dysfunction. For these patients, the
main purpose of therapy is to relieve symp-
toms (pain, pruritus, jaundice and cholan-
gitis) and improve their quality of life.
The high success rate and low risk of
endoscopic biliary drainage achieved by
developments in endoscopic apparatus and
technology has encouraged its use in
patients with denite unresectable CCA.72
Compared with endoscopic drainage, per-
cutaneous biliary drainage has a similar
success rate and procedure-related risk, but
can better image the proximal extent of the
tumour.73 It is often performed when endo-
scopic drainage has failed, when there is
infection of isolated obstructive segments or
in the absence of high level endoscopic
expertise for complex procedures. The two
modalities should be used complementally
in the management of biliary obstruction,
especially after failure of ERCP.74
A number of studies have demonstrated
that EUS-guided biliary drainage is an
eective technique in obstructive jaun-
dice.7577 As several randomized controlled
trials have suggested the superiority of metal
stents over plastic stents for patency,7880 the
use of a metal stent is preferred in patients
expected to survive for more than 6 months.
Besides the choice of the stent, whether one
or both lobes of the liver should be drained
is also controversial. Drainage of 30% of the
liver volume has been shown to be eca-
cious in the relief of symptoms.81 A rando-
mized trial demonstrated that unilateral
drainage had a higher success rate (88.6%
versus 76.9%, P 0.04) and lower post-
procedure cholangitis rate (18.9% versus
26.9%, P 0.02) than bilateral drainage;
however, there was no signicant dierence
in long-term survival between the two pro-
cedures.82 In a subsequent study, the same
investigators reported that the use of a
unilateral metallic stent was safe, feasible
and achieved adequate drainage in the great
majority of patients with non-resectable
hilar CCA.83
The classic palliative surgery for patients
with malignant biliary obstruction is a bil-
iaryenteric bypass. However, surgical
drainage procedures show no superiority
in terms of procedure-related mortality,
survival or cost-eciency rates over non-
surgical drainage procedures such as PTBD,
endoscopic nasobiliary drainage and endo-
scopic or percutaneous stent implantation.84
Therefore, non-operative biliary drainage
should be the rst choice to resolve biliary
obstruction in non-resectable CCA, with
surgical bypass being reserved for patients
with failed endoscopic/percutaneous drain-
age and a good life expectancy.85
Chemotherapy
Chemotherapy has been used in an attempt
to control disease and to improve survival
and quality of life in patients with unresect-
able, recurrent or metastatic CCA. In a
retrospective study of 93 patients with
unresectable or metastatic CCA, those trea-
ted with chemotherapy had a signicantly
higher median overall survival than those
who did not receive chemotherapy
(P 0.002).86 Eckmann et al.87 reported
that gemcitabine/cisplatin and other alter-
native combinations (including capecita-
bine/oxaliplatin, gemcitabine/capecitabine
and gemcitabine/oxaliplatin) were eective
regimens in maintaining disease control in
ICC and hilar CCA. In addition, two sep-
arate case reports observed patients with
unresectable CCA who were successfully
downstaged by chemotherapy and con-
verted to curative resection.88,89 In a
Japanese study, postoperative gemcitabine-
based adjuvant chemotherapy was reported
to provide additional survival benet in
patients with hilar CCA.90 One randomized
controlled test investigated the ecacy of
gemcitabine and oxaliplatin plus erlotinib
versus chemotherapy alone for advanced
Yao et al.
biliary tract cancer. Although no signicant
dierence in progression-free survival (PFS)
was found, the addition of erlotinib to
gemcitabine and oxaliplatin showed antitu-
mour activity and might be a treatment
option for patients with CCA.91 Zhu et al.
also showed that combined bevacizumab
with gemcitabine and oxaliplatin
(GEMOX-B) increased the antitumour
activity with a tolerable safety prole in
patients with advanced biliary tract cancers;
there was a decrease in the standardised
uptake value (SUVmax) on [18F]FDG-PET
scans after treatment, which was associated
with disease control and increases in PFS
and overall survival.92 The Raf/MEK/ERK
kinase pathway is disrupted in many cancers,
so sorafenib should in theory be eective in
CCA. Dealis et al. evaluated the activity of
sorafenib in advanced CCA and showed
control of the disease in 31.7% of patients,93
while the study of Bengala et al. showed that
sorafenib as a single agent had a low eect-
iveness in CCA, but patients in a better
condition had an improvement in PFS.94
To reduce the drug toxicity of systemic
chemotherapy and improve eectiveness in
unresectable CCA, chemotherapeutic agents
have been given via transcatheter arterial
infusion. van Riel et al.95 observed that
gemcitabine given via a 24-h hepatic arterial
infusion was well tolerated and resulted in
signicantly lower systemic gemcitabine
plasma concentrations than intravenous
infusion. However, Inaba et al.96 reported
that the toxicity of 1000 mg/m2 gemcitabine
via transcatheter arterial infusion in patients
with unresectable ICC was tolerable, but the
desired ecacy could not be reached. A
retrospective study by Kuhlmann et al.97
reported that progression-free survival and
overall survival in transarterial chemoem-
bolization with irinotecan-eluting beads
were similar to those for systemic chemo-
therapy with oxaliplatin and gemcitabine
(3.9 months versus 6.3 months, and 11.7
months versus 11.0 months, respectively),
9
but were superior to rates in transarterial
chemoembolization with mitomycin-C (pro-
gression-free survival of 1.8 months, overall
survival of 5.7 months). A further study also
found that treatment with transarterial
chemoembolization with gemcitabine and
cisplatin resulted in signicantly longer sur-
vival than transarterial chemoembolization
with gemcitabine alone (13.8 months versus
6.3 months).98
Micro-RNA (miRNA) can modulate gene
expression. Alterations in miRNA expres-
sion lead to tumour response to chemother-
apy. The inhibition of miR-21 and miR-200b
have been shown to increase sensitivity to
gemcitabine in CCA.6 Suppression of galec-
tin-3 expression in CCA cells with siGal-3-
K402 signicantly enhanced apoptosis
induced by cisplatin or 5-uorouracil,
whereas overexpression of Gal-3 led to an
increased resistance to drugs.99
Radiotherapy
Radiotherapy, including external beam
radiotherapy and intraductal radiotherapy,
uses high-energy X-rays to damage DNA,
resulting in tumour tissue necrosis. In
patients with advanced CCA that is unsuit-
able for curative resection, radiotherapy
alone or in combination with other
approaches such as chemotherapy and/or
biliary decompression is an eective treat-
ment option, prolonging survival and
improving quality of life.100104 Patients
with resectable ECC who had microscopic-
ally positive resection margins showed
higher median disease-free survival rates
(21 months versus 10 months, P 0.042)
and decreased local failure (35.6% versus
61.7%, P 0.02) with postoperative adju-
vant radiation than with resection alone;
these outcomes were doubled compared
with no adjuvant therapy in patients with a
positive resection margin and lymph node
metastasis.105 In patients with resected ICC
and concurrent lymph node metastases,
10
postoperative adjuvant radiotherapy
improved the median survival time com-
pared with no radiotherapy (19.1 months
versus 9.5 months, P 0.011).106 However,
in the studies of Stein et al.107 and Oh
et al.,108 patients with lymph-node negative
hilar CCA or ECC with a positive resection
margin beneted from postoperative adju-
vant radiotherapy, but not those with lymph
node metastases.
Chemoradiation therapy
A combination of chemotherapy with radi-
ation should theoretically be more eective
than either method alone. Leong et al.109
demonstrated the additional benet of
chemoradiation in patients with either unre-
sectable or locally advanced CCA. A retro-
spective study by Nelson et al.110 also
suggested that postoperative chemora-
diotherapy had a possible benet in terms
of local control in patients with advanced,
resected ECC. Preoperative adjuvant che-
moradiotherapy is mainly used in patients
preparing for liver transplantation. Selected
patients with localized, node-negative, unre-
sectable hilar CCA treated by liver trans-
plantation in combination with neoadjuvant
chemoradiotherapy achieved signicantly
higher 5-year survival rates, lower incidences
of tumour recurrence and later recurrence
than those of patients with resectable hilar
CCA after R0 resection,70 and orthotopic
liver transplant combined with neoadjuvant
and adjuvant therapies was associated with
better survival rates than transplant alone or
transplant with adjuvant therapy in patients
with intrahepatic or hilar CCA.71 Some
small studies have also reported an added
benet in patients treated with preoperative
chemoradiotherapy before resection.110,111
Photodynamic therapy
Photodynamic therapy is the use of a laser to
activate in vivo photosensitizing agents and
Journal of International Medical Research 42(1)
to generate oxygen free radicals, which then
kill cancer cells. Because of the limitations of
in vivo therapy, photodynamic treatment is
mostly applied using percutaneous transhe-
patic or endoscopic techniques in patients
with unresectable CCA. Photodynamic ther-
apy alone or in combination with biliary duct
stenting or chemotherapy has been reported
to be eective in the palliative treatment of
biliary obstruction, with prolongation of the
survival time.112,113 In a retrospective ana-
lysis of patients with advanced hilar CCA,
photodynamic therapy not only extended the
median survival, but also the median metal
stent patency period.114
Conclusion
In conclusion, though many advances have
been made in the management of CCA, the
standard modality of treatment has not yet
been established. This review focuses on the
clinical options for dierent stages of CCA.
Declaration of conflicting interest
The authors declare that there are no conicts of
interest.
Funding
This work was supported by The National
Natural Science Foundation of China (grant
no. 81171444).
References
1. Anderson CD, Pinson CW, Berlin J, et al.
Diagnosis and treatment of cholangiocarci-
noma. Oncologist 2004; 9: 4357.
2. Khan SA, Toledano MB and Taylor-
Robinson SD. Epidemiology, risk factors, and
pathogenesis of cholangiocarcinoma. HPB
(Oxford) 2008; 10: 7782.
3. Khan SA, Taylor-Robinson SD, Toledano
MB, et al. Changing international trends in
mortality rates for liver, biliary and pancreatic
tumours. J Hepatol 2002; 37: 806813.
Yao et al.
4. Khan SA, Emadossadaty S, Ladep NG, et al.
Rising trends in cholangiocarcinoma: is the
ICD classification system misleading us?
J Hepatol 2012; 56: 848854.
5. Shaib Y and El Serag HB. The epidemiology
of cholangiocarcinoma. Semin Liver Dis
2004; 24: 115125.
6. Patel T. Increasing incidence and mortality
of primary intrahepatic cholangiocarcinoma
in the United States. Hepatology 2001; 33:
13531357.
7. Patel T. Worldwide trends in mortality from
biliary tract malignancies. BMC Cancer
2002; 2: 10.
8. Su CH, Shyr YM, Lui WY, et al.
Hepatolithiasis associated with
cholangiocarcinoma. Br J Surg 1997; 84:
969973.
9. Watanapa P and Watanapa WB. Liver fluke-
associated cholangiocarcinoma. Br J Surg
2002; 89: 962970.
10. Pitt HA, Dooley WC, Yeo CJ, et al.
Malignancies of the biliary tree. Curr Probl
Surg 1995; 32: 190.
11. Chen CY, Shiesh SC, Tsao HC, et al. The
assessment of biliary CA 125, CA 19-9 and
CEA in diagnosing cholangiocarcinoma
the influence of sampling time and hepato-
lithiasis. Hepatogastroenterology 2002; 49:
616620.
12. Patel AH, Harnois DM, Klee GG, et al. The
utility of CA 19-9 in the diagnoses of
cholangiocarcinoma in patients without pri-
mary sclerosing cholangitis. Am J
Gastroenterol 2000; 95: 204207.
13. Leelawat K, Sakchinabut S, Narong S, et al.
Detection of serum MMP-7 and MMP-9 in
cholangiocarcinoma patients: evaluation of
diagnostic accuracy. BMC Gastroenterol
2009; 9: 30.
14. Li Y and Zhang N. Clinical significance of
serum tumour M2-PK and CA19-9 detection
in the diagnosis of cholangiocarcinoma. Dig
Liver Dis 2009; 41: 605608.
15. Sawanyawisuth K, Silsirivanit A, Kunlabut
K, et al. A novel carbohydrate antigen
expression during development of
Opisthorchis viverrini-associated cholangio-
carcinoma in golden hamster: a potential
marker for early diagnosis. Parasitol Int
2012; 61: 151154.
11
16. Zabron AA, Horneffer-van der Sluis VM,
Wadsworth CA, et al. Elevated levels of
neutrophil gelatinase-associated lipocalin in
bile from patients with malignant pancrea-
tobiliary disease. Am J Gastroenterol 2011;
106: 17111717.
17. Subrungruang I, Thawornkuno C,
Chawalitchewinkoon-Petmitr P, et al. gene
expression profiling of intrahepatic cholan-
giocarcinoma. Asian Pacific J Cancer
Prevent 2013; 14: 557563.
18. Shigehara K, Yokomuro S, Ishibashi O,
et al. Real-time PCR-based analysis of the
human bile micrornaome identifies Mir-9 as
a potential diagnostic biomarker for biliary
tract cancer. PLoS One 2011; 6, e23584.
19. Fingas CD, Katsounas A, Kahraman A,
et al. Prognostic assessment of three single-
nucleotide polymorphisms (Gnb3 825C>T,
Bcl2 938C>A, Mcl1 386C>G) in extra-
hepatic cholangiocarcinoma. Cancer Invest
2010; 28: 472478.
20. Unno M, Okumoto T, Katayose Y, et al.
Preoperative assessment of hilar cholangio-
carcinoma by multidetector row computed
tomography. J Hepatobiliary Pancreat Surg
2007; 14: 434440.
21. Jung AY, Lee JM, Choi SH, et al. CT
features of an intraductal polypoid mass:
differentiation between hepatocellular car-
cinoma with bile duct tumor invasion and
intraductal papillary cholangiocarcinoma.
J Comput Assist Tomogr 2006; 30: 173181.
22. Sasaki R, Kondo T, Oda T, et al. Impact of
three-dimensional analysis of multidetector
row computed tomography cholangioporto-
graphy in operative planning for hilar cho-
langiocarcinoma. Am J Surg 2011; 202:
441448.
23. Chen HW, Lai EC, Pan AZ, et al.
Preoperative assessment and staging of hilar
cholangiocarcinoma with 16-multidetector
computed tomography cholangiography and
angiography. Hepatogastroenterology 2009;
56: 578583.
24. Endo I, Shimada H, Sugita M, et al. Role of
three-dimensional imaging in operative
planning for hilar cholangiocarcinoma.
Surgery 2007; 142: 666675.
25. Sugiura T, Nishio H, Nagino M, et al. Value
of multidetector-row computed tomography
12
in diagnosis of portal vein invasion by
perihilar cholangiocarcinoma. World J Surg
2008; 32: 14781484.
26. Vanderveen KA and Hussain HK. Magnetic
resonance imaging of cholangiocarcinoma.
Cancer Imaging 2004; 4: 104115.
27. Manfredi R, Brizi MG, Masselli G, et al.
[Malignant biliary hilar stenosis: MR chol-
angiography compared with direct cholan-
giography]. Radiol Med 2001; 102: 4854 [in
Italian].
28. Zidi SH, Prat F, Le Guen O, et al.
Performance characteristics of magnetic res-
onance cholangiography in the staging of
malignant hilar strictures. Gut 2000; 46:
103106.
29. Vogl TJ, Schwarz WO, Heller M, et al.
Staging of Klatskin tumours (hilar cholan-
giocarcinomas): comparison of MR cholan-
giography, MR imaging, and endoscopic
retrograde cholangiography. Eur Radiol
2006; 16: 23172325.
30. Choi BI, Han JK, Shin YM, et al. Peripheral
cholangiocarcinoma: comparison of MRI
with CT. Abdom Imaging 1995; 20: 357360.
31. Kim JY, Kim MH, Lee TY, et al. Clinical
role of 18F-FDG PET-CT in suspected and
potentially operable cholangiocarcinoma: a
prospective study compared with conven-
tional imaging. Am J Gastroenterol 2008;
103: 11451151.
32. Mohammad Alizadeh AH, Mousavi M,
Salehi B, et al. Biliary brush cytology in the
assessment of biliary strictures at a tertiary
center in Iran. Asian Pac J Cancer Prev 2011;
12: 27932796.
33. Macken E, Drijkoningen M, Van Aken E,
et al. Brush cytology of ductal strictures
during ERCP. Acta Gastroenterol Belg 2000;
63: 254259.
34. Geraci G, Pisello F, Arnone E, et al.
Endoscopic cytology in biliary strictures.
Personal experience. G Chir 2008; 29:
403406.
35. Weber A, von Weyhern C, Fend F, et al.
Endoscopic transpapillary brush cytology
and forceps biopsy in patients with hilar
cholangiocarcinoma. World J Gastroenterol
2008; 14: 10971101.
36. Curcio G, Traina M, Mocciaro F, et al.
Intraductal aspiration: a promising new
Journal of International Medical Research 42(1)
tissue-sampling technique for the diagnosis
of suspected malignant biliary strictures.
Gastrointest Endosc 2012; 75: 798804.
37. Tamada K, Tomiyama T, Wada S, et al.
Endoscopic transpapillary bile duct biopsy
with the combination of intraductal ultra-
sonography in the diagnosis of biliary stric-
tures. Gut 2002; 50: 326331.
38. Jung GS, Huh JD, Lee SU, et al. Bile duct:
analysis of percutaneous transluminal for-
ceps biopsy in 130 patients suspected of
having malignant biliary obstruction.
Radiology 2002; 224: 725730.
39. Xing GS, Geng JC, Han XW, et al.
Endobiliary brush cytology during percu-
taneous transhepatic cholangiodrainage in
patients with obstructive jaundice.
Hepatobiliary Pancreat Dis Int 2005; 4:
98103.
40. Savader SJ, Prescott CA, Lund GB, et al.
Intraductal biliary biopsy: comparison of
three techniques. J Vasc Interv Radiol 1996;
7: 743750.
41. Sakata J, Shirai Y, Wakai T, et al. Catheter
tract implantation metastases associated
with percutaneous biliary drainage for
extrahepatic cholangiocarcinoma. World J
Gastroenterol 2005; 11: 70247027.
42. Takahashi Y, Nagino M, Nishio H, et al.
Percutaneous transhepatic biliary drainage
catheter tract recurrence in cholangiocarci-
noma. Br J Surg 2010; 97: 18601866.
43. Kim HM, Park JY, Kim KS, et al.
Intraductal ultrasonography combined with
percutaneous transhepatic cholangioscopy
for the preoperative evaluation of longitu-
dinal tumor extent in hilar cholangiocarci-
noma. J Gastroenterol Hepatol 2010; 25:
286292.
44. Byrne MF, Gerke H, Mitchell RM, et al.
Yield of endoscopic ultrasound-guided fine-
needle aspiration of bile duct lesions.
Endoscopy 2004; 36: 715719.
45. Eloubeidi MA, Chen VK, Jhala NC, et al.
Endoscopic ultrasound-guided fine needle
aspiration biopsy of suspected cholangio-
carcinoma. Clin Gastroenterol Hepatol 2004;
2: 209213.
46. Fritscher-Ravens A, Broering DC, Knoefel
WT, et al. EUS-guided fine-needle aspiration
of suspected hilar cholangiocarcinoma in
Yao et al.
potentially operable patients with negative
brush cytology. Am J Gastroenterol 2004; 99:
4551.
47. Ohshima Y, Yasuda I, Kawakami H, et al.
EUS-FNA for suspected malignant biliary
strictures after negative endoscopic transpa-
pillary brush cytology and forceps biopsy.
J Gastroenterol 2011; 46: 921928.
48. Levy MJ, Heimbach JK and Gores GJ.
Endoscopic ultrasound staging of cholan-
giocarcinoma. Curr Opin Gastroenterol 2012;
28: 244252.
49. Boberg KM, Jebsen P, Clausen OP, et al.
Diagnostic benefit of biliary brush cytology
in cholangiocarcinoma in primary sclerosing
cholangitis. J Hepatol 2006; 45: 568574.
50. Moff SL, Clark DP, Maitra A, et al. Utility
of bile duct brushings for the early detection
of cholangiocarcinoma in patients with pri-
mary sclerosing cholangitis. J Clin
Gastroenterol 2006; 40: 336341.
51. Charatcharoenwitthaya P, Enders FB,
Halling KC, et al. Utility of serum tumor
markers, imaging, and biliary cytology for
detecting cholangiocarcinoma in primary
sclerosing cholangitis. Hepatology 2008; 48:
11061117.
52. Naitoh I, Nakazawa T, Ohara H, et al.
Endoscopic transpapillary intraductal ultra-
sonography and biopsy in the diagnosis of
IgG4-related sclerosing cholangitis. J
Gastroenterol 2009; 44: 11471155.
53. Huddleston BJ, Lamb RD, Gopez EV, et al.
Cholangiocarcinoma in a 17-year-old boy
with primary sclerosing cholangitis and
UroVysionTM fluorescent in situ hybridiza-
tion. Diagn Cytopathol 2012; 40: 337341.
54. DeOliveira ML, Cunningham SC, Cameron
JL, et al. Cholangiocarcinoma: thirty-one-
year experience with 564 patients at a single
institution. Ann Surg 2007; 245: 755762.
55. Jiang BG, Ge RL, Sun LL, et al. Clinical
parameters predicting survival duration after
hepatectomy for intrahepatic cholangiocar-
cinoma. Can J Gastroenterol 2011; 25:
603608.
56. Farges O, Fuks D, Boleslawski E, et al.
Influence of surgical margins on outcome
in patients with intrahepatic
cholangiocarcinoma: a multicenter study
13
by the AFC-IHCC-2009 study group.
Ann Surg 2011; 254: 824829.
57. Yusoff AR, Razak MM, Yoong BK, et al.
Survival analysis of cholangiocarcinoma: a
10-year experience in Malaysia. World J
Gastroenterol 2012; 18: 458465.
58. Kow AW, Wook CD, Song SC, et al. Role of
caudate lobectomy in type IIIA and IIIB
hilar cholangiocarcinoma: a 15-year experi-
ence in a tertiary institution. World J Surg
2012; 36: 11121121.
59. Guglielmi A, Ruzzenente A, Campagnaro T,
et al. Intrahepatic cholangiocarcinoma:
prognostic factors after surgical resection.
World J Surg 2009; 33: 12471254.
60. Ito F, Agni R, Rettammel RJ, et al.
Resection of hilar cholangiocarcinoma:
concomitant liver resection decreases hepatic
recurrence. Ann Surg 2008; 248: 273279.
61. van Gulik TM, Kloek JJ, Ruys AT, et al.
[Improved treatment results in hilar cholan-
giocarcinoma after transition to more
extensive procedure: 20 years experience
AMC]. Ned Tijdschr Geneeskd 2010; 154:
A1815 [in Dutch].
62. Tsuda M, Kurihara N, Saito H, et al.
Ipsilateral percutaneous transhepatic portal
vein embolization with gelatin sponge par-
ticles and coils in preparation for extended
right hepatectomy for hilar cholangiocarci-
noma. J Vasc Interv Radiol 2006; 17:
989994.
63. Nagino M, Nimura Y, Kamiya J, et al. Right
or left trisegment portal vein embolization
before hepatic trisegmentectomy for hilar
bile duct carcinoma. Surgery 1995; 117:
677681.
64. Madoff DC, Gupta S, Pillsbury EP, et al.
Transarterial versus transhepatic portal vein
embolization to induce selective hepatic
hypertrophy: a comparative study in swine.
J Vasc Interv Radiol 2007; 18: 7993.
65. El-Hanafy E. Pre-operative biliary drainage
in hilar cholangiocarcinoma, benefits and
risks, single center experience.
Hepatogastroenterology 2010; 57: 414419.
66. Kondo S, Takada T, Miyazaki M, et al.
Guidelines for the management of biliary
tract and ampullary carcinomas: surgical
treatment. J Hepatobiliary Pancreat Surg
2008; 15: 4154.
14
67. Nagino M, Nimura Y, Nishio H, et al.
Hepatectomy with simultaneous resection of
the portal vein and hepatic artery for
advanced perihilar cholangiocarcinoma: an
audit of 50 consecutive cases. Ann Surg 2010;
252: 115123.
68. Patel SH, Kooby DA, Staley CA 3rd, et al.
The prognostic importance of lymphovas-
cular invasion in cholangiocarcinoma above
the cystic duct: a new selection criterion for
adjuvant therapy? HPB (Oxford) 2011; 13:
605611.
69. de Jong MC, Hong SM, Augustine MM,
et al. Hilar cholangiocarcinoma: tumor
depth as a predictor of outcome. Arch Surg
2011; 146: 697703.
70. Rea DJ, Heimbach JK, Rosen CB, et al.
Liver transplantation with neoadjuvant che-
moradiation is more effective than resection
for hilar cholangiocarcinoma. Ann Surg
2005; 242: 451458.
71. Hong JC, Jones CM, Duffy JP, et al.
Comparative analysis of resection and liver
transplantation for intrahepatic and hilar
cholangiocarcinoma: a 24-year experience in
a single center. Arch Surg 2011; 146:
683689.
72. Gerhards MF, den Hartog D, Rauws EA,
et al. Palliative treatment in patients with
unresectable hilar cholangiocarcinoma:
results of endoscopic drainage in patients
with type III and IV hilar cholangiocarci-
noma. Eur J Surg 2001; 167: 274280.
73. Singhal D, van Gulik TM and Gouma DJ.
Palliative management of hilar cholangio-
carcinoma. Surg Oncol 2005; 14: 5974.
74. Sciume C, Geraci G, Pisello F, et al.
[Rendez-vous technique for palliation of
neoplastic jaundice: personal experience].
Ann Ital Chir 2004; 75: 643647 [in Italian].
75. Nguyen-Tang T, Binmoeller KF, Sanchez-
Yague A, et al. Endoscopic ultrasound
(EUS)-guided transhepatic anterograde self-
expandable metal stent (SEMS) placement
across malignant biliary obstruction.
Endoscopy 2010; 42: 232236.
76. Will U, Meyer F, Schmitt W, et al.
Endoscopic ultrasound-guided transesopha-
geal cholangiodrainage and consecutive
endoscopic transhepatic Wallstent insertion
Journal of International Medical Research 42(1)
into a jejunal stenosis. Scand J Gastroenterol
2007; 42: 412415.
77. Bories E, Pesenti C, Caillol F, et al.
Transgastric endoscopic ultrasonography-
guided biliary drainage: results of a pilot
study. Endoscopy 2007; 39: 287291.
78. Moss AC, Morris E, Leyden J, et al.
Malignant distal biliary obstruction: a sys-
tematic review and meta-analysis of endo-
scopic and surgical bypass results. Cancer
Treat Rev 2007; 33: 213221.
79. Tsuyuguchi T, Takada T, Miyazaki M, et al.
Stenting and interventional radiology for
obstructive jaundice in patients with unre-
sectable biliary tract carcinomas.
J Hepatobiliary Pancreat Surg 2008; 15:
6973.
80. Katsinelos P, Paikos D, Kountouras J, et al.
Tannenbaum and metal stents in the pallia-
tive treatment of malignant distal bile duct
obstruction: a comparative study of patency
and cost effectiveness. Surg Endosc 2006; 20:
15871593.
81. Dowsett JF, Vaira D, Hatfield AR, et al.
Endoscopic biliary therapy using the com-
bined percutaneous and endoscopic tech-
nique. Gastroenterology 1989; 96: 11801186.
82. De Palma GD, Galloro G, Siciliano S, et al.
Unilateral versus bilateral endoscopic hep-
atic duct drainage in patients with malignant
hilar biliary obstruction: results of a pro-
spective, randomized, and controlled study.
Gastrointest Endosc 2001; 53: 547553.
83. De Palma GD, Pezzullo A, Rega M, et al.
Unilateral placement of metallic stents for
malignant hilar obstruction: a prospective
study. Gastrointest Endosc 2003; 58: 5053.
84. Shaib YH, Davila JA, Henderson L, et al.
Endoscopic and surgical therapy for intra-
hepatic cholangiocarcinoma in the United
States: a population-based study. J Clin
Gastroenterol 2007; 41: 911917.
85. Witzigmann H, Lang H and Lauer H.
Guidelines for palliative surgery of cholan-
giocarcinoma. HPB (Oxford) 2008; 10:
154160.
86. Kose F, Abali H, Sezer A, et al. Patients with
advanced cholangiocarcinoma benefit from
chemotherapy if they are fit to receive it:
single center experience. J BUON 2011; 16:
469472.
Yao et al.
87. Eckmann KR, Patel DK, Landgraf A, et al.
Chemotherapy outcomes for the treatment
of unresectable intrahepatic and hilar cho-
langiocarcinoma: a retrospective analysis.
Gastrointest Cancer Res 2011; 4: 155160.
88. Kamo N, Mori A, Nitta T, et al. [Two cases
of curatively resected intrahepatic cholan-
giocellular carcinomas through effective
response to neoadjuvant chemotherapy].
Gan To Kagaku Ryoho 2011; 38: 305308 [in
Japanese].
89. Tada S, Fujikawa T, Tanaka A, et al. [A case
of unresectable hilar cholangiocarcinoma
successfully treated by gemcitabine and S-1
combination chemotherapy]. Gan To Kagaku
Ryoho 2012; 39: 12791282 [in Japanese].
90. Murakami Y, Uemura K, Sudo T, et al.
Gemcitabine-based adjuvant chemotherapy
improves survival after aggressive surgery
for hilar cholangiocarcinoma. J Gastrointest
Surg 2009; 13: 14701479.
91. Jeeyun L, Se Hoon P, Heung-Moon C, et al.
Gemcitabine and oxaliplatin with or without
erlotinib in advanced biliary-tract cancer: a
multicentre, open-label, randomised, Phase 3
study. Lancet Oncol 2012; 13: 181188.
92. Zhu AX, Meyerhardt JA, Blaszkowsky LS,
et al. Efficacy and safety of gemcitabine,
oxaliplatin, and bevacizumab in advanced
biliary-tract cancers and correlation of
changes in 18-fluorodeoxyglucose pet with
clinical outcome: a Phase 2 study. Lancet
Oncol 2010; 11: 4854.
93. Dealis C, Bertolini F, Malavasi N, et al. A
Phase II trial of sorafenib (Sor) in patients
(Pts) with advanced cholangiocarcinoma
(Cc). J Clin Oncol (Meeting Abstracts) 2008:
4590.
94. Bengala C, Bertolini F, Malavasi N, et al.
Sorafenib in patients with advanced biliary
tract carcinoma: a Phase II trial. Brit J
Cancer 2009; 102: 6872.
95. van Riel JM, Peters GJ, Mammatas LH,
et al. A phase I and pharmacokinetic study
of gemcitabine given by 24-h hepatic arterial
infusion. Eur J Cancer 2009; 45: 25192527.
96. Inaba Y, Arai Y, Yamaura H, et al. Phase I/
II study of hepatic arterial infusion chemo-
therapy with gemcitabine in patients with
unresectable intrahepatic
15
cholangiocarcinoma (JIVROSG-0301). Am
J Clin Oncol 2011; 34: 5862.
97. Kuhlmann JB, Euringer W, Spangenberg
HC, et al. Treatment of unresectable cho-
langiocarcinoma: conventional transarter-
ial chemoembolization compared with drug
eluting bead-transarterial chemoemboliza-
tion and systemic chemotherapy. Eur J
Gastroenterol Hepatol 2012; 24: 437443.
98. Gusani NJ, Balaa FK, Steel JL, et al.
Treatment of unresectable cholangiocarci-
noma with gemcitabine-based transcatheter
arterial chemoembolization (TACE): a
single-institution experience. J Gastrointest
Surg 2008; 12: 129137.
99. Hou Y-J, Dong L-W, Tan Y-X, et al.
Inhibition of active autophagy induces
apoptosis and increases chemosensitivity in
cholangiocarcinoma. Lab Invest 2011; 91:
11461157.
100. Ishii H, Furuse J, Nagase M, et al. Relief of
jaundice by external beam radiotherapy
and intraluminal brachytherapy in patients
with extrahepatic cholangiocarcinoma:
results without stenting.
Hepatogastroenterology 2004; 51: 954957.
101. Zeng ZC, Tang ZY, Fan J, et al.
Consideration of the role of radiotherapy
for unresectable intrahepatic cholangiocar-
cinoma: a retrospective analysis of 75
patients. Cancer J 2006; 12: 113122.
102. Valek V, Kysela P, Kala Z, et al.
Brachytherapy and percutaneous stenting
in the treatment of cholangiocarcinoma: a
prospective randomised study. Eur J Radiol
2007; 62: 175179.
103. Saxena A, Bester L, Chua TC, et al.
Yttrium-90 radiotherapy for unresectable
intrahepatic cholangiocarcinoma: a pre-
liminary assessment of this novel treatment
option. Ann Surg Oncol 2010; 17: 484491.
104. Ghafoori AP, Nelson JW, Willett CG, et al.
Radiotherapy in the treatment of patients
with unresectable extrahepatic cholangio-
carcinoma. Int J Radiat Oncol Biol Phys
2011; 81: 654659.
105. Gwak HK, Kim WC, Kim HJ, et al.
Extrahepatic bile duct cancers: surgery
alone versus surgery plus postoperative
radiation therapy. Int J Radiat Oncol Biol
Phys 2010; 78: 194198.
16
106. Jiang W, Zeng ZC, Tang ZY, et al. Benefit
of radiotherapy for 90 patients with
resected intrahepatic cholangiocarcinoma
and concurrent lymph node metastases.
J Cancer Res Clin Oncol 2010; 136:
13231331.
107. Stein DE, Heron DE, Rosato EL, et al.
Positive microscopic margins alter outcome
in lymph node-negative cholangiocarci-
noma when resection is combined with
adjuvant radiotherapy. Am J Clin Oncol
2005; 28: 2123.
108. Oh D, Lim do H, Heo JS, et al. The role of
adjuvant radiotherapy in microscopic
tumor control after extrahepatic bile duct
cancer surgery. Am J Clinl Oncol 2007; 30:
2125.
109. Leong E, Chen WW, Ng E, et al. Outcomes
from combined chemoradiotherapy in
unresectable and locally advanced resected
cholangiocarcinoma. J Gastrointest Cancer
2012; 43: 5055.
110. Nelson JW, Ghafoori AP, Willett CG, et al.
Concurrent chemoradiotherapy in resected
Journal of International Medical Research 42(1)
extrahepatic cholangiocarcinoma. Int J
Radiat Oncol Biol Phys 2009; 73: 148153.
111. McMasters KM, Tuttle TM, Leach SD,
et al. Neoadjuvant chemoradiation for
extrahepatic cholangiocarcinoma. Am J
Surg 1997; 174: 605608.
112. Fuks D, Bartoli E, Delcenserie R, et al.
Biliary drainage, photodynamic therapy
and chemotherapy for unresectable cho-
langiocarcinoma with jaundice.
J Gastroenterol Hepatol 2009; 24:
17451752.
113. Harewood GC, Baron TH, Rumalla A,
et al. Pilot study to assess patient outcomes
following endoscopic application of
photodynamic therapy for advanced cho-
langiocarcinoma. J Gastroenterol Hepatol
2005; 20: 415420.
114. Cheon YK, Lee TY, Lee SM, et al.
Longterm outcome of photodynamic ther-
apy compared with biliary stenting alone in
patients with advanced hilar cholangiocar-
cinoma. HPB (Oxford) 2012; 14: 185193.