Expert Review of Gastroenterology & Hepatology

ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: https://www.tandfonline.com/loi/ierh20

Challenges of surgical management of

intrahepatic cholangiocarcinoma

Malcolm H. Squires, Jordan M. Cloyd, Mary Dillhoff, Carl Schmidt & Timothy
M. Pawlik

To cite this article: Malcolm H. Squires, Jordan M. Cloyd, Mary Dillhoff, Carl Schmidt & Timothy
M. Pawlik (2018) Challenges of surgical management of intrahepatic cholangiocarcinoma, Expert
Review of Gastroenterology & Hepatology, 12:7, 671-681, DOI: 10.1080/17474124.2018.1489229

To link to this article: https://doi.org/10.1080/17474124.2018.1489229

Published online: 27 Jun 2018.

Submit your article to this journal

Article views: 347

View related articles

View Crossmark data

Citing articles: 1 View citing articles

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ierh20
EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY
2018, VOL. 12, NO. 7, 671–681
https://doi.org/10.1080/17474124.2018.1489229

REVIEW

Challenges of surgical management of intrahepatic cholangiocarcinoma

Malcolm H. Squires, Jordan M. Cloyd, Mary Dillhoff, Carl Schmidt and Timothy M. Pawlik
Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA

ABSTRACT ARTICLE HISTORY

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy arising from biliary tract Received 10 March 2018
epithelium within bile ducts proximal to the secondary biliary radicles. The majority of patients are Accepted 12 June 2018
diagnosed with locally advanced or metastatic disease at presentation. Surgical resection remains the KEYWORDS
only potentially curative option, but poses unique challenges due to the large size and aggressive Cholangiocarcinoma; bile
behavior of these tumors. duct; biliary tract cancer;
Areas covered: The goal of surgical management of iCCA is margin negative (R0) hepatic resection with intrahepatic; resection;
preservation of adequate size liver remnant and function. Data regarding role of staging laparoscopy, surgery
margin status, portal lymphadenectomy, and vascular resection for iCCA are reviewed. Perioperative
systemic therapy may have value, although prospective data have been lacking. Recurrence rates remain
high even after R0 resection; among patients with recurrent disease limited to the liver, re-resection or
locoregional therapies may play a role. Liver transplantation may be an option for select patients with
very early-stage iCCA, although this should be done on a protocol-only basis.
Expert commentary: Appropriate preoperative patient selection and surgical technique are paramount
to ensure optimal oncologic outcomes for patients with resectable iCCA. Improving systemic and
locoregional therapy options may help decrease recurrence rates and improve long-term survival for
this aggressive malignancy.

1. Introduction 2. Preoperative evaluation

Intrahepatic cholangiocarcinoma (iCCA) is the second most-com-
mon primary liver malignancy worldwide after hepatocellular
carcinoma and makes up 10–15% of liver tumors. iCCA arises
from cholangiocytes within the liver in peripheral bile ducts
proximal to the second-order bile ducts (Figure 1). While still
much less common than extrahepatic cholangiocarcinoma, the
incidence of iCCA has been increasing worldwide over the last 3
decades [1–3]. Surgery offers the only opportunity for long-term
survival. Unfortunately, the majority of patients are diagnosed
with advanced or metastatic disease and only 15–30% of
patients present with resectable disease at the time of diagnosis.
Even with curative-intent resection, recurrence rates are high and
long-term survival remains poor. Median overall survival (OS)
estimates range from 27 to 36 months, with 5-year OS of
15–40% [4–7].
Risk factors for the development of iCCA include states of
chronic biliary inflammation, such as viral hepatitis, primary scler-
osing cholangitis (PSC), liver fluke or parasite infections, non-
alcoholic steatohepatitis, hemochromatosis, hepatolithiasis, and
cirrhosis [8–10]. Classification of iCCA by macroscopic growth
pattern into the mass-forming (MF), periductal infiltrating (PI),
and intraductal growth (IG) subtypes has been proposed by the
Liver Cancer Study Group of Japan [11]. The MF subtype refers to
a defined mass within the liver, the PI subtype refers to long-
itudinal growth pattern along the bile duct, and the IG subtype
refers to tumor growth within the bile duct lumen [11,12].
Similar to evaluation of colorectal liver metastases or hepatocellu-
lar carcinoma, the consideration of surgical resection for iCCA
should take into account both technical and oncologic resectabil-
ity. Technical resectability of iCCA is defined as the ability to
perform an R0 margin negative resection with preservation of an
adequate future liver remnant (FLR), namely two or more contin-
uous segments, with intact hepatic arterial and portal venous
inflow, hepatic venous outflow, and biliary drainage [13].
Preoperative analysis of both liver quality as well as the liver
volume of the FLR remaining after resection is crucial for minimiz-
ing the risk of postoperative hepatic insufficiency (PHI). As resec-
tion of iCCA often requires formal hemi-hepatectomy or extended
hepatectomy to achieve R0 margins, volumetric analysis of the FLR
is critical [14]. In patients with normal hepatic function and no
evidence of underlying liver disease, an FLR size of >20% should be
physiologically adequate to preserve hepatic function [15]. The
volume and anticipated function of the FLR after resection are
known to directly impact the risk of postoperative hepatic insuffi-
ciency (PHI) and, in turn, perioperative mortality [16]. A FLR of less
than 20% of the total volume is associated with a 20% rate of
hepatic failure and a 13% perioperative mortality rate [17]. The
presence of preexisting liver dysfunction requires a greater volume
of FLR in order to minimize the risk of PHI, with FLR volume of
>30% recommended for patients with underlying hepatic steatosis
and FLR >40% for those with cirrhosis [18,19]. Preoperative volu-
metric analysis of the FLR can be supplemented by functional

CONTACT Timothy M. Pawlik Tim.Pawlik@osumc.edu Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Oncology,
Health Services Management and Policy, The Ohio State University, Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH, USA
© 2018 Informa UK Limited, trading as Taylor & Francis Group
672 M. H. SQUIRES ET AL.

(single vs. multicentric), vascular invasion, lymph node invol-

vement, and margin status.
For solitary iCCA lesions ≤5 cm, a 5-year OS of 70–75% can be
achieved following R0 resection [31]. Not surprisingly, smaller
asymptomatic lesions have been associated with more favorable
pathologic features: lower rates of perineural and lymphovascu-
lar invasion, as well as lymph node metastasis and satellite
nodules. Patients with multifocal iCCA, node-positive disease,
or large tumors have the least benefit from curative-attempt
resection [32]. Multifocal bilobar liver lesions are typically a
strongly relative contraindication to resection as these patients
likely have intrahepatic metastatic disease [33]. Less well under-
stood is whether true multifocal disease versus satellite nodules
impact recurrence and survival outcomes differently [13]. While
increasing tumor size and tumor multifocality are more likely to
require extended hepatectomy and are associated with worse
long-term outcomes, these factors should not be considered
absolute contraindications to attempts at resection. A multi-
institutional analysis by Spolverato et al. demonstrated that
Figure 1. Anatomic distribution of cholangiocarcinomas. dCCA, distal cholangiocar-
cinoma; iCCA, intrahepatic cholangiocarcinoma; pCCA, perihilar cholangiocarcinoma. patients with iCCA tumors ≥7 cm or multifocal (≥2) tumors
Reprinted with permission from: Brown KW, Parmar AD, Gellar DA. Intrahepatic cholangio- could safely undergo resection without significantly increased
carcinoma. Surg Oncol Clin N. Am 2014; 23(2):231–246. perioperative complications or mortality [34]. While OS and DFS
were inferior among this cohort versus patients with small, uni-
focal iCCA, tumor size in particular was not associated with
prognosis. Other studies have shown that, while extended hepa-
evaluations such as indocyanine green clearance or 99mTc- tectomy is associated with increased risk of major postoperative
Mebrofenin Hepatobiliary Scintigraphy [20–22]. complications, DFS and OS are not negatively impacted [35].
Significant anatomic variations in hepatic volumes have The 7th edition of the AJCC staging system was the first itera-
been observed among patients, with the right hepatic lobe tion to define a separate TNM staging of iCCA distinct from hepa-
comprising >75% of volume in 10% of patients and the left tocellular carcinoma. The recent 8th edition revisions have
lateral sector comprising <20% of hepatic volume in 75% of incorporated tumor size (≤5 or >5 cm) into the T-stage classifica-
patients [23]. This anatomic variability reinforces the impor- tion (Table 1). An assessment of the 8th edition AJCC staging
tance of routine volumetric analysis prior to major hepatect- system’s prognostic performance was recently performed using
omy for iCCA, as the estimated incidence of PHI can approach data from the Surveillance, Epidemiology, and End Results (SEER)
10% after right hepatectomy and 75% after extended right
hepatectomy without PVE and compensatory preoperative
Table 1. AJCC 8th edition staging classification for intrahepatic
hypertrophy [15]. For patients with marginal or inadequate cholangiocarcinoma.
predicted FLR volume and function, portal vein embolization
Classification Description
offers a safe, well-tolerated means to typically achieve hyper-
T Category T criteria
trophy of the contralateral lobe and achieve greater FLR
Tis Carcinoma in situ (intraductal tumor)
volume prior to planned resection [24–26]. Along with the T1a Solitary tumor ≤5 cm without vascular invasion
success rate of PVE, improvements in anesthesia, perioperative T1b Solitary tumor >5 cm without vascular invasion
management, and surgical techniques have improved the T2 Solitary tumor w/intrahepatic vascular invasion or multiple
tumors ± vascular invasion
safety and outcomes of major hepatectomy and broadened T3 Tumor perforating visceral peritoneum
the indications for resection of iCCA [27,28]. The presence of T4 Tumor involving local extrahepatic structures by direct
well-compensated Child A cirrhosis or chronic biochemical invasion
N Category N criteria
liver disease such as hemochromatosis do not in themselves N0 No regional lymph node metastasis
appear to be associated with worse perioperative and long- N1 Regional lymph node metastasis present
term oncologic outcomes after resection, in appropriately M Category M criteria
M0 No distant metastasis
selected patients [9]. M1 Distant metastasis
Oncologic resectability refers to consideration of iCCA AJCC Prognostic Stage Groups
tumor biology to guide appropriate patient selection. For T1a/N0/M0 IA
T1b/N0/M0 IB
example, the presence of extrahepatic disease, including dis- T2/N0/M0 II
tant lymph node disease, should be considered an absolute T3/N0/M0 IIIA
contraindication to attempting iCCA resection [13]. With care- T4/N0/M0 IIIB
Any T/N1/M0 IIIB
ful consideration of patient selection criteria, 5-year OS after Any T/Any IV
resection of iCCA can approach 30–40% [29,30]. Various stu- N/M1
dies have demonstrated prognosis of patients after resection Adapted from: Edge SB, Byrd DR, Compton CC, et al, editors. AJCC cancer
of iCCA may be impacted by tumor size, tumor centricity staging manual. 8th edition. New York: Springer, 2017, with permission.

Figure 2. Kaplan–Meier survival curves of patients who underwent surgical resection of intrahepatic cholangiocarcinoma from 1998–2913, as extracted from the
SEER cancer registry, stratified by stage. Figure 2A. AJCC 8th edition staging system. Figure 2B. AJCC 7th edition staging system.
Reprinted with permission from: Kim Y et al. Evaluation of the 8th edition American Joint Commission on Cancer (AJCC) staging system for patients with intrahepatic cholangiocarcinoma: A
surveillance, epidemiology, and end results (SEER) analysis.J Surg Oncol. 2017 Nov;116(6):643-650.
registry [36]. The 8th edition staging demonstrated reasonably
discrete stratification of 5-year OS estimates: stage IA 57.8%,
stage IB 44.5%, stage II 30.5%, stage IIIA 24.4%, stage IIIB 12.4%,
and stage IV 8.6% (Figure 2). While locally advanced iCCA with
nodal involvement (AnyT/N1/M0) had previously been classified as
stage IVA in the 7th edition AJCC staging, these patients have been
reclassified as stage IIIB in the 8th edition. In the absence of distant
metastatic disease, a subset of these patients clearly may benefit
from curative intent resection [37]. Patients with lymph node
involvement in the setting of a solitary iCCA have been associated
with significantly better survival than those with lymph node
involvement plus multifocal disease (3-year OS 35% vs. 0%) [38].
In addition to the AJCC staging guidelines, multiple prognostic
nomograms have been proposed. The nomogram proposed by
Wang et al. incorporated serum carcinoembryonic antigen (CEA)
and CA 19–9 levels along with tumor size, centricity, vascular
invasion, lymph node involvement, and local extrahepatic metas-
tasis [39]. The predictive accuracy of this nomogram (concordance
index (C-index) of 0.74) was superior to multiple other staging
systems examined in an Asian patient cohort, including the AJCC
7th edition. Analysis of an international database of patients at
centers across the USA, Europe, and Asia reported that OS was
impacted by variables including age at diagnosis, tumor size,
tumor multifocality, cirrhosis, lymph node metastasis, and macro-
vascular invasion. A prognostic nomogram for OS following resec-
tion of iCCA was constructed and validated incorporating these
variables [7].
3. Surgical considerations
3.1. Staging laparoscopy
Staging laparoscopy has a potential role for evaluation of
patients with iCCA to detect subclinical metastatic peritoneal
or distant lymph node disease or determine unresectability of
EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 673
the primary tumor, thereby avoiding an unnecessary laparot-
omy [40,41]. In the largest prospective evaluation of staging
laparoscopy to date, occult metastatic disease was detected in
84 patients (29%) among a cohort of 291 patients with hepa-
tobiliary malignancy, including iCCA, who underwent staging
laparoscopy [41]. Laparoscopic ultrasound may have addi-
tional utility for evaluation of the extent of intrahepatic dis-
ease and major vascular invasion in high-risk patients.
3.2. Lymphadenectomy
Although still somewhat controversial, recent consensus guide-
lines recommend routine lymphadenectomy at the time of hepa-
tic resection for iCCA due to the important prognostic implications
of nodal involvement [13,42]. Some studies have suggested that
lymphadenectomy may have a therapeutic benefit by decreasing
the risk of locoregional recurrence, but no prospective data have
shown a survival advantage associated with lymph node dissec-
tion [43,44]. Lymphadenectomy does, however, provide important
prognostic information and improve the accuracy of staging for
iCCA and therefore is recommended at the time of resection
[13,45–47]. Lymph node involvement appears to be perhaps the
single most important prognostic pathologic feature in patients
undergoing resection of iCCA, as the associated survival benefit of
R0 margins are abrogated in the presence of N1 disease [48].
The portal triad structures should be skeletonized in order
to facilitate removal of all peri-portal nodal tissue. Studies
have shown the lymphatic drainage of the liver to be some-
what predictable, with the left lobe typically draining through
the lesser omentum to the nodes along the lesser curve and
cardia of the stomach, and the right lobe draining to the
hepatoduodenal ligament and portocaval and retropancreatic
lymph nodes (Figure 3) [49]. The lymph nodes along the
common hepatic artery should be routinely resected and
674 M. H. SQUIRES ET AL.
Figure 3. Lymph node drainage patterns for intrahepatic carcinomas vary with tumor location within the liver. Segments 2 and 3 drain to lymph nodes along the
lesser curvature of the stomach and subsequently to the celiac nodal basin. Intrahepatic cholangiocarcinomas of the right liver (segments 5–8) may preferentially
drain to hilar lymph nodes and subsequently to caval and periaortic lymph nodes.
Reprinted with permission from: Compton CC, Byrd DR, Garcia-Aguilar J, et al. ‘Intrahepatic Bile Ducts.’ AJCC Cancer Staging Atlas. Springer, 2012.
further lymphadenectomy tailored based on the location of
the primary iCCA and its associated draining nodes.
For patients with preoperative radiographic findings concern-
ing for portal lymph node involvement, systemic chemotherapy
is typically recommended as initial treatment, with subsequent
re-staging interval scans prior to consideration for hepatectomy
[13]. Evidence of gross lymph node involvement beyond the
primary nodal basins, such as celiac or para-aortic lymph nodes,
should be considered a contraindication to hepatic resection, as
this represents metastatic disease.
3.3. Resection margin status
The goal of curative-intent resection of iCCA is to achieve micro-
scopically negative (R0) resection margins, although given the
invasive nature of iCCA and the large size of tumors at presenta-
tion, R0 resections can be challenging to achieve. Historically, R0
margin rates of 50–96% have been reported [47,50–53]. Margin
status appears to be associated with prognosis in at least a subset
of patients undergoing resection. In a multi-institutional study of
212 patients, Farges et al. reported that R0 margin status and
margin width were only associated with survival among patients
without lymph node metastasis [50]. Among patients with N1
disease, an R1 (microscopically positive) resection margin was
not associated with worse survival, suggesting the presence of
nodal metastases may be the predominant pathologic feature
driving oncologic outcomes. Among patients with N0 disease,
however, R1 resection was independently associated with worse
survival and incrementally increasing resection margin width was
independently associated with improved median OS (≤1 mm:
15 months; 2–4 mm: 36 months; 5–9 mm: 57 months; ≥10 mm:
64 months; p < 0.001) [50].
A multi-institutional analysis by the Italian Intrahepatic
Cholangiocarcinoma Study Group reported a decreased risk of
recurrence and greater 5-year OS for patients who underwent R0
resection versus those with R1 resections [30]. Among R0 patients,
however, increasing negative margin width was not associated
with risk of recurrence, site of recurrence, or survival within this
cohort [30]. Subsequently a multi-institutional study of 584
patients by Spolverato et al. also reported that R1 resection status
was independently associated with decreased RFS and OS [54].
Among patients who underwent R0 resection, increasing margin
distance was associated with improved RFS and OS, leading the
authors to advocate a resection margin of ≥10 mm when feasible.
Other studies have not demonstrated a prognostic impact of
margin status. Tamandi et al. analyzed 74 patients who under-
went curative intent resection of iCCA and noted no difference
in RFS or OS among patients who had R1 resection margins,
wide negative margins (>10 mm), or narrow negative margins
(1–10 mm) [51]. Based on available data, consensus guidelines
recommend at least an R0 margin, with consideration of adju-
vant therapies for positive or narrow margins, although prospec-
tive data to support the benefit of such therapies are lacking.
3.4. Vascular resection
Vascular involvement is a common feature of iCCA due to
the locally invasive nature of the disease, and 9–14% of

patients may require vascular resection to achieve an R0
margin at the time of iCCA resection [32,53,55,56]. A retro-
spective cohort study by Ali et al. of 121 patients who
underwent major hepatectomy for resection of iCCA
reported that 14 patients (12%) required a major vascular
resection, including portal vein (n = 5) or IVC (n = 9) resec-
tion [57]. Although one patient in the vascular resection
cohort died of postoperative liver failure, the need for vas-
cular resection was not associated with greater risk of peri-
operative complications or worse median OS. A recent multi-
institutional analysis of 1,087 patients similarly demon-
strated that 12% of patients required major vascular resec-
tion; hepatectomy combined with portal vein or IVC
resection was successfully performed without an increase
in perioperative morbidity or mortality or worse oncologic
outcomes [58]. These findings suggest that in appropriately
selected patients, major vascular involvement is not a con-
traindication to attempting curative-intent resection of iCCA.
4. Treatment of recurrence
Following radical R0 hepatic resection for iCCA, disease recur-
rence unfortunately remains common with 5-year recurrence
rates of 50–79% reported in some series [59–62]. The majority
of disease recurrences are typically intrahepatic (60–80%) with
intraperitoneal and distant extraperitoneal recurrences occur-
ring roughly 15–30% [60,62]. A multi-institutional analysis of
time-dependent recurrence patterns among patients who
underwent resection of iCCA reported that recurrences within
24 months of primary resection typically involved the liver
(83%), whereas recurrences beyond 24 months tended to be
extrahepatic (61%) [63]. Tumor size, vascular invasion, and the
presence of lymph node metastases were independent risk
factors for recurrence within this cohort [63].
Given that intrahepatic disease is the most common site of
recurrence, surgical re-resection may offer potential utility and
some data suggest an aggressive multimodality approach to
recurrent iCCA can improve survival outcomes in select patients.
Consideration must obviously be given to patient performance
status and the size of the FLR when assessing candidacy for re-
resection. In a single institution series reported by Ercolani et al.,
3-year OS from the time of diagnosis of recurrent disease was
60% among treated patients, which included 6 patients who
underwent re-resection, versus 0% in untreated patients [64].
Survival outcomes were not further stratified by the type of
treatment undertaken for disease recurrences. Additional single
institution series have suggested that repeat hepatectomy for
liver-only recurrence of iCCA may afford a survival benefit in
highly selected patients [65,66].
In a large multi-institutional international retrospective analy-
sis of 563 patients undergoing curative-intent resection of iCCA,
the recurrence rate was nearly 70% (n = 400), of which 60% were
liver-only recurrences [61]. Among all patients who developed
recurrent disease, median OS from the time of recurrence was
11.1 months. Median OS was significantly greater for the 41
patients who underwent repeat hepatectomy versus patients
treated with intra-arterial therapy or systemic chemotherapy
(26.1 months vs. 9.6 months vs. 16.8 months, respectively;
p = 0.01). Among the patients who underwent re-resection for
EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 675
recurrent iCCA, unfortunately more than half developed a second
recurrence within a median time of 11.5 months.
Y-90 radioembolization or other regional therapies may
also have a potential role for the treatment of recurrent
iCCA, particularly in patients who are not candidates for re-
resection. No prospective studies to date have directly com-
pared outcomes after surgical re-resection with liver-directed
therapy or systemic therapy for patients with recurrent iCCA
limited to the liver, thus treatment decisions should be made
in a multidisciplinary fashion and potential clinical trial options
considered [13]. For extrahepatic metastatic disease, treatment
options are limited to systemic cytotoxic chemotherapy,
newer targeted therapies, or immunotherapy.
5. Liver transplantation
The use of orthotopic liver transplantation (OLT) for the
treatment of select patients with unresectable iCCA or
iCCA arising in the setting of underlying advanced cirrhosis
has been proposed, although reported recurrence rates and
survival outcomes have historically been poor [67–70]. A
2008 review of 18 years of UNOS data for patients with
iCCA who underwent OLT revealed 1- and 5-year OS of
74% and 38%, respectively [71]. These results were markedly
inferior survival compared with patients undergoing trans-
plant for hepatocellular carcinoma or end stage liver dis-
ease [71].
One retrospective comparative analysis of OLT (n = 38)
versus hepatic resection (n = 19) for a cohort including 37
patients with iCCA and 20 patients with hilar cholangiocarci-
noma, however, demonstrated better RFS associated with OLT
vs. hepatectomy (33% vs. 0%, p = 0.05) [72]. The combination
of neoadjuvant and adjuvant therapy for patients within the
OLT cohort was associated with significantly improved 5-year
OS versus no therapy or adjuvant therapy only [72].
More recent data suggest that patients with cirrhosis and
small, solitary iCCA ≤2 cm treated with OLT can achieve excellent
results, with 5-year RFS greater than 80% and 5-year actuarial OS
of 65% [73–75]. These favorable results, however, appear to be
limited to well-differentiated iCCA, as moderately differentiated
tumors were associated with unacceptably high recurrence rates
and poor survival [76]. Given the scarcity of donor organs and
historically poor outcomes for iCCA, at this time OLT for patients
with iCCA should only be considered for very select patients or
within the confines of a clinical trial protocol.
6. Neoadjuvant therapy
No prospective randomized trials have demonstrated a significant
benefit of neoadjuvant chemotherapy on outcomes for patients
with iCCA. Although single institution series and retrospective data
have suggested a role for neoadjuvant chemotherapy and/or
locoregional therapy to treat occult metastatic disease, decrease
recurrence rates and improve survival after resection, and to
attempt downstaging of initially unresectable iCCA in select
patients, these treatments remain controversial [77]. Based on
extrapolation of data from the ABC-02 trial performed among
patients with metastatic biliary tract malignancy, regimens of
gemcitabine and cisplatin have been commonly employed in the
676 M. H. SQUIRES ET AL.
neoadjuvant setting as well [78]. Limited experience with gemci-
tabine/cisplatin therapy in patients with initially unresectable
locally advanced biliary tract malignancies including iCCA has
demonstrated successful downstaging rate in roughly 25% of
patients [79,80]. A multi-institutional retrospective analysis by
Buettner et al. suggested a trend toward improved DFS and OS
among patients receiving neoadjuvant chemotherapy compared
with propensity score-matched patients managed with resection
alone, though this benefit was not statistically significant [81].
Locoregional intra-arterial therapies such as trans-arterial
chemoembolization (TACE), Y-90 radioembolization, and hepa-
tic arterial infusion (HAI) have been employed for unresectable
iCCA, with partial or complete radiographic response rates of
20–25% and associated improvements in survival [82–84].
These modalities may also have utility in the neoadjuvant
setting or as a means to downstage locally advanced iCCA
limited to the liver. Rayar et al. reported on a series of 45
patients with unresectable iCCA treated with a combination of
Y-90 radioembolization and systemic chemotherapy of gemci-
tabine ± platinum agent [85]. Among this cohort, 10 patients
had ‘potentially resectable’ tumors, defined as a primary single
tumor in the absence of cirrhosis or extrahepatic metastatic
disease, but were deemed initially unresectable due to tumor
involvement of hepatic vein outflow or portal vein inflow of
the FLR. Eight of these 10 patients ultimately had a radio-
graphic response and underwent curative-intent resection,
which necessitated extended hepatectomy in all 8 patients.
Two perioperative deaths occurred, while 5 patients were still
alive at a median follow up of 16.9 months, two of whom had
developed distant metastases.
HAI in combination with systemic chemotherapy may also
play a potential role in the downstaging of patients with
initially unresectable iCCA. Phase I/II trials of HAI employing
various chemotherapy regimens for the treatment of unresect-
able iCCA have demonstrated encouraging results [86–90]. In
the largest single institution series of HAI for iCCA, reported
from Memorial Sloan Kettering, 8 of 104 patients with initially
unresectable disease treated with HAI floxuridine (FUDR) and
systemic chemotherapy were successfully downstaged and
ultimately underwent R0 resection, with a median OS of
37 months (range, 10–4.92.3 months) [91].
7. Adjuvant therapy
In light of the substantial recurrence risk and overall poor
long-term survival outcomes following curative-intent resec-
tion of iCCA, there has been interest in the role of adjuvant
therapy. A 2012 meta-analysis by Horgan et al. examined the
role of adjuvant treatments among 6700 patients pooled from
20 nonrandomized studies spanning 40 years [92]. A statisti-
cally significant improvement in OS was associated with adju-
vant chemotherapy or chemoradiation but not radiation
alone. The greatest benefit associated with adjuvant therapy
was observed among patients who underwent R1 resection or
who had lymph node involvement.
In a retrospective multi-institutional analysis of 1154 patients
who underwent curative intent resection of iCCA by Reames
et al., 347 patients (30%) received adjuvant chemotherapy [93].
Adjuvant therapy was associated with a trend toward improved
OS in subsets of patients at particularly high risk of recurrence,
namely those with N1 disease (5-year OS 18% vs. 12%, p = 0.050)
and those with T2/T3/T4 tumors (37% vs. 30%; p = 0.006). A
recent single institution retrospective matched-pair analysis by
Schweitzer et al. also supported the use of adjuvant chemother-
apy after resection of iCCA [94]. Median survival of patients
receiving adjuvant chemotherapy was 33.5 months versus
18 months for those who underwent resection only.
Prospective data from initial phase III trials in patients
undergoing resection of iCCA had failed to show significant
improvement in recurrence rates or survival with the addition
of adjuvant chemotherapy [95]. The PRODIGE-12/ACCORD-18
(UNICANCER GI) phase III trial showed no significant improve-
ment in RFS among patients randomized to receive 6 months
of adjuvant gemcitabine/oxaliplatin chemotherapy versus
observation alone after resection of iCCA or other biliary
tract malignancies [96].
Recent data on the role of adjuvant therapy of iCCA resec-
tion, however, appear more encouraging. In the results of the
recently reported phase III BILCAP trial that randomized 447
patients after resection of biliary tract malignancy, including
368 patients with cholangiocarcinoma, to 6 months of adju-
vant capecitabine versus observation, adjuvant therapy was
associated with significantly improved OS [53 vs. 36 months,
HR = 0.75 (95% CI: 0.58–0.97; p = 0.028)] [97]. The reported
Grade 3–4 toxicity rate for capecitabine was 31% (69 of 223
patients), suggesting the therapy was overall well tolerated.
The ACTICCA-1 trial (NCT 02170090), a multicenter phase III
trial randomizing patients to adjuvant gemcitabine and cispla-
tin versus observation after resection of cholangiocarcinoma
or gallbladder cancer, is still open and may shed further light
on the role of adjuvant therapy [98].
Given the substantial locoregional recurrence rates
observed among patients undergoing resection of iCCA, adju-
vant radiation therapy also has been proposed, particularly for
those with risk factors for recurrence such as R1 resection
margins, major vascular involvement, or nodal involvement.
Prospective data are lacking, but retrospective institutional
data suggest radiation may offer some benefit to reducing
recurrence risk [99–102]. Stereotactic body radiation therapy
(SBRT) has been used for locally advanced, unresectable iCCA,
with some proposing extrapolation of these results to the
adjuvant setting [103]. In a cohort of 38 patients undergoing
resection of iCCA with adherence to major blood vessels,
adjuvant intensity modulated radiotherapy (IMRT) was asso-
ciated with a trend toward improved DFS and OS versus
surgery alone [99]. Limited data suggest that the use of
TACE in the adjuvant setting is not associated with improved
recurrence-free survival [104].
8. Conclusion
The only potentially curative treatment for iCCA remains surgi-
cal resection, although the majority of patients will present with
unresectable locally advanced or metastatic disease at diagno-
sis. Similar to the treatment of other liver malignancies, the
principle of the surgical approach for iCCA should be a margin
negative hepatic resection with preservation of a liver remnant
of adequate size and function. Portal lymphadenectomy is

recommended at the time of hepatectomy due to the impact of
nodal involvement on the accuracy of staging and prognosis.
Given the substantial recurrence rates even after curative-intent
resection, perioperative systemic therapy may have value,
although positive prospective data have been lacking until
recently. Systemic chemotherapy and locoregional modalities
such as HAI may be selectively employed as a downstaging
therapy for patients with initially unresectable iCCA without
evidence of extrahepatic disease, although only a small minor-
ity of patients is likely to ultimately achieve R0 resection. While
historically liver transplantation for iCCA was associated with
unacceptably high recurrence rates and poor survival out-
comes, transplant warrants further study in highly select
patients with early stage iCCA enrolled in protocol based clin-
ical trials.
9. Expert commentary
iCCA is an aggressive liver malignancy for which surgery
offers the only potential curative treatment. As resection
of iCCA routinely requires major or extended hepatect-
omy, preoperative volumetric analysis is essential. Portal
vein embolization should be used liberally for patients
with borderline FLR size and function. Appropriate patient
selection is essential, as RFS and OS after resection of
iCCA appear to be largely influenced by adverse patholo-
gic features such as tumor size, focality, vascular invasion,
and lymph node involvement, all variables beyond the
control of the surgeon.
Given the high rate of occult metastatic disease detected,
routine staging laparoscopy and laparoscopic ultrasonography
should be considered, particularly in higher-risk patients with
concerning radiologic findings. While staging laparoscopy
potentially avoids the morbidity of a laparotomy, in clinical
practice, true determination of the intrahepatic extent of dis-
ease and vascular involvement, and thus determination of
resectability, may still require open exploration with at least
a mini-laparotomy.
Regional lymphadenectomy performed at the time of hepa-
tectomy should be considered standard of care, as the pre-
sence of nodal metastases appears to be the single most
important prognostic factor for patients undergoing curative
intent resection. In addition to the valuable prognostic infor-
mation provided by an adequate lymphadenectomy, lymph
node metastasis has implications for adjuvant therapy recom-
mendations, particularly now in light of phase III data demon-
strating improved survival associated with adjuvant
chemotherapy. The goal of resection should be a microscopi-
cally negative margin; evidence is insufficient to advocate for a
specific margin distance beyond R0 resection. As with other
gastrointestinal malignancies, surgical technique cannot over-
come adverse tumor biology; the presence of lymph node
involvement appears to trump the impact of an R0 vs. R1
margin. Liver transplantation may be appropriate for very
select patients with well-differentiated, extremely early stage
iCCA, but at present transplant can only be recommended
within the confines of a clinical trial.
Patients with pathologic risk factors for recurrence and worse
long-term survival, particularly nodal involvement, should be
EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 677
evaluated in a multi-disciplinary fashion and considered for adju-
vant therapy. Patients with R1 resection margins or gross residual
disease (R2 margins) may derive benefit from systemic chemother-
apy or chemoradiation. Investigation of the role for traditional
systemic chemotherapy, newer targeted therapies, immunothera-
pies, and locoregional liver-directed therapies in the adjuvant
setting or for iCCA recurrence following prior curative-intent resec-
tion is ongoing. Given the rarity of iCCA and the paucity of pro-
spective data on such therapies, efforts to treat patients within the
auspices of perioperative clinical trials should be encouraged.
10. Five-year view
Over the next five years, the options for and efficacy of systemic
and locoregional therapies for iCCA are likely to improve. Newer
targeted therapies, immunotherapies, and locoregional liver-
directed therapies will become increasingly important treatment
modalities. As such, oncologic outcomes may be most impacted
by the addition of adjuvant therapy after resection of iCCA in
appropriately selected patients. Neoadjuvant therapy may also
begin to play a role, if prospective data are able to demonstrate
improved recurrence and survival associated with the delivery of
preoperative chemotherapy and/or radiation. Margin-negative
resection and adequate regional lymphadenectomy will remain
mainstays of appropriate surgical therapy.
Key issues
● The majority of patients with intrahepatic cholangiocarci-
noma present with locally advanced or metastatic disease
at the time of diagnosis.
● As the majority of patients will require formal hepatic
lobectomy or extended hepatectomy, preoperative volu-
metric analysis of the future liver remnant (FLR) and con-
sideration of portal vein embolization for patients with
borderline FLR size and/or function is essential.
● Although the impact of margin status among patients with
lymph node involvement remains unclear, the goal of sur-
gical management for iCCA should remain an R0 resection.
● Regional lymphadenectomy should be performed for all
patients at the time of hepatectomy.
● Adjuvant systemic therapy or locoregional therapy should
be considered for patients after resection of iCCA, particu-
larly those with high-risk features such as lymph node
involvement or microscopically positive (R1) margins.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
678 M. H. SQUIRES ET AL.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Bergquist A, von Seth E. Epidemiology of cholangiocarcinoma. Best
Pract Res Clin Gastroenterol. 2015 Apr;29(2):221–232. PubMed
PMID: 25966423.
2. Shaib YH, Davila JA, McGlynn K, et al. Rising incidence of intrahe-
patic cholangiocarcinoma in the United States: a true increase? J
Hepatol. 2004 Mar;40(3):472–477. PubMed PMID: 15123362.
3. Patel T. Increasing incidence and mortality of primary intrahepatic
cholangiocarcinoma in the United States. Hepatology. 2001 Jun;33
(6):1353–1357. PubMed PMID: 11391522.
4. Mavros MN, Economopoulos KP, Alexiou VG, et al. Treatment and
prognosis for patients with intrahepatic cholangiocarcinoma: sys-
tematic review and meta-analysis. JAMA Surg. 2014 Jun;149(6):565–
574. PubMed PMID: 24718873.
5. Nathan H, Pawlik TM, Wolfgang CL, et al. Trends in survival after
surgery for cholangiocarcinoma: a 30-year population-based SEER
database analysis. J Gastrointest Surg. 2007 Nov;11(11):1488–1496.
discussion 1496–7. PubMed PMID: 17805937.
6. Bridgewater J, Galle PR, Khan SA, et al. Guidelines for the diagnosis
and management of intrahepatic cholangiocarcinoma. J Hepatol.
2014 Jun;60(6):1268–1289. PubMed PMID: 24681130.
7. Hyder O, Marques H, Pulitano C, et al. A nomogram to predict long-
term survival after resection for intrahepatic cholangiocarcinoma:
an Eastern and Western experience. JAMA Surg. 2014 May;149
(5):432–438. PubMed PMID: 24599477.
8. Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic
cholangiocarcinoma in the United States: a case-control study.
Gastroenterology. 2005 Mar;128(3):620–626. PubMed PMID: 15765398.
9. Sulpice L, Rayar M, Boucher E, et al. Intrahepatic cholangiocarci-
noma: impact of genetic hemochromatosis on outcome and overall
survival after surgical resection. J Surg Res. 2013 Mar;180(1):56–61.
PubMed PMID: 23183056.
10. Reddy SK, Hyder O, Marsh JW, et al. Prevalence of nonalcoholic
steatohepatitis among patients with resectable intrahepatic cholan-
giocarcinoma. J Gastrointest Surg. 2013 Apr;17(4):748–755. PubMed
PMID: 23355033; PubMed Central PMCID: PMCPMC4007003.
11. Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and
stage classification. J Hepatobiliary Pancreat Surg. 2003;104:288–291.
PubMed PMID: 14598147.
12. Bagante F, Spolverato G, Weiss M, et al. Impact of morphological
status on long-term outcome among patients undergoing liver
surgery for intrahepatic cholangiocarcinoma. Ann Surg Oncol.
2017 Sep;24(9):2491–2501. PubMed PMID: 28466403.
13. Weber SM, Ribero D, O’Reilly EM, et al. Intrahepatic cholangiocarci-
noma: expert consensus statement. HPB (Oxford). 2015 Aug;17
(8):669–680. PubMed PMID: 26172134; PubMed Central PMCID:
PMCPMC4527852.
•• Consensus guidelines derived from the joint 2014 AHPBA/SSAT/
SSO/ASCO Consensus Conference on the Multidisciplinary
Management of Bile Duct Cancer.
14. Nagino M, Kamiya J, Nishio H, et al. Two hundred forty consecutive
portal vein embolizations before extended hepatectomy for biliary
cancer: surgical outcome and long-term follow-up. Ann Surg. 2006
Mar;243(3):364–372. PubMed PMID: 16495702; PubMed Central
PMCID: PMCPMC1448943.
15. Chakedis J, Squires MH, Beal EW, et al. Update on current problems
in colorectal liver metastasis. Curr Probl Surg. 2017 Nov;54(11):554–
602. PubMed PMID: 29198365.
16. Thirunavukarasu P, Aloia TA. Preoperative assessment and optimi-
zation of the future liver remnant. Surg Clin North Am. 2016 Apr;96
(2):197–205. PubMed PMID: 27017859; eng.
17. Abdalla EK. Resection of colorectal liver metastases. J Gastrointest
Surg. 2011 Mar;15(3):416–419. PubMed PMID: 21301986; eng.
18. Shindoh J, Tzeng CW, Aloia TA, et al. Optimal future liver remnant
in patients treated with extensive preoperative chemotherapy for
colorectal liver metastases. Ann Surg Oncol. 2013 Aug;20(8):2493–
2500. PubMed PMID: 23377564; PubMed Central PMCID: PMCPMC
3855465. eng.
19. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated
hepatotoxicity and surgery for colorectal liver metastases. Br J
Surg. 2007 Mar;94(3):274–286. PubMed PMID: 17315288; eng.
20. Hoekstra LT, de Graaf W, Nibourg GA, et al. Physiological and
biochemical basis of clinical liver function tests: a review. Ann
Surg. 2013 Jan;257(1):27–36. PubMed PMID: 22836216; eng.
21. Vauthey JN, Chaoui A, Do KA, et al. Standardized measurement of
the future liver remnant prior to extended liver resection: metho-
dology and clinical associations. Surgery. 2000 May;127(5):512–519.
PubMed PMID: 10819059.
22. Simpson AL, Geller DA, Hemming AW, et al. Liver planning software
accurately predicts postoperative liver volume and measures early
regeneration. J Am Coll Surg. 2014 Aug;219(2):199–207. PubMed
PMID: 24862883; PubMed Central PMCID: PMCPMC4128572.
23. Abdalla EK, Denys A, Chevalier P, et al. Total and segmental liver
volume variations: implications for liver surgery. Surgery. 2004
Apr;135(4):404–410. PubMed PMID: 15041964; eng.
24. Kosuge T, Makuuchi M, Takayama T, et al. [Preoperative portal
embolization increases safety of hepatectomy]. Nihon Geka Gakkai
Zasshi. 1991 Sep;92(9):1320–1323. PubMed PMID: 1944212; jpn.
25. Cieslak KP, Huisman F, Bais T. et al. Future remnant liver function as
predictive factor for the hypertrophy response after portal vein
embolization. Surgery. Mar 2017. PubMed PMID: 28365007; eng.
DOI:10.1016/j.surg.2016.12.031
26. Ribero D, Chun YS, Vauthey JN. Standardized liver volumetry for
portal vein embolization. Semin Intervent Radiol. 2008 Jun;25
(2):104–109. PubMed PMID: 21326551; PubMed Central PMCID:
PMCPMC3036478.
27. Huntington JT, Royall NA, Schmidt CR. Minimizing blood loss dur-
ing hepatectomy: a literature review. J Surg Oncol. 2014 Feb;109
(2):81–88. PubMed PMID: 24449171.
28. Ebata T, Yokoyama Y, Igami T, et al. Portal vein embolization before
extended hepatectomy for biliary cancer: current technique and
review of 494 consecutive embolizations. Dig Surg. 2012;29(1):23–
29. PubMed PMID: 22441616.
29. de Jong MC, Nathan H, Sotiropoulos GC, et al. Intrahepatic cholan-
giocarcinoma: an international multi-institutional analysis of prog-
nostic factors and lymph node assessment. J Clin Oncol. 2011 Aug
10;29(23):3140–3145. PubMed PMID: 21730269.
30. Ribero D, Pinna AD, Guglielmi A, et al. Surgical approach for long-
term survival of patients with intrahepatic cholangiocarcinoma: a
multi-institutional analysis of 434 patients. Arch Surg. 2012 Dec;147
(12):1107–1113. PubMed PMID: 22910846.
31. Tarchi P, Tabrizian P, Prigoff J, et al. Outcomes of resection for
solitary </=5 cm intrahepatic cholangiocarcinoma. Surgery. 2017
Dec 22 PubMed PMID: 29277385. DOI:10.1016/j.surg.2017.09.058.
32. Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma:
rising frequency, improved survival, and determinants of outcome
after resection. Ann Surg. 2008 Jul;248(1):84–96. PubMed PMID:
18580211.
33. Wright GP, Perkins S, Jones H, et al. Surgical resection does not
improve survival in multifocal intrahepatic cholangiocarcinoma: a
comparison of surgical resection with intra-arterial therapies. Ann
Surg Oncol. 2018 Jan;25(1):83–90. PubMed PMID: 29063296.
34. Spolverato G, Kim Y, Alexandrescu S, et al. Is hepatic resection for
large or multifocal intrahepatic cholangiocarcinoma justified?
results from a multi-institutional collaboration. Ann Surg Oncol.
2015 Jul;22(7):2218–2225. PubMed PMID: 25354576; PubMed
Central PMCID: PMCPMC4834710.
35. Bergeat D, Sulpice L, Rayar M, et al. Extended liver resections for
intrahepatic cholangiocarcinoma: friend or foe? Surgery. 2015
Apr;157(4):656–665. PubMed PMID: 25704428.

36. Kim Y, Moris DP, Zhang XF, et al. Evaluation of the 8th edition
American Joint Commission on Cancer (AJCC) staging system for
patients with intrahepatic cholangiocarcinoma: a surveillance, epi-
demiology, and end results (SEER) analysis. J Surg Oncol. 2017
Nov;116(6):643–650. PubMed PMID: 28608424.
37. Yuan L, Luo X, Lu X, et al. Liver resection for intrahepatic cholan-
giocarcinoma in AJCCstage: an evaluation of the survival benefit
and prognostic accuracy of current AJCC staging system on N and
M classification. Oncol Rep. 2016 Nov;36(5):2663–2672. PubMed
PMID: 27666632.
38. Uenishi T, Kubo S, Yamazaki O, et al. Indications for surgical treat-
ment of intrahepatic cholangiocarcinoma with lymph node metas-
tases. J Hepatobiliary Pancreat Surg. 2008;15(4):417–422. PubMed
PMID: 18670844.
39. Wang Y, Li J, Xia Y, et al. Prognostic nomogram for intrahepatic
cholangiocarcinoma after partial hepatectomy. J Clin Oncol. 2013
Mar 20;31(9):1188–1195. PubMed PMID: 23358969.
40. Goere D, Wagholikar GD, Pessaux P, et al. Utility of staging laparo-
scopy in subsets of biliary cancers: laparoscopy is a powerful
diagnostic tool in patients with intrahepatic and gallbladder carci-
noma. Surg Endosc. 2006 May;20(5):721–725. PubMed PMID:
16508808.
41. D’Angelica M, Fong Y, Weber S, et al. The role of staging laparoscopy
in hepatobiliary malignancy: prospective analysis of 401 cases. Ann
Surg Oncol. 2003 Mar;10(2):183–189. PubMed PMID: 12620915.
42. Maithel SK, Gamblin TC, Kamel I, et al. Multidisciplinary approaches
to intrahepatic cholangiocarcinoma. Cancer. 2013 Nov 15;119
(22):3929–3942. PubMed PMID: 23963845.
43. Nakagawa T, Kamiyama T, Kurauchi N, et al. Number of lymph node
metastases is a significant prognostic factor in intrahepatic cholan-
giocarcinoma. World J Surg. 2005 Jun;29(6):728–733. PubMed
PMID: 15880276.
44. Shimada K, Sano T, Nara S, et al. Therapeutic value of lymph node
dissection during hepatectomy in patients with intrahepatic cho-
langiocellular carcinoma with negative lymph node involvement.
Surgery. 2009 Apr;145(4):411–416. PubMed PMID: 19303990.
45. Bagante F, Gani F, Spolverato G, et al. Intrahepatic cholangiocarci-
noma: prognosis of patients who did not undergo lymphadenect-
omy. J Am Coll Surg. 2015 Dec;221(6):1031–40 e1–4. PubMed PMID:
26474514.
46. Kim DH, Choi DW, Choi SH, et al. Is there a role for systematic
hepatic pedicle lymphadenectomy in intrahepatic cholangiocarci-
noma? A review of 17 years of experience in a tertiary institution.
Surgery. 2015 Apr;157(4):666–675. PubMed PMID: 25682172.
47. Choi SB, Kim KS, Choi JY, et al. The prognosis and survival outcome
of intrahepatic cholangiocarcinoma following surgical resection:
association of lymph node metastasis and lymph node dissection
with survival. Ann Surg Oncol. 2009 Nov;16(11):3048–3056.
PubMed PMID: 19626372.
48. Luo X, Yuan L, Wang Y, et al. Survival outcomes and prognostic
factors of surgical therapy for all potentially resectable intrahe-
patic cholangiocarcinoma: a large single-center cohort study.
J Gastrointest Surg. 2014 Mar;18(3):562–572. PubMed PMID:
24395070.
49. Okami J, Dono K, Sakon M, et al. Patterns of regional lymph node
involvement in intrahepatic cholangiocarcinoma of the left lobe. J
Gastrointest Surg. 2003 Nov;7(7):850–856. PubMed PMID: 14592657.
50. Farges O, Fuks D, Boleslawski E, et al. Influence of surgical margins
on outcome in patients with intrahepatic cholangiocarcinoma: a
multicenter study by the AFC-IHCC-2009 study group. Ann Surg.
2011 Nov;254(5):824–829. Discussion 830. PubMed PMID:
22042474.
51. Tamandl D, Herberger B, Gruenberger B, et al. Influence of hepatic
resection margin on recurrence and survival in intrahepatic cho-
langiocarcinoma. Ann Surg Oncol. 2008 Oct;15(10):2787–2794.
PubMed PMID: 18685896.
52. Shimada K, Sano T, Sakamoto Y, et al. Clinical impact of the surgical
margin status in hepatectomy for solitary mass-forming type intra-
hepatic cholangiocarcinoma without lymph node metastases. J
Surg Oncol. 2007 Aug 1;96(2):160–165. PubMed PMID: 17443744.
EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 679
53. Weber SM, Jarnagin WR, Klimstra D, et al. Intrahepatic cholangio-
carcinoma: resectability, recurrence pattern, and outcomes. J Am
Coll Surg. 2001 Oct;193(4):384–391. PubMed PMID: 11584966.
54. Spolverato G, Yakoob MY, Kim Y, et al. The impact of surgical
margin status on long-term outcome after resection for intrahepa-
tic cholangiocarcinoma. Ann Surg Oncol. 2015 Nov;22(12):4020–
4028. PubMed PMID: 25762481.
55. Konstadoulakis MM, Roayaie S, Gomatos IP, et al. Fifteen-year,
single-center experience with the surgical management of intrahe-
patic cholangiocarcinoma: operative results and long-term out-
come. Surgery. 2008 Mar;143(3):366–374. PubMed PMID: 18291258.
56. Shen WF, Zhong W, Xu F, et al. Clinicopathological and prognostic
analysis of 429 patients with intrahepatic cholangiocarcinoma.
World J Gastroenterol. 2009 Dec 21;15(47):5976–5982. PubMed
PMID: 20014463; PubMed Central PMCID: PMCPMC2795186.
57. Ali SM, Clark CJ, Zaydfudim VM, et al. Role of major vascular
resection in patients with intrahepatic cholangiocarcinoma. Ann
Surg Oncol. 2013 Jun;20(6):2023–2028. PubMed PMID: 23263702.
58. Reames BN, Ejaz A, Koerkamp BG, et al. Impact of major vascular
resection on outcomes and survival in patients with intrahepatic
cholangiocarcinoma: A multi-institutional analysis. J Surg Oncol.
2017 Aug;116(2):133–139. PubMed PMID: 28411373.
59. Tabrizian P, Jibara G, Hechtman JF, et al. Outcomes following
resection of intrahepatic cholangiocarcinoma. HPB (Oxford). 2015
Apr;17(4):344–351. PubMed PMID: 25395176; PubMed Central
PMCID: PMCPMC4368399.
60. Hyder O, Hatzaras I, Sotiropoulos GC, et al. Recurrence after opera-
tive management of intrahepatic cholangiocarcinoma. Surgery.
2013 Jun;153(6):811–818. PubMed PMID: 23499016; PubMed
Central PMCID: PMCPMC3980567.
61. Spolverato G, Kim Y, Alexandrescu S, et al. Management and out-
comes of patients with recurrent intrahepatic cholangiocarcinoma
following previous curative-intent surgical resection. Ann Surg
Oncol. 2016 Jan;23(1):235–243. PubMed PMID: 26059651.
62. Yamamoto M, Takasaki K, Otsubo T, et al. Recurrence after surgical
resection of intrahepatic cholangiocarcinoma. PubMed PMID:
11455472 J Hepatobiliary Pancreat Surg. 2001;82:154–157.
63. Doussot A, Gonen M, Wiggers JK, et al. Recurrence patterns and
disease-free survival after resection of intrahepatic cholangiocarci-
noma: preoperative and postoperative prognostic models. J Am
Coll Surg. 2016 Sep;223(3):493–505. e2. PubMed PMID: 27296525;
PubMed Central PMCID: PMCPMC5003652.
64. Ercolani G, Vetrone G, Grazi GL, et al. Intrahepatic cholangiocarci-
noma: primary liver resection and aggressive multimodal treatment
of recurrence significantly prolong survival. Ann Surg. 2010 Jul;252
(1):107–114. PubMed PMID: 20531002.
65. Ohtsuka M, Kimura F, Shimizu H, et al. Significance of repeated
resection for recurrent intrahepatic cholangiocarcinoma.
Hepatogastroenterology. 2009 Jan-Feb;56(89):1–5. PubMed PMID:
19453018.
66. Sulpice L, Rayar M, Boucher E, et al. Treatment of recurrent intra-
hepatic cholangiocarcinoma. Br J Surg. 2012 Dec;99(12):1711–1717.
PubMed PMID: 23132419.
67. Fu BS, Zhang T, Li H, et al. The role of liver transplantation for
intrahepatic cholangiocarcinoma: a single-center experience. Eur
Surg Res. 2011;47(4):218–221. PubMed PMID: 22041581. .
68. Sotiropoulos GC, Kaiser GM, Lang H, et al. Liver transplantation as a
primary indication for intrahepatic cholangiocarcinoma: a single-
center experience. Transplant Proc. 2008 Nov;40(9):3194–3195.
PubMed PMID: 19010231.
69. Casavilla FA, Marsh JW, Iwatsuki S, et al. Hepatic resection and
transplantation for peripheral cholangiocarcinoma. J Am Coll
Surg. 1997 Nov;185(5):429–436. PubMed PMID: 9358085; PubMed
Central PMCID: PMCPMC2958518.
70. Meyer CG, Penn I, James L. Liver transplantation for cholangiocar-
cinoma: results in 207 patients. Transplantation. 2000 Apr 27;69
(8):1633–1637. PubMed PMID: 10836374.
71. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for
280 patients with cholangiocarcinoma treated with liver
680 M. H. SQUIRES ET AL.
transplantation over an 18-year period. J Gastrointest Surg. 2008
Jan;12(1):117–122. PubMed PMID: 17963015.
72. Hong JC, Jones CM, Duffy JP, et al. Comparative analysis of resec-
tion and liver transplantation for intrahepatic and hilar cholangio-
carcinoma: a 24-year experience in a single center. Arch Surg. 2011
Jun;146(6):683–689. PubMed PMID: 21690444.
73. Sapisochin G, de Lope CR, Gastaca M, et al. Intrahepatic cholangio-
carcinoma or mixed hepatocellular-cholangiocarcinoma in patients
undergoing liver transplantation: a Spanish matched cohort multi-
center study. Ann Surg. 2014 May;259(5):944–952. PubMed PMID:
24441817.
74. Sapisochin G, Facciuto M, Rubbia-Brandt L, et al. Liver transplanta-
tion for “very early” intrahepatic cholangiocarcinoma: international
retrospective study supporting a prospective assessment.
Hepatology. 2016 Oct;64(4):1178–1188. PubMed PMID: 27481548.
75. Facciuto ME, Singh MK, Lubezky N, et al. Tumors with intrahepatic
bile duct differentiation in cirrhosis: implications on outcomes after
liver transplantation. Transplantation. 2015 Jan;99(1):151–157.
PubMed PMID: 25029385.
76. Takahashi K, Obeid J, Burmeister CS, et al. Intrahepatic cholangio-
carcinoma in the liver explant after liver transplantation: histologi-
cal differentiation and prognosis. Ann Transplant. 2016 Apr;12
(21):208–215. PubMed PMID: 27068242.
77. Buettner S, van Vugt JL, IJzermans JN, et al. Intrahepatic cholangio-
carcinoma: current perspectives. Onco Targets Ther. 2017;10:1131–
1142. PubMed PMID: 28260927; PubMed Central PMCID:
PMCPMC5328612. .
78. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine
versus gemcitabine for biliary tract cancer. N Engl J Med. 2010
Apr 8;362(14):1273–1281. PubMed PMID: 20375404.
• The ABC-02 trial established chemotherapy regimen of gemcita-
bine and cisplatin as standard of care for cholangiocarcinoma.
79. Kato A, Shimizu H, Ohtsuka M, et al. Surgical resection after down-
sizing chemotherapy for initially unresectable locally advanced
biliary tract cancer: a retrospective single-center study. Ann Surg
Oncol. 2013 Jan;20(1):318–324. PubMed PMID: 23149849.
80. Kato A, Shimizu H, Ohtsuka M, et al. Downsizing chemotherapy for
initially unresectable locally advanced biliary tract cancer patients
treated with gemcitabine plus cisplatin combination therapy fol-
lowed by radical surgery. Ann Surg Oncol. 2015 Dec;22(3):S1093–9.
Suppl. PubMed PMID: 26240009.
81. Buettner S, Koerkamp BG, Ejaz A, et al. The effect of preoperative
chemotherapy treatment in surgically treated intrahepatic cholan-
giocarcinoma patients-A multi-institutional analysis. J Surg Oncol.
2017 Mar;115(3):312–318. PubMed PMID: 28105651.
82. Hyder O, Marsh JW, Salem R, et al. Intra-arterial therapy for
advanced intrahepatic cholangiocarcinoma: a multi-institutional
analysis. Ann Surg Oncol. 2013 Nov;20(12):3779–3786. PubMed
PMID: 23846786.
83. Seidensticker R, Ricke J, Seidensticker M. Integration of chemoem-
bolization and radioembolization into multimodal treatment of
cholangiocarcinoma. Best Pract Res Clin Gastroenterol. 2015
Apr;29(2):319–332. PubMed PMID: 25966431.
84. Kuhlmann JB, Euringer W, Spangenberg HC, et al. Treatment of
unresectable cholangiocarcinoma: conventional transarterial che-
moembolization compared with drug eluting bead-transarterial
chemoembolization and systemic chemotherapy. Eur J
Gastroenterol Hepatol. 2012 Apr;24(4):437–443. PubMed PMID:
22261548.
85. Rayar M, Sulpice L, Edeline J, et al. Intra-arterial yttrium-90 radio-
embolization combined with systemic chemotherapy is a promis-
ing method for downstaging unresectable huge intrahepatic
cholangiocarcinoma to surgical treatment. Ann Surg Oncol. 2015
Sep;22(9):3102–3108. PubMed PMID: 25623598.
86. Cantore M, Mambrini A, Fiorentini G, et al. Phase II study of hepatic
intraarterial epirubicin and cisplatin, with systemic 5-fluorouracil in
patients with unresectable biliary tract tumors. Cancer. 2005 Apr
1;103(7):1402–1407. PubMed PMID: 15726542.
87. Mambrini A, Guglielmi A, Pacetti P, et al. Capecitabine plus hepatic
intra-arterial epirubicin and cisplatin in unresectable biliary cancer:
a phase II study. Anticancer Res. 2007 Jul–Aug;27(4C):3009–3013.
PubMed PMID: 17695488.
88. Inaba Y, Arai Y, Yamaura H, et al. Phase I/II study of hepatic arterial
infusion chemotherapy with gemcitabine in patients with unresect-
able intrahepatic cholangiocarcinoma (JIVROSG-0301). Am J Clin
Oncol. 2011 Feb;34(1):58–62. PubMed PMID: 20177362.
89. Jarnagin WR, Schwartz LH, Gultekin DH, et al. Regional chemother-
apy for unresectable primary liver cancer: results of a phase II
clinical trial and assessment of DCE-MRI as a biomarker of survival.
Ann Oncol. 2009 Sep;20(9):1589–1595. PubMed PMID: 19491285;
PubMed Central PMCID: PMCPMC2731015.
90. Ghiringhelli F, Lorgis V, Vincent J, et al. Hepatic arterial infusion
of gemcitabine plus oxaliplatin as second-line treatment for
locally advanced intrahepatic cholangiocarcinoma: preliminary
experience. Chemotherapy. 2013;59(5):354–360. PubMed PMID:
24821200.
91. Konstantinidis IT, Groot Koerkamp B, Do RK, et al. Unresectable
intrahepatic cholangiocarcinoma: systemic plus hepatic arterial
infusion chemotherapy is associated with longer survival in com-
parison with systemic chemotherapy alone. Cancer. 2016 Mar 1;122
(5):758–765. PubMed PMID: 26695839; PubMed Central PMCID:
PMCPMC4764409.
92. Horgan AM, Amir E, Walter T, et al. Adjuvant therapy in the treat-
ment of biliary tract cancer: a systematic review and meta-analysis.
J Clin Oncol. 2012 Jun 1;30(16):1934–1940. PubMed PMID:
22529261.
93. Reames BN, Bagante F, Ejaz A, et al. Impact of adjuvant chemother-
apy on survival in patients with intrahepatic cholangiocarcinoma: a
multi-institutional analysis. HPB (Oxford). 2017 Oct;19(10):901–909.
PubMed PMID: 28728891.
94. Schweitzer N, Weber T, Kirstein MM, et al. The effect of adjuvant
chemotherapy in patients with intrahepatic cholangiocarcinoma: a
matched pair analysis. J Cancer Res Clin Oncol. 2017 Jul;143
(7):1347–1355. PubMed PMID: 28314929.
95. Neoptolemos JP, Moore MJ, Cox TF, et al. Effect of adjuvant che-
motherapy with fluorouracil plus folinic acid or gemcitabine vs
observation on survival in patients with resected periampullary
adenocarcinoma: the ESPAC-3 periampullary cancer randomized
trial. JAMA. 2012 Jul 11;308(2):147–156. PubMed PMID: 22782416.
96. Edeline J, Bonnetain F, Phelip JM, et al. Gemox versus surveillance
following surgery of localized biliary tract cancer: results of the
PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial. J Clinical
Oncol. 2017;35(4):225. _suppl.
97. Primrose JN, Fox R, Palmer D, et al. Adjuvant capecitabine for
biliary tract cancer: the BILCAP randomized study. J Clin Oncol.
2017;35(suppl:abstr): 4006.
98. Stein A, Arnold D, Bridgewater J, et al. Adjuvant chemotherapy
with gemcitabine and cisplatin compared to observation after
curative intent resection of cholangiocarcinoma and muscle inva-
sive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multi-
disciplinary, multinational phase III trial. BMC Cancer. 2015 Jul
31;15:564. PubMed PMID: 26228433; PubMed Central PMCID:
PMCPMC4520064.
99. Jia AY, Wu JX, Zhao YT, et al. Intensity-modulated radiotherapy
following null-margin resection is associated with improved survi-
val in the treatment of intrahepatic cholangiocarcinoma. J
Gastrointest Oncol. 2015 Apr;6(2):126–133. PubMed PMID:
25830032; PubMed Central PMCID: PMCPMC4311098.
100. Song S, Kim K, Chie EK, et al. Locoregional recurrence after curative
intent resection for intrahepatic cholangiocarcinoma: implications
for adjuvant radiotherapy. Clin Transl Oncol. 2015 Oct;17(10):825–
829. PubMed PMID: 26041722.
101. Gil E, Joh JW, Park HC, et al. Predictors and patterns of recurrence
after curative liver resection in intrahepatic cholangiocarcinoma,
for application of postoperative radiotherapy: a retrospective
study. World J Surg Oncol. 2015 Jul 29;13:227. PubMed PMID:
26216347; PubMed Central PMCID: PMCPMC4517555.

102. Shinohara ET, Mitra N, Guo M, et al. Radiation therapy is asso-
ciated with improved survival in the adjuvant and definitive
treatment of intrahepatic cholangiocarcinoma. Int J Radiat
Oncol Biol Phys. 2008 Dec 1;72(5):1495–1501. PubMed PMID:
18472359.
103. Shen ZT, Zhou H, Li AM, et al. Clinical outcomes and prognostic
factors of stereotactic body radiation therapy for intrahepatic
EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 681
cholangiocarcinoma. Oncotarget. 2017 Nov 7;8(55):93541–93550.
PubMed PMID: 29212171; PubMed Central PMCID: PMCPMC
5706817.
104. Shen WF, Zhong W, Liu Q, et al. Adjuvant transcatheter arterial che-
moembolization for intrahepatic cholangiocarcinoma after curative
surgery: retrospective control study. World J Surg. 2011 Sep;35
(9):2083–2091. PubMed PMID: 21698503.