Gastrointest Interv 2017;6:94–104

Gastrointestinal Intervention
journal homepage: www.gi-intervention.org

Review Article
Comprehensive management of cholangiocarcinoma:
Part II. Treatment
Charilaos Papafragkakis, Jeffrey H. Lee*

A B S T R A C T

Cholangioarcinoma is a rare but dreadful malignancy which poses much difficulties in the management. If detected early with only localized disease,
curative resection is possible. However, most patients present in the late stages of the disease, which are managed with endoscopic biliary drainage
and/or chemoradiation. Liver transplantation offers a possibility for cure in the distal and the perihilar tumors for selected candidates. Local treat-
ments, such as hepatic artery-based therapies, brachytherapy, and photodynamic therapy, may offer some benefit in cases of the advanced disease.
In this review, we will assess the role of preoperative biliary drainage, how best to drain biliary obstruction, and the intricate details of various treat-
ments that are currently available.
Copyright © 2017, Society of Gastrointestinal Intervention. All rights reserved.

Keywords: Cholangiocarcinoma; Cholestasis; Endoscopic ultrasonography; Liver transplantation; Self expandable metal stents

Management of Cholangiocarcinoma eration rates compared to non-drained cases.4,5 The prospective

Preoperative biliary drainage
Preoperative biliary drainage (PBD) is achieved with endo-
scopic or percutaneous approach. The topic is controversial and
the review of the literature revealed conflicting results. PBD of
the future remnant hepatic lobe is supposed to decrease hepatic
dysfunction and liver failure postoperatively.1 The meta-analysis
found no difference in mortality between patients with and with-
out PBD and the authors advised that such procedure should not
be performed routinely.2 Another meta-analysis of almost 5,000
patients with distal obstruction (425 with distal cholangiocarci-
noma [DCC]) did not find any evidence that PBD (without distin-
guishing between endoscopic or percutaneous approach) increases
morbidity or mortality. However it was associated with significant
bacterial infection of the bile and possibly adverse outcomes after
surgery.3 Other studies showed that PBD reduced jaundice, which
positively affected outcomes, but not survival, and that it might
be associated with more intraoperative blood loss, but less reop-
randomized study of almost 200 patients with cancer of the head
of the pancreas demonstrated that PBD was associated with more
non-surgical adverse events compared to those managed only
with surgery (46% vs 2%, respectively). Surgical adverse events
were also more in the PBD group (47% vs 37%). The high inci-
dence of cholangitis in those treated with PBD may be associated
with the long lag time between PBD and surgery (5 weeks) and
the high occlusion rate of plastic stents (PSs) (15%), prompting
other authors to suggest that use of short, self-expandable metal
stents (SEMS) may result in better outcomes for distal bile duct
strictures. In accordance with other studies, there was no effect
of PBD on mortality.6,7 In perihilar cholangiocarcinoma (PCC),
the systematic review of 700 patients with and without PBD sug-
gested that there is higher incidence of postoperative infections
(18%–52% vs 0%–27%) and overall adverse events (36%–100%
vs 29%–72%) in the PBD compared to the non-PBD group. There
was no difference in mortality in the two groups.8 Other studies
favor the use of PBD in the preoperative management of PCC. The
study of 350 patients demonstrated reduction in in-hospital mor-

Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Received December 8, 2015; Accepted January 17, 2016
* Corresponding author. Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Unit 1466, 1515 Holcombe Blvd.,
Houston, TX 77030, USA.
E-mail address: jefflee@mdanderson.org (J.H. Lee).
This article is the second part of a two-part article. The first part “Comprehensive management of cholangiocarcinoma: Part I. Diagnosis” can be found under https://doi.org/10.18528/
gii1500341.

pISSN 2213-1795 eISSN 2213-1809 https://doi.org/10.18528/gii1500342

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0)
which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Charilaos Papafragkakis and Jeffrey H. Lee / Comprehensive management of cholangiocarcinoma
tality in those treated with endoscopic biliary drainage (EBD) or
percutaneous biliary drainage (PTBD).9 Results from a multicenter
European retrospective study demonstrated no effect of EBD or
PTBD on overall post-surgical mortality; however, there was a
suggestion that mortality was higher in patients with PBD and
with left compared to right hepatectomy, likely due to more chol-
angitis episodes in the left hepatectomy group.10
Other studies assessed the use of endoscopic nasobiliary
drainage (ENBD) in patients with PCC. The study of 116 patients
showed that ENBD was associated with a low rate of pancreatitis
and cholangitis.11 Another study compared EBD, ENBD, and PTBD
in 128 patients and concluded that all three approaches did not
differ significantly in morbidity and mortality.12 However, a high-
er incidence of cholangitis was observed with EBD (60% vs 10%
with ENBD and 2% with PTBD). Nevertheless, PTBD had 6% can-
cer dissemination and 8% portal vein (PV) injury rates.12 PBD has
been shown to benefit patients with < 30% functional liver rem-
nant (FLR) as shown in a study of 60 patients that were managed
with PTBD and EBD. The absence of PBD in patients with FLR <
30% was associated with a higher incidence of liver dysfunction (as
measured by persistent rise in bilirubin) and death.13
In conclusion, it seems that for DCC, PBD has to be applied
on a case-by-case basis. If surgery is planned within 1 to 2 weeks,
PBD is usually not recommended. If surgery is delayed more than
3 weeks, then PBD should be considered.14 Strong debate still con-
tinues whether PBD should be used in proximal biliary cancers.
However, PBD would provide benefits in cases such as usage as a
bridge to surgery, treatment of cholangitis, correction of malnu-
trition, correction of coagulopathy, treatment of jaundice-induced
liver or kidney dysfunction, induction of hypertrophy of the post-
surgical liver and plan for neo-adjuvant therapy. Nonetheless,
potential disadvantages of PBD such as tumor seeding, injury of
vasculature, perforation and increased difficulties during surgery
(e.g., in bilioenteral anastomosis after natural downsizing of the
bile duct following stent removal) should be also considered
(Table 1).12,15–17
Endoscopic ultrasound-guided biliary drainage
Occasionally, endoscopic retrograde cholangiopancreatog-
raphy (ERCP) is unsuccessful and biliary drainage remains to be
achieved by PTBD or surgery. A new approach with endoscopic
ultrasound (EUS)-guided biliary drainage (EGBD) provides a po-
tentially useful alternative. With this technique, a fistula is created
between the duct proximal to the obstruction and the duode-
Table 1 Advantages and Disadvantages of Preoperative Biliary Drainage Approaches12,15–17
PTBD
Advantages Ability to drain the entire liver
Performance of complete cholangiography
Easily palpated during surgery
May facilitate postoperative bilio-enteric drain
Disadvantages Displacement
Obstruction and need for repeat procedure
Tumor seeding
Pain
Leaks
Increased psychological burden
Discomfort
Abscesses
Fluid and electrolyte loss
PTBD, percutaneous transhepatic biliary drainage; ENBD, endoscopic nasobiliary drainage; EBD, endoscopic biliary drainage.
95
num or the stomach. Currently there are no studies with regard
to EGBD specifically in the setting of PBD.18 The recent study
of EGBD in 101 patients showed that the procedure had very
high success rate (> 92% overall) and there was no significant
difference in efficacy among different approaches.19 There was,
however, 12% rate of adverse events, mostly in the hepatogas-
trostomy approach, and notable procedure-associated mortality (6
deaths).19 The technical success of EGBD was found to be inferior
to the PTBD (86% vs 100%, respectively) for distal malignant bili-
ary strictures. PTBD, however, was associated with more adverse
events, such as bile leak and hemobilia and increased need for re-
intervention.20 Another multicenter retrospective study in 240 pa-
tients showed that EGBD had high success rate in both intra- and
extrahepatic approach, but was associated with a high incidence
of adverse events, mainly bleeding (11%) and bile leak (10%).21
The role of stents in unresectable cholangiocarcinoma
Endoscopic biliary sphincterotomy is not required prior to PS
or SEMS insertions and this practice is not associated with de-
creased stent patency or increased risk of pancreatitis.22,23 Accord-
ing to the 2015 American Society of Gastrointestinal Endoscopy
guidelines, antibiotics to cover gram negatives and enterococci
should be administered prior to ERCP with stent placement when
incomplete drainage is anticipated. Because episodes of acute
cholecystitis after SEMS have been reported to be 1.9%–12%,
prophylactic antibiotics may have a role, but this requires further
studying.24,25 Endoscopy societies have specific recommendations
for placement of PS or SEMS with regard to patient’s predicted
survival. The European Society for Gastrointestinal Endoscopy
and the Asia-Pacific Working Group on hepatobiliary cancers
recommend SEMS if predicted survival is more than 3 months.22,26
Stents for perihilar cholangiocarcinoma
The use of PS in biliary strictures was studied retrospectively
in 70 patients (31 with PCC). Use of two stents for complete drain-
age of complex hilar strictures was associated with longer sur-
vival compared to drainage with only one stent (176 vs 119 days).
However, PS was associated with 27% incidence of occlusion due
to sludge and subsequent cholangitis and 8% dislocation rate.27
The 2013 Asia Pacific consensus for hilar cholangiocarcinoma (CC)
recommends adequate drainage of ≥ 50% of the liver. This may
be achieved by unilateral or bilateral stenting.28 For Bismouth-
Corlette (BC) lesions III and IV, it has been shown that percutane-
ously placed SEMS are associated with a higher technical success
ENBD EBD
Less invasive than PTBD Least invasive
Easy to replace Likely better psychological impact
Less discomfort
Frequent displacement Cholangitis
Discomfort Pancreatitis
Inability for bilateral drainage Surgical difficulties
Fluid and electrolyte loss Difficulty to perform cholangiography
96 Gastrointestinal Intervention 2017 6(2), 94–104
rate than endoscopic SEMS (93% vs 77%).29 Mukai and colleagues
demonstrated that SEMS have significantly better patency rate
than PS at 6-month follow-up (80% vs 20%) and remained patent
at patient’s death in 60% of the cases, compared to 30% with PS.
The main reason for occlusion was sludge and tumor ingrowth for
PS and SEMS, respectively.30
Many authors have argued in favor of bilateral stenting. A
study of 46 patients demonstrated significantly longer patency in
bilateral compared to unilateral stenting (488 vs 210 days, 23%
vs 59% occlusion rates, respectively).31 Another study on PS and
SEMS showed that the patency of bilateral SEMS and PS was
better than unilateral approach (29 vs 24 weeks for SEMS and 18
vs 17 weeks for PS).32 That study also showed significantly more
occlusion rates of PS (52%) compared to SEMS (24%), longer pa-
tency of SEMS, and more incidence of cholangitis with PS use.32
Bilateral stenting can be achieved by stent-in-stent (SIS) or side-
by-side (SBS) techniques. The SIS and SBS approaches have over-
all functional success of almost 100%, technical success of 80%–
100% and 73%–100%, revision rates 6%–100% and 3%–45%;
and patency on average 140–217 days and 130–169 days, respec-
tively.33 Very high technical and functional success rates and easy
re-intervention were also demonstrated in a study of large cell SIS
approach in a single session. The occlusion rate was 42%, mainly
due to sludge and tumor ingrowth.34 Simultaneous deployment
of SBS or SIS with the 6 Fr delivery system showed similar suc-
cess rates, occlusion rate of 25% and re-intervention rate of 50%
in about 3 months of follow-up. It is suggested that SBS or SIS
should be chosen on a case-by-case basis, probably favoring SIS
placement in primary sclerosing cholangitis (PSC) due to narrower
ducts.35 The concept of placing bilateral stents for complete drain-
age of the obstructed hilum has been challenged in many studies.
In the prospective study of 157 patients showed that unilateral
stent placement was more technically feasible than bilateral (87%
vs 77%) and was associated with less cholangitis (9% vs 17%),
probably due to less contrast injection and wire manipulation of
the unstented duct.36 A recent study did not find benefit in us-
ing bilateral SEMS or PS in perihilar lesions. The authors found
73% and 50% incidences of occlusion in bilateral PS and bilat-
eral SEMS respectively.30 Another study showed higher incidence
of liver abscesses with bilateral compared to unilateral stenting
(18% vs 1.5%).37 A recent meta-analysis did not find benefit of
bilateral stenting compared to unilateral regarding occlusion and
stent failures.38 Nevertheless, in cases of cholangitis of the und-
rained lobe, persistent jaundice after unilateral stent placement,
or when brachytherapy is anticipated, bilateral stenting should be
implemented.33,39 De Palma et al40 conducted a prospective study
in 61 patients with BC type II, III, and IV lesions using uncovered
SEMS and showed that successful drainage was achieved in 97%
of the cases. The median stent patency was 169 days, and most
occlusion occurred after one month following the stent placement
(23%).
Many authors have suggested that use of covered stents for
hilar strictures may be associated with a high likelihood of chol-
angitis. The retrospective study of 36 patients with PCC showed
that the use of uncovered SEMS was associated with median pa-
tency of 169 days and occlusion rates of 9% within a month and
23% after one month of stent placement.41
In order to overcome some of the technical difficulties of SBS
SEMS for bilateral drainage, a Y-configuration stent with wide
mesh design was developed. In a pilot study in 10 patients the Y-
stent demonstrated median patency of 217 days and occlusion
rate of 25% without any early adverse events.42 Multiple studies
have shown excellent technical and clinical success rates with
the use of Y-stents ranging between 87% and 100%. Stent oc-
clusion rates are usually between 25% and 39%.43–46 Cholecystitis
(28% late and 9% early) and cholangitis (16% late and 6% early)
are reported complications of Y-stents.47 Another stent without
wide mesh in the middle was evaluated in 35 patients and dem-
onstrated 94% placement success rate, mean patency of 150 days
and very low rate of cholangitis (6%). However, recent compari-
son of stents with large and small cells did not demonstrate any
differences in tumor ingrowth or overgrowth, stent occlusion, or
success in drainage.47,48 With the SIS technique, multiple stents
to drain three or 4 ducts simultaneously can be placed. This ap-
proach has been associated with better patency and survival com-
pared to one or two-branch drainage to control disease. Occlusion
rates range from 33% to 68%.49–51
Stents for distal cholangiocarcinoma
The role of stents for DCC is more clearly established. SEMS
have larger diameter than PS and subsequently have longer pa-
tency. The 30 Fr covered SEMS were compared with 10 Fr PS
in a prospective study of 100 patients (9 with CC). The patency
was longer in the covered SEMS compared to the PS (3.8 and
1.8 months respectively). The reason of the short patency in that
study was attributed to short survival (4.5 months). Sludge was
the primary reason for PS occlusion.52 Covered and uncovered
SEMS have been compared in multiple studies. Overall there is
significantly higher rate of stent occlusion with uncovered stents
mainly due to tumor ingrowth, ranging between 21% and 38%
compared to 14%–19% with covered stents where occlusion oc-
curs usually due to tumor overgrowth. The rate of stent migration
is higher with covered stents, between 3% and 36%, compared
to 0%–2% with uncovered stents. Pancreatitis is more common
with covered stents (6% vs 1%) and there seems to be no associa-
tion of stent type and incidence of cholecystitis.53–57 The recent
multicenter study of fully covered SEMS with flared ends showed
excellent success rates, median patency of 328 days and very low
late adverse events, including 4 cases of SEMS migration. Remov-
ability of fully covered stents is acceptable. With an attention to
place the stent below the cystic duct, the incidence of cholecystitis
is very low (0.75%).58 SEMS are not associated with leak either
at the anastomosis or the surgical margins, and do not affect 30-
day mortality or length of stay.59,60 The recent meta-analysis of
2,000 patients with distal and proximal strictures demonstrated
that SEMS have lower early and late occlusion rates for both hilar
and distal lesions compared to PS. There was 13% therapeutic
failure with PS compared to 7% with SEMS and less need for re-
interventions with the latter. Cholangitis is more common with
PS than with SEMS (21% vs 8%). Stent migration is non-existent
with uncovered SEMS, 12% with partially covered and 6.5% with
PS.38 Placement of stents under EUS guidance with an antero-
grade approach (rendezvous) has been shown to be technically
(90%–100%) and clinically successful (80%–100%). Unsuccessful
cases may be due to inability to traverse the biliary stricture, pres-
ence of choledochocele, failed guidewire passage, or loss of scope
position. Adverse events have been documented in about 15% of
the cases. The EUS-guided anterograde or choledochoduodenal
approach was equally successful with the ERCP approach (94% vs
93%) with similar incidence of adverse events, except for pancre-
atitis, which was higher with ERCP (5% vs 0%).61–63
Surgery for cholangiocarcinoma
Intrahepatic cholangiocarcinoma
Surgery for intrahepatic cholangiocarcinoma (ICC) is usu-
 Charilaos Papafragkakis and Jeffrey H. Lee / Comprehensive management of cholangiocarcinoma
ally not indicated in tumors that invade the vasculature, multiple
tumors, bilobar disease, and metastases. Regional lymph node
(LN) involvement is not a contraindication for surgery.1 Child-
Pugh class B and C, Model for End Stage Liver Disease score > 9,
or portal hypertension are relative contraindications.64 There is
not enough data to suggest routine staging laparoscopy prior
to surgery.65 Preoperative PV embolization may be performed if
FLR is anticipated to be less than 30%.66 A recent multinational
study calculated the median survival after resection of ICC at 27
months.67 The survival rate after 1, 3, and 5 years was 75%, 39%,
and 25%, respectively. For American Joint Committee on Cancer
7th stage I and II lesions, the overall survival rate was 33% vs
16% for stages III and IV. Patients with and without LN metastasis
had 5-year survival rates of 11% and 35% respectively. Vascular
invasion decreased 5-year survival rate to from 28% to 16%. Tu-
mor size ≥ 5 cm in size was associated with a survival rate of 22%
at 5 years compared to that of 33% for tumors < 5 cm. Multiple
lesions were associated with a poor 5-year survival rate of 17%
compared to 29% in those patients with only one lesion. Interest-
ingly, the presence of cirrhosis did not influence survival. The
study calculated the conditional probability for survival in pa-
tients with ICC. Among other interesting data, it was shown that
patients who survived 3 years after index operation had 53% and
39% chance to be alive at 5 and 7 years respectively.67 Extended
liver resection is frequently attempted in order to resect the whole
tumor with R0 margins. Extended resections have been associated
with increased postoperative mortality and bile leaks compared to
more conservative resections.68,69 Readmission rate after surgery is
8%–10% and is higher in patients with preoperative jaundice and
major postsurgical adverse events such as bilomas, infections and
pleural effusions.70 Recurrence of ICC, even after R0 resections, is
high with the main site of recurrence being the liver.71,72
LN dissection and extended lymphadenectomy for ICC are a
topic of debate. For staging and exclusion of positive regional LN,
dissection may be indicated in patients with mass forming (MF)
type and mixed MF + periductal infiltrating (PI) type of ICC. LN
dissection confers no survival benefit if there are no intrahepatic
metastases or clinically negative LN.73,74 LN metastases has been
shown to be more common in MF, PI, or mixed types and less in
the intraductal growth type of ICC. Well differentiated tumors and
carbohydrate antigen 19-9 less than 135 U/mL seem to be associ-
ated with less frequent LN involvement.75 Patients with solitary,
small tumor (< 5 cm), and peripherally located tumors may not
require LN dissection.76
Perihilar cholangiocarcinoma
Surgery is the only way to achieve cure in PCC. Criteria for
unresectability have been proposed to be 1) distant metastases,
2) N2 stage, 3) bilateral proximal ductal involvement deep above
the second order ducts, 4) involvement of the common hepatic
artery (HA) or PV main trunk, 5) unilateral involvement of second
order ducts with contralateral vascular involvement, 6) lobar at-
rophy with contralateral involvement of second order ducts, and
7) lobar atrophy with involvement of contralateral PV or HA.77
The surgical approach for PCC has changed significantly over the
last decades. Currently the followed surgical approach is major
hepatectomy, caudate segmentectomy, and extrahepatic bile duct
resection.78,79 However, more radical surgeries with pancreatoduo-
denectomy (PD) have been proposed.80 Data from various studies
indicate that the median 5-year survival rate after resection of
PCC is about 11%–44% in studies done until 2010 and 14%–66%
thereafter, with surgical mortality 0%–23% and 0%–14%, respec-
tively. A recent meta-analysis found mortality after hepatectomy
97
for PCC of 3.7%.81,82 The 5-year survival, although longer, has not
been significantly different in R0 and R1 resections.83,84 Achieve-
ment of R0 and R1 surgical margins in non-metastatic disease has
been associated with median survival of 40–74 months and 9–24
months respectively in some studies. For R2 resection, the 3year
survival drops significantly (7%) and it is extremely poor for un-
resectable tumors (9% at 12 months).13,85–88 The goal of surgery is
to resect as much liver as possible in order to achieve R0 margins
and maintain more than 40% remnant liver after hepatectomy.
Therefore, preoperative PV embolization is the standard of care
before hepatectomy to minimize postoperative liver failure.82 It
has been shown that macroscopic tumor invasion of the PV im-
pacts survival.89 However, PV resection and reconstruction (PVR)
remain debatable. de Jong et al90 reported that PVR did not im-
prove the 5-year survival (28% vs 33% in those without PVR), but
was associated with an increased 30- and 90-day mortality. When
the tumor invades the PV or the HA, vascular resection with re-
construction can be attempted. The recent meta-analysis of 669
patients who underwent vascular resection for PCC demonstrated
higher mortality in those who had HA resection and reconstruc-
tion, with adverse events, such as thrombosis, hemorrhage, pseu-
doaneurysms, and anastomotic leaks.91 PVR is associated with
adverse events such as late anastomotic strictures, thrombosis,
and variceal bleeding.92 The right trisectionectomy combined with
PVR en bloc resection is a more radical approach performed in or-
der to avoid manipulation and spreading of the tumor. It has been
shown to be an independent predictor of survival and has been
associated with 1-, 3-, and 5-year survival rates of 87%, 70%,
and 59%, respectively.93 A controversial topic is the extent of re-
section in BC class I and II tumors. These tumors may still require
liver resection, but so far, there is no consensus in the literature in
regards to the most appropriate surgical approach. Some authors
recommend resection of extrahepatic duct, gallbladder, regional
lymphadenectomy, and Roux-en-Y hepaticojejunostomy.1,81
LN sampling is indicated for PCC staging, but its utility in
curative resection is still debatable.94 The incidence of LN involve-
ment in PCC ranges between 24% to more than 50%. Presence
of LN metastasis and the number of malignant LN are associated
with survival.95,96 A recent meta-analysis reported higher rate of
LN metastases in patients who underwent PVR compared to those
who did not, and significantly poorer overall survival.97
Distal cholangiocarcinoma
Due to its anatomic location, DCC may involve the head of
the pancreas or may be confused for pancreatic cancer.98 The sur-
gical procedure for DCC is PD. Tumors in the middle of the com-
mon bile duct may be managed with duct resection and Roux-en-
Y hepaticojejunostomy.99 Surgery is generally not recommended
in the presence of distant metastases, LN involvement beyond the
PV, HA and peripancreatic and celiac axis, more than 180 de-
grees involvement of the HA and superior mesenteric artery, and
if more than 2 cm of resection is anticipated in cases of portal
and superior mesenteric vein involvement.100 The role of stag-
ing laparoscopy for DCC is along the lines of ICC and PCC, and
has not been clearly established.99 Postoperative survival rate for
DCC has been reported between 18%–54%.101 Twenty-three per-
cent 5-year survival rate and median survival of 18 months were
reported in a series of 563 patients.102 Surgical mortality in large
published series has been less than 3%. Adverse outcomes after
PD are pancreatic leaks, delayed gastric emptying, abscesses, bile
leaks, sepsis, surgical site infections, and cardiopulmonary adverse
events.102,103 For very aggressive tumors involving the common
bile duct from the ampulla to the hepatic hilum, hepatectomy
98 Gastrointestinal Intervention 2017 6(2), 94–104

combined with PD has been suggested to be the recommended
approach. A mortality of 2.4% was reported in a recent series, but
the procedure was accompanied by a high morbidity.80 Palliative
biliary drainage for DCC and PCC is in favor of the endoscopic
approach, so surgical biliary bypass may be indicated only for pa-
tients who fail stenting.104
A recent multicenter study from Japan assessed the prognostic
impact of LN metastases in DCC.105 It was demonstrated that in
DCC, LNs were involved in 42% of the cases and the overall sur-
vival was 53%, 41%, and 28% at 3, 5, and 10 years, respectively.
The mean survival without LN involvement was 5.7 years vs 1.9
years for patients with positive LN. Four or more positive LNs
were associated with low survival (median, 1.3 years vs 2.2 years
with less than 4 LN).105 Factors that affect postoperative survival
are adjuvant chemotherapy, higher degree of differentiation, tu-
mor size < 2 cm, R0 margins, negative LN, and earlier stage of
disease.101,102
Liver transplantation
Intrahepatic cholangiocarcinoma
At this time, liver transplantation (LT) for ICC should be
considered within research trials along with neoadjuvant and/or
adjuvant therapy.65 Survival benefit of LT for ICC does not reach
the rate achieved for HCC and thus it is perceived with skepticism
among physicians.106 The 5-year survival rates for ICC managed
with LT have been reported to be suboptimal.106 A small study
showed 5-year survival of 33% and a larger one demonstrated
29% survival rate; however, the latter included large tumors (≤ 8
cm).107 In patients with cirrhosis and ICC, it has been shown that
LT is associated with poorer outcomes compared to LT for HCC
(5-year survival rate 51%). However, for uninodular and smaller
than 2 cm tumors (including mixed HCC–ICC), LT delivered much
better survival results (62%–73%).108,109
Perihilar cholangiocarcinoma
LT is indicated in patients with unresectable PCC after admin-
istration of neoadjuvant chemoradiotherapy. Staging laparoscopy
with LN sampling is performed to exclude LN malignant infiltra-
tion, which is an absolute contraindication for LT. Recent studies
have demonstrated good 5-year survival rates of around 65%–
82%.110–113 Surgical or percutaneous biopsy of the tumor is a con-
traindication for LT due to the risk of tumor seeding.114 In patients
with PSC, who are rarely optimal candidates for R0 resection due
to multifocal nature of the tumor, LT preceded by neoadjuvant
protocol is the treatment of choice. The decision of resection vs LT
is often challenging. Attempted surgical resection for PCC deems
a patient non-transplantable if LNs are positive intraoperatively or
R0 margins are not achieved postoperatively. Also, neoadjuvant
radiation protocol for LT induces liver damage to such extent
that probably precludes surgical resection.115 In patients with de
novo PCC or PCC arising in the setting of PSC, a specific protocol
should be followed. The recommended tumor size for LT should
be < 3 cm. If LN involvement is suspected by imaging, then EUS-
fine needle aspiration (EUS-FNA) should be performed. If LN
involvement is confirmed, the patient becomes ineligible for LT.
In the scenario of negative LN, neoadjuvant chemoradiotherapy is
administered followed by staging laparotomy to exclude progres-
sion of the disease and to proceed with either standard model for
end stage liver disease (MELD)-based deceased- or living-donor
LT.116 For patients with de novo PCC, the indications for LT vs
resection are less defined. A recent study showed that LT for de
novo BC type IV, borderline-resectable PCC was associated with
better survival outcomes compared to surgical resection.115
Neo-adjuvant and adjuvant chemotherapy for resectable
cholangiocarcinoma
The role of neo-adjuvant chemotherapy for CC is not estab-
lished and has an unclear benefit. Although solid evidence is lack-
ing, its use aims to downsize the tumor and increase the possibil-
ity of R0 resection, as shown with neo-adjuvant gemcitabine.117
Pathologic response has been rarely reported in the literature
with combinations of gemcitabine, cisplatin, doxorubicin, or

Table 2 National Comprehensive Cancer Network® (NCCN®) Hepatobiliary Cancers, Version 2.2016 Recommendations for the Management of Resectable
Intrahepatic and Extrahepatic Cholangiocarcinoma122
ICC ECC
R0 (for ICC) • O  bservation • Observation
R0, (–) regional LN or carcinoma in situ • Enrollment in trial • Fluoropyrimidine- or gemcitabine-based chemotherapy
at resection margins (for ECC) • Fluoropyrimidine- or gemcitabine-based • Fluoropyrimidine-based chemoradiation
chemotherapy • Enrollment in trial
R1 or (+) LN • Fluoropyrimidine- or gemcitabine-based • Fluoropyrimidine chemoradiotherapy followed by
chemotherapy additional fluoropyrimidine- or gemcitabine-based
• Fluoropyrimidine-based chemoradiation chemotherapy
• Fluoropyrimidine- or gemcitabine-based chemotherapy
for positive LN
R2 • Gemcitabine/cisplatin combination • Same as R1
(category 1)
• Fluoropyrimidine- or gemcitabine-based
chemotherapy
• Enrollment in trial
• Locoregional (category 2B)
• Supportive care
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancers V2.2016.122 © 2017 National
Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose
without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL
COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer
Network, Inc.
ICC, intrahepatic cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; R0, no residual tumor; LN, lymph node; R1, microscopic residual tumor; R2,
macroscopic residual tumor.
 Charilaos Papafragkakis and Jeffrey H. Lee / Comprehensive management of cholangiocarcinoma 99

5-fluorouracil (5-FU).118–120 Neo-adjuvant chemoradiotherapy for
advanced, resectable PCC and DCC has yielded good results with
improvement in 5-year survival compared to adjuvant therapy
alone.121
Adjuvant therapy for ICC is a matter of debate. It may be of
benefit in cases of lymphovascular and perineural invasion, posi-
tive surgical margins, LN involvement, and tumor size above 5
cm. According to the National Comprehensive Cancer Network®
(NCCN®) (hepatobiliary cancers version 2.2016), R0 resections
may not benefit from adjuvant therapy, so observation is an op-
tion and participation in a clinical trial is encouranged (Table 2).122
Adjuvant chemotherapy and radiotherapy for ICC have been
associated with statistically improved survival in patients with
postoperative positive LN and surgical margins, but not in those
with negative LN and surgical margins.123 A systematic review
found the combination of adjuvant chemotherapy and radio-
therapy was beneficial in the minority of the patients.124 A meta-
analysis demonstrated significant improvement in survival with
the adjuvant combination of chemotherapy and radiotherapy
than adjuvant radiotherapy or surgery alone.125 Recent data from
the National Cancer Database demonstrated that for patients with
R1/R2 resection, LN involvement, and T3–T4 stage of disease,
adjuvant chemotherapy improved the overall survival compared
to surgery alone (20 vs 11 months for LN positive patients, 21 vs
16 months for advanced stage, and 19.5 vs 12 months for R1/R2
resection, respectively).126 The meta-analysis of the prospective
ABC-02 and BT-22 trials comparing gemcitabine plus cisplatin
combination to gemcitabine monotherapy for biliary malignan-
cies, concluded that the combination significantly improved the
performance status and overall survival (11.6 vs 8 months).127 A
study from MD Anderson Cancer Center on patients with extra-
hepatic CC (ECC) demonstrated equal survival in R0N0 patients
treated with surgery alone and R1N1 patients treated with surgery
and chemoradiation, suggesting a benefit of adjuvant chemora-
diation in these patients.128 Adjuvant radiotherapy for ECC was
found to be well tolerated and to have a significant impact on
survival in a recent meta-anaysis.129 A phase II trial in postopera-
tive R0 and R1 patients with CC and gallbladder cancer showed
that capecitabine/gemcitabine followed by capecitabine and ra-
diotherapy was associated with an overall 2-year survival rate of
65% and disease-free survival rate of 51%.130
Chemotherapy for unresectable or metastatic disease
The NCCN recommends biliary drainage in patients with jaun-
dice if chemotherapy is planned (Table 3).122 A study of almost
400 patients with either unresectable or metastatic cholangiocarci-
noma treated with cisplatin and gemcitabine vs gemictabine alone
demonstrated a significant improvement in overall survival with
the combination therapy (12 and 8 months, respectively) and bet-
ter progression-free survival (8 vs 5 months).131 The recent pooled
analysis of 161 trials demonstrated that gemcitabine-platinum
therapy was associated with overall survival of 9.5 months and
time-to-tumor growth of 5 months. Addition of fluoropyrimidine
or gemcitabine based chemotherapy plus targeted therapy mainly
against epidermal growth factor receptor yielded even better out-
comes compared to gemcitabine platinum alone.132
Radiotherapy for unresectable cholangiocarcinoma
External-beam radiotherapy (EBRT) and brachytherapy are
used in patients with unresectable CC and may have a role in
relieving jaundice and pain.65 EBRT in unresectable ICC has been
shown to benefit the overall survival. In a retrospective study,
survival with radiotherapy was 7 months compared to 3 months
without any treatment, whereas surgery plus radiotherapy con-
ferred 11-month survival.133 EBRT may downsize the tumor, but
is associated with radiation injury to the adjacent organs.134 Two
studies of radiotherapy in unresectable ICC have demonstrated
a good local disease control and improved survival (13 months),
however associated with significant toxicity (liver failure, biliary
stenosis).135,136
Stereotactic body radiation (SBRT) delivers higher doses of
radiation in attempt to control tumor progression. Small stud-
ies have shown good local disease control and potential survival
benefit of SBRT alone or combined with EBRT for unresectable
and recurrent CC.136,137 To minimize the radiation-induced toxic-
ity, treatment with proton beams has been suggested. A recent
study demonstrated that after percutaneous implantation of fidu-
cial markers for localization, proton beam therapy was associated

Table 3 National Comprehensive Cancer Network® (NCCN®) Hepatobiliary Cancers, Version 2.2016 Recommendations for the Management of Unresectable and
Metastatic Intrahepatic (ICC) and Extrahepatic (ECC) Cholangiocarcinoma122
ICC ECC
Unresectable • Gemcitabine/cisplatin combination (category 1) • Biliary drainage, if indicated
• Fluoropyrimidine- or gemcitabine-based chemotherapy • Biopsy (if not transplantable)
• Fluoropyrimidine chemoradiotherapy • Gemcitabine/cisplatin combination (category 1)
• Enrollment in trial • Fluoropyrimidine- or gemcitabine-based chemotherapy
• Locoregional (category 2B) • Fluoropyrimidine chemoradiotherapy
• Supportive care • Enrollment in trial
• Supportive care
Metastatic • Gemcitabine/cisplatin combination (category 1) • Biliary drainage, if indicated
• Fluoropyrimidine- or gemcitabine-based chemotherapy • Biopsy
• Enrollment in trial • Gemcitabine/cisplatin combination (category 1)
• Locoregional • Fluoropyrimidine- or gemcitabine-based chemotherapy
• Supportive care • Enrollment in trial
• Supportive care
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancers V2.2016.122 © 2017 National
Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose
without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL
COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer
Network, Inc.
ICC, intrahepatic cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma.
100 Gastrointestinal Intervention 2017 6(2), 94–104
with an increased median survival compared to palliative care (27.5
vs 10 months), making it a potentially promising modality in the
management of locally advanced ICC.138
Brachytherapy is a form of radiotherapy that may be used
to treat postoperative local CC recurrence or as palliative treat-
ment in unresectable CC. Due to its local effect, it is less toxic to
the adjacent organs compared to other forms of radiotherapy. It
has been shown to improve the biliary stent patency and maybe
the overall survival.139 The combination of brachytherapy and
EBRT has been shown to be better than brachytherapy alone.140
Brachytherapy with iridium71 plus SEMS placement was shown
to improve survival from PCC by 90 days compared to SEMS
alone.141 A retrospective study demonstrated that brachytherapy,
with or without EBRT, was associated with significantly improved
survival (11 vs 4 months) compared to patients who received
no radiation for ICC and ECC (distal and hilar).142 Iodine125 seeds
along with biliary stents have been used for brachytherapy in pa-
tients with PCC, without causing obstruction of the ducts.143 The
recent study from Mayo Clinic showed that brachytherapy may
be administered safely via endoscopically placed nasobiliary tubes
in patients with unresectable CC.144
Hepatic artery-based therapies
Hepatic artery infusion (HAI) delivers the drug to the tumor
after implantation of a pump or port. Combination of weekly
pegylated interferon α-2b and intra-arterial infusion of 5-FU has
been shown to confer 1-year survival rate of 54% and median
survival of almost 15 months in a recent study.145 The recent
phase I/II study from Japan showed that gemcitabine infusion
was associated with tumor response of 8%, with neutropenia be-
ing the major side effect of this treatment. HAI has been reported
with 5-FU-based regimens and has shown effectiveness, but large
trials are lacking.146
Transarterial chemoembolization (TACE) is another approach
for unresectable ICC that targets the tumor with chemotherapeutic
drugs followed by embolization. It is usually contraindicated in
the setting of PV thrombosis.147 A large study comparing triple
combination of gemcitabine plus mitomycin C plus cisplatin to
either dual-drug or single-drug approach showed partial tumor
response of 9%, median survival of 13 months, but no statistical
difference among all drug combinations.148 A similar median sur-
vival was demonstrated with mitomycin C (11 months), compa-
rable to the survival of patients with positive LN or positive surgi-
cal margins.149 Treatment of unresectable ICC with doxorubicin-
eluting beads has shown 100% tumor response rate and median
survival of 13 months.150 TACE with irinotecan eluting beads has
shown a better progression-free survival and overall survival
compared to conventional TACE with mitomycin C, and compa-
rable results to gemcitabine/oxaliplatin chemotherapy (survival
12, 6, and 11 months, respectively), with no observed hematologi-
cal side effects.151
The retrospective analysis of 20 studies compared the arterial-
based therapies for ICC.152 It demonstrated that HAI was associ-
ated with the longest median overall survival compared to Yt-
trium-90 chemoembolization, TACE, and drug-eluting bead TACE
(23, 14, 12, and 12 months, respectively). Patients treated with
HAI responded better compared to the other modalities, however
with higher rate of adverse events.152 Radioembolization with Yt-
trium-90 microspheres is a form of transarterial brachytherapy for
ICC. The recent pooled analysis of current studies demonstrated
median survival of 15.5 months, partial tumor response in 28%,
and no progression in 54% of the cases at 3 months. Side effects
usually include abdominal pain, fever, and nausea, but ascites and
ulcers may occur as well.153 Yttrium-90 radioembolization with
systemic chemotherapy shows a promise in downstaging unre-
sectable ICC for attempted R0 resection. The largest study to-date
demonstrated successful R0 resections in all cases, mostly after
extended hepatectomy. In carefully selected patients with good
performance status and liver function, this might be a reasonable
approach.154
Radiofrequency ablation
Radiofrequency ablation (RFA) is a minimally invasive mo-
dality for inoperable CC. The recent meta-analysis of published
data on RFA in ICC demonstrated 1-, 3-, and 5-year survival rates
of 82%, 47%, and 24%, respectively. Ablated tumor size ranged
between 0.7 cm and 10 cm. Most of these tumors were treated
with ultrasound-guided RFA, which might be the reason for re-
sidual disease in cases of large-size primary tumor. In cases where
stereotactic RFA was used, even tumors as large as 10 cm were
effectively ablated without residual disease. Potential side effects
of RFA include liver abscesses, pleural effusions, and bleeding.
Subcapsular location and proximity of the tumor to major vessels
influence decision for RFA.155 RFA may be delivered percutane-
ously or endoscopically through a duodenoscope. It may be used
to reduce tumor burden in ECC and prolong patency of biliary
SEMS. A recent study showed that percutaneous RFA and SEMS
for DCC was associated with median SEMS patency of 149 days
and median survival of 181 days respectively.156 A retrospective
European study demonstrated median stent patency of 170 days
and overall survival of 11 months after RFA treatment in patients
with PCC. Hepatic infarct is a rare complication of RFA.157 An-
other study from the United States showed that endoscopically-
administered RFA improved stricture diameter, though more
pronounced for pancreatic cancer-related strictures.158 RFA every
3 months had a complete technical success and stent patency (with
PS or SEMS) of 66% at 1 month after RFA.158 The role of RFA in
clearing occluded SEMS needs further studying.159 ERCP-guided
RFA was compared with photodynamic therapy (PDT) in patients
with unresectable CC and was found to have an equal overall
survival, stent migration rate, incidence of abscesses, and need for
PTBD, but more episodes of stent occlusion and cholangitis than
PDT.160
Photodynamic therapy
PDT is a technique that uses laser irradiation after adminis-
tration of a photosensitizer. The patient needs to be aware that
exposure to sunlight may cause skin blisters, pruritus, and ery-
thema, and should avoid exposure 4–6 weeks after PDT.161 PDT
may be applied endoscopically or percutateously in patients with
unresectable PCC and DCC, patients with anticipated R1 or R2
resection, or poor surgical candidates. Due to limited tissue pen-
etration, deep lesions may not be appropriate for PDT. Nondrain-
ing liver segments should not be treated with PDT.162,163 PDT with
cholangioscopy is an attractive approach to deliver therapy pre-
cisely at the tumor site.164,165 Biliary stenting followed by PDT has
been shown to prolong survival compared to stenting alone (493
and 98 days, respectively).166 The study from the United States
demonstrated a similar survival benefit (16 vs 7 months).167 Stent
patency was also improved with use of PDT.168
 Charilaos Papafragkakis and Jeffrey H. Lee / Comprehensive management of cholangiocarcinoma
Conclusion
This is definitely an exciting time for CC. Currently, the di-
agnosis and management are challenging and the outcomes are
frequently disappointing for the patient and physician. Early
diagnosis and surgery may prove curative, but this is rarely the
case. Advances in imaging will certainly improve preoperative
staging. EUS-FNA is the best modality to assess the status of LN.
A combination of brush cytology, biopsy and fluorescence in
situ hybridization, along with current and new tumor markers,
such as CCA-CA, may increase the chances of early diagnosis.
Cholangioscopy and probe-based confocal laser endomicroscopy
(pCLE) may minimize the need for multiple ERCP, expedite surgi-
cal resections, and avoid unnecessary surgeries in patients with
biliary strictures. However, improvement in imaging quality and
better interobserver agreement in interpretation of pCLE findings
are needed. The utility of metal stents for preoperative or pallia-
tive drainage is rapidly evolving. Extended hepatectomies perhaps
deliver better outcomes but are challenging. LT is an option in se-
lected cases of PCC, and possibly for ICC as well. However, organ
shortage mandates a proper organ allocation, only to ideal candi-
dates. New chemotherapeutic drugs have shown a promise in neo-
or adjuvant chemotherapy. External or local radiotherapies, and
ablation techniques are constantly developing to improve survival
or downsize the tumor for possible curative resection.
Conflicts of Interest
No potential conflict of interest relevant to this article was re-
ported.
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