Intrahepatic

Cholangiocarcinoma

Diagnosis and Management

Timothy M. Pawlik
Jordan M. Cloyd
Mary Dillhoff
Editors

123
Intrahepatic Cholangiocarcinoma
Timothy M. Pawlik • Jordan M. Cloyd  
Mary Dillhoff
Editors

Intrahepatic
Cholangiocarcinoma
Diagnosis and Management
Editors
Timothy M. Pawlik Jordan M. Cloyd
Wexner Medical Center Wexner Medical Center
The Ohio State University The Ohio State University
Columbus, OH Columbus, OH
USA USA

Mary Dillhoff
Wexner Medical Center
The Ohio State University
Columbus, OH
USA

ISBN 978-3-030-22257-4    ISBN 978-3-030-22258-1 (eBook)

https://doi.org/10.1007/978-3-030-22258-1

© Springer Nature Switzerland AG 2019

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Preface

The up-to-date management of intrahepatic cholangiocarcinoma (ICC) is growing

increasingly complex as advances in basic and translational sciences highlight the
unique genetic and molecular features that distinguish it from other biliary tract
cancers. These advances called to attention the need for a single comprehensive
resource focused specifically on ICC. Intrahepatic Cholangiocarcinoma: Diagnosis
and Management was written to provide a comprehensive review of the epidemiol-
ogy, molecular pathogenesis, diagnosis, and treatment of ICC. The textbook brings
together an impressive group of international experts in cholangiocarcinoma
research and clinical care. The book was organized and written to aid the clinician’s
understanding of emerging research in cholangiocarcinoma and its application to
the clinical care of patients with ICC. Each chapter details the scientific evidence to
support clinical decisions that are needed to care for these complex patients. The
text is a concise but thorough guide to clinical care.
While the long-term outcomes of patients with cholangiocarcinoma have largely
remained poor, recent developments in translational sciences have offered hope for
treatment breakthroughs. Indeed, our understanding of the molecular pathogenesis
of ICC is rapidly evolving which should lead to the development of targeted thera-
pies and/or immunotherapies. For example, mutations in IDH1/2, BAP1, and
FGFR2 are common in ICC and make for attractive targets for novel therapies. The
wealth of basic science knowledge is being rapidly translated to the bedside into
novel clinical trials with new agents that interfere with these pathways. At the same
time, there has been a recent explosion of large prospective clinical trials evaluating
adjuvant therapies for patients with resected biliary tract cancers. These trials are
pivotal to understanding the optimal components of multimodality therapy. Although
the survival for patients with ICC remains poor, these advances bring hope for pro-
longing life and increasing quality of life.
Multidisciplinary care in ICC is crucial in improving outcomes in this deadly
disease, and this textbook is truly a collaborative transdisciplinary effort. Focused
chapters detail the epidemiology, diagnostic evaluation, as well as staging and prog-
nosis of this disease. In addition to dedicated chapters on surgical management of
ICC, a broad emphasis on locoregional therapies, including percutaneous ablation

v
vi Preface

and transarterial therapies, is included. An up-to-date overview of the molecular

pathogenesis and pathological assessment of ICC is detailed prior to chapters focus-
ing on systemic chemotherapy and emerging novel therapy options. Our sincere
appreciation is owed to the authors for their contributions not only to this textbook
but also to the science, advancement of research, and improvement of care for
patients with cholangiocarcinoma. We hope that this textbook is not only an invalu-
able resource for many as they seek to provide the best multidisciplinary cancer care
to patients with ICC but also an opportunity to identify new avenues of scientific
discovery that lead to significant advances in the diagnosis and management of ICC.

Columbus, OH, USA  Timothy M. Pawlik, MD, MPH, MTS, PhD, FACS, FRACS
 Jordan M. Cloyd, MD
 Mary Dillhoff, MD, MS
Contents

1 Epidemiology and Risk Factors��������������������������������������������������������������    1

Riham Katkhuda and Yun Shin Chun
2 Clinical Presentation and Diagnosis������������������������������������������������������   11
Arezou Abbasi, Amir A. Rahnemai-Azar,
Sean M. Ronnekleiv-Kelly, Daniel E. Abbott, and Sharon M. Weber
3 Staging and Prognosis������������������������������������������������������������������������������   21
Janelle F. Rekman and Flavio G. Rocha
4 Imaging ����������������������������������������������������������������������������������������������������   53
Pegah Khoshpouri, Timothy M. Pawlik, and Ihab R. Kamel
5 Surgical Treatment����������������������������������������������������������������������������������   67
Georgios Antonios Margonis and George A. Poultsides
6 Management of the Nodal Basin������������������������������������������������������������   85
Alfredo Guglielmi, Fabio Bagante, Andrea Ruzzenente,
Tommaso Campagnaro, Simone Conci, and Calogero Iacono
7 Pathologic Assessment ����������������������������������������������������������������������������   95
Benjamin J. Swanson
8 Systemic Therapy������������������������������������������������������������������������������������ 107
Ning Jin and Laith Abushahin
9 Percutaneous Ablation���������������������������������������������������������������������������� 123
Guojun Qian, Jinglei Zhang, and Feng Shen
10 Transarterial Therapies�������������������������������������������������������������������������� 135
Susan Shamimi-Noori and Michael C. Soulen
11 Radiotherapy�������������������������������������������������������������������������������������������� 151
Florence K. Keane and Theodore S. Hong

vii
viii Contents

12 Molecular Pathogenesis: From Inflammation and Cholestasis

to a Microenvironment-Driven Tumor�������������������������������������������������� 167
Eleonora Milani, Mario Strazzabosco, Luca Fabris,
and Massimiliano Cadamuro
13 Clinical Trials and Novel/Emerging Treatment������������������������������������ 183
Jonathan D. Mizrahi, Reham Abdel-Wahab, and Milind Javle
Index������������������������������������������������������������������������������������������������������������������ 209
Contributors

Arezou Abbasi, MD Department of Surgery, University of Washington Medical

Center, Seattle, WA, USA
Daniel E. Abbott, MD, FACS Department of Surgery, Division of Surgical
Oncology, University of Wisconsin School of Medicine and Public Health,
Madison, WI, USA
Reham Abdel-Wahab, MD, PhD Department of Gastrointestinal Medical
Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Clinical Oncology Department, Faculty of Medicine, Assiut University, Asyut, Egypt
Laith Abushahin, MD Division of Medical Oncology, Department of Internal
Medicine, Columbus, OH, USA
Department of Oncology, The Ohio State University Wexner Medical Center,
Columbus, OH, USA
Fabio Bagante, MD Department of Surgery, University of Verona, Verona, Italy
Massimiliano Cadamuro, PhD Department of Molecular Medicine, University of
Padua, Padua, Italy
International Center for Digestive Health (ICDH), University of Milano-Bicocca,
Milano, Italy
Tommaso Campagnaro, MD, PhD Department of Surgery, University of Verona,
Verona, Italy
Yun Shin Chun, MD Department of Surgical Oncology, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Simone Conci, MD, PhD Department of Surgery, University of Verona,
Verona, Italy

ix
x Contributors

Luca Fabris, MD, PhD Department of Molecular Medicine, University of Padua,

Padua, Italy
International Center for Digestive Health (ICDH), University of Milano-Bicocca,
Milano, Italy
Section of Digestive Diseases, Department of Internal Medicine, Yale University,
New Haven, CT, USA
Alfredo Guglielmi, MD Department of Surgery, University of Verona, Verona, Italy
Theodore S. Hong, MD Department of Radiation Oncology, Massachusetts
General Hospital, Boston, MA, USA
Calogero Iacono, MD Department of Surgery, University of Verona, Verona, Italy
Milind Javle, MD Department of Gastrointestinal Medical Oncology, The
University of Texas MD Anderson Cancer Center, Houston, TX, USA
Ning Jin, MD, MS Department of Oncology, The Ohio State University Wexner
Medical Center, Columbus, OH, USA
Ihab R. Kamel, MD, PhD Russell H. Morgan Department of Radiology and
Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA
Riham Katkhuda, MD Department of Molecular Pathology, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA
Florence K. Keane, MD Department of Radiation Oncology, Massachusetts
General Hospital, Boston, MA, USA
Pegah Khoshpouri, MD Russell H. Morgan Department of Radiology and
Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA
Georgios Antonios Margonis, MD, PhD John L. Cameron Division of Pancreatic
and Hepatobiliary Surgery, Department of Surgery, The Johns Hopkins Hospital,
Baltimore, MD, USA
Eleonora Milani, MD Department of Molecular Medicine, University of Padua,
Padua, Italy
Jonathan D. Mizrahi, MD Division of Cancer Medicine, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Timothy M. Pawlik, MD, MPH, MTS, PhD, FACS, FRACS Wexner Medical
Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
George A. Poultsides, MD, MS, FACS Department of Surgery, Stanford
University Hospital, Stanford, CA, USA
Guojun Qian, MD Department of Ultrasound Interventional Therapy, Eastern
Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
Contributors xi

Amir A. Rahnemai-Azar, MD Department of Surgery, Division of Surgical

Oncology, University of Wisconsin School of Medicine and Public Health, Madison,
WI, USA
Janelle F. Rekman, MD, MAEd, FRCSC Section of General, Thoracic and
Vascular Surgery, Virginia Mason Medical Center, Seattle, WA, USA
Flavio G. Rocha, MD Section of General, Thoracic and Vascular Surgery, Virginia
Mason Medical Center, Seattle, WA, USA
Sean M. Ronnekleiv-Kelly, MD Department of Surgery, Division of Surgical
Oncology, University of Wisconsin School of Medicine and Public Health, Madison,
WI, USA
Andrea Ruzzenente, MD, PhD Department of Surgery, University of Verona,
Verona, Italy
Susan Shamimi-Noori, MD Division of Interventional Radiology, Department of
Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
Feng Shen, MD Department of Hepatic Surgery, Eastern Hepatobiliary Surgery
Hospital, Naval Medical University, Shanghai, China
Michael C. Soulen, MD Department of Radiology, Abramson Cancer Center,
University of Pennsylvania, Philadelphia, PA, USA
Division of Interventional Radiology, Department of Radiology, Hospital of the
University of Pennsylvania, Philadelphia, PA, USA
Mario Strazzabosco, MD, PhD International Center for Digestive Health (ICDH),
University of Milano-Bicocca, Milano, Italy
Section of Digestive Diseases, Department of Internal Medicine, Yale University,
New Haven, CT, USA
Benjamin J. Swanson, MD, PhD Department of Pathology and Microbiology,
University of Nebraska Medical Center, Omaha, NE, USA
Sharon M. Weber, MD Department of Surgery, Division of Surgical Oncology,
University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Jinglei Zhang, MMed Department of Ultrasound Interventional Therapy, Eastern
Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
Chapter 1
Epidemiology and Risk Factors

Riham Katkhuda and Yun Shin Chun

Introduction

Cholangiocarcinoma arises from the epithelial lining of the intrahepatic or extrahe-

patic biliary tract. In the United States (USA), extrahepatic bile duct cancers located
in the perihilar and distal bile duct account for 50–60% and 20–30% of all cholan-
giocarcinomas, respectively. Intrahepatic cholangiocarcinoma comprises 20% of all
cholangiocarcinomas and is the second most common primary liver cancer, follow-
ing hepatocellular carcinoma [1, 2]. The incidence of intrahepatic cholangiocarci-
noma is rising, partly due to improved diagnosis, and is highly dependent upon
geographic location. In the USA, approximately 5000 to 8000 patients are affected
with intrahepatic cholangiocarcinoma annually [2]. In contrast, the prevalence is
tenfold higher in Southeast Asia, due to endemic liver fluke infection [3].

Epidemiology

In the USA, the incidence of intrahepatic cholangiocarcinoma parallels advanc-

ing age, with a progressive increase starting in the sixth decade of life. The annual
age-­adjusted incidence of intrahepatic cholangiocarcinoma is 0.7–1.5 cases per
100,000 population [2]. Worldwide, there is variation in incidence rates related to

R. Katkhuda
Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center,
Houston, TX, USA
e-mail: [email protected]
Y. S. Chun (*)
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center,
Houston, TX, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 1

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_1
 2 R. Katkhuda and Y. S. Chun

risk factors. The highest recorded incidence is in Thailand because of endemic

liver fluke infection, leading to chronic injury and inflammation of the bile ducts.
In Thailand, the age-adjusted incidence rate is greater than 80 per 100,000
­population [4].
Several studies have reported a rising global incidence of intrahepatic cholan-
giocarcinoma and corresponding increased mortality. In England and Wales,
from 1968 to 1996, Taylor-Robinson et al. reported a 15-fold increase in age-
adjusted death rate from intrahepatic cholangiocarcinoma per 100,000 popula-
tion aged 45 years and older [5]. The age-adjusted incidence rate for men in
England and Wales rose from 0.11 per 100,000 population in 1971–1973 to
1.33 in 1999–2001; the rate in women also rose from 0.09 to 1.06 [6]. A study by
Patel et al., based on the Surveillance, Epidemiology, and End Results (SEER)
database in the USA, reported a rise in age-adjusted death rate from 0.07 per
100,000 in 1973 to 0.69 in 1997 (Fig. 1.1) [7]. Another SEER analysis by Shaib
et al. found that age-adjusted incidence rates rose from 0.32 in 1975–1979 to
0.85 in 1995–1999, reflecting a 165% increase [8]. Men had higher age-adjusted
incidence rates than women.
Although the reported increasing incidence of intrahepatic cholangiocarcinoma
may reflect a true rise in the disease, it may also be attributable to improved diagno-
sis and coding misclassification. The International Classification of Disease for

Patel et al.
Age-adjusted incidence rate per 100,000

1
Shaib et al.
Khan et al.
0.8

0.6

0.4

0.2

0
74 79 84 89 94 99 04 08
-19 -19 -19 -19 -19 -19 -2
0
-20
71 75 80 85 90 95 00 05
19 19 19 19 19 19 20 20

Years

Fig. 1.1 Trends in age-adjusted incidence rates of intrahepatic cholangiocarcinoma per 100,000
population in the USA according to 3 analyses of the Surveillance, Epidemiology, and End Results
(SEER) database
1 Epidemiology and Risk Factors 3

Oncology (ICD-O) editions are revised every few years and adopted by countries
at different times. ICD-O comprises 2 coding systems to describe a tumor: a
­topographical code based on anatomic site and a morphological code based upon
histology. The term “Klatskin tumor” is an eponym for perihilar cholangiocarci-
noma, named after an American physician who described unique features of chol-
angiocarcinoma at the confluence of the right and left hepatic ducts. The second
edition of the ICD-O designated a unique morphological code for Klatskin tumors
which was cross-referenced to the topographical code for intrahepatic cholangio-
carcinoma. The third edition of the ICD-O cross-referenced Klatskin tumors to
either intra- or extrahepatic cholangiocarcinoma. In the USA, the third edition of the
ICD-O (ICD-O-3) was adopted in 2001.
An analysis of the SEER database by Khan et al. showed an increase in age-­
adjusted incidence rate for intrahepatic cholangiocarcinoma from 0.59 per 100,000
population in 1990 to 0.91 in 2000 [9]. However, in 2001, coincident with adoption
of the ICD-O-3, the rate fell and plateaued at 0.60 in 2007 (Fig. 1.1). Another SEER
analysis found that, between 1992 to 2000, 91% of perihilar cholangiocarcinomas
were incorrectly coded as intrahepatic cholangiocarcinoma, leading to an overesti-
mation of intrahepatic cholangiocarcinoma by 13% [10]. However, even after
­excluding Klatskin tumors, the age-adjusted incidence rate of intrahepatic cholan-
giocarcinoma increased between 1992 and 2000. Taken together, these data suggest
a true rise in incidence of intrahepatic cholangiocarcinoma between the 1970s and
1990s, followed by possibly a plateau in the 2000s.

Risk Factors

Risk factors for intrahepatic cholangiocarcinoma in Western countries include viral

hepatitis, cirrhosis, and obesity, which are rising in incidence. The magnitude of risk
of developing cholangiocarcinoma depends upon the factor and population studied
(Table 1.1). Most patients diagnosed with intrahepatic cholangiocarcinoma do not
have any identifiable risk factors. Environmental exposure to toxic chemicals, such
as radon and Thorotrast, are primarily of historical interest and not applicable to
patients today. In parts of Asia, liver fluke infection remains endemic, leading to
high prevalence rates of intrahepatic cholangiocarcinoma.

Liver Flukes

The highest recorded incidence of cholangiocarcinoma is in northeast Thailand,

where the liver fluke Opisthorchis viverrini is endemic. Here, approximately,
5000 cases are diagnosed annually, and the incidence rate among adults aged
35–64 is more than 100 per 100,000 population annually [11]. Another liver
fluke, Clonorchis sinensis, is implicated in cholangiocarcinoma carcinogenesis
 4

Table 1.1 Studies on risk factors for intrahepatic cholangiocarcinoma. Data presented as odds ratios (95% confidence interval)
Author, country, years of study
Petrick, USA, 2000– Welzel, USA, Zhou, China, Kamsa-ard, Thailand,
Risk factor 2011 [38] Palmer, 1990–2011a [33] 1993–2005 [30] 2004–2006 [40] 1985–2014 [18]
Bile duct cyst 15.66 (11.58–21.18) 43.03 (29.16–63.49)
Cirrhosis 8.26 (6.83–9.99) 22.92 (18.24–26.79) 22.11 (16.47–29.68)
Opisthorchis viverrini 6.35 (2.87–14.05)
infection
Hepatolithiasis 5.77 (1.97–16.85)
Hepatitis C 4.67 (3.57–6.11) 4.84 (2.41–9.71) 8.05 (5.08–12.75)
Hepatitis B 2.97 (1.97–4.46) 5.10 (2.91–8.95) 3.07 (1.43–6.58) 8.88 (5.97–13.19)
Excess alcohol 3.72 (3.17–4.35) 2.81 (1.52–5.21) 5.69 (3.65–8.86) 3.01 (2.00–4.54)
Diabetes 1.54 (1.41–1.68) 1.89 (1.74–2.07) 1.82 (1.56–2.11)
Obesity 1.42 (1.21–1.66) 1.56 (1.26–1.94) 1.71 (1.30–2.23)
Cigarette smoking 1.46 (1.28–1.66) 1.31 (0.95–1.82) 2.21 (1.74–2.81) 1.46 (1.10–1.94)
a
Meta-analysis of studies from Japan, Korea, the USA, Italy, China, and Denmark
R. Katkhuda and Y. S. Chun
1 Epidemiology and Risk Factors 5

in China and Korea. Both parasites are classified by the World Health Organization
as group 1 carcinogens for cholangiocarcinoma. Unlike the distribution of chol-
angiocarcinoma in Western countries, where extrahepatic cancers predominate,
up to 60% percent of cholangiocarcinomas associated with liver fluke infection
are intrahepatic [12].
Liver fluke infections are endemic in areas where raw or poorly cooked fish
is consumed. Human beings represent the definitive host of O. viverrini, which
travels from the infected person’s duodenum into the ampulla of Vater and bile
duct. The adult fluke can live up to 20 years in the bile duct, mainly intrahepatic
bile ducts, and lay eggs, which are passed with the infected person’s feces [11].
The eggs are ingested by snails and metamorphose into free-swimming larvae,
which then penetrate between the scales of freshwater fish, mostly cyprinoids
such as carp. C. sinensis has a similar life cycle. Inside bile ducts, the liver
flukes lead to DNA damage, periductal fibrosis, and periportal inflammation.
Chronic injury and inflammation of the bile duct lead to cholangiocarcinoma
development [13].
Among patients chronically infected with liver flukes, an estimated 8–10%
will develop intrahepatic cholangiocarcinoma [14]. O. viverrini is prevalent not
only in Thailand, but also in Laos, Vietnam, and Cambodia. In these countries,
approximately 700 million people are at risk of liver fluke infection [15]. In
Thailand, an estimated 6 million people are infected, with the highest prevalence
in the Northeast region, where the prevalence of O. viverrini infection is as high
as 67%, compared with only 0.1% in South Thailand [16]. Consequently, the
incidence of cholangiocarcinoma in 2013 was significantly higher in Northeast
Thailand than in the South (28.83 per 100,000 population, Northeast Thailand
vs. 2.98, South).
Efforts to eradicate endemic liver fluke infection include education on eating raw
fish, treatment with the antiparasitic praziquantel, and improvements in hygiene and
sewage systems to interrupt disease transmission [11, 17]. With these measures, the
incidence of O. viverrini infection in Thailand has fallen from greater than 60% in
1984 to less than 10% after 1997 [18]. However, infection rates remain high in the
Mekong River where uncooked or improperly fermented fish remains a staple in the
diet, particularly among the elderly. Treatment with praziquantel is effective, but
reinfection often occurs [13].
C. sinensis is endemic in China, Korea, Vietnam, and East Russia. The highest
prevalence is in China, where an estimated 15 million people are infected [19].
Worldwide, an estimated 5500 cases of cholangiocarcinoma annually are attrib-
uted to C. sinensis infection. Clonorchiasis is associated with two precancerous
lesions, intraductal papillary neoplasm of the bile duct (IPNB) and biliary
intraepithelial neoplasia. [20] IPNB is characterized by prominent intraductal
papillary growth, mucin production, and potential to transform into invasive
cholangiocarcinoma (Fig. 1.2). The incidence of IPNB is higher in Asia, where it
accounts for up to 30% of bile duct tumors, in contrast to only 7–11% in Western
countries [21].
6 R. Katkhuda and Y. S. Chun

Fig. 1.2 Computed tomography images of intraductal papillary neoplasm of the bile duct that
transformed to invasive intrahepatic cholangiocarcinoma

Hepatolithiasis

Hepatolithiasis, the formation of stones in the intrahepatic biliary tree, is more com-
mon in Asian countries than the West and leads to the development of intrahepatic
cholangiocarcinoma in 7% of patients [22]. The stones are pigmented calcium bili-
rubinate stones and thought to arise from factors associated with poor hygiene and
malnutrition [23]. Up to 30% of patients with hepatolithiasis also suffer from liver
fluke infection [24]. Hepatolithiasis results in biliary strictures, bacterial infection,
and secondary sclerosing cholangitis. The resultant chronic inflammation leads to
hyperplasia and dysplasia, including precancerous lesions IPNB and biliary epithe-
lial neoplasia, which can undergo malignant transformation.

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic disease of unclear etiology charac-

terized by progressive inflammation and fibrosis of the bile ducts. Patients with PSC
have a 5–10% lifetime risk of developing cholangiocarcinoma, primarily perihilar
cholangiocarcinoma [14]. Patients with PSC present with cholangiocarcinoma ear-
lier, between the third and fifth decades of life, compared with patients with sporadic
cholangiocarcinoma, whose mean age at presentation is the seventh decade [22].

Bile Duct Cysts

Bile duct cysts are congenital cystic dilatations of the biliary tree, classified by their
location, shape, and extent [25]. The most common types are type I, solitary,
­extrahepatic cyst, and type IV, multiple extrahepatic, or extra- and intrahepatic
1 Epidemiology and Risk Factors 7

cysts. A meta-analysis of 2904 patients with bile duct cysts reported a 7.3% preva-
lence of malignancy [26]. Cyst drainage had a higher risk of malignancy compared
with complete cyst excision, with an odds ratio of 3.97. Bile duct cysts are more
prevalent in Asia than in Western countries. Furthermore, the incidence of cholan-
giocarcinoma is higher in Asian patients with bile duct cysts, approximately 18%,
compared with 5% in the US patients [14, 27]. Average age at diagnosis with chol-
angiocarcinoma is 33, and incidence increases with age.
Type V bile duct cysts, also known as Caroli’s disease, are rare and characterized
by saccular ectasia of intrahepatic bile ducts. Caroli’s disease can be associated with
congenital hepatic fibrosis and autosomal recessive disease as Caroli’s syndrome.
Patients with Caroli’s disease reportedly harbor a 100-fold greater risk of develop-
ing cholangiocarcinoma than the general population [28].

Viral Hepatitis

Two studies based on the SEER database demonstrated an increased risk of intra-
hepatic cholangiocarcinoma with hepatitis C infection, but not with hepatitis B
[29, 30]. In contrast, a study from Italy reported a hepatitis B rate of 13% among
patients with intrahepatic cholangiocarcinoma, compared with 6.7% in controls
without cholangiocarcinoma [31]. Hepatitis C is consistently found to be a stron-
ger risk factor for intrahepatic cholangiocarcinoma than hepatitis B [22]. The risk
of developing intrahepatic cholangiocarcinoma with hepatitis C is 3.5% at 10 years,
which is significantly lower than the risk of developing hepatocellular carcinoma
[32]. With both hepatitis B and C, it is unclear if the viral infection itself or the
cirrhotic, diseased liver plays a greater role in the development of intrahepatic
cholangiocarcinoma.

Cirrhosis

Cirrhosis is a strong risk factor for development of both hepatocellular carcinoma

and intrahepatic cholangiocarcinoma. In a meta-analysis of risk factors for intra-
hepatic cholangiocarcinoma, cirrhosis had the highest combined odds ratio of
22.92, compared with other risk factors including viral hepatitis, diabetes, and
obesity [33]. Cirrhosis confers a 30-fold increased risk of hepatocellular carci-
noma and a 10- to 20-fold increase in intrahepatic cholangiocarcinoma [34]. The
mechanisms leading to cirrhosis, including hepatocyte cell death, proliferation,
and fibrosis, promote hepatocarcinogenesis. Shared risk factors for both hepato-
cellular carcinoma and intrahepatic cholangiocarcinoma support the hypothesis of
a common pathogenesis. The term “combined hepatocellular-cholangiocarci-
noma” includes a heterogeneous group of tumors that have varying degrees of
hepatocytic and cholangiocytic differentiation [35]. Stem cell features are
8 R. Katkhuda and Y. S. Chun

observed histologically and by immunohistochemistry, suggesting a single pre-

cursor population that can give rise to both hepatocellular carcinoma and intrahe-
patic cholangiocarcinoma [33].

Obesity

Lifestyle is increasingly recognized as a risk factor for malignancy and higher

cancer-­related mortality [36]. Obesity is an epidemic in the USA, with one third of
the adult population classified as obese. Nonalcoholic fatty liver disease (NAFLD)
occurs in 30% of US adults due to the prevalence of the metabolic syndrome,
marked by obesity, diabetes, hypertension, and/or hyperlipidemia. NAFLD can
progress to nonalcoholic steatohepatitis, cirrhosis, and primary liver cancer [37]. In
addition, NAFLD may exert synergistic effects with viral hepatitis in the develop-
ment of intrahepatic cholangiocarcinoma.
A study of the SEER database found that 29.7% of patients who developed intra-
hepatic cholangiocarcinoma had the metabolic syndrome compared with 17.1% in the
control group [30]. Another SEER analysis reported that NAFLD conferred a three-
fold increased risk of intrahepatic cholangiocarcinoma [38]. In addition, a meta-anal-
ysis by Palmer et al. identified diabetes and obesity as major risk factors for intrahepatic
cholangiocarcinoma, with odds ratios of 1.89 and 1.56, respectively [33].

Smoking and Alcohol

Studies on the association between smoking and risk of intrahepatic cholangiocarci-

noma have demonstrated inconsistent results [22]. In contrast, excess alcohol intake
was shown in a meta-analysis to be a risk factor, with an odds ratio of 2.81 [33].
Petrick et al. analyzed pooled data from a consortium of 14 US-based prospective
cohort studies and found that consuming ≥5 alcoholic beverages a day was associ-
ated with a 68% increased risk of developing intrahepatic cholangiocarcinoma [39].

Conclusion

The highest prevalence of intrahepatic cholangiocarcinoma is in Southeast Asia

and is attributed to endemic liver fluke infection. Rates are also high in China and
Korea due to clonorchiasis and hepatolithiasis, which give rise to premalignant
neoplasms that can transform into invasive cancer. In Western countries, most
patients do not have an identifiable risk factor. The most prevalent risk factors
associated with intrahepatic cholangiocarcinoma in the USA are cirrhosis, obesity,
and viral hepatitis. Due to the epidemic of obesity in the USA, the incidence of
1 Epidemiology and Risk Factors 9

intrahepatic cholangiocarcinoma may rise, paralleling the rise in hepatocellular

carcinoma related to NAFLD. Lifestyle changes in the East and West can reduce
the prevalence of risk factors and potentially reduce the incidence of intrahepatic
cholangiocarcinoma.

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Chapter 2
Clinical Presentation and Diagnosis

Arezou Abbasi, Amir A. Rahnemai-Azar, Sean M. Ronnekleiv-Kelly,

Daniel E. Abbott, and Sharon M. Weber

Introduction

Cholangiocarcinoma (CCA) is a diverse group of malignancies arising from the

epithelial lining of the biliary tract and encompasses three distinct anatomic cat-
egories, namely intrahepatic (ICC), perihilar (pCCA), and distal (dCCA) cholan-
giocarcinoma. Each of the categories demonstrates different clinical, morphologic,
and epidemiologic features [1]. The ICC variant develops from the malignant
transformation of the cholangiocytes located proximal to the second-degree bile
ducts.
In the classic model of ICC pathogenesis, chronic biliary inflammation and
­cholestasis triggered by external stimuli (e.g., liver fluke or hepatitis viral infection)
instigate malignant transformation of cholangiocytes [2]. However, recent findings
have challenged the classic model of a single cholangiocyte progenitor to explain
both intratumoral heterogeneity and subtype phenotypic heterogeneity in
ICC. Malignant transformation of multiple peribiliary stem cell niches as well as
hepatic progenitor cells has been proposed as potential progenitors rather than a
single cholangiocyte [3].
The majority of cholangiocarcinomas are adenocarcinomas (>90%), with the
rare occurrence of other histologic subtypes such as squamous cell carcinoma,

A. Abbasi
Department of Surgery, University of Washington Medical Center, Seattle, WA, USA
A. A. Rahnemai-Azar · S. M. Ronnekleiv-Kelly · D. E. Abbott · S. M. Weber (*)
Department of Surgery, Division of Surgical Oncology, University of Wisconsin School of
Medicine and Public Health, Madison, WI, USA
e-mail: [email protected]; [email protected];
[email protected]; [email protected]

© Springer Nature Switzerland AG 2019 11

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_2
12 A. Abbasi et al.

signet-­ring carcinoma, papillary adenocarcinoma, clear cell, and lymphoepithelial

types [4]. The mixed hepatocellular-cholangiocarcinoma subtype is a histologically
distinct presentation, especially in patients with chronic liver disease, and is associ-
ated with poor prognosis. In contrast to the described histologic subtypes, ICC is
also classified according to pathologic growth pattern. Under this system, morpho-
logic subtypes of cholangiocarcinoma have been described: mass-forming, periduc-
tal infiltrating, intraductal growth, and mixed type (periductal infiltrating and
mass-forming) ICC [5]. In addition to distinct characteristics in cross-sectional
imaging, these three subtypes are associated with different proliferative activity and
biologic behavior. Mass-forming subtype is the most common type of ICC, which
usually spreads to the liver parenchyma via the portal system at early stages fol-
lowed by invasion of the lymphatic vessels [6–8]. In contrast, the periductal infil-
trating subtype grows longitudinally along and within the biliary tract with resultant
ductal dilatation. Finally, the intraductal type grows into the bile duct with a papil-
lary growth pattern. As a result of different biologic behavior and spreading pat-
terns, the mass-forming subtype typically develops intrahepatic metastasis, while
periductal subtype presents with pedicular lymph node metastasis.
Due to silent nature of the disease in early stages, especially in patients without
a previous history of liver disease, the majority of patients present at advanced
stages when the tumor has already metastasized or progressed locally to involve
adjacent vital structures. Unfortunately, delayed clinical diagnosis limits the benefit
of surgical treatment and curative management options, contributing to the poor
outcome of ICC patients. Similarly, due to the tumor burden and complex biologic
heterogeneity, the currently available systemic and targeted therapies pose a limited
therapeutic benefit. Therefore, early diagnosis and screening of high-risk patients
play a crucial role in optimizing the outcomes of patients with ICC.

Epidemiology and Risk Factors

ICC is the second most common primary liver tumor after hepatocellular carcinoma
(HCC) [9]. Despite its lower frequency compared to other biliary tract carcinomas
and HCC, there has been an increasing trend in incidence and mortality rate of ICC
globally in recent years [10–14]. In the United States, the age-adjusted incidence
rate has increased by 165% from 0.32 per 100,000 (95% CI 0.28–0.36) in 1975–
1979 to 0.85 per 100,000 (95% CI 0.80–0.90) in 1995–1999 [10]. Likewise, the
age-adjusted mortality rate increased from 0.07 per 100,000 in 1973 to 0.69 per
100,000 in 1997, with an estimated annual percent change of 9.44% (95% CI, 8.46–
10.41) [15].
Primary sclerosing cholangitis (PSC), hepatolithiasis, biliary tract cysts, hepato-
biliary flukes (Clonorchis sinensis, Opisthorchis viverrini), cirrhosis, chronic hepa-
titis B and C, diabetes, alcohol, obesity and nonalcoholic fatty liver disease, and
toxins such as nitrosamines and vinyl chloride are some of the known risk factors of
ICC [16]. The chronic biliary inflammatory process caused by some of these risk
2 Clinical Presentation and Diagnosis 13

factors has been identified as a trigger of increased cholangiocyte turnover and sub-
sequent tumorigenesis [17]. However, most ICC cases occur de novo in otherwise
healthy individuals without a known underlying liver disease.

Clinical Presentation

Most patients with ICC remain asymptomatic until advanced stages of the disease
[18]. In 28% of cases, the tumor is detected incidentally during a physical examina-
tion or cross-sectional imaging, which is performed for other reasons. Furthermore,
in some cases, abnormal liver function tests may initiate clinical suspicion. Vague
nonspecific abdominal pain or constitutional symptoms such as malaise, fatigue,
night sweats, and weight loss are some of the most common complains of the patient
at the time of presentation [19]. Unlike other biliary tract and hepatic malignancies,
jaundice is an infrequent presentation, involving only 11–16% of patients with ICC
[20, 21]. Compression of the biliary duct confluence by tumor located in an adjacent
location or malignant infiltration of the Glissonian sheath, mostly in periductal ICC,
is the leading cause of jaundice in ICC patients. The presence of hepatomegaly or
ascites at the time of presentation is an ominous sign of advanced disease.

Diagnosis

Due to the nonspecific presenting symptoms, history taking and physical examina-
tion have a limited role in the diagnosing of ICC. Once there is a clinical suspicion,
thorough diagnostic investigations are mandatory to confirm the diagnosis and plan
for the treatment.

Laboratory Biomarkers

Although liver function tests and tumor markers are routinely assessed in the con-
text of suspicious liver masses, there is low sensitivity and specificity for a conclu-
sive diagnosis. Serum bilirubin level usually is not elevated in patients with ICC,
unless there is biliary confluence compression or infiltration of the Glissonian ped-
icle by the tumor. The elevated serum aminotransferases are mostly observed in
advanced disease due to extensive liver parenchyma replacement by the tumor and
associated hepatocytes damage [22].
CA 19-9 is a sialylated Lewis blood group antigen that is naturally produced
by normal human pancreatic cells, biliary ductal cells, and gastric and colonic
epithelial cells. Hence, it may be elevated in a variety of benign biliary diseases
(e.g., cholangitis, primary biliary cirrhosis) as well as other gastrointestinal malig-
14 A. Abbasi et al.

nancies (e.g., pancreatic and gastric cancers). Therefore, the majority of studies
examining CA 19-9 as a biomarker for detection of CCA have noted suboptimal
accuracy with a wide variation of reported sensitivity (38–93%) and specificity
(67–98%) [23, 24]. Furthermore, CA 19-9 is not detectable in 7% of the general
population due to the absence of the Lewis antigen. Notwithstanding these limita-
tions, utilization of CA 19-9 may still have a role. A recent meta-analysis of 31
articles including 1264 CCA patients and 2039 controls concluded that serum CA
19-9 was a useful diagnostic biomarker for CCA with 72% and 84% diagnostic
sensitivity and specificity, respectively [24]. Shen et al. demonstrated that serum
concentrations of CA19-9 were elevated in 57% of 429 patients with ICC and that
high levels of CA19-9 (>37 U/mL) effectively predicted the incidence of lymph
node metastasis (LNM) and survival [25]. A separate meta-analysis by Liu et al.
also demonstrated that elevated preoperative CA19-9 levels correlated with a poor
prognosis [26].
Carcinoembryonic antigen (CEA), an effective marker for colorectal cancer, is
also frequently elevated in the setting of other gastrointestinal and gynecologic
malignancies, but with demonstrated low diagnostic yield in the diagnosis of ICC.
Serum alpha-fetoprotein (AFP), a well-known and commonly used biomarker for
HCC, can sometimes be used to differentiate between HCC and ICC. Tao et al. used
a combination of AFP and CA242 to increase the specificity of AFP to differentiate
between ICC and HCC [27]. Recent advances have elucidated molecular and genetic
characteristics of ICC and offered the potential for molecular-based diagnosis of
ICC. Several genomic (e.g., secreted phosphoprotein 1 (SPP1), KRAS and PIK3CA
mutations, expression of SMAD4 and TGF-β) and proteomic markers (e.g., IL-6,
14-3-3 protein, serum cytokeratin 19 fragments) have been demonstrated to play a
role in the diagnosis and prediction of the prognosis of ICC [28]. However, the clini-
cal applicability of most existing markers is limited due to a lack of adequate sensi-
tivity and specificity.

Imaging Modalities

Ultrasonography (US) is frequently the initial abdominal imaging in the investi-

gation of patients with vague abdominal pain. The mass-forming ICC presents as
an irregular lesion with intermediate to increased echogenicity and a peripheral
hypoechoic halo with or without intrahepatic biliary ductal dilation. However,
these findings are not specific and cannot be used to differentiate ICC from other
liver malignancies. Recently, contrast-enhanced US (CEUS) has been used with
increasing frequency to investigate liver lesions. Different morphologic types of
ICC show distinct diagnostic features on CEUS (Fig. 2.1). On CEUS images,
hyperenhancing areas are indicative of increased cancer cells density, whereas
hypoenhancing parts are correlated with the presence of fibrous stroma. In the
arterial phase, the mass-­forming ICC might present as four different enhancement
2 Clinical Presentation and Diagnosis 15

a b

c d

Fig. 2.1 Ultrasonographic studies of intrahepatic cholangiocarcinoma: Sagittal B-mode image (a)
shows a heterogeneous predominantly hyperechoic lesion with a hypoechoic halo (arrows) in the
right liver lobe. Contrast-enhanced ultrasound (b–d) demonstrates that the lesion (arrows) has
homogenous arterial phase enhancement (b), followed by early and heterogeneous washout in the
portal venous phase within 60 s (c) as well as hypoenhancement in the late phase (d). (Reprinted
by permission from SpringerNature: Durot et al. [37])

patterns: (1) peripheral irregular rim-like enhancement, (2) heterogeneous hyper-

enhancement, (3) homogeneous hyperenhancement, or (4) heterogeneous hypoen-
hancement. These patterns have been demonstrated to correspond with the
histopathological characteristics of the tumor [29]. Peripheral irregular rim-like
enhancement corresponds with a central fibrous stroma surrounded by cancerous
cells. Hyperenhancing ICC, both homogenous and heterogeneous, are associated
with malignant cells located both centrally and peripherally. Ultimately, heteroge-
neous hypoenhancing tumors have a scarce number of cancerous cells.
Furthermore, the size of the tumor correlates with either homogeneous or hetero-
geneous enhancement as well [30]. Small ICC with less fibrous tissue and abun-
dant cancerous cells has homogeneous pattern, while large ICC that mostly
comprised of fibrous tissue enhances heterogeneously. Periductal infiltrating ICC
16 A. Abbasi et al.

appears as a heterogeneously enhancing lesion in the arterial phase and stays

hypoenhancing in both the portal and late phases [30]. Intraductal ICC has a pat-
tern of homogenous hyperenhancement in the arterial phase and hypoenhance-
ment in both the portal and late phases. As CEUS contrast materials are blood
pool tracers without extravasation to the stroma, delayed enhancement pattern
cannot be detected on delayed phase. Therefore, on CEUS, ICC may resemble
HCC with early enhancement and subsequent washout. The delayed enhancement
pattern on computed tomography (CT) scan with intravenous contrast images is a
sign of contrast material washout from the blood pool and retention in the fibrous
stroma. Of note, rim-like enhancement pattern might also be visualized in other
primary liver cancers and further investigations are required prior to definitive
diagnosis [29].
Cross-sectional imaging studies such as CT scan and magnetic resonance imag-
ing (MRI) are diagnostic modalities used to improve assessment of the type of
tumor, the extent of the tumor invasion locally, for the presence of metastatic dis-
ease, and the tumor’s resectability. On the other hand, ICC imaging features on CT
scan often are not specific enough to render tissue biopsy unnecessary [16]. ICC
typically presents as a hypo- to isodense mass with irregular and infiltrative margins
on noncontrast CT [31]. Mild peripheral rim enhancement with central hypodensity
is the dominant feature in the arterial phase, which may become iso- or hypodense
in the portal venous phase (Fig. 2.2). The central hypodensity progressively hyper-
attenuates during the delayed phase, unless there is abundant central mucin or
necrosis. The central fibrous stroma retaining the slowly diffused contrast material
is the reason for delayed and progressive enhancing of the ICC lesions. This pattern
can differentiate ICC from HCC, which presents as an enhancing lesion in the arte-
rial phase with rapid washout during the venous and delayed phases, mainly due to
the hypercellular characteristic of HCC with scarce fibrous tissue. However, small
size ICC might have a similar presentation to HCC on CT scan images due to hyper-
cellularity of the tumor.
On MRI, ICC mass presents as a hypo- to isointense lesion compared to the liver
parenchyma on the T1-weighted study [32]. In the presence of abundant fibrosis,
T2-weighted study tends to show slight hyperintensity along with pooling of the
contrast on delayed images, while strong hyperintensity is a sign of necrosis or
mucous secretion [33]. Similar to contrast-enhanced CT, gadolinium-enhanced
MRI shows a hypovascular mass with progressive concentric filling. Additionally,
MRI with cholangiopancreatography (MRI/ MRCP) permits an improved visualiza-
tion of the intra- and extrahepatic bile ducts, vascular structures, and anatomic
extent of the tumor.
Unlike other imaging techniques, [18] F-fluorodeoxyglucose positron emission
tomography (FDG-PET) is regarded as a staging modality rather than a diagnostic
tool. The role of FDG-PET in management of biliary tract cancers is ill-identified.
However, there is emerging evidence that, in patients with potentially resectable
tumors based on conventional imaging, FDG-PET can identify occult metastatic
disease that may alter treatment decision making [34, 35].
2 Clinical Presentation and Diagnosis 17

a d

Fig. 2.2 CompuRadiographic features of intrahepatic cholangiocarcinoma: (a–c) Computed tomog-

raphy showing a low-density mass with a regular and distinct boundary on arterial (b) and portal
venous phases (c). (d–g) Magnetic resonance imaging showing a mass low signal on T1-W1 (d) and
a heterogeneous high signal on T2-W1 (e) with a regular and distinct boundary. The same features
are present on the enhanced T1-W1, with a sharp ring-like enhancement, during the arterial (f) and
portal venous phases (g). (From Jiang et al. [38], by permission of Oxford University Press)

Tissue Diagnosis

Although clinical presentation, laboratory analyses, and radiologic studies raise the
clinical suspicion, the definitive diagnosis of ICC is possible only via tissue biopsy.
In the case of high clinical suspicion, even a negative biopsy does not rule out the
disease due to sampling error. The pathologic confirmation is mandatory in patients
18 A. Abbasi et al.

who are unresectable due to underlying liver disease. Furthermore, tissue biopsy is
recommended in patients who are being considered for clinical trials or neoadjuvant
therapy [31].
The most common pathologic feature of ICC is adenocarcinoma showing tubular
and/or papillary structures with variable fibrous stroma [16]. Histologically, ICC
and metastatic adenocarcinoma from other primary tumors, especially foregut
malignancies, have similar features and further immunohistochemical evaluation
warrants a definitive diagnosis [31]. Similarly, differentiating between ICC and
mixed hepatocellular tumors requires further investigation using specific markers of
hepatocellular progenitor cells (e.g., Hep-Par-1, GPC3, HSP70, EpCAM, etc.) [36]

Conclusion

In summary, the majority of patients with ICC present as either an incidental finding
or with vague abdominal symptoms. Several serum lab tests and/or radiographic
features are suggestive of ICC, but tissue biopsy is needed to confirm the diagnosis.
Despite recent advances in the development of novel diagnostic modalities, the
majority of patients with ICC present at an advanced stage when the tumor is locally
advanced or has already metastasized. Therefore, novel methods that permit earlier
diagnosis of ICC are imperative to improve patient outcomes from this aggressive
malignancy. Future studies are required to focus on improved understanding of the
molecular pathogenesis of ICC with the hope of identifying novel molecular bio-
markers with higher diagnostic and prognostic accuracy.

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Chapter 3
Staging and Prognosis

Janelle F. Rekman and Flavio G. Rocha

Introduction

The incidence of intrahepatic cholangiocarcinoma (ICC) has been steadily increas-

ing worldwide. It is the second most common primary liver cancer, next to hepato-
cellular carcinoma (HCC), currently accounting for approximately 5–30% of all
primary hepatic malignancies [1, 2]. While the clinical presentation in patients may
vary, the ultimate goal is to make a timely diagnosis and determine eligibility for
hepatic resection, the treatment of choice. Unfortunately, only a small proportion of
patients are eligible for surgical resection, and even those who undergo curative-­
intent hepatectomy often experience recurrent disease. In order to better prepare
patients for the expected outcomes of treatment, and to provide information to
treating physicians regarding the likelihood of recurrence and need for adjuvant
therapy, there has been a recent interest to identify and validate prognostic factors
specific to ICC.
Until recently, the staging of ICC was combined with HCC given its relative
­rarity and the difficulty of establishing strong evidence derived from small patient
cohorts. Over the last two decades, there has been a significant effort to form
multi-­institution, international database collaborations to study this uncommon
tumor, providing a higher volume of patients for statistical data analysis. In addi-
tion to the ­challenge of creating a prognostic system for primary liver cancer, the

J. F. Rekman · F. G. Rocha (*)

Section of General, Thoracic and Vascular Surgery, Virginia Mason Medical Center,
Seattle, WA, USA
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2019 21

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_3
22 J. F. Rekman and F. G. Rocha

patient’s projected course is also intimately related to their underlying liver

­function. Many patients in Eastern countries, where primary liver cancer is more
common, have underlying hepatitis and liver dysfunction that must be taken into
account [3].

A Brief History of ICC Staging

Until the 7th edition of the American Joint Committee on Cancer/Union for
International Cancer Control (AJCC/UICC) TMN staging system in 2010, all pri-
mary liver tumors fell under the same staging system in Western countries. Distinct
staging systems for ICC, providing the foundation for current staging systems, were
first proposed and used in Japan where cholangiocarcinoma is more prevalent. The
National Cancer Center of Japan (NCCJ) and the Liver Cancer Study Group of
Japan (LCSGJ) staging systems each investigated factors predicting prognosis in
order to guide clinical care (see Table 3.1) [4, 5].
The NCCJ presented a staging system specific for mass-forming intrahepatic
cholangiocarcinoma based on a small cohort of 60 patients. Multivariate model-
ing, including 14 clinical and 12 postoperative surgical and pathologic param-
eters, identified several independent factors associated with worse long-term
survival including: multiple tumors, vascular invasion, symptomatic disease,
and regional lymph node metastasis. Based on these data, this staging system
was proposed: Stage 1 disease, solitary tumor without vascular invasion; Stage
2 disease, solitary tumor with vascular invasion; Stage 3a disease, multiple
tumors with or without vascular invasion; Stage 3b disease, any tumor with
regional lymph node metastasis; and Stage 4 disease, ICC with distant metasta-
sis [4]. This staging system was criticized for both its small population base
(N = 60) and for its lack of generalizability given that the patient population
had only mass-forming ICC and one third of them were Hepatitis B or C
positive [6, 7].
In contrast to the NCCJ, the LCSGJ staging system included tumor size as a
factor and highlighted all three morphological subtypes of ICC (mass-forming,
periductal-­infiltrating, and intraductal-growth type). Specifically, the system
stratified patients based on: number of tumors, presence of vascular or serosal
invasion, and tumor size >2 cm. One point was assigned to each of these factors
and staging was a summation of the points [5]. Lymph nodes and distant metas-
tases were included in a binary fashion similar to the subsequent AJCC/UICC 7th
edition.
These two Japanese staging systems were first analyzed in a large Western
cohort by Nathan et al. in 2009 [7] in a large Surveillance, Epidemiology, and End
Results (SEER) database study of 598 patients having undergone surgery for
ICC. Both the LCSGJ and the NCCJ exhibited poor correlation among the T
stages and for survival prediction in this population. Specifically, the LCSGJ
3 Staging and Prognosis 23

Table 3.1 Comparison of TMN Staging Systems for Intrahepatic Cholangiocarcinoma

Stage Liver cancer study group National Cancer Center
Classification AJCC/UICC 7th edition of Japan Japan
Criteria:
1 – tumor size ≤2 cm
2 – tumor number = 1
3 – no portal vein, hepatic
vein, or serosal
involvement
Primary tumor
TX Primary tumor cannot be – –
assessed
Tis Carcinoma in situ – –
(intraductal tumor)
T0 No evidence of primary – –
tumor
T1 Solitary tumor without All three criteria Solitary tumor without
vascular invasion vascular invasion
T2a Solitary tumor with Two of three criteria Solitary tumor with
vascular invasion vascular invasion
T2b Multiple tumors, with or – –
without vascular
invasion
T3 Tumors perforating the One of three criteria Multiple tumors with or
visceral peritoneum without vascular
invasion
T4 Tumors with periductal None of three criteria –
invasion
Regional lymph nodes (LN)
NX Regional LN metastases – –
cannot be assessed
N0 No regional LN No regional LN No regional LN
metastases present metastases present metastases present
N1 Regional LN metastases Regional LN metastases Regional LN metastases
present present present
Metastatic disease (M)
M0 No distant metastases No distant metastases No distant metastases
M1 Distant metastases Distant metastases Distant metastases

failed to identify differences between patients for stages I-III in this Western
cohort [7] (see Fig. 3.1).
Up until this point, ICC had been staged with HCC under ‘primary liver tumors’
in the AJCC/UICC 6th edition, ignoring clinicopathologic features specific to
ICC. The SEER analysis used a Cox proportional hazard model to predict
­independent predictors of survival identified multiple tumors [hazard ratio (HR)
1.42, c­onfidence interval (CI) 1.01–2.01], lymph node status in nonmetastatic
24 J. F. Rekman and F. G. Rocha

a b
Proportion Proportion
Surviving Surviving
1.0 Stage I 1.0 Stage I
Stage II Stage II
Stage IIIa Stage IIIa
0.8 Stage IIIb
Stage IIIc
0.8 Stage IIIb
Stage IV
Stage IV
0.6 0.6

0.4 0.4

0.2 0.2

0 12 24 36 48 60 0 12 24 36 48 60
Survival Time (Months) Survival Time (Months)
c d
Proportion Proportion
Surviving Surviving
1.0 Stage I 1.0 Stage I
Stage II Stage II
Stage III Stage III
0.8 Stage IVa 0.8 Stage IV
Stage IVb

0.6 0.6

0.4 0.4

0.2 0.2

0 12 24 36 48 60 0 12 24 36 48 60
Survival Time (Months) Survival Time (Months)

Fig. 3.1 Kaplan-Meier survival curves for all patients. (a) AJCC/UICC 6th edition TMN liver
cancer staging system. (b) Okabayashi ICC staging system. (c) Liver Cancer Study Group of Japan
ICC staging system. (d) AJCC 7th edition ICC staging system (proposed by National et al). (Used
with permission from Springer: Nathan et al. [7])

patients (HR 3.21, CI 1.23–8.37), and vascular invasion (HR 1.53, CI 1.10–2.120),
as previously reported by Okabayashi, to predict adverse outcomes. Size of the
primary tumor was not an independent predictor of survival in the Nathan study
(HR 0.97, CI 0.72–1.30). Interestingly, this study did not show an additive effect of
tumor number and vascular invasion, with the impact of having both on survival
being similar to either alone. However, it was limited by the confines of the SEER
database itself. No morphologic details of the primary tumor were included (mass-
forming, ­intraductal, etc.), and there was no information regarding serosal invasion
of the primary tumor (meaning exact evaluation of the LCSGJ system was not pos-
sible). It is, therefore, possible that the true performance of the LCSGJ staging sys-
tem was underestimated.
The predictive features for survival of patients with ICC described by Nathan
et al. were confirmed in a multi-institutional, international study of 449 patients
from 11 institutions who had undergone hepatic resection for ICC [8]. Overall,
5-year survival rates improved if final pathology showed: a single tumor, no
3 Staging and Prognosis 25

v­ ascular invasion, and no lymph node spread. Overall, survival dropped in an

accumulated fashion if patients had 1, 2, or 3 of these factors (38.3%, 27.3%, and
18.1%, respectively). Lymph node status was found to be the worst prognostic
indicator, in that multiple tumors and vascular invasion were only relevant for
survival in N0 patients. In this study, although tumor size was relevant to survival
in the univariate analysis, there was no prognostic significance on multivariate
confirmation.
At this time, with the help of these studies, AJCC/UICC developed the first inde-
pendent TMN staging system for ICC [9]. T-stage categories were broken down into
the following: T1, solitary tumor without vascular invasion; T2a, solitary tumor
with vascular invasion; T2b, multiple tumors with or without vascular invasion; T3,
tumors perforating the visceral peritoneum or involving local hepatic structures by
direct invasion; and T4, tumor with periductal invasion. N1 disease was considered
stage IVa disease. See Table 3.2 for a comparison of 6th and 7th AJCC/UICC ICC
staging system. Farges et al. [10] of the French Association of Surgery intrahepatic
cholangiocarcinoma (AFC-IHCC) study group validated the 7th edition system on
a resectable ICC patient population of 163, showing that the proposed TMN
­classification could be used to predict survival. Those with stage 1 disease did not

Table 3.2 Different AJCC staging definitions for intrahepatic cholangiocarcinoma based on the
AJCC 6th edition (2004), AJCC 7th edition (2010), and AJCC 8th edition (2017) staging systems
AJCC staging classification (6th edition, 2004) AJCC staging classification (7th edition, 2010)
T1 Single tumor T1 Solitary tumor without
without vascular vascular invasion
invasion
T2 Single tumor with T2a Solitary tumor with vascular
vascular invasion invasion
or multiple tumors
none more than
5 cm
T3 Multiple tumors T2b Multiple tumors, with or
more than 5 cm or without vascular invasion
tumors involving
major branch of
portal or hepatic
veins
T4 Tumors with direct T3 Tumor perforating the
invasion of visceral peritoneum or
adjacent organs involving the local extra
other than the hepatic structures by direct
gallbladder or with invasion
perforation of
visceral
peritoneum
T4 Tumor with periductal
invasion
(continued)
26 J. F. Rekman and F. G. Rocha

Table 3.2 (continued)

AJCC staging classification (6th edition, 2004) AJCC staging classification (7th edition, 2010)
N0 No regional lymph N0 No regional lymph node
node metastasis metastasis
N1 Regional lymph N1 Regional lymph node
node metastasis metastasis
M0 No distant M0 No distant metastasis
metastasis
M1 Distant metastasis M1 Distant metastasis
AJCC staging classification (8th edition, 2017)
T1a Solitary tumor ≤5 cm without vascular
invasion
T1b Solitary tumor >5 cm without vascular
invasion
T2 Solitary tumor with intrahepatic vascular
invasion or multiple tumors, with or without
vascular invasion
T3 Tumor perforating the visceral peritoneum
T4 Tumor involving the local extrahepatic
structures by direct invasion
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis present
M0 No distant metastasis
M1 Distant metastasis
AJCC (6th edition, 2004) AJCC (7th edition, 2010) AJCC (8th edition, 2017)
Stage T N M Stage T N M Stage T N M
I T2 N0 M0 I T1 N0 M0 Ia T1a N0 M0
II T2 N0 M0 II T2a N0 M0 Ib T1b N0 M0
IIIa T3 N0 M0 T2b N0 M0 II T2 N0 M0
IIIb T4 N0 M0 III T3 N0 M0 IIIa T3 N0 M0
IIIc Any T N1 M0 IVa T4 N0 M0 IIIb T4 N0 M0
IV Any T Any N M1 Any T N1 M0 Any T N1 M0
IVb Any T Any N M1 IV Any T Any N M1
From Meng et al. [54]

reach the median survival cut-off at the median follow-up of 34 months, patients
with stage 2 tumors had a median survival of 53 months (p = 0.01), and stage 3
patients had a median survival of 16 months (p < 0.0001), thus demonstrating prog-
nostic stratification.
While the LCSGJ and AJCC/UICC 7th edition staging systems do stratify
patients into categories, their discriminatory ability is still relatively poor. In Nathan
et al.’s [7] comparison of the T-staging systems to date at that time (AJCC/UICC 6th
edition, NCCJ/Okabayashi, LCSGJ, and their proposed system), the discriminatory
abilities of these various systems were evaluated by calculating the c-indices for
Cox proportional hazards models, both for the T classification systems and the over-
all stage groupings [7]. In fact, all the systems had comparable c-statistics in their
3 Staging and Prognosis 27

T-staged model (Nathan’s proposed system c = 0.61, AJCC/UICC 6th edition

c = 0.6, Okabayashi/NCCJ 0.59), except the LCSGJ (c = 0.51) which was difficult
to evaluate using the SEER database. The overall stage groupings performed simi-
larly and are shown in Fig. 3.1. If the model perfectly predicted the ICC patients
who would experience diminished overall survival, the c-statistic would be equal to
1 [11]. These models provide a prediction that is moderate to good, but not strong
[12], and therefore, continued work to discover discriminatory factors was felt to be
necessary [13].

 ransitioning from the 7th AJCC/UICC Edition

T
to the 8th Edition

As soon as the AJCC 7th edition was published, some concerns began to surface.
The SEER database that formed the backbone of its patient population had some
notable missing information including status of the resection margins, tumor mor-
phology, and serosal penetration of the tumor. In addition, most notably, half of the
patients in the database had not undergone a lymphadenectomy [7]. The AFC-­
IHCC-­2009 study group (French Association of Surgery) produced a registry of
patients with resected ICC, including only patients who had undergone a curative
operation and had complete clinical and pathologic data including lymphadenec-
tomy. Of 522 patients resected for ICC, only 163 fit the inclusion criteria. Their
analysis of the 7th edition, compared to historical systems achieved the most uni-
form distribution of patients among the stages and behaved in exactly the same way
as Japanese patients, suggesting worldwide applicability [10].
The Mayo Clinic also sought to validate the AJCC 7th edition on their patient
population and found differing results [14]. One hundred twenty-six patients with
resected ICC were included and median length of follow-up was 4.5 years. In con-
trast to previous studies, the 7th edition did not stratify patients according to sur-
vival. Their univariate analysis showed worse prognosis with the following variables:
tumor size >5 cm (HR 2.50, 95% CI 1.27–4.93), multiple tumors (HR 1.79, 95% CI
1.05–3.04), pN1 status (HR 3.14, 95% CI 1.84–5.38), presence of grade 4 disease
(HR 3.72, 95% CI 1.74–7.95), and microvascular invasion (HR 1.87, CT 1.12–
3.09). Final stepwise multivariate analysis showed similar results with significantly
worse survival for high grade/dedifferentiated tumors, pN1 disease, and microvas-
cular invasion (see Table 3.3).
The median overall survival for node-positive patients in the Mayo clinic study
was 20 months, with 1- and 5-year survival rates of 61% and 13%, respectively.
Interestingly, the more positive LNs, the worse the survival (P < 0.001). This leads
to an analysis of what was called the ‘lymph node ratio’ (number of positive nodes/
total number removed), and an impact on survival was seen with a ratio of >0.1 (HR
1.34, 95% CI 1.20–1.50). Therefore, it seemed that achieving a greater lymph node
harvest would give a more accurate and discriminatory prognosis for the patient
[14]. This was later reflected in the 8th edition of the AJCC/UICC staging [15].
Table 3.3 Univariate and multivariate hazard ratios for node-negative and metastasis-negative (N0 M0) patients and all patients

28
Variables N0 M0 patients (n = 93) All patients (n = 126)
Median survival, Median survival,
n months HR (95% CI) P-value n months HR (95% CI) P-value
Univariate analysis
Tumor size of >5 cm Yes 58 60 1.91 (0.87–4.20) 0.102 Yes 88 38 2.50 (1.27–4.93) 0.008
No 35 99 No 38 99
Grade 4 disease Yes 6 14 4.23 (1.58–11.28) 0.004 Yes 10 6 3.72 (1.75–7.95) <0.001
No 87 81 No 116 49
Periductal invasion Yes 28 66 1.75 (0.85–3.61) 0.123 Yes 41 38 1.61 (0.96–2.69) 0.064
No 65 84 No 85 60
Direct invasion Yes 11 70 0.85 (0.30–2.41) 0.762 Yes 18 43 1.21 (0.61–2.39) 0.582
No 82 99 No 108 49
Macrovascular Yes 9 49 1.36 (0.48–3.86) 0.561 Yes 11 44 1.32 (0.60–2.89) 0.491
invasion
No 84 81 No 115 49
Microvascular Yes 37 66 1.12 (0.57–2.17) 0.741 Yes 60 32 1.87 (1.13–3.09) 0.016
invasion
No 56 79 No 66 70
Multiple tumors Yes 30 81 1.40 (0.67–2.92) 0.362 Yes 38 31 1.79 (1.05–3.04) 0.031

J. F. Rekman and F. G. Rocha

No 63 79 No 88 57
Positive lymph nodes – – – – – Yes 33 20 3.14 (1.83–5.39) <0.001
No 93 79
Multivariate analysis
Grade 4 disease Yes 10 6 7.84(3.35–18.35) <0.001
No 116 49
Positive lymph nodes Yes 33 20 2.93 (1.65–5.21) <0.001
 3
No 93 79

Staging and Prognosis

Microvascular Yes 60 32 1.85 (1.06–3.22) 0.030
invasion
No 66 70
Multiple tumors Yes 38 31 1.68 (0.96–2.92) 0.067
No 88 57
Periductal invasion Yes 41 38 1.53 (0.87–2.68) 0.136
No 85 60
Tumor size of >5 cm Yes 88 38 1.51 (0.75–3.06) 0.248
No 38 99 1.51 (0.75–3.06) 0.248
Resection margin – – – – – R0 110 66 – –
– – – – – Non-R0 16 25 – –
Margin width – – – – – >5 mm 70 99 <0.001
<5 mm 56 38
Reprinted from Ali et al. [14], with permission from Elsevier
CI confidence interval, HR hazard ratio, N0 M0 node-negative and metastasis-negative disease

29
30 J. F. Rekman and F. G. Rocha

Ali et al. at Mayo [14] constructed a new model using their data, which included
a tumor size >5 cm as a negative prognostic factor. The concordance of their model
reached 0.66 (95% CI 0.58–0.74), slightly improved from the c = 0.61 seen in the
Nathan study 5 years earlier [7]. There had been considerable debate since before
the 7th edition AJCC was written regarding the prognostic significance of tumor
size for ICC. Although the 7th edition did not include tumor size in their criteria, it
became evident that the impact of size was likely more nuanced and nonlinear in
terms of its effect. For example, the survival of a patient with a 1 cm tumor did not
seem to be significantly different than one with a 4 cm tumor, but if the tumor
reached 10 cm, survival worsened. Differing size plateaus were suggested, from
2 cm to 7 cm [16]. There is some evidence that tumor size ≥5 cm had been associ-
ated with microscopic vascular invasion and worse tumor grade in patients with
resected ICC, which may account for this difference in size [17].
In 2017, the 8th edition of the AJCC/UICC TMN staging was published and
contained these changes described above, as well as a few additional factors based
on evolution of knowledge in the intervening 8 years. ICC staging remains separate
from both extrahepatic cholangiocarcinomas and HCCs, but rare mixed hepato-­
cholangiocarcinomas and intrahepatic primary hepatic neuroendocrine masses are
now also included in the system. T1 disease has been broken up based on the size of
the lesion (T1a, solitary tumor ≤5 cm vs. T1b, solitary tumor >5 cm), the T2 cate-
gory has been modified to indicate the equivalent survival outcomes of patients with
multiple lesions and vascular invasion (rather than separating them into T2a and
2b), and the T4 category has become defined by local peri-tumoral extension to
adjacent organs rather than based on morphology and periductal infiltration. It
seems that the significance of periductal infiltration was overstated in the initial
studies (prompting its prominence in the 7th edition), and further studies have not
shown this to be true.
T categories in the 8th edition of the AJCC were thus redefined as: T1, single
large tumor (T1a <5 cm, T1b > 5 cm); T2, solitary tumor +/− vascular invasion or
multiple tumors +/− vascular invasion; T3, tumor on the verge of local extrahepatic
invasion; and T4, overt extrahepatic invasion. It is worth mentioning that ‘multiple
tumors’ in the T2 category could refer to: multifocal disease, satellitosis, or intrahe-
patic metastases. Clinically, at this time it is challenging to determine on preopera-
tive imaging, but from a staging perspective, it does not seem to affect outcomes [1].
See Table 3.4 for AJCC 8th edition staging system.
In addition to T-stage categories, N1 disease has been reclassified as stage IIIb
rather than stage IV disease. This downstaging reflects findings that there is the
possibility of prolonged survival in LN-positive patients, rarely mimicked in those
with true metastatic spread [18]. Given that the number of harvested LNs and the
number of positive LNs are highly predictive of survival [14, 19], an adequate
nodal harvest is considered 6 LNs in the 8th edition. Although not officially part of
the staging system, Ca19–9 level greater than 200 IU/mL is introduced as an addi-
tional risk factor, along with underlying liver fibrosis/cirrhosis and primary scle-
rosing cholangitis [15, 20].
3 Staging and Prognosis 31

Table 3.4 AJCC 8th edition staging classification for intrahepatic cholangiocarcinoma. Compiled
from The AJCC Cancer Staging Manual, Eighth Edition (2017), Springer International Publishing
Classification Description
T category T criteria
Tis Carcinoma in situ (intraductal tumor)
T1a Solitary tumor ≤5 cm without vascular invasion
T1b Solitary tumor >5 cm without vascular invasion
T2 Solitary tumor with intrahepatic vascular invasion or multiple tumors
± vascular invasion
T3 Tumor perforating visceral peritoneum
T4 Tumor involving local extrahepatic structures by direct invasion
N category N criteria
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis present
M category M criteria
M0 No distant metastasis
M1 Distant metastasis
AJCC prognostic stage groups
T1a/N0/M0 IA
T1b/N0/M0 IB
T2/N0/M0 II
T3/N0/M0 IIIA
T4/N0/M0 IIIB
Any T/N1/M0 IIIB
Any T/Any N/M1 IV

Validation of the AJCC 8th Edition

To date, two high volume studies have attempted to validate the prognostic impact
of the 8th edition of the AJCC staging system. The first, an international study
group, containing 14 hepatobiliary centers and 1154 patients with resected ICC
between 1990 and 2015 staged each patient according to the 7th and 8th edition
criteria [21]. The second was a study in the USA conducted on the SEER database
including 1008 patients [22]. They both found similar results; that the prognostic
power of the AJCC/UICC 8th edition is either just partially improved or comparable
with that of the 7th edition.
Spolverato et al. [21] performed a validation analysis to compare the ability of
the two editions (7th and 8th AJCC) to stratify patients. The 7th edition T-category
had a C-index of 0.59 in their cohort and the 8th edition was only marginally
improved at 0.609. Interestingly, although T3 patients had a high HR of death com-
pared with T1 patients in the 8th edition (HR 1.65, 95% CI 1.22–2.24 P = 0.001),
they survived longer than T1b and T2 patients in this cohort. A similar effect was
noted when looking closer at the overall staging groups. Overall, stage IIIa patients
32 J. F. Rekman and F. G. Rocha

had a higher risk of death (39.7% 5y OS) versus stage Ia (38.8% 5y OS) patients,
but the difference was not statistically significant (P > 0.05). These data suggest that
perforation of the visceral peritoneum may not carry as poor a prognostic impact as
tumors with vascular invasion [20, 21].
The large, US-representative SEER database study by Kim et al. [22] also dem-
onstrated only marginal discrimination improvements between the 7th and 8th
AJCC/UICC staging systems. Previous studies [14, 23] indicated a c-index between
0.62 and 0.65 for the 7th edition, and this study was roughly the same with a c-index
of 0.669 (see Fig. 3.2).
It did confirm the prognostic significance of >5 cm tumor size as the risk of death
in this cohort was 36% higher than patients with ICC lesions measuring <5 cm (HR
1.36, 95% CI 1.14–1.62; P = 0.001). The data from this study also supported the
alteration of LN positivity from stage IV disease to a separate stage IIIb definition,
given that the median survival among patients with 8th edition stage IIIb disease
was 16 months, significantly better than the 9 months seen for those with distant
metastases (8th edition stage IV disease).

Role of Lymphadenectomy

Although recommended by International and National consensus guidelines

[National Comprehensive Cancer Network (NCCN) [24], International Hepato-­
Pancreato Biliary Association (IHPBA) consensus statement [1], and the European
Association for the Study of the Liver (EASL) statement [25]], the role of lymphad-
enectomy is still controversial, especially in the West. A multi-institutional study of
449 patients at 11 institutions indicated that only 55.2% of patients undergoing
resection for ICC have at least 1 lymph node removed and pathologically evaluated
[8], despite LN metastases being universally cited as a negative prognostic factor [8,
26, 27]. Of those who had LNs harvested in the previous study, the median number
resected was 3 and the number with lymph node-positive disease was 29.8%. This
incidence is as high as 40% in some studies [27]. Similar results were noted by Kim
et al. [22] when they reported on 749 patients from the SEER database who under-
went surgical resection between 1988 and 2011.
The AJCC 8th edition recommends a minimum of 6 LNs to be resected for ade-
quate nodal staging [15] and the IHPBA Expert Consensus Statement recommends
clearing all locoregional nodal stations. Locoregional nodal stations (N1), or what
are also named the first echelon nodes, differ depending on the hemiliver involved.
Clinical and pathologic data indicate that LNs in the porta hepatis and along the
hepatic artery (see Fig. 3.3) are the first to become involved and should be removed
in all patients. See Fig. 3.4 for an intraoperative picture of the result of a complete
porta hepatis lymph node dissection. If the ICC originates in the right hemiliver
(segments 5–8), resection of the retropancreatic nodes should occur. In contrast, a
lymphatic drainage pathway along the lesser omentum from the left hemiliver (seg-
ments 2 and 3) to the lesser curve of the stomach is recognized. Therefore, left-sided
 3

a b
1.00 IA IB II 1.00 I II III
IIIA IIIB IV IVA IVB
0.80 0.80

0.60 0.60

0.40 0.40
Staging and Prognosis

0.20 0.20

Proportion of patient alive

Proportion of patient alive
0.00 0.00
0 12 24 36 48 60 0 12 24 36 48 60
Time (Months) Time (Months)
Number at risk Number at risk
IA 192 145 112 90 63 49 358 270 209 157 107 80
I 34
IB 166 125 97 67 44 31 II 234 151 103 67 40
II 234 151 103 67 40 34 132 79 45 27 22 15
III
IIIA 48 31 20 9 8 5 181 108 45 23 12 5
IVA 4
IIIB 265 156 70 41 26 15 IVB 103 39 16 9 6
IV 103 39 16 9 6 4

Median OS (months) 95% CI Median OS (months) 95% CI

IA 81 60-116 I 67 54-87

IB 57 42-87 II 33 27-41

II 33 27-41 III 19 15-23

IIIA 24 15-31 IVA 15 13-17
IIIB 15 13-19 IVB 9 6-12
IV 9 6-12

Fig. 3.2 Kaplan-Meier curves stratified by (a) AJCC/UICC 8th edition, and (b) AJCC/UICC 7th ed staging systems. (Used with permission from Kim et al. [22])
33
34 J. F. Rekman and F. G. Rocha

Aorta

Hepatic artery
nodes
Hilar nodes
Celiac axis
nodes
Cystic duct
nodes

Bile duct
nodes

Portal vein
nodes
Celiac axis
Common
Portal vein hepatic artery

Superior
mesenteric
artery

Fig. 3.3 Lymph node drainage patterns vary based on intrahepatic location of ICC. Segments 2
and 3 tumors can drain to lymph nodes (LNs) along the lesser curvature of the stomach and subse-
quently to the celiac nodal basin. ICCs of the right liver (segments 5–8) may preferentially drain to
the hilar LNs and subsequently to the caval and periaortic LNs. (Used with the permission of the
American College of Surgeons. Adapted from Compton et al. [55])

Fig. 3.4 Intraoperative

picture following portal
lymph node dissection for
ICC. Blue vessel loops
demonstrate the common
bile duct on the left and the
common hepatic artery
looped on the right with
the portal vein
demonstrated between and
lying behind
3 Staging and Prognosis 35

Study Year of Number of %

name study patients ES (95% CI) Weight

No LNM
Suzuki et al. 2002 5 80.00 (44.94–115.06) 2.24
Nakagawa et al. 2005 15 61.70 (37.10–86.30) 4.55
Miva et al. 2006 25 68.20 (49.94–86.46) 8.27
Uneshi et al. 2008 70 57.00 (45.40–68.60) 20.49
Li et al. 2009 83 51.40 (40.65–62.15) 23.84
Uchimaya et al. 2011 141 52.90 (44.66–61.14) 40.60
Subtotal (I-squared =0.0%, P=0.418) 55.66 (50.41–60.91) 100.00

LNM
Suzuki et al. 2002 14 21.40 (–0.08–42.88) 0.06
Nakagawa et al. 2005 13 25.20 (1.60–48.80) 0.05
Miva et al. 2006 16 0.00 (–0.15–0.16) 48.60
Uneshi et al. 2008 63 13.00 (4.70–21.30) 0.40
Li et al. 2009 53 0.00 (–0.08–0.09) 50.07
Uchimaya et al. 2011 139 13.90 (8.15–19.65) 0.83
Subtotal (I-squared =87.5%, P=0.000) 0.19 (–0.33–0.72) 100.00

NOTE: Weights are from random effects analysis

0 50 100

Fig. 3.5 Meta-analysis of 3-year survival among patients with intrahepatic cholangiocarcinoma
stratified by lymph node (LN). Patients without LN involvement experienced 55.3% 3-year sur-
vival compared to 0.2% 3-year survival in those with LN metastases. (Used with permission from
SpringerNature: Amini et al. [29])

ICC should also involve resection of LNs around the cardia and lesser curve of the
stomach along the left gastric artery [1, 9]. Evidence of gross LN involvement out-
side of these first echelon LNs, such as celiac or para-aortic LNs, should be consid-
ered a contraindication to hepatic resection, representing metastatic disease [28].
There is no evidence that overall survival is improved when a lymphadenectomy
is performed; however, important prognostic information and accurate staging have
been shown in multiple studies following lymphadenectomy [8, 22, 27]. A recent
meta-analysis of 3-year survival in patients with ICC stratified by LN status showed
approximately 55.7% 3-year survival compared to 0.2% 3-year survival in those
possessing lymph node metastases [29]. See Fig. 3.5 for the forest plot from the
meta-analysis performed by Amini et al.
Lymph node involvement is one of the single most important prognostic pieces
of information for patients with ICC. Even in patients with negative margins after
resection, the presence of N1 disease appears to negate all the benefit of surgery
[26]. DeJong et al. [8] found that N1 disease translated to a survival of 22.9 com-
pared to 30.1 months in N0 patients, and that patients with N1 disease had the same
overall survival regardless of number of tumors or vascular invasion in the liver.
However, the presence of vascular and biliary invasion was strongly associated with
the risk of LN positivity, and even those without vascular and biliary invasion had a
9.1% and 20.7% chance of LN metastases, respectively. Tumor number and size,
36 J. F. Rekman and F. G. Rocha

Table 3.5 Factors associated with increased risk of lymph node metastasis (n = 258)a
Prognostic factor OR 95% CI P
Size of largest lesion (continuous) 0.99 0.92 to 1.07 0.80
Multiple tumors 1.56 0.81 to 3.02 0.19
Vascular invasion 2.89 1.56 to 5.35 0.001
Direct invasion of adjacent organ 1.74 0.68 to 4.47 0.25
Perineural invasion 1.87 0.78 to 4.49 0.16
Biliary invasion 4.03 1.94 to 8.36 < 0.001
Morphologic subtype
Mass-forming Reference
Papillary 0.65 0.15 to 2.74 0.55
Periductal-infiltrating 0.19 0.02 to 1.56 0.12
Mass-forming plus periductal-infiltrating 0.15 0.65 to 2.74 0.55
Reprinted from de Jong et al. [8]. Reprinted with permission © American Society of Clinical
Oncology. All rights reserved
Abbreviation: OR odds ratio
a
Univariate analysis

direct invasion of other organs, and mass-forming morphology were not associated
with increased rates of LN positivity in this study (see Table 3.5).
Long-term survival is possible, although rare, in the setting of LN metastases.
These long-term survivors likely had occult involved LNs on preoperative imaging
rather than grossly positive nodes on exploration. Bagante et al. [30] attempted to
answer the question of prognostic relevance of preoperative radiographic versus
pathologic LN status on long-term outcomes following resection. In this multi-­
institutional, international cohort of 1154 patients, 44.6% of patients had a lymph-
adenectomy. On final pathology, 200 (17.3% of total) patients had positive LNs and
315 (27.3% of total) patients had negative LNs. Preoperative imaging used to iden-
tify LN status was assessed by EUS, CT, MRI, or PET and was found to be inac-
curate in 40% of patients, suggesting it should not replace a formal lymphadenectomy.
Despite this fact, for those patients who did have positive LNs on imaging, 5y OS
was 25.8% or roughly half of the 5y OS (49.7%) among patients without LN disease
on preoperative imaging (see Fig. 3.6).
In addition to studying predictive power of preoperative imaging for ICC LNs,
Bagante et al. assessed the AJCC 8th edition recommendation for a minimum recov-
ery of 6 LNs and whether this number was truly necessary. According to the AJCC
8th edition staging system, N1 disease patients have a 2.5-fold increased risk of
death at 5 years [15]. The findings of Bagante et al. [30] support both the survival
advantage and the quality of the LN harvest (6+ LNs). The 5y OS of N0 patients was
54.9% (IQR, 41.6–66.3) versus 15.2% (IQR, 8.7–23.4) for N1 patients (p < 0.001)
(see Fig. 3.7). Hazard of death for N1 patients compared to N0 patients increased
from 1.6 to 1.8 with radiologic assessment, to 2.4 with pathologic assessment, and
using the AJCC 8th edition recommendations for nodal harvest, to 3-fold (HR 3.03;
p < 0.001).
3 Staging and Prognosis 37

100% Negative
Positive
75% Not Harvested

50%

25%

0%
0 1 2 3 4 5
Time, Year
Number at risk

Negative 315 232 167 112 65 45

Positive 200 112 51 29 16 9
Not Harvested 638 474 311 212 143 88

Fig. 3.6 Kaplan-Meier overall survival curves for patients with intrahepatic cholangiocarcinoma
stratified by pathologic nodal status. (Reprinted by permission from SpringerNature. Adapted from
Bagante et al. [30])

100%
N0
N1
75%

50%

25%

0%
0 1 2 3 4 5
Time, Year

Number at risk

N0 117 86 60 42 24 16

N1 200 113 51 29 16 9

Fig. 3.7 Kaplan-Meier overall survival curves for patients with intrahepatic cholangiocarcinoma
stratified by AJCC/UICC 8th edition nodal stages. (Reprinted by permission from SpringerNature.
Adapted from Bagante et al. [30])
38 J. F. Rekman and F. G. Rocha

Some studies have suggested lymphadenectomy may have a therapeutic effect on

local recurrence; however, prospective evidence to support this statement is lacking.
Because of the poor outcome in patients with gross N1 disease in the porta hepatis
on imaging (median survival 7–14 months), most authors advocate beginning with
systemic chemotherapy as an initial treatment, with restaging prior to considering
resection [1].

Role of Staging Laparoscopy

Staging laparoscopy for ICC is still controversial as consensus among surgeons

is lacking. NCCN guidelines suggest considering staging laparoscopy, and the
IHPBA guidelines suggest considering it if there are high-risk features (i.e., mul-
ticentric disease, high Ca19-9, possible peritoneal disease, or vascular invasion)
in order to avoid unnecessary laparotomy [1]. The yield of staging laparoscopy
for occult metastatic disease was 25–36% in two prospective studies [31, 32],
and therefore, a substantial portion of ICC patients would benefit from this pro-
cedure (see Fig. 3.8). In addition to surveying for peritoneal deposits, N2 lymph
node basins should be inspected, and laparoscopic ultrasound of the liver should
be considered to look for extensive intrahepatic disease or vascular invasion
­precluding resection [28]. Although this is recommended, practice variation
does occur.

Fig. 3.8 Intraoperative photographs during staging laparoscopy for intrahepatic cholangiocarci-
noma. Biopsies of white areas on peritoneal were positive for cholangiocarcinoma peritoneal car-
cinomatosis not visualized on preoperatively CT scan
3 Staging and Prognosis 39

Role of Tumor Markers

The AJCC/UICC has recently begun incorporating tumor markers into staging sys-
tems for tumors other than ICC. For example, the staging system for testicular can-
cer includes serum AFP measurements [9] and decreased survival in pancreatic
cancer patients has recently been shown to be independently associated with
increased Ca19-9 [33]. Both Ca 19-9 and CEA levels have been shown to have
potential prognostic significance for ICC independent of the LN status and tumor
morphologic characteristics in single-institution studies [23, 34].
Bergquist et al. [33] from the Mayo Clinic performed a review of 2816 patients
in the National Cancer Database to investigate the prognostic significance of Ca19-9
levels in ICC. They hypothesized that any Ca19-9 elevation in a resectable ICC
signifies a biologically aggressive phenotype and should indicate the need for mul-
tidisciplinary therapy. A Ca19-9 of 37 was considered the upper limit of normal in
this study and a multivariate Cox proportions hazard model was used to estimate
impact on survival. Elevated CA 19-9 was seen in 1878 (66.7%) of patients. Among
those patients with elevated Ca19-9, stage-specific survival was decreased in every
stage. In the resected cohort, elevated Ca19-9 resulted in similar perioperative out-
comes, but decreased long-term survival (median OS 22.6 months in Ca19-9 ele-
vated versus 47.8 months in Ca 19-9 normal patients, P < 0.001). In addition, they
contrasted the survival analysis, after incorporating Ca19-9 into the AJCC 7th edi-
tion staging system; with the original stage, the patient would have been assigned in
the original AJCC 7th TMN system. The new staging system had a concordance of
60.2%, as opposed to 54.6% for the AJCC 7th edition, with a Gamma statistic (mea-
sure of rank correlation) of 0.321 (improved from 0.144). This indicates a potential
improvement in prognostic staging power [35].
Despite having good evidence that Ca19-9 is associated with survival in ICC, the
optimal cut-off value has not yet been identified. Sasaki et al. [2] used a multi-­
institutional dataset to attempt to answer this question for both Ca19-9 and CEA
levels. The association of Ca19-9 levels with long-term survival had a bimodal dis-
tribution. At a threshold level of 100 IU/mL, the hazard of death increased (HR 1.66
95%CI 1.29–2.12), and then it increased again at 500 IU/mL (HR 3.55 95%CI
2.44–5.15). CEA elevation also showed prognostic significance in this study, but it
was not bimodal; prognostic power of CEA was noted only above a 5 ng/mL (HR
2.20 95%CI 1.57–2.81) threshold (see Fig. 3.9).
Based on these data, Ca19-9 cut-off values of 100 IU/mL and 500 IU/mL, and
5 ng/mL for CEA, were suggested as the best cut-off values for stratifying patients.
Kaplan-Meier estimates show that these values are prognostic of survival. Patients
with a Ca19-9 less than 100 IU/mL had a median OS of 50.0 months, whereas those
with a preoperative Ca19-9 of 100-500 IU/mL were found to have a median of
28.1 months (p < 0.001). Those with a Ca19-9 > 500 IU/mL had an even worse
prognosis, showing a median overall survival of only 15.5 months (p < 0.001). CEA
values provided a similar prognostic stratification.
 40

a Hazard ratio b
5
95% confidence intervals 4
4.5

3.5
3
3

2.5

Hazard Ratio
Hazard Ratio
2 2

1.5
Hazard ratio
1 95% confidence intervals
Log CA19-9 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 1
CA19-9 (IU/mL) CEA (ng/ml)
40 100 150 200 400 500 1000 3 4 5 6 7 8 9 10 11 12 13 14 15

Fig. 3.9 (a) The hazard of death remained relatively unchanged among patients with a Ca19-9 ranging from 20 IU/mL to 100 IU/mL. Following a plateauing
from 200 IU/mL to 500 IU/mL, there was a continuous increase in the hazard of death associated with Ca19-9 levels from 500 IU/mL to 1000 IU/mL (b) The
risk of death increased as CEA levels rose from 3 ng/mL to 5 ng/mL. (Reprinted from Sasaki et al. [2], with permission from Elsevier)
J. F. Rekman and F. G. Rocha
3 Staging and Prognosis 41

Similar to Bergquist [35], Sasaki et al. noted that both Ca19-9 and CEA are asso-
ciated with tumor biology. They are not simply surrogates for morphometric find-
ings such as tumor size and number, but are independently associated with overall
survival, even once controlling for these other factors using a multivariate model.
Both CEA and 19–9 were independently associated with increased risk of death in
their patient dataset. Using both markers, as compared to either alone, demonstrated
increased prognostic power. They concluded that the addition of these biomarkers
into the AJCC/UICC 8th edition and the LCSGJ schema improved prognostic strati-
fication and increased the Harrell’s C-index from 0.540 to 0.626 (p < 0.001) and
from 0.553 to 0.626 (p < 0.001), respectively.

Effect of Morphologic Subtype on Prognosis

Perhaps, an often-overlooked clinicopathologic prognostic indicator for ICC is

tumor morphology. The LCSGJ has classified cholangiocarcinoma into several cat-
egories based on gross appearance of the tumor: mass-forming (see Fig. 3.10), intra-
ductal growth (or papillary cholangiocarcinomas as they are sometimes termed),
and periductal-infiltrating (PI) type. The mass-forming type, as its name implies,
presents as a defined mass in the liver parenchyma. The intraductal-growth subtype
spreads inside the ducts by growing inward or within the lumen of the duct. PI types
are seen spreading along outside the ducts longitudinally, often causing enhance-
ment of the duct on cross-sectional imaging [5]. The precursor lesion to intraductal-­
growth cholangiocarcinoma, termed IPNBs (intraductal papillary neoplasm of the
bile duct), is thought to represent a similar carcinogenic pathway of intraductal
papillary neoplasms of the pancreas (IPMN) to pancreatic cancer. If an IPNB is
found, it should be resected as they have been shown to harbor invasive carcinoma
70% of the time [36].
Among 1083 patients in an international cohort undergoing liver resection for
ICC, 911 (84.1%) had mass-forming type, 30 (2.8%) intraductal growth, 54

Fig. 3.10 Large mass-

forming ICC in right liver
on CT scan
42 J. F. Rekman and F. G. Rocha

(5.0%) had a periductal-infiltrating type, and 88 (8.1%) had a mixed mass-form-

ing/periductal-­infiltrating type. Compared with mass-forming and intraductal-
growth patients, those tumors with a periductal-infiltrating component (even if
they were the mixed type) had more major vascular invasion (26.8% vs. 9.5%,
p < 0.001), lymphovascular invasion (46.1% vs. 28.8%, p < 0.001), perineural
invasion (37.7% vs. 17.9%, p < 0.001), positive margin resection (23.4% vs.
10.8%, p < 0.001), and N1 disease (59.2% vs. 34.7%, p < 0.001). Applying the
AJCC 8th edition, periductal-­infiltrating (and mixed mass-forming and periduc-
tal-infiltrating) tumors had more advanced T categories and 95.0% of these
patients were staged II/IIIa/IIIb versus 86.0% of mass-forming or intraductal-
growth type tumor patients (p = 0.017). After propensity score matching, patients
with mass-forming and intraductal-growth type tumors ICC had a significantly
better 5 year OS of 35.7% (95% CI 24.0–47.6) compared with the 26.2% (95% CI
16.4–37.1, p = 0.03) in periductal-infiltrating masses (p < 0.001) (see Fig. 3.11 for
Kaplan-Meier survival curves) [37]. These data are consistent with other studies
reporting that patients with mass-forming ICC tumors have a more favorable
prognosis [38] and that periductal-infiltrating tumors have increased association

100% MF/IG
PI/MF+PI

75%

50%

25%

0%
0 1 2 3 4 5
Time, Year

Number at risk

MF/IG 941 693 450 301 190 132

PI/MF+PI 142 85 50 29 16 10

Fig. 3.11 Kaplan-Meier overall survival curves stratified by morphological type classification.
MF mass-forming, IG intraductal growth, PI periductal-infiltrating, MF + PI mixed mass-forming
& periductal-infiltrating type. (Reprinted by permission from SpringerNature. Adapted from
Bagante et al. [37])
3 Staging and Prognosis 43

100%

90%

80%

70%
Incidence of recurrence

60%

50%
MF
40% PI/MF+PI
IG
30%

20%

10%

0%

0 1 2 3 4 5 6 7 8 9 10
Years

Fig. 3.12 Cumulative incidence of recurrence after surgery stratified by the morphological clas-
sification (mass-forming [MF], intraductal growth [IG], and periductal-infiltrating/mixed [PI/
MF + PI]) . (Adapted from Bagante et al. [42], with permission from Elsevier)

with jaundice, bile duct invasion, portal vein invasion, lymph node metastases,
and R1 margins [19]. There are also studies that have pointed to intraductal-
growth tumors having improved survival [39–41] but the data cannot be consid-
ered complete.
It is possible that data are mixed given the trend found by Bagante et al. in 2018
[42] of differing patterns of recurrence. Mass-forming and periductal-infiltrating
ICC patients are more likely to experience an early recurrence after surgery, whereas
intraductal ICC requires long-term follow-up past 5 years given their tendency for
late recurrence (see Fig. 3.12). Nearly 1 in 10 intraductal-growth ICC patients expe-
rienced a recurrence of 5 years after surgery (recurrence >5 years from surgery:
mass-forming, 2%, periductal-infiltrating ICC, 3%, intraductal growth, 9%;
p = 0.03). These recurrences occur both in intra- and extrahepatic. Until now, most
studies have failed to consider, or even report, tumor morphologic subtype, but
given recent evidence, this aspect of ICCs should likely be studied in depth prior to
future staging system revisions [37].
44 J. F. Rekman and F. G. Rocha

Prognosis Post-Resection

Margin Status

Long-term survival after surgery for ICC is dependent on several factors, the
majority of which have already been discussed in this chapter. One of those not
yet discussed is how margin status affects survival and recurrence. Complete R0
resection is the only potential cure for ICC, but the optimal surgical margin is
under debate. Some reports have described R0 margin status to be an important
predictor of survival and recurrence [43–45]. Ribero et al. [45] from the Italian
Intrahepatic Cholangiocarcinoma Study group found a significantly lower recur-
rence rate (53.9% vs. 73.6%) between R0 resections and those with a positive
margin. The same study group also found that survival rates were significantly
higher with negative margin rates (5 yr. survival 39.8% vs. 4.7%) with no impact
on survival of margin width. Other groups have suggested that margin status is not
a significant factor in outcome [10, 46]. Despite this, current recommendations
(NCCN, IHPBA) opt for R0 resection margins if at all possible, aiming for a mini-
mum of 0.5 cm.

Recurrence

Recurrences post-resection for ICC can occur in as many as 70% of patients [25,
27]. The prognosis after recurrence tends to be dismal (5-year survival ranging from
15% to 45% post-resection) and treatment strategies tend to be limited [27]. In con-
trast to hilar and distal extrahepatic cholangiocarcinoma, intrahepatic recurrence is
a major issue for ICC. Systemic failure tends to be a secondary consideration.
Following resection, 50–60% of patients experience recurrence in the liver, 20% in
the peritoneum, and 20–30% in the portal LNs [1, 16].
In one single-institution study out of Korea, cumulative survival rates for 128
patients who underwent hepatic resection for ICC were 73% at 1 year, 52% at
3 years, and 43% at 5 years [47]. Recurrent ICC developed in 81 patients with a
median time from resection to recurrence of 9 months (range, 0–124 months). The
median survival time after recurrence was 8 months (range 0–108 months), with
survival after documented recurrence noted to be 47% at 1 year, 23% at 3 years, and
15% at 5 years (see Kaplan-Meier survival curves for this population in Fig. 3.13).
On univariate analysis, nine factors were significant: male gender, site of recur-
rence, DFS, LN metastasis, lymphatic invasion, perineural invasion, bile duct inva-
sion, high initial CA 19-9 (>50 IU/mL), and high Ca19–9 at recurrence (>200 IU/
mL). Interestingly, multivariate analysis of this small patient cohort showed dis-
ease-free survival time shorter than 1 year and bile duct invasion to be the only
significant prognostic factor. Various treatment strategies were attempted for this
patient population as shown in Table 3.6.
 3 Staging and Prognosis 45

100

80
Survival after recurrence (%)

60
47%

40

21%

20 15%

0
0 12 24 36 48 60
Months

Number at risk

84 33 21 11 6 5

Fig. 3.13 Overall 1-, 3-, and 5-year survival rates after recurrence in ICC patients after resection
(n = 81) by Kaplan-Meier method. (Reprinted by permission from SpringerNature: Adapted from
Park et al. [47])

Table 3.6 Number of recurrences by type of treatment for recurrent intrahepatic cholangiocarcinoma
(n = 81)
Median DFS months Median survival after recurrence months
Type No (range) (range)
Surgery 12 13 (1–54) 21 (1–66)
TACE 2 21 (9–32) 66 (38–94)
RFA 4 5 (2–22) 17 (13–108)
Chemotherapy 21 6 (1–28) 10 (2–54)
Radiotherapy 3 7 (1–9) 7 (4–23)
CCRT 5 6 (0–28) 9 (5–17)
Supportive 34 5 (0–38) 4 (0–42)
care
Reprinted by permission from SpringerNature: Park et al. [47]
No number, DFS disease-free survival, TACE transarterial chemoembolization, RFA radiofre-
quency ablation, CCRT concurrent chemoradiotherapy
46 J. F. Rekman and F. G. Rocha

 rognosis for Locally Advanced Unresectable

P
and Metastatic ICC

Unfortunately, patients with advanced unresectable and metastatic ICC have a very
poor prognosis. Outcome is largely dictated by tumor extent at presentation, the
underlying quality of the liver and patient comorbidities. Patients with disease con-
fined to their liver have an overall better prognosis than those with metastatic dis-
ease at presentation [27]. There is limited data on adjuvant treatment for this
population, and most trials to date have included patients with not only intra- and
extrahepatic cholangiocarcinoma, but also gallbladder and ampullary cancers. One
of these trials, the Advanced Biliary Cancer (ABC)-02 trial, was a randomized
phase II-III trial that showed improvement in survival (11.7 months versus
8.1 months; P < 0.001) for this mixed population when treated with gemcitabine
and cisplatin rather than just gemcitabine alone. Progression-free survival was also
improved on the order of months (8 months versus 5 months; P < 0.001) [48].
There has been some study of anti-angiogenic therapy and disruption of the epi-
dermal growth factor receptor (EGFR) pathway for biliary cancers with the addition
of erlotinib 100 mg daily to a gemcitabine/oxaliplatin regime [49]. Although there
was no statistical difference for the primary outcome of progression-free survival
(PFS) for the entire cohort, a subgroup analysis showed patients with advanced
cholangiocarcinoma experienced 5.9 months of PFS with chemo and erlotinib com-
pared with just chemo alone (HR 0.73, 95% CI 0.53–1.00; P = 0.049). There is
increasing evidence for local treatments for locally advanced ICC, including TACE
(transarterial chemoembolization), DEB-TACE (doxorubicin eluting beads), and
HAI (hepatic arterial infusion) therapy [50]. However, these are experimental with-
out established prognostic estimates and will be discussed elsewhere in this
textbook.

Prognostic Nomograms

A nomogram is a graphical representation of a complex statistical formula accept-

ing multiple complex input variables to provide an easy to understand answer [11].
Nomograms tend to have a high discriminatory power since they can include more
variables and have less need for simplicity. In addition, they tend to be patient-­
specific, without the need to be applicable to wide populations. The use of a nomo-
gram to help answer patients’ questions regarding individualized prognostication is
becoming more common in clinical oncology management.
There are several nomograms available for ICC [16, 23, 51]. One of these, the
Wang nomogram, exceeded the discriminatory ability of the AJCC 7th edition stag-
ing system in a large multicenter cohort of 1054 patients. The nomogram was devel-
oped to predict prognosis post-resection for ICC, using data from a single institution
in China. Factors included were: serum CEA, vascular invasion, LN metastases,
3 Staging and Prognosis 47

0 1 2 3 4 5 6 7 8 9 10
Points

65 75 85
Age, y
55 45 35 25
15
Size, cm
1 3 5 7
>1
No. of Tumors
1
Nx
Nodal Status
N0 N1
Microscopic
Vascular Invasion
No Microscopic
Yes
Cirrhosis
No

Total Points
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

3-Year Survival, %
90 80 70 60 50 40 30 20 10

5-Year Survival, % 80 70 60 50 40 30 20 10

Fig. 3.14 A prognostic nomogram for predicting postsurgical survival of patients with resectable
intrahepatic cholangiocarcinoma. (Reprinted from Burkhart and Pawlik [3]. https://doi.
org/10.1177/1073274817729235)

direct invasion of other organs, and local extrahepatic metastasis. More recently,
Hyder et al. [16] developed a refined nomogram, also for patients undergoing resec-
tion for ICC (Fig. 3.14) from an international multi-institutional cohort collabora-
tion. Additional factors included were age at diagnosis and presence of cirrhosis.
External validation of this nomogram has confirmed its discriminatory ability ver-
sus the AJCC/UICC 7th edition [52], but likely should be reevaluated in light of the
new AJCC 8th edition.
Another prognostic score, called the MEGNA (Multifocality, Extrahepatic exten-
sion, Grade, Node positivity, and Age older than 60 years) prognostic score, based
on evaluation of data from 275 patients listed in the California Cancer Registry
undergoing resection for ICC between 2004 and 2011, was published recently [53].
The authors developed the prognostic score claiming all the factors in a nomogram
should be available prior to resection if it is to be useful for surgical decision-­
making. Based on multivariate analysis, the simplified MEGNA prognostic score
48 J. F. Rekman and F. G. Rocha

assigns 1 point each for the presence of: multifocality, extrahepatic contiguous
organ involvement, grade (high), node positivity, and age older than 60 years. The
score was validated in a SEER database cohort of ICC patients and offered an
improved discrimination index (0.21; 95% CI, 0.11–0.33) compared with the AJCC
7th edition (0.18; 95% CI, 0.08–0.30). Again, this prognostic score should be vali-
dated using the new AJCC 8th edition.

Conclusion

The goal of a staging system is to provide “high prognostic contrast” between groups
of patients to support patient education regarding long-term clinical outcomes, to
help plan the frequency of postoperative surveillance, and to aid in selecting patients
for adjuvant treatment. The AJCC/UICC is the most commonly used system world-
wide for ICC, but arguably provides only moderate prognostic contrast. Continued
active investigation based on the data provided in this chapter is necessary. In the
near future, molecular and tumor markers indicative of disease biology will likely be
used in clinicopathologic staging systems. Currently, more individualized prognostic
information may come from the clinical use of a nomogram.
Outcomes for patients with ICC who have unresectable and metastatic disease
are unfortunately dismal, and long-term results after hepatic resection continue to
be plagued by frequent recurrence. This high recurrence rate should reinforce a
multidisciplinary approach to ICC treatment. At present, however, hepatectomy is
the standard of care for resectable ICC, and lymphadenectomy for every case, with
consideration of diagnostic laparoscopy, should be part of every HPB surgeon’s
algorithm for accurate staging and prognosis.

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Chapter 4
Imaging

Pegah Khoshpouri, Timothy M. Pawlik, and Ihab R. Kamel

Introduction

Cholangiocarcinoma comprises less than 2% of all malignancies [1]. Even though

it is a rare type of cancer, it is the second most common primary malignancy of the
liver [2], accounting for 10–15% of all primary liver cancers. Imaging has a funda-
mental role in the diagnosis, staging, management, and assessment of response to
therapy of cholangiocarcinoma. To date, surgery is the only potentially curative
treatment for cholangiocarcinoma and imaging plays a significant role in surgical
planning.
Most cases of cholangiocarcinoma are extrahepatic (80–90%) [3]. Intrahepatic
cholangiocarcinoma can be divided into three subtypes including mass-forming,
periductal-infiltrating, and intraductal growing. The most common intrahepatic sub-
type is the mass-forming cholangiocarcinoma (>85%), which is also called periph-
eral cholangiocarcinoma. ICC usually has central fibrosis with progressive centripetal
enhancement on the delayed phase. The periductal-infiltrating subtype mostly arises
at the hilum of the liver, where it is called a Klatskin tumor. The growth of periductal-
infiltrating cholangiocarcinoma along the biliary ductal walls results in both dilata-
tion and narrowing of the biliary tree. The intraductal growing subtype conveys a
better prognosis due to its slow growth. This subtype often causes focal dilatation of
the biliary system likely due to mucin production [4]. These three subtypes of intra-
hepatic cholangiocarcinoma are differentiated on imaging by different features.

P. Khoshpouri · I. R. Kamel (*)

Russell H. Morgan Department of Radiology and Radiological Sciences,
Johns Hopkins Hospital, Baltimore, MD, USA
e-mail: [email protected]; [email protected]
T. M. Pawlik
Wexner Medical Center, The Ohio State University Wexner Medical Center,
Columbus, OH, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 53

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_4
54 P. Khoshpouri et al.

Imaging Techniques

Ultrasonography

Ultrasonography is often the first diagnostic imaging modality utilized in patients

with jaundice or right upper quadrant pain, which can be the initial presentation of
cholangiocarcinoma due to proximal biliary dilatation. A curved linear array trans-
ducer (2–6 MHz range) is suitable for assessment of the liver parenchyma.
Ultrasonography is also useful intraoperatively to guide surgical planning for
several reasons: (1) Ultrasonography provides live images that are free of radiation
risk. (2) Intraoperative ultrasonography can clearly demonstrate the intrahepatic
vasculature, which is very valuable for surgical procedures, for instance, during
partial hepatectomies. (3) Known and occult masses can be detected by intraopera-
tive ultrasonography, which is especially helpful during laparoscopic surgery, when
palpation of the mass is not possible [5]. (4) Intraoperative ultrasonography also
provides valuable information about intraductal biliary stones before their removal.
(5) Intraoperative ultrasonography can guide oncologic treatments such as radiofre-
quency ablation of liver tumors [6].

Computed Tomography (CT)

Computed tomography using multiphasic contrast enhancement protocol is very use-

ful for assessment of intrahepatic cholangiocarcinoma. Intraductal calculi could be
better differentiated from an intraductal mass on the pre-contrast phase imaging, since
the intraductal mass could enhance after the administration of the intravenous contrast
[7]. The arterial phase (20–25 sec postinjection) is useful to assess the vasculature
anatomy in surgical planning. Both the portal venous phase (60 sec postinjection) and
delayed phase (150–180 sec after the portal venous phase or 3–10 min after contrast
injection) can show progressive/persistent enhancement of the fibrous stroma [8].

Magnetic Resonance Imaging (MRI)

MRI with different sequences provides excellent tissue characterization. Useful

sequences for the detection and characterization of cholangiocarcinoma include
T1-weighted sequence (including pre and post-contrast, and in and out of phase
sequences), T2-weighted sequence, and diffusion-weighted imaging (DWI). Fat sup-
pression is important in reduction of fat signal within the liver parenchyma and in the
porta hepatis on T1-weighted imaging. Post-contrast images can be obtained at differ-
ent predetermined times including the arterial phase (20–25 sec postinjection), portal
venous phase (60 sec postinjection), and delayed phase (3 min postinjection). Bolus
tracking technique can also be used to accurately time post-contrast images [7, 9].
4 Imaging 55

Hepatobiliary contrast agents including gadobenic acid (MultiHance) and gadox-

etate disodium (EOVIST) are lipophilic. Therefore, these agents are useful in func-
tional assessment of hepatocytes when taken up by hepatocytes and then secreted
into the biliary system. Both gadobenic acid and gadoxetate disodium are hyperin-
tense on T1-weighted sequence images. Hepatobiliary phase imaging can be
obtained approximately 120 min post-administration of MultiHance and 10–20 min
after administration of EOVIST. Due to the combined extracellular and rapid hepa-
tobiliary features of EOVIST, cholangiocarcinoma demonstrates some progressive
enhancement from arterial phase to delayed phase on post-EOVIST T1-weighted
sequence images. However, it still appears hypoenhanced compared with the liver
parenchyma on the delayed phase. The best tumor delineation can be appreciated on
the delayed phase images due to high uptake of contrast by liver parenchyma [10].
In patients with poor hepatic function, the liver parenchyma and the biliary system
will be poorly opacified [11].

Magnetic Resonance Cholangiopancreaticography (MRCP)

MRCP obtained by a heavily T2-weighted signal sequence is very helpful for assess-
ment of cholangiocarcinoma. MRCP shows detailed anatomy of the biliary system,
which can help distinguish benign from malignant obstruction. Unlike endoscopic
retrograde cholangiopancreaticography (ERCP) that is limited to the assessment of
biliary system distal to the area of obstruction, MRCP is a noninvasive imaging
modality that can assess the biliary system proximal to the area of obstruction. On
MRCP, slow-moving fluids including bile, appear hyperintense, while fast-moving
fluids, like blood, and background soft tissue including liver parenchyma and fat
appear hypointense. At least 4-hour fasting is recommended for MRCP to distend the
gallbladder and decrease gastric secretions and bowel movements [12].
It is well documented that DWI increases sensitivity of MRI for detection of
cholangiocarcinoma. DWI is based on the fact that intact cell membrane limits
motion of the water molecules. Highly cellular microenvironments, like malignant
neoplasms, cause restricted diffusion and low ADC values. Therefore, DWI may
help in distinguishing malignant from benign strictures which is critical for
periductal-­infiltrating subtypes of cholangiocarcinoma. The degree of restriction on
DWI-MR has been shown to be an independent preoperative prognostic biomarker
for intrahepatic cholangiocarcinoma [13].

Positron Emission Tomography (PET)

Functional imaging of cholangiocarcinoma is feasible by PET. PET can be fused

with CT or MRI to add anatomic details to functional assessment. PET is based on
increased utilization of glucose by tumor cells. A radiotracer, 18-­fluorodeoxyglucose
56 P. Khoshpouri et al.

(18 FDG), is administered intravenously and is transferred into the tumor cells by
glucose transporter type 1 (GLUT-1). FDG is then trapped inside the cell after phos-
phorylation by a hexokinase into FDG-6-phosphate. Overexpression of GLUT-1
and hexokinase by tumor cells causes FDG accumulation inside the cells, which is
detected as hot spots on PET. Although not all the neoplasms are FDG avid, all
types of intrahepatic cholangiocarcinoma are FDG avid, which makes PET a useful
functional imaging modality for assessment of cholangiocarcinoma [3, 14].
Detection of distant metastasis can significantly affect medical and surgical man-
agement of patients with cholangiocarcinoma. PET provides sensitivity close to
100% for detection of cholangiocarcinoma metastasis >1 cm, and therefore, can add
value to surgical planning [14]. Although PET is less helpful with infiltrative tumors,
it can detect focal tumors as small as 1 cm [15]. Of note, the sensitivity of PET is
higher in the detection of intrahepatic cholangiocarcinoma (90%) compared to
extrahepatic cholangiocarcinoma (60%) [14].

Mass-Forming Cholangiocarcinoma

Ultrasonography

Ultrasonographic manifestation of mass-forming cholangiocarcinoma depends on

tumor size. Tumors less than 3 cm are usually isoechoic to hypoechoic, while tumors
greater than 3 cm are usually echogenic relative to the surrounding liver paren-
chyma. A hypoechoic halo is noted in 35% of cases, which corresponds to tumor
compression on, and infiltration into, the peripheral liver parenchyma [16, 17]
(Fig. 4.1a). Mass-forming cholangiocarcinoma usually has a well-demarcated, yet
irregular margin. Capsular retraction is often an additional imaging feature [18].

Computed Tomography

On noncontrast CT, mass-forming cholangiocarcinomas are usually seen as homo-

geneously hypodense masses with lobular margins [19]. In the arterial and portal
venous phase images, heterogeneous peripheral enhancement is seen, with progres-
sive central enhancement in the delayed phases [19, 20] (Fig. 4.1b, c). The amount
of delayed enhancement indicates the fibrous tissue content of the tumor. More
fibrotic interstitial tissue is usually associated with a worse prognosis. Some data
suggest that more than two-thirds enhancement of the tumor on delayed phase
images is associated with a poor prognosis [19, 21].
CT can show biliary dilatation distal to the mass [21]. Cholangiocarcinoma
rarely invades the vasculature to cause tumor thrombosis; however, narrowing of the
hepatic and portal veins can be seen on CT [22]. In case of severe portal stenosis,
atrophy of the associated liver segment can occur [23]. Similar to ultrasonography,
liver capsular retraction can be appreciated on CT [20] (Fig. 4.1c).
4 Imaging 57

a b

c d

e f

Fig. 4.1 Mass-forming cholangiocarcinoma. Ultrasonography (a) shows a heterogeneous

echotexture mass with hypoechoic halo (arrows) and dilated bile ducts (arrowheads). Axial (b) and
coronal (c) contrast-enhanced CT in portal venous phase shows a centrally hypoenhancing mass
with lobular enhancing margins (arrows). Capsular retraction adjacent to the tumor (notched
arrows) and necrotic hilar adenopathy (arrowhead) are also noted on coronal (c) view. T1-weighted
post-contrast images (d–f) demonstrate progressive centripetal enhancement of the mass that cor-
relates with progressive enhancement of the fibrous stroma. T2-weighted sequence (g) shows cen-
tral dark signal suggestive of fibrous stroma (arrow). DWI sequence (h) shows peripheral diffusion
restriction of the tumor (arrows). PET CT (i) demonstrates high FDG uptake in the periphery of the
tumor (arrows)
58 P. Khoshpouri et al.

g h

Fig. 4.1 (continued)

 agnetic Resonance Imaging and Magnetic Resonance

M
Cholangiopancreatography

Mass-forming cholangiocarcinoma appears as a homogeneous T1 hypointense and

T2 hyperintense mass with an irregular border. Peripheral biliary dilatation can be
seen similar to that on CT imaging. Contrast enhancement is also similar to that on
CT, with early peripheral and progressive central enhancement on more delayed
phase imaging (Fig. 4.1d–f). Slow diffusion of contrast through the tumor is attrib-
utable to the fibrous stroma. A central low signal focus on T2-weighted imaging
represents severe fibrosis (Fig. 4.1g). Peripheral early enhancement and rapid wash-
out correspond to an area of active growth [17, 24]. The tumor is hypoenhancing on
the delayed and hepatobiliary phases using a hepatobiliary contrast agent, due to
lack of normal hepatocytes in the tumor.
Cholangiocarcinoma can be differentiated from hepatocellular carcinoma (HCC)
based on its enhancement pattern. HCC demonstrates diffuse heterogeneous
enhancement on early post-contrast phase imaging and washout of contrast on
delayed imaging. In addition, cholangiocarcinoma usually does not invade the
hepatic vasculature which is more common in HCC. The presence of cirrhosis
favors HCC over cholangiocarcinoma [25, 26]. There can be an overlap in dynamic
contrast enhancement pattern of intrahepatic cholangiocarcinoma and HCC in
4 Imaging 59

tumors less than 3 cm. DWI may help distinguish these tumors when other sequences
are equivocal [13] (Fig. 4.1h).

Positron Emission Tomography

Sensitivity of FDG PET imaging to detect mass-forming intrahepatic cholangiocar-

cinoma is 85% versus only 18% for infiltrating cholangiocarcinoma [15]. High
tracer uptake indicates high metabolism of the lesion that determines the activity of
the tumor (Fig. 4.1i).

Periductal-Infiltrating Cholangiocarcinoma

Ultrasonography

Periductal-infiltrating cholangiocarcinoma is characterized by biliary duct narrow-

ing/obliteration or dilatation without a mass-forming tumor [27]. Periductal-­
infiltrating cholangiocarcinoma can present as thickening of the biliary system with
or without a mass-like lesion around dilated or narrowed bile ducts. Findings are
usually isoechoic, but echogenicity is not specific and the tumor can be hypoechoic
or hyperechoic [24]. Non-visualization of the right and left biliary duct junction is a
characteristic ultrasonographic finding for periductal-infiltrating cholangiocarci-
noma at the liver hilum, also known as Klatskin tumor [27].

Computed Tomography

CT presentation of periductal-infiltrating cholangiocarcinoma includes biliary dil-

atation or narrowing with periductal parenchymal thickening. Segmental dilatation
of the biliary system indicates more proximal tumor involvement [23, 28]. These
tumors are usually hilar and present with biliary dilatation in both liver lobes and
contraction of the gallbladder (Fig. 4.2a–c). Peripheral tumors are usually not
purely periductal-infiltrating and are often associated with mass-forming cholan-
giocarcinoma [28]. Normal bile ducts demonstrate water density unless there is
intraductal sludge or stone.
Hilar periductal-infiltrating cholangiocarcinoma can be confused with periportal
lymphangitic metastasis of an extrahepatic tumor. Unlike periductal-infiltrating
cholangiocarcinoma, periportal metastasis usually involves both hepatic lobes and
may not cause ductal dilatation [23, 29].
60 P. Khoshpouri et al.

a b

c d

e f

Fig. 4.2 Periductal-infiltrating cholangiocarcinoma (Klatskin tumor). Axial CT in arterial phase

(a), portal venous phase (b), and coronal reconstruction (c) demonstrate dilatation of the biliary
tree in both liver lobes (arrows). T1-weighted MR images show small heterogeneously enhancing
lesion (arrow) adjacent to the hepatic hilum with progressive enhancement during arterial phase
(d) and portal venous phase (e) T2-weighted sequence (f) shows centrally hypointense signal
(arrow). MRCP (g) demonstrates significant dilatation of the biliary system in both liver lobes with
abrupt cut-off in the hepatic hilum at the level of tumor (arrow)
4 Imaging 61

 agnetic Resonance Imaging and Magnetic Resonance

M
Cholangiopancreatography

Elongated and branching growth pattern along an irregularly narrowed or dilated

bile duct is characteristic of periductal-infiltrating cholangiocarcinoma. This tumor
demonstrates periductal thickening and increased enhancement and is T1 hypoin-
tense and T2 hyperintense (Fig. 4.2d–f). Benign stricture in its early stages can
present similar to periductal-infiltrating cholangiocarcinoma on MRCP. These
tumors present as irregular wall thickening of the bile duct, which is suggestive of
cholangiocarcinoma when the thickening is greater than 5 mm. There is also
upstream dilation of the intrahepatic ducts [5, 23] (Fig. 4.2g). The tumor demon-
strates progressive enhancement on delayed phase. Portal vein invasion is also pos-
sible, which can be detected on MR (Fig. 4.3).

a b

Fig. 4.3 Periductal-infiltrative cholangiocarcinoma. Axial T1-weighted post-contrast image (a) in

the arterial phase demonstrates ill-defined infiltrative tumor centered in the right liver lobe with
extension to the periphery. Axial (b) and coronal (c) portal phase images demonstrate progressive
enhancement of the tumor. Note extensive tumor invasion of the portal vein (arrow in c)
62 P. Khoshpouri et al.

Intraductal Cholangiocarcinoma

Ultrasonography

Intraductal growing cholangiocarcinoma usually presents with biliary duct dilata-

tion and sometimes ductal narrowing. Occasionally, a polypoid hyperechoic mass
can be seen, which is usually confined to the wall of the biliary system. Anechoic
mucin that is produced by the tumor can obscure visualization of the mass [7, 30].

Computed Tomography

Intraductal growing cholangiocarcinoma usually manifests as biliary ectasia on

CT. This subtype of cholangiocarcinoma can present as a polypoid intraductal
lesion with proximal ductal dilatation, as intraductal cast-like lesion with biliary
stricture and proximal duct ectasia, or as diffuse biliary dilatation with or without a
polypoid intraductal lesion [17, 30]. Mucin production by tumor can result in biliary
dilatation with intraductal material higher in attenuation than simple fluid. Biliary
dilatation can be out of proportion to the tumor size [18, 31, 32].
Since these tumors are intraductal, these lesions can be mistaken with intraductal
stones. As such, accurate interpretation of images can be challenging when intra-
ductal cholangiocarcinoma and hepatolithiasis coexist. The tumor itself, if visual-
ized, shows enhancement on post-contrast images. Noncontrast images can be
helpful, which show high attenuation in intraductal stones. Intraductal cholangio-
carcinoma is hypoattenuating on noncontrast CT when large enough (more than
1 cm) to be seen [17, 33]. Hepatolithiasis can cause benign biliary strictures second-
ary to inflammation, which should be differentiated from malignant biliary stricture
caused by cholangiocarcinoma [7, 34]. Imaging features to suggest malignant stric-
ture include asymmetric and irregular long segment narrowing, presence of enhanc-
ing ducts and periductal lesion, and lymphadenopathy [23, 35].

 agnetic Resonance Imaging and Magnetic Resonance

M
Cholangiopancreatography

Intraductal growing cholangiocarcinoma lesions are usually hypointense on

T1-weighted sequence and hyperintense on T2-weighted sequence. These lesions
demonstrate heterogeneous enhancement on the arterial and portal venous phase
post-contrast, and nodular, well-defined mass-like progressively enhancing lesions
are visible on the more delayed phase. This feature reflects the desmoplastic nature
of intraductal cholangiocarcinoma tumors [13]. Proximal biliary duct dilatation can
be appreciated on different sequences. High tissue characterization of MRI allows
4 Imaging 63

detection of multifocal tumors since these tumors are spreading along the mucosal
surface of the biliary tree [30].

Response to Treatment

Surgical resection is still the only well-established treatment option for patients
with intrahepatic cholangiocarcinoma [36]. However, less than a third of cases are
resectable at the time of diagnosis [37]. Systemic intravenous chemotherapy pro-
vides a limited benefit for unresectable cases. Recent studies have suggested an
increased survival with intra-arterial therapies including trans-arterial chemoembo-
lization (TACE) [38]. Assessment of treatment response after intra-arterial treat-
ment of unresectable intrahepatic cholangiocarcinoma can be challenging.
Traditionally, decrease in size and enhancement of the tumor on axial view have
been accepted as indicators of tumor response to therapy by the World Health
Organization, the Response Evaluation Criteria in Solid Tumors (RECIST), the
modified RECIST (mRECIST), and the European Association for the Study of the
Liver [39] (Fig. 4.4).

a b

Fig. 4.4 Baseline T1-weighted post-contrast image (a) shows a mass-forming intrahepatic chol-
angiocarcinoma with central enhancement (arrow) and capsular retraction (notched arrow) before
treatment. T1-weighted post-contrast images show favorable response to trans-arterial chemoem-
bolization therapy with decrease in tumor enhancement and size (double arrows), 4 months (b) and
10 months (c) following therapy, respectively
64 P. Khoshpouri et al.

Since cholangiocarcinoma is a hypovascular tumor with irregular peripheral rim

enhancement, assessment of enhancement on bidirectional images could be subopti-
mal. Rather, volumetric enhancement can be measured more reliably [40]. Changes in
size of the tumor after treatment may also be delayed, while functional MR techniques
can provide information about early cellular changes. Diffusion-weighted imaging,
apparent diffusion coefficient (ADC) map, and contrast-enhanced volumetric MR
imaging can add value in assessment of tumor response to treatment. In particular,
DWI and ADC values can provide information on tumor viability and structure.
Specifically, intact cellular membrane in viable tissue restricts motion of water mole-
cules that results in low ADC values. In contrast, increased permeability of cell mem-
brane in necrotic tissue allows free motion of water molecules, which results in higher
ADC values. Volumetric ADC, percentage viable tumor volume, and viable tumor
burden and changes after treatment are novel MR imaging parameters that provide
prognostic information in unresectable intrahepatic cholangiocarcinoma undergoing
TACE [39, 41]. In addition, baseline multiparametric MRI assessment including per-
centage viable tumor volume and volumetric ADC can help predict mortality among
patients with intrahepatic cholangiocarcinoma undergoing TACE [42].

Conclusion

Imaging has a significant role in diagnosis, staging, management, and assessment of

response to treatment for intrahepatic cholangiocarcinoma. MRI/MRCP and PET
can add value to the management of these patients. Recent advances in MR technol-
ogy have revolutionized assessment of response of unresectable intrahepatic chol-
angiocarcinoma to more modern treatment options.

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Chapter 5
Surgical Treatment

Georgios Antonios Margonis and George A. Poultsides

Introduction

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy

(after hepatocellular carcinoma) arising from the liver, comprising 10–15% of liver
tumors. Importantly, its incidence is increasing worldwide. ICC arises from cholan-
giocytes in peripheral bile ducts proximal to the second-order bile ducts and can
grow in different patterns. Specifically, it can grow as a mass within the liver (i.e.,
mass-forming subtype), along the bile duct in a longitudinal fashion (i.e., periductal
infiltration subtype), or within the bile duct lumen (i.e., intraductal subtype).
Irrespective of growth pattern, ICC commonly lacks specific symptoms, such as
jaundice (as only a portion of intrahepatic bile ducts are usually obstructed and a
sufficient number of liver segments have adequate biliary drainage), and, in turn, is
frequently diagnosed incidentally or at an advanced stage. Surgery is the mainstay
of treatment and the only modality that can potentially achieve cure in a small sub-
set of patients. Unfortunately, only a minority (20–30%) of patients present with
resectable disease at the time of diagnosis. As such, defining and expanding resect-
ability criteria both from technical and oncologic perspectives are critical.

G. A. Margonis
John L. Cameron Division of Pancreatic and Hepatobiliary Surgery, Department of Surgery,
The Johns Hopkins Hospital, Baltimore, MD, USA
e-mail: [email protected]
G. A. Poultsides (*)
Department of Surgery, Stanford University Hospital, Stanford, CA, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 67

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_5
68 G. A. Margonis and G. A. Poultsides

Resectability and Patient Selection

As with any solid tumor, resectability is defined by technical and oncologic param-
eters. Regarding the former, technically resectable ICCs are those that can be com-
pletely extirpated with preservation of an adequate future liver remnant (FLR),
namely two or more continuous segments, with intact hepatic arterial and portal
venous inflow, hepatic venous outflow, and biliary drainage. What percentage of
liver constitutes an adequate FLR depends on the quality of the liver parenchyma.
According to the generic 20/30/40 rule, an FLR of at least 20% is needed in patients
with otherwise healthy livers, at least 30% in those pretreated with chemotherapy or
with steatosis, and at least 40% in those with early cirrhosis [1]. FLR can be esti-
mated by several ways. The ratio of future liver remnant (FLR) volume to standard-
ized total liver volume has been traditionally used. In cases where the FLR is
borderline or less than the abovementioned cut offs, portal vein embolization (PVE)
can be used to induce FLR hypertrophy. The degree of hypertrophy and kinetic
growth rate have also been found to be protective factors against postoperative liver
failure, in addition to FLR volume, for patients undergoing resection of colorectal
liver metastasis after PVE [2]. PVE has been studied specifically in biliary tract
cancers, and its benefit for patients with advanced biliary cancer who are to undergo
extended, complex hepatectomies has been confirmed [3]. Nonetheless, it has been
shown that FLR function may precede FLR size. For example, 99mTc-mebrofenin
hepatobiliary scintigraphy (HBS), a technique that assesses the function of the FLR
instead of its volume, is more predictive of postoperative liver failure compared to
traditional CT volumetry [4].
After establishing that a patient with ICC is technically resectable, the surgeon
needs to assess the oncologic benefit conferred by the operation. Lymph node
metastasis beyond the porta hepatis or distant metastatic disease (including intrahe-
patic metastases) is a clear contraindication to resection. Regarding the latter,
besides cross-sectional imaging including Positron Emission Tomography (PET),
diagnostic laparoscopy (DL) can be used to enhance detection of metastatic disease.
Prior studies have demonstrated that the use of DL can identify occult metastatic
disease in 25–36% [5]. As such, the National Comprehensive Cancer Network
(NCCN) guidelines suggest that, if imaging does not reveal any metastatic disease,
DL to rule out unresectable disseminated disease should be considered [6]. The
Americas Hepato-Pancreato-Biliary Association (AHPBA) expert consensus rec-
ommended DL, but only in high-risk patients [7], such as patients with multicentric
disease, elevated CA 19-9, questionable vascular invasion, or suspicion for perito-
neal disease. Further, they suggested adding laparoscopic intraoperative ultrasound
of the liver in high-risk patients to assess for intrahepatic tumors and vascular inva-
sion. In contrast with the liberal policy of NCCN and the more restrictive of AHPBA,
The International Liver Cancer Association (ILCA) guidelines did not support rou-
tine use of DL because of limited amount of supportive data and suggested further
research [8]. Lastly, a recent expert commentary suggested that, in some cases, DL
may not be sufficient to safely determine resectability and an open exploration with
at least a mini-laparotomy may be required [9].
5 Surgical Treatment 69

If a patient is technically resectable and distant metastatic disease has been ruled
out, patient selection for surgery may be further refined by evaluating factors associ-
ated with poor outcomes, such as microscopically positive surgical margin, nodal
status, tumor size, multifocality, and major vascular invasion [10].

Surgical Margin Status

R0 Versus R1 Although an R0 margin is the gold standard in most malignancies,

the fact that ICC is commonly diagnosed at an advanced stage (e.g., large tumors,
invading adjacent structures) often renders an R0 resection technically challenging.
As such, many studies have assessed whether an R1 resection truly impairs long-­
term outcomes. Some earlier studies (before 2010) failed to demonstrate a survival
detriment from R1 resections [11, 12], but may have been underpowered to detect
survival differences between R0 and R1. Larger subsequent studies have indicated
oncological benefit from R0 resections. For example, in a large cohort of 224
patients with ICC, Yeh et al. compared R0 vs R1 vs R2 and showed that median
survival was 26.2 vs 11.4 vs only 5.8 months, respectively [13]. Similarly, a 2016
meta-analysis that collectively analyzed all eligible studies concluded that “patients
with negative surgical margin had significantly favorable overall survival and
progression-­free survival after surgical resection for ICC.” [14] Thus, there is a
consensus that surgeons should strive for an R0 margin as it is substantially associ-
ated with long-term outcomes.
This is reflected in various guidelines. For example, the ILCA guidelines pub-
lished in 2014 stated that “The goal of surgical resection is to remove all the disease
with negative microscopic (R0) margins while preserving an adequate remnant liver
volume.” [8] Similarly, the AHPBA expert consensus statement from 2015 con-
cluded that “Resectability for ICC is defined by the ability to completely remove the
disease with curative intent (R0) while leaving an adequate liver remnant.” [7]
Lastly, the 2014 NCCN guidelines stated that “Available evidence (although not
conclusive) supports the recommendation that hepatic resection with negative mar-
gins should be the goal of surgical therapy for patients with potentially resectable
disease.” [6]
Width of Negative Margin Given the consensus on the necessity of R0 margins,
the next question centers around the optimal margin width. Although many studies
have compared R0 vs R1, a much smaller number of studies examined margin
width. Farges et al. were among the first to suggest an optimal margin width [15].
They demonstrated that among patients with N0 disease, an incremental increase of
margin width was associated with improved median survival (≤1 mm: 15 months;
2–4 mm: 36 months; 5–9 mm: 57 months; ≥10 mm: 64 months, P < 0.001), and a
margin >5 mm independently predicted long-term survival (OR 2.2). Subsequently,
in the largest study to date (n = 583), our group suggested that surgeons should
strive to achieve at least a 1 cm margin when resecting ICC to optimize long-term
70 G. A. Margonis and G. A. Poultsides

Product-Limit Survival Estimates

a
With Number of Subjects at Risk
1.0 Censored
Proportion Patients
Recurrence-Free

0.8

0.6

0.4

0.2

0.0
0 12 24 36 48 60

Follow-Up Time (months)

positivity
1: 1-4 mm 2: 5-9 mm 3: >=10 mm 4: POSITIVE_MARGIN

b Product-Limit Survival Estimates

With Number of Subjects at Risk
1.0
Proportion Patients Alive

Censored

0.8

0.6

0.4

0.2

0.0
0 12 24 36 48 60

Follow-Up Time (months)

positivity
1: 1-4 mm 2: 5-9 mm 3: >=10 mm 4: POSITIVE_MARGIN

Fig. 5.1 Recurrence-free (a) and overall survival (b) following hepatic resection in 583 patients
with intrahepatic cholangiocarcinoma stratified by margin status and width of negative margin. R1
margin status was associated with an inferior long-term outcome. Moreover, there was an incre-
mental worsening RFS and OS as margin width decreased. (Adapted with permission from
SpringerNature: Spolverato et al. [16])

outcomes (Fig. 5.1) [16]. This conclusion was confirmed by a study from Hong
Kong that found that the disease-free survival increased from 14.1 to 86 months
with a width of more than 1 cm (P = 0.008) [17]. Similarly, a meta-analysis per-
formed in 2016 confirmed that 10 mm should be the optimal margin width when
overall survival outcome was the main endpoint [18].
5 Surgical Treatment 71

In contrast with margin status (R0 vs R1), the most recent guidelines do not
make any specific recommendations regarding the optimal margin width.
Specifically, neither the NCCN guidelines or the AHPBA expert consensus, nor the
ILCA guidelines specify an optimal margin width [6–8]. The lack of specific rec-
ommendations may be attributed to the fact that, with the exception to the Farges
study, all other studies and the meta-analysis were published after the guidelines
were proposed. Given that margin width is the only surgeon-controlled variable,
we believe that the aforementioned studies on optimal margin width will form the
basis for specific recommendations in the upcoming revision of the consensus
guidelines for ICC.
Surgical Margin Versus Extent of Resection Performing an R0 resection and
striving for a wide margin may warrant a more extensive hepatectomy. In fact, to
achieve an R0 margin, extended hepatectomy and/or resection of the extrahepatic
bile duct bifurcation may be necessary in 78% and 29% of ICC cases, respectively
[19]. In turn, one could hypothesize that these major resections, and not the margin
width per se, may be the reason why survival is improved with wide margins. To
our knowledge, only one study explicitly addressed this question. In 2017, Zhang
et al. demonstrated that margin width, rather than the extent of resection, was asso-
ciated with long-term outcomes. As such, if parenchymal-sparing resections can
achieve a margin width of ≥5 mm, they should be preferable to major hepatic
resections for ICC [20].

Margin Status and Nodal Disease Although there is a consensus that surgical mar-
gin status impacts survival, two studies have demonstrated that this is not applicable
in the setting of nodal metastases. First, Farges et al. found that although an R1
resection was an independent predictor of poor survival in N0 patients, survival was
comparable between R0 and R1 patients in those with N1 disease [15]. In 2014, Luo
and colleagues similarly showed that while surgical margin was a strong prognostic
factor in N0 patients, in the presence of LN metastasis, patients with R0 resections
had similar survival as those with R1 resections. In fact, in the presence of nodal
disease, the 5-year OS rates for the two groups were equally unfavorable (0% and
5.3%, P = 0.266) [21]. The surgeon should keep this information in mind when
treating an ICC patient with N1 disease, as extending the resection to address a
potential R1 margin may increase the morbidity of the surgery without an associ-
ated improvement in long-term outcome.

Margin Status and Adjuvant Therapy In surgical oncology, adjuvant therapy is

used in theory to “sterilize” an R1 margin and eradicate microscopic residual dis-
ease. Although prospective data are lacking, there are a few retrospective studies
that have explored whether adjuvant therapy may be useful in the R1 setting. For
example, a meta-analysis identified patients with an R1 resection as one of the few
groups that derived the greatest benefit from adjuvant therapy [22]. However, this
meta-analysis included different biliary tract cancers, and ICC was underrepre-
sented. More recently, ICC was the sole focus of a retrospective analysis of National
Cancer Database data, which showed that ICC patients with an R1/R2 surgical
72 G. A. Margonis and G. A. Poultsides

­ argin were among the few subsets of patients who derived oncological benefit
m
from adjuvant chemotherapy (19.5 vs. 11.6 months; P = 0.006) [23]. Subset analy-
ses, stratified by margin status, of the recently presented BILCAP trial (a multi-
center phase III trial randomizing patients to adjuvant capecitabine versus
observation after resection of cholangiocarcinoma or gallbladder cancer) and the
publication of ongoing trials such as the ACTICCA-1 (a multicenter phase III trial
randomizing patients to adjuvant gemcitabine and cisplatin versus observation, after
resection of cholangiocarcinoma or gallbladder cancer) will shed further light on
the role of adjuvant therapy, but still these trials may be underpowered for ICC spe-
cifically (as this is the rarest type of biliary tract cancers) [24, 25].
Although, similar to adjuvant chemotherapy, prospective data on the use of adju-
vant radiation are lacking, retrospective studies have suggested that adjuvant radia-
tion therapy may be of value. In fact, given that 60–80% of all recurrences are
locoregional, adjuvant radiation may be indicated at least for those with confirmed
or suspected locoregional residual disease (e.g., R1 resections, preoperative major
vascular involvement, or N1 disease) [26, 27]. Regarding the latter, in a study of
patients who underwent R0 resections but had ICC adherent to major blood vessels,
median OS was marginally better in the adjuvant intensity modulated radiotherapy
(IMRT) group compared to the surgery-only group (21.8 months vs 15 months,
P = 0.049) [28]. Similarly, another study demonstrated that tumor recurrence was
common (60.8%), even after an R0 resection, and suggested that adjuvant RT might
prevent locoregional recurrence [27]. Limited data on the use of adjuvant transarte-
rial chemoembolization (TACE), on the other hand, showed no association with
improved recurrence-free survival [29]. Lastly, stereotactic body radiation therapy
(SBRT) has been used for locally advanced, unresectable ICC, with some proposing
extrapolation of these results in the adjuvant setting [30].

Nodal Disease

Portal lymphadenectomy is routinely recommended for ICC to facilitate staging and

inform prognosis. There is no doubt that regional lymph node metastasis is one of
the strongest negative prognostic factors, as it likely reflects aggressive tumor biol-
ogy. In fact, its prognostic significance is so strong that when patients are classified
by LN status, other prognostic factors lose their significance. Nodal status has a
profound impact on AJCC staging. For example, in the 7th edition of AJCC, ICC
with regional lymph node metastasis was classified as stage IVA. Subsequently in
the 8th edition, regional lymph node metastasis was downstaged from IVA to
IIIB. To accurately establish N staging, previous data from our group have sug-
gested that at least three nodes should be removed from the porta hepatis [31].
However, the most recent recommendation of the AJCC staging schema is to dissect
at least six lymph nodes.
5 Surgical Treatment 73

N staging is not only informative but may guide the selection of neoadjuvant or
adjuvant treatment, which in turn may improve outcomes. The issue is that, as dis-
cussed in the case of R1, no phase III data exist on outcomes in ICC patients with
nodal disease treated with adjuvant treatment. However, three phase III trials (that
include other biliary tract cancers and have been recently completed or are under-
way) have evaluated the use of adjuvant therapy in resected ICC. The PRODIGE
12–ACCORD 18 study was completed recently and did not identify any subset of
patients who may benefit from adjuvant GEMOX. In the BILCAP study, a prespeci-
fied sensitivity analysis noted a statistically significant difference in overall survival
in favor of the capecitabine group, after adjusting for nodal status (along with other
risk factors) [32]. Of note, the BILCAP study included a higher number of patients
with LN-positive disease compared to PRODIGE 12 (54% vs 37%), which may in
part explain the different result. The results of the ACTICCA-1 study are pending.
Similar to BILCAP, both a meta-analysis of adjuvant treatment in biliary tract can-
cer (in which, however, ICC was dramatically underrepresented) and a recent retro-
spective study exclusively on ICC patients suggested that, among all patients with
resected disease, those with nodal disease may derive the greatest benefit from adju-
vant treatment (OR: 0.49 and HR: 0.54, respectively) [22, 33]. Lastly, a retrospec-
tive analysis of NCDB data demonstrated that, although median OS between
adjuvant chemotherapy and surgery alone was comparable (23 versus 20 months),
when stratified by lymph node status, chemotherapy was associated with a signifi-
cant improvement in median OS among N1 patients (19.8 vs. 10.7 months,
P < 0.001) [23].
As such, LN dissection may help select patients who will benefit from adjuvant
therapy. With regard to adjuvant therapy in N1 disease, the guidelines are conserva-
tive but consistent. Specifically, the AHPBA expert consensus suggested that “For
node-positive ICC, systemic therapy with either gemcitabine or 5-FU, or 5-FU-based
radiation should be considered.” [7] The NCCN guidelines state that lymph node
metastasis, among other factors, is a risk factor that could be considered as a crite-
rion for selecting patients for adjuvant treatment [6]. Similar to the other two guide-
lines, the ILCA guidelines state that “For those patients undergoing resection – especially
those with N1 disease – adjuvant therapy should be strongly considered.” [8]

Tumor Size and Multifocal Disease

Some earlier studies suggested that surgical resection for multifocal disease may be
futile due to high rates of local failure and poor survival [12]. However, in 2015, our
group compared patients with large or multifocal disease, defined as ≥7 cm or ≥2
tumors, vs those with single, solitary tumors and concluded that, although survival
is decreased in the former cohort, this group should still be carefully assessed for the
possibility of surgical resection [34]. In particular, patients with large or multifocal
tumors without any of three additional risk factors (more than three tumors, nodal
74 G. A. Margonis and G. A. Poultsides

metastasis, and poor tumor differentiation) had a 5-year OS rate of 28.8%, which
was comparable to the 30.5% OS rate of patients with a small, solitary tumor. In a
subsequent study from Pittsburgh, Wright et al. defined multifocal disease as two or
more tumors and compared intra-arterial treatments (IAT) vs surgery in those
patients [35]. Although no tumor size cut off was used as an inclusion criterion,
median tumor size of the surgery group was 7.5 cm, which is comparable to the
tumor size in our study (all tumors were equal or larger than 7 cm), compared to
10.6 cm for the IAT group. As expected, the surgery and IAT groups were not com-
parable. Many adverse prognostic factors were more commonly associated with the
IAT group: macrovascular invasion (44.1% vs 24.6%, P = 0.027), nodal metastases
(57.6% vs 28.6%, P = 0.002), bilobar disease, (88.1% vs 47.4%, P < 0.001), and
portal vein thrombosis (22% vs 10.5%, P = 0.09). As such, the IAT group was heav-
ily biased towards worse baseline prognosis. Interestingly, despite this, survival was
comparable in the two groups (20 months for surgery vs 16 months for IAT,
P = 0.627). As such, surgery did not appear to confer any significant incremental
benefit over IAT to those patients with multifocal ICC. A third study from Kyoto
University compared survival in patients with intrahepatic metastasis (IM), vascular
invasion (VI), and regional lymph node metastasis (LM). Among the three groups,
patients with nodal disease had the worst survival at 12.8 months vs 18.7 for IM and
23.4 for VI. After comparing with similar but non-resected patients, they concluded
that surgical resection may be justified for some advanced ICC patients with IM, VI,
or LM [36].
Of note, a potential pitfall in interpreting outcomes of studies in patients with
multifocal ICC concerns satellite lesions vs intrahepatic metastases. In the afore-
mentioned Pittsburgh study, the authors mentioned that they did not distinguish
between those two and both were included as multifocal disease. In our study,
there is no specific mention to these two entities. In an editorial, however, it was
suggested that, before including them in the same category, it should first be
investigated whether these two entities are prognostically different [37]. To this
end, a recent study from Italy compared the long-term outcomes of patients with
satellite nodules in the same liver segment vs those with multifocal scattered
tumors in different liver segments [38]. The former may correspond to nodules
that spread from the primary tumor, while the latter may correspond to “true”
metastatic disease. Importantly, 5-year overall survival after resection was much
lower in the latter group (34.2% vs 9.9%, P < 0.001), indicating that “true” meta-
static disease may reflect more aggressive tumor biology, compared to nodules
that are spread in a close distance from the primary tumor. Perhaps, more impor-
tantly, from a practical standpoint, they found that, specifically in patients with
“true” metastatic disease, the presence of LN metastases and the inability to
achieve an R0 resection portend such poor prognosis that surgical resection should
not be considered.
The cited studies on multifocal ICC are not directly comparable as both design
(single vs multi-institutional design) and comparison groups (Surgery vs IAT,
Surgery in multifocal vs Surgery in unifocal, “true” multifocal vs satellite nodules)
5 Surgical Treatment 75

differed. Interestingly, although the conclusions drawn about eligibility for surgery
of patients with multifocal ICC appear disparate, the results are similar to an extent.
Specifically, median OS of the multifocal group was 21.1 months in the study from
our group vs 20 months in the Pittsburgh study vs 18.7 months in the Kyoto study
vs 25–30 months in the Italian study. As such, the decision to offer surgery in a
patient with multifocal ICC should take into consideration the morbidity of the sur-
gery, the number and location of additional tumors (distance from main tumor), the
presence of other unfavorable factors (nodal disease, anticipated margin), and the
efficacy of alternative treatments.
ILCA guidelines recommend that “Patients demonstrating intrahepatic metas-
tases should not undergo resection; Recommendation B1.” [8] This recommenda-
tion is in line with that made by the AHPBA expert consensus statement: “Multiple
bilobar or multicentric tumours are formal contraindications to resection.” [7] In
contrast, NCCN guidelines are more liberal and state that “although multifocal
liver disease is generally representative of metastatic disease and is a contraindi-
cation to resection, in highly selected cases with limited multifocal disease resec-
tion can be considered.” [6] It is obvious, from the variability of the aforementioned
guidelines, that further study is warranted to more accurately define what consti-
tutes “highly selected ICC cases with limited multifocal disease,” where surgical
resection may be of benefit. Furthermore, future guidelines and studies will need
to assess the “optimal threshold” between the two ends of the spectrum of multi-
focal disease, one being limited satellitosis and the other being “true” intrahepatic
metastases.

Major Vascular Invasion

A study from Kyoto University suggested that major vascular invasion into the
Portal Vein (PV) or Inferior Vena Cava (IVC) may be the least harmful of all prog-
nostic factors and that surgical resection in this case may be associated with accept-
able oncological outcomes [36]. Indeed, Ali et al. from Mayo Clinic found that
median OS in those with treated major vascular invasion (n = 14) was not worse
than OS in patients without major vascular invasion (32 vs. 49 months, respectively,
P = 0.268) [39]. The most recent study by Reames et al. (n = 128) corroborated
those findings by reporting comparable median OS between the two patient groups
(33.4 vs 40.2, P > 0.05) [40]. These two studies also demonstrated that rates of
perioperative morbidity and mortality are not increased when major vascular resec-
tion is performed. Collectively, PV or IVC invasion should not be considered a
contraindication to resection, at least when performed at experienced centers. These
studies are in line with the AHPBA consensus statement, which states that “even
patients with advanced complex tumors that will require extensive resections and
major vascular and biliary reconstruction should be considered as potential candi-
dates for resection” [7].
76 G. A. Margonis and G. A. Poultsides

Long-Term Outcomes Following Surgery

Overall Survival

A systematic review and meta-analysis from 2014 summarized data from a large
number of studies and reported on a median and 5-year overall survival of 28 months
and 35%, respectively [10]. These data are most probably representative, as they are
consistent with the median and 5-year OS reported by the largest 5 studies included
in the same review (18–33 months and 21–35%). Unfortunately, it appears that sur-
vival has not improved in more contemporary studies. For example, although most
cohorts of the studies analyzed in the meta-analysis included patients from the early
90s, Raoof et al. reported a median survival of 35 months for a cohort who under-
went surgery for ICC between 2004 and 2013, a value similar to OS rates reported
in the meta-analysis of older studies [41]. Of note, markedly better outcomes can be
expected in subsets of patients, like those with solitary ICC ≤5 cm. Specifically,
these patients can achieve 5-year survival rates up to 71% [42].

Intrahepatic Recurrence and Repeat Hepatectomy

The 5-year recurrence risk following curative-intent resection of ICC is around

70% [43]. Given that around 60% of these recurrences occur in an intrahepatic
location, repeat hepatectomy may be considered, at least for a subset of those
patients. Some studies report a small fraction of patients with recurrence (9%)
being treated with repeat resection, but with only modest outcomes [43]. Although
modest, these survival rates were better compared to those for patients treated with
intra-arterial therapy or systemic chemotherapy (26.1 months vs. 9.6 months vs.
16.8 months, respectively. P = 0.01). In another study, 72 patients underwent repeat
R0 resection for liver-only recurrence and had a 5-year OS rate of 41.9% [44]. A
survival benefit was noted particularly in those who recurred at least 1 year after
the first surgery (3-year recurrence-to-death survival: 46.6% vs 23.0%, P = 0.022).
Similarly, a study by Zhang et al. demonstrated that patients with early recurrence
fared worse than those with late recurrence (median OS: 10 versus 18 months,
respectively; P = 0.029) [45]. This phenomenon may be attributed to different pat-
terns of recurrence associated with the timing of recurrence. Specifically, patients
with early recurrence were more likely to develop extrahepatic disease (44.1% vs
28.3%, P < 0.001), whereas those with late recurrence were more likely to have
liver-only recurrence (71.7% vs 55.9%, P < 0.001). Interestingly, independent fac-
tors associated with early intrahepatic recurrence included tumor-related factors
such as tumor size, number of lesions, and satellite lesions, whereas only the pres-
ence of liver cirrhosis was independently associated with late intrahepatic recur-
rence. This is an interesting finding, as it suggests that early recurrences are related
to the dissemination of the original tumor, while late recurrences may be
5 Surgical Treatment 77

associated with “de novo” metachronous ICCs, which is similar to what is occa-
sionally observed in HCC. Studies assessing clonality of tumors are needed to
confirm this hypothesis.

Long-Term Survivors

Despite the overall moderate prognosis, long-term survival may be feasible for a
small subset of patients with ICC. A study from Asia demonstrated that around 8%
of ICC patients may be “cured” (survive at least 10 years after their surgery). Low
serum tumor marker levels and favorable tumor-related characteristics such as soli-
tary, small N0 tumors were associated with “cure”. A Western study defined long-­
term survivors as those who survived ≥5 years and identified 153 patients (22.5%)
as long-term survivors [46]. Interestingly, around 10% of those long-term survivors
had negative prognostic factors such as perineural invasion, multifocal disease,
nodal disease, and large tumors. As such, the mere presence of these negative fac-
tors at the time of surgery did not preclude patients from surviving 5 years post-­
resection. This seemingly paradoxical observation may be explained by the concept
of “conditional survival,” which refers to the changing probability of survival over
time and has been applied to other malignancies [47]. Specifically, the more time
that accrues from the date of surgery, the higher the likelihood that some patients
with worse baseline disease will live longer than was expected at the time of
surgery.

Neoadjuvant Therapy

No prospective randomized data exist on outcomes in ICC patients treated with

preoperative systemic or locoregional treatment. In turn, no formal indications for
the use of pre-hepatectomy therapy exist. Nonetheless, based on extrapolation of
data from the ABC-02 trial performed among patients with stage 4 biliary tract
adenocarcinomas, gemcitabine and cisplatin combination has been employed in the
neoadjuvant setting as well (Fig. 5.2). A few retrospective studies have assessed the
outcomes of these therapies, which are administered either to eradicate occult meta-
static disease or facilitate resection by downstaging initially unresectable
ICC. Regarding the former indication, in the largest study to date, Buettner and
colleagues compared propensity-score matched patients (matched based on the fac-
tors associated with receipt of pre-hepatectomy chemotherapy) who received pre-­
hepatectomy chemotherapy to patients who had upfront surgery [48]. Although a
trend for improved OS and DFS was noted in the pre-hepatectomy chemotherapy
group, these differences did not reach statistical significance.
Regarding the latter indication, a few retrospective studies have assessed the role
of pre-hepatectomy transarterial therapies and chemotherapy in downstaging locally
78 G. A. Margonis and G. A. Poultsides

Fig. 5.2 Locally advanced intrahepatic cholangiocarcinoma managed with neoadjuvant chemo-
therapy and surgical resection: Fifty-one year old man who presented with abdominal pain and
weight loss. Computed tomography (CT) at presentation (left column) showed a large liver tumor
encasing the retrohepatic IVC and right hepatic vein origin (top left image), in addition to abutting
the left portal vein (bottom left image, green arrow). There was no evidence of portal lymphade-
nopathy or distant metastatic disease. Given the borderline resectable nature of the tumor, 4 months
of gemcitabine-cisplatin chemotherapy were administered. CT images (middle column) after neo-
adjuvant chemotherapy and before resection show significant response in terms of size with persis-
tent vascular abutment (top middle image: white arrow, middle hepatic vein). The patient underwent
an extended right hepatectomy and portal lymphadenectomy. No IVC or portal vein resection was
required intraoperatively. The tumor was 90% viable, and there was carcinoma within 1 mm of the
surgical margin. All 7 portal lymph nodes were negative. The tumor was unifocal. The patient
received 2 more months of adjuvant gemcitabine-cisplatin chemotherapy and is alive with no evi-
dence of disease 4 years postoperatively (right column)

advanced, unresectable ICC to allow for curative-intent resection. For example,

Rayar et al. reported on ten patients with a single locally advanced ICC (mostly
tumors invading major vascular structures) that were deemed unresectable [49].
After receiving a combination of yttrium-90 radioembolization and chemotherapy,
eight of the ten patients were successfully downstaged and subsequently underwent
a curative-intent resection. Of those eight patients, two died postoperatively and
other two recurred (at 19 and 7 months after surgery, respectively). The limited
follow-up, the small cohort size, and the lack of a comparison arm do not allow to
draw conclusions regarding the oncologic benefit of downstaging. A different
approach of downstaging unresectable ICC has been reported by the Memorial
Sloan Kettering group [50]. Specifically, 236 patients with locally advanced ICC
(tumor confined to the liver) or with metastatic regional lymph nodes (but no
­evidence of distant extrahepatic disease) were treated with either hepatic artery
infusion (HAI) floxuridine (FUDR), systematic chemotherapy, or the combination
5 Surgical Treatment 79

of the two. Only eight patients (one had received HAI alone, four had received sys-
temic chemotherapy alone, and three had received a combination of the two) had
their initially unresectable tumors converted and, in turn, underwent a curative-­
intent resection. Of those eight patients, two patients died perioperatively and five
patients recurred within 1 year. The conversion rate in the study was low and, simi-
lar to the Rayar study, definitive conclusions on long-term outcomes following con-
version cannot be made. Collectively, systemic chemotherapy and locoregional
modalities such as Y90 radioembolization and HAI may be selectively employed as
a downstaging therapy for patients with initially unresectable ICC without evidence
of extrahepatic disease, although only a small minority of patients is likely to ulti-
mately achieve a curative resection [9].

Liver Transplantation

Earlier studies that evaluated outcomes of orthotopic liver transplantation (OLT) in

ICC included patients with both hilar and intrahepatic cholangiocarcinoma. Given
that these two entities differ significantly, it may be hard to interpret those results.
Nonetheless, their outcomes have been so poor for ICC that OLT has been contrain-
dicated for ICC in most transplant centers globally. As such, it may not be surprising
that most recent OLT series for ICC include patients who were either transplanted
because of decompensated cirrhosis and were found to have a small ICC in the
remnant, or were transplanted with an erroneous preoperative diagnosis of HCC and
were only proved to be ICC in the explant. Interestingly, post hoc analysis, mainly
from UNOS (n = 440), and an international, multi-institutional collaboration
(n = 48) have revitalized interest in OLT for ICC [51, 52]. In fact, the latter study
identified a group of patients who benefited the most from OLT. Namely, these were
patients with “very early” ICC (defined as single tumor ≤2 cm,) who fared much
better when compared to those who had “advanced disease” (i.e., single tumor
>2 cm or multifocal disease) with 5-year OS of 65% vs 45%, respectively, and
recurrence risk at 5 years of 18% vs 61%, respectively. Of note, according to a sub-
sequent study, these favorable outcomes may be limited only to patients with well-­
differentiated tumors [53]. Although another study from Mayo Clinic reported on a
higher recurrence rate of 33.3% for early ICC, notably, they grouped hepatocellular
carcinoma-cholangiocarcinoma cases together with ICC, thus rendering the three
studies incomparable [54]. Prospective studies and matched comparisons with
resected “very early” ICC (well differentiated, solitary and <2 cm) are needed to
investigate whether OLT has a role in ICC patients, although these small solitary
tumors may also be adequately managed with thermal ablation, SBRT, or other
locoregional modalities in patients with cirrhosis. At this time, OLT for ICC patients
should only be considered in this cohort of very early stage, select tumors, ideally
on a clinical trial protocol.
80 G. A. Margonis and G. A. Poultsides

Conclusion and Future Directions

Although surgical resection is associated with moderate survival, it remains the best
option for many patients with ICC, and in fact, some of them may survive long
enough to be considered cured. Margin negative resection and adequate regional
lymphadenectomy remain the mainstay of appropriate surgical therapy. Advances in
surgical techniques, systemic chemotherapy, and locoregional therapies will increase
the “pool” of technically resectable patients. In parallel, as our understanding of this
disease will evolve to further comprehend the prognostic significance of margin sta-
tus, tumor size, multifocality, and vascular invasion, we will have a more balanced
approach between “what can be technically removed” and “whether resection will
provide a long-term benefit”. At present, this notion is limited by the lack of studies
about the interplay between traditional clinicopathologic factors and tumor biology.
In the future, along with progress made in systemic therapy (including targeted and
immunologic therapies), biomarkers may aid in answering questions such as when to
operate on patients with large, multifocal disease, when to offer neoadjuvant therapy
(and what type), and what the optimal margin width should be. Similar approaches
have been suggested for other liver malignancies [55].

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Chapter 6
Management of the Nodal Basin

Alfredo Guglielmi, Fabio Bagante, Andrea Ruzzenente,

Tommaso Campagnaro, Simone Conci, and Calogero Iacono

Introduction

Lymph node status is the most important characteristic associated with the
prognosis of patients with intrahepatic cholangiocarcinoma (ICC) [1]. While
­
patients without lymph node metastasis can reach a long-term survival after cura-
tive-intent surgery, patients with metastatic disease involving lymph nodes are sel-
dom considered amenable for surgery, and when surgically treated, present a poor
prognosis after hepatectomy [2]. The importance of lymph node status has also
been emphasized by the American Joint Committee on Cancer (AJCC) in the stag-
ing of patients with ICC. The 7th edition AJCC staging manual introduced, for the
first time, a TNM staging system specific for ICC [3]. While the AJCC 7th edition
was based on an analysis of data extracted from a large population-based database,
the Surveillance, Epidemiology, and End Results (SEER) program, which included
598 patients who underwent surgery for ICC, it did not adequately stage the tumor
and lymph node status [4]. In fact, several studies have reported only a poor to
moderate ability to predict the patient’s prognosis based on the criteria proposed by
the AJCC 7th edition for the lymph-node staging [4, 5]. For these reasons, the new
8th edition of the AJCC staging system has introduced some modifications includ-
ing a reclassification of the tumor (T) category and for the lymph-node staging [6].
Even though these advantages seem to recognize the importance of an accurate
evaluation of the lymph node status, the role and extension of lymphadenectomy
for ICC are still debated.

A. Guglielmi · F. Bagante · A. Ruzzenente · T. Campagnaro · S. Conci · C. Iacono (*)

Department of Surgery, University of Verona, Verona, Italy
e-mail: [email protected]; [email protected];
[email protected]; [email protected]

© Springer Nature Switzerland AG 2019 85

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_6
86 A. Guglielmi et al.

Anatomy of the Lymph Node Drainage

Similar with the other organs in the human body, the lymphatic vessels and lymph
nodes for the liver and the bile duct go with the blood vessels supplying and drain-
ing the organ. In particular, the lymph node drainage for the liver includes a super-
ficial and a deep pathway [7]. The superficial lymphatic pathway is found beneath
the Glisson’s capsule of the liver and can be classified into three major groups. The
first group includes the most common lymph node sites of metastasis through the
hepatoduodenal and gastro-hepatic ligament pathway (Fig. 6.1a). The second group
includes the diaphragmatic lymphatic plexus as the liver is directly in contact with
the diaphragm with the liver bare area and indirectly through the coronary and tri-
angular ligaments. The third group is along the falciform ligament to the deep supe-
rior epigastric node in the anterior abdominal wall and along the deep superior
epigastric artery below the xiphoid cartilage. Moreover, the deep lymphatic drain-
age follows the portal veins, drains into the lymph nodes at the hilum of the liver,
the hepatic lymph nodes, then to the nodes in the hepatoduodenal ligament
(Fig. 6.1b). Two major lymph node chains can be identified in the hepatoduodenal
ligament: the hepatic artery chain and the posterior periportal chain. The hepatic
artery chain follows the common hepatic artery to the node at the celiac axis and
then into the cisterna chyli. The posterior periportal chain, located posterior to the
portal vein in the hepatoduodenal ligament, drains into the retro-pancreatic nodes
and the aortocaval node into the cisterna chyli and the thoracic duct. A more detailed
classification of the lymph node basin has been provided by the Japanese Society of
Hepato-Biliary-­Pancreatic Surgery (JSHBPS), which defined the regional lymph
nodes of cholangiocarcinoma as the nodes in the hepatoduodenal ligament (#12),
the nodes along the left gastric artery (#7), the nodes along the common hepatic
artery (#8), the nodes along the celiac artery (#9), the nodes in the right cardial

a b

Fig. 6.1 (a) Superficial and (b) deep pathways of lymphatic drainage for the liver. (From
Harisinghani [7])
6 Management of the Nodal Basin 87

Table 6.1 Classification of the lymph node basin provided by the Japanese Society of Hepato-­
Biliary-­Pancreatic Surgery (JSHBPS) [8]
No. Definition
1 Right paracardial LNs
2 Left paracardial LNs
3 LNs along the lesser curvature of the stomach
4 LNs along the greater curvature of the stomach
5 Supra-pyloric LNs
6 Infra-pyloric LNs
7 LNs along the trunk of left gastric artery
8 LNs along the common hepatic artery
9 LNs around the celiac artery
10 LNs at the splenic hilum
11 LNs along the splenic artery including LNs on the distal part of posterior surface of the
pancreas end to the left border of the portal vein or superior mesenteric vein
12 LNs in the hepatoduodenal ligament
13 LNs on the posterior surface of the head of the pancreas
14 LNs at the root of the superior mesenteric artery
15 LNs along the middle colic vessels
16 LNs around the abdominal aorta

region (#1), the nodes along the lesser curvature of the stomach (#3), and on the
posterior surface of the head of the pancreas (#13) [8]. Furthermore, JSHBPS
defined distant lymph node basins as the inter-aortocaval lymph nodes (#16)
(Table 6.1).

Recommendation and Staging of Lymph Node Status

The European Society for Medical Oncology (ESMO) recommended in the Clinical
Practice Guidelines for Biliary Cancer, published in 2016, a routine lymphadenec-
tomy at the level of the hepatoduodenal ligament during surgery given that the pres-
ence of lymph node metastasis is a well-documented prognostic parameter [9, 10].
Conversely, in the National Comprehensive Cancer Network (NCCN) guidelines
for ICC, a portal lymphadenectomy is considered only “reasonable,” while in the
2014 European Association for the Study of the Liver (EASL) guidelines for ICC,
only removal of clinically suspicious nodal disease is defined as “mandatory” and
lymphadenectomy be “strongly considered” at the time of surgery [11, 12].
Moreover, different staging systems for ICC have been proposed by the National
Cancer Center of Japan (NCCJ) staging system (Okabayashi), the Liver Cancer
Study Group of Japan (LCSGJ), and the American Joint Committee on Cancer
(AJCC), but the characterization of the lymph node involvement is similar among
them [13, 14]. In detail, regional lymph node metastases are defined as N1 disease
and include involvement of hilar (hepatoduodenal), periduodenal, and peripancre-
88 A. Guglielmi et al.

atic nodes. As reported in the first edition of the LCSGJ guidelines in 1997, regional
lymph node dissection of groups 1 and 2 lymph node basins should be performed
depending on whether the ICC tumor is located on the right (group 1: #12; group 2:
#7, #8, #9, and # 13) or left side (group 1: #12, #1, and #3; group 2: #7, #8, #9, and
# 13) of the liver [15, 16]. While first proposed by the LCSGJ, this recommendation
has been removed in the last version of the Japanese guidelines given the insuffi-
cient data supporting a classification of the lymph nodes basins draining the liver
[17]. Recently, the 8th edition of the AJCC TNM staging system has modified the
criteria for lymph node staging, adding a minimum number of six lymph nodes
harvested for an adequate staging [6].

Lymphadenectomy

Even though the lymph-node status has been identified as the most important factor
associated with patient’s prognosis, routine lymphadenectomy is not always per-
formed [15, 18–20]. In particular, national and international guidelines recom-
mend removal of clinically suspicious lymph nodes, but the role and extension of
routine lymphadenectomy is poorly defined [9, 11, 21, 22]. Moreover, while in the
Japanese centers lymphadenectomy is always performed as a fundamental step in
the surgical treatment of ICC, lymphadenectomy is not routinely performed at
many Western centers [23]. In a recent analysis of 561 patients who underwent
curative-intent surgery for ICC at 12 major international hepatobiliary centers in
Europe, Asia, Australia, and USA, only 48% (n = 272) of patients underwent a
concomitant lymphadenectomy and, among these patients, the incidence of meta-
static lymph-node (N1 patients) was 45.2% (n = 123) [20]. In this study, although
other risk factors, such as tumor morphology and number of lesions, contributed to
patients’ survival, lymph-node status was the strongest independent predictor of
disease-specific survival (DSS). Moreover, the authors reported that the DSS of Nx
patients varied over the time after surgery. While DSS was worse among Nx
patients compared to N0 patients within the first 18 months after surgery, among
patients who survived to 18 months after surgery, DSS of Nx patients was compa-
rable to DSS of N0 patients. The authors suggest that the heterogeneous outcomes
of Nx patients confirmed the hypothesis that Nx patients are a combination of N0
and (under-staged) N1 patients. Recently, Zangh and colleagues have investigated
the trend in lymph-nodal evaluation during the last 13 years using the information
of 1496 patients who underwent curative-intent resection for ICC included in the
SEER database [24]. The authors reported that, at the time of surgery, a lymphad-
enectomy was performed only in 52% of patients and that only 11% of patients had
six or more than six lymph nodes evaluated [24]. Moreover, while the incidence of
lymphadenectomy did not change over time (2000–2004: 50% vs. 2005–2009:
52% vs. 2010–2013: 54%; p = 0.636), the proportion of patients who had six or
more than six lymph nodes evaluated increased during the study period (2000–
2004: 7% vs. 2005–2009: 11% vs. 2009–2013: 14%; p = 0.003) [24].
6 Management of the Nodal Basin 89

Radiological Assessment of Node Status

The data on the incidence of lymphadenectomy confirm that it is underutilized as a

routine practice on patients undergoing surgery for ICC. Some surgeons have
pointed out that one of the possible reasons for this trend is that the preoperative
imaging might provide enough information to stage patients’ lymph node status,
allowing a selective use of lymphadenectomy for ICC [25]. To this side, several
papers have reported that preoperative imaging might not be reliable to assess nodal
status and direct selective lymphadenectomy only in “high-risk” patients, describ-
ing only a sensitivity of 40–50% and a specificity of 77–92% to detect nodal metas-
tases with preoperative CT or MRI [21, 26]. Moreover, Bagante et al. compared the
concordance between pathological and radiological evaluation of lymph node status
among ICC patients who underwent preoperative EUS (2%), CT (49%), MRI
(39%), and PET (10%) [5]. Among 317 patients who had data on both radiological
and pathological nodal evaluation, the incidence of negative lymph node was 66%
among patients initially deemed radiologically negative lymph nodes compared
with 42% among patients who were preoperatively staged as suspicious lymph node
status. In contrast, the incidence of negative lymph nodes was 35% among patients
deemed radiologically metastatic lymph nodes. The incidence of metastatic lymph
nodes increased from 34%, among patients who were radiologically negative to
58% and 65% among patients who were radiologically suspicious or radiologically
metastatic, respectively (p < 0.001). The area under the receiver operating charac-
teristic (ROC) curve comparing radiological and pathological nodal evaluation was
only 0.63 [5]. Based on these data, radiological lymph node assessment does not
adequately stage the nodal basin and should not replace the pathological evaluation
of the lymph node staging.

Number of Lymph Node Harvested

Even though the newly released AJCC 8th edition recommends the recovery of at
least six lymph nodes for complete pathologic staging, consistent data supporting
this cut-off are still lacking [6]. To validate this indication, a recent analysis of 1154
patients undergoing hepatectomy for ICC between 1990 and 2015 at one of 14
major hepatobiliary centers sought to define outcomes and risk of death among
patients who were‑ “adequately” (≥6 lymph nodes harvested) versus “inadequately”
staged (<6 lymph nodes harvested) according to the eighth edition of the AJCC
staging manual [5].
The authors reported that, at the time of hepatectomy, lymph nodes were har-
vested in only 45% of patients with a median number of harvested lymph node of 4
(inter-quartile range, 2–8). Among the 315 patients with negative lymph nodes, 21%
of patients had only one harvested lymph node, 42% 2–5 harvested lymph nodes,
and 37% ≥6 harvested lymph nodes. While the 5-year OS of patients with negative
90 A. Guglielmi et al.

lymph nodes was 44% compared with 15% for patients with metastatic lymph
nodes, patients with negative lymph node and ≥6 harvested lymph nodes had a
5-year OS of 55% compared with 39% for patients with negative lymph nodes and
<6 harvested lymph nodes [5].

Extension of Lymphadenectomy

The extension of lymphadenectomy for ICC is not clear based on available data.
The majority of recommendations come from retrospective analyses that include
heterogeneous groups of patients with bile duct cancers resulting in a low grade of
evidence supporting the decision-making process on the extension of lymphadenec-
tomy. There is a general consensus defining the regional lymph node stations as the
nodes in the hepatoduodenal ligament (#12), along the left gastric artery (#7), the
common hepatic artery (#8), the celiac artery (#9), the nodes in the right cardial
region (#1), along the lesser curvature of the stomach (#3), and on the posterior
surface of the head of the pancreas (#13). Para-aortic lymph node metastasis has
traditionally been defined as distant metastasis [27]. Although the number of meta-
static lymph nodes is prognostic, some suggest that the location of the metastatic
disease might be associated with the prognosis of patients with bile duct cancers.
Several studies have identified the importance of negative para-aortic lymph nodes
for a curative resection of ICC [28–31]. Moreover, a recent meta-analysis including
ten retrospective studies has reported that an extended lymphadenectomy including
regional and para-arotic lymph nodes did not provide a survival benefit for patients
with bile duct cancers. This study suggests that radical resection with extended
lymphadenectomy should be abandoned when a positive para-aortic lymph node
was confirmed pathologically during exploration [32]. Regional lymphadenectomy
should include regional lymph node basins as #12, #7, #8, #9, and #13 and might be
extended to the stations (#1 and #3) for ICC of the left side of the liver (Fig. 6.2).

Lymphadenectomy in Patients with ICC and Cirrhosis

Lymphadenectomy has been shown to alter short-term outcomes of patients with

cirrhosis undergoing surgery for other abdominal malignancies. There is little data
regarding the possible implication of lymphadenectomy in ICC patients with cir-
rhosis. This topic is of particular importance because chronic liver disease and cir-
rhosis are well-known risk factors of developing ICC and these patients might be at
increased risk of morbidity [33]. In recent analysis of the impact of lymphadenec-
tomy on peri-operative outcomes of ICC patients with cirrhosis, the frequency of
cirrhotic patients was 10% and lymphadenectomy was associated with an increased
risk of complications among these patients compared with non-cirrhotics [34]. The
authors reported that patients who had cirrhosis were less likely to undergo a major
6 Management of the Nodal Basin 91

a b

c
d

Fig. 6.2 (a) CT showing intrahepatic cholangiocarcinoma involving left lobe and anterior seg-
ments of the right liver. (b) Left trisectionectomy with standard lymphadenectomy (basins #12, #7,
#8, #9, and #13) and isolation of the portal vein (blue loop), hepatic artery (red loop), and bile duct
(yellow loop). (c) CT showing intrahepatic cholangiocarcinoma involving segment 8 and caudate
lobe. (d) Right hepatectomy extended to caudate lobe standard lymphadenectomy (basins #12, #7,
#8, #9, and #13) and isolation of the portal vein (blue loop) and hepatic artery (red loop)

hepatectomy and were about one third less likely to undergo lymphadenectomy at
the time of surgery, even though the incidence of metastatic lymph node was com-
parable among cirrhotic and non-cirrhotic patients when lymph-node evaluation
was performed [34]. As such, the AJCC 8th edition recommendation to perform a
lymphadenectomy to harvest at least 6 lymph nodes should be considered in light of
higher risk of complication when operating on patients with ICC and cirrhosis [34].

What Is the Best Method to Assess Lymph Node Status?

In the recent literature, different approaches have been proposed to estimate the prog-
nostic impact of lymph node status on the prognosis of patients with ICC similar to
perihilar cholangiocarcinoma [28]. While the AJCC N-stage system considers only
92 A. Guglielmi et al.

the presence of lymph node metastasis, Kim et al. using the SEER database investi-
gated the impact of the lymph node ratio(LNR) and the logarithm of the ratio of the
number of metastatic lymph nodes and the number of negative lymph nodes
(LODDS) [35]. The incidence of patients with 1, 2, 3, or ≥4 metastatic lymph nodes
was 60%, 18%, 9%, and 13% among patients with positive lymph nodes, respec-
tively. When modeled as a continuous variable, number of metastatic lymph nodes
was associated with disease-free survival with a HR 1.26 per each added lymph node
metastasis [35]. Moreover, both LODDS and LNR were better predictors of disease-
specific survival than the AJCC N staging. In particular, LNR performed well among
patients who had >3 lymph nodes harvested, while LODDS was better in predicting
the disease specific survival of patients with ≤3 lymph nodes examined [35].

Conclusion

While there is a lack of evidence on the optimal lymph node staging for ICC, several
retrospective studies have reported the benefit of lymphadenectomy, confirming the
AJCC recommendation to harvest at least six lymph nodes. According to the Liver
Cancer Study Group of Japan (LCSGJ) recommendation, lymphadenectomy for
ICC should include basin #12 (hepatoduodenal ligament), #7 (left gastric artery), #8
(common hepatic artery), #9 (celiac artery), and # 13 (posterior surface of the head
of the pancreas) and might be extended to basin #1 (right cardiac nodes) and #3
(lesser curvature of the stomach) for ICC of the left side of the liver [15, 17].
Furthermore, rather than a simple binary classification (negative vs. positive lymph
node status), number of positive nodes and combined scores as lymph node ratio
(LNR) and log of odds (LODDS) can improve the prognostic stratification of
patients undergoing curative-intent surgery for ICC. Based on the data in the litera-
ture and on our center experience, lymph node dissection is a fundamental part of
the surgical treatment of ICC.

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5. Bagante F, Spolverato G, Weiss M, et al. Assessment of the lymph node status in patients
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giocarcinoma from the viewpoint of liver lymphatics. J Gastroenterol. 2015;50:913–27.
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institution. Surgery. 2015;157:666–75.
24. Zhang XF, Chen Q, Kimbrough CW, et al. Lymphadenectomy for intrahepatic cholangiocar-
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curative intent for intrahepatic cholangiocarcinoma. Br J Surg. 2018;105:857–66.
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Chapter 7
Pathologic Assessment

Benjamin J. Swanson

Introduction

The diagnosis of intrahepatic cholangiocarcinoma (ICC) is usually made by needle

biopsy of a liver mass. The vast majority of ICCs are adenocarcinomas, with the
most common growth pattern being acinar or tubular growth. Other less common
types include mucinous, clear cell, and adenosquamous carcinoma. Precursor
lesions include biliary intraepithelial neoplasia and intraductal papillary neoplasms
of bile ducts. The differential diagnosis of ICC is large and includes many tumors
metastatic to the liver. The most common tumors to metastasize to the liver include
colorectal, breast, lung, pancreas and upper gastrointestinal tract. In addition, hepa-
tocellular carcinoma (HCC) enters the differential diagnosis whenever the tumor is
poorly differentiated. Immunohistochemistry is very helpful to distinguish ICC
from several metastatic tumors and hepatocellular carcinoma. Brush cytology can
also be used to diagnose suspicious intrahepatic strictures, with fluorescent in-situ
hybridization analysis employed for challenging cases. Specimens resected for ICC
should be evaluated for their gross growth pattern, precursor lesions, and other
pathologic risk factors. Ancillary testing includes DNA mismatch repair immuno-
histochemistry and next generation DNA sequencing. In this chapter, we provide a
comprehensive review of the histopathologic assessment of ICC.

B. J. Swanson (*)
Department of Pathology and Microbiology, University of Nebraska Medical Center,
Omaha, NE, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 95

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_7
96 B. J. Swanson

Biopsy Interpretation of Intrahepatic Cholangiocarcinoma

The vast majority of intrahepatic cholangiocarcinomas (ICC) are adenocarcino-

mas. Like adenocarcinomas throughout the gastrointestinal and biliary system,
they are composed of malignant glands [1]. The precursor for ICC is thought to be
a progenitor/stem cell of biliary epithelium. Thus, the cells of ICC are cuboidal
cells that lack mucin, recapitulating their progenitor. The most common growth
pattern is gland forming, also known as tubular or acinar (Fig. 7.1a). The tumors
can also grow in trabecular (ribbon-like) and micropapillary (glands with projec-
tions and tufts that lack fibrovascular cores) patterns. Tumors are conventionally
graded as well-­differentiated (>95% of the tumor composed of glands), moderately
differentiated (50–95% gland formation), and poorly differentiated (<50% gland
formation).
The typical immunohistochemical staining pattern for ICC is that they are posi-
tive for CK7, variably positive for CK20, and variably positive for CDX2 [2]. The
tumors are also positive for CK19, and broad spectrum keratins such as AE1/AE3
and CAM5.2. Usually, the tumors are negative for TTF-1, GATA3, estrogen recep-
tor, and progesterone receptor.
When greater than 50% of the glands show mucinous morphology (malignant
glands floating in mucin), the diagnosis of mucinous adenocarcinoma is made
(Fig. 7.1b). This is a very rare tumor that may have a worse prognosis compared to
conventional ICC [3]. A minor (<50%) mucinous component can also be seen in
conventional (acinar) cholangiocarcinoma. Some studies have suggested that the
immunochemistry profile for these tumors is CK7 positive, CK20 negative, CDX2
negative. This variant of ICC must be distinguished from metastatic mucinous ade-
nocarcinoma, especially from the colon. Metastatic mucinous adenocarcinoma
from the colon is usually CK7 negative, CK20 positive, and CDX2 positive by
immunohistochemistry.
Signet ring cell morphology is defined by discohesive cells with an eccentrically
placed nucleus and a mucin vacuole[4]. Tumors with greater than 50% signet rings
(signet ring cell carcinoma) are incredibly rare. Signet ring cells are more com-
monly a minor component (<50%) of a mucinous adenocarcinoma (Fig. 7.1e).
Clear cell ICC is diagnosed when the tumor is predominately (>50%) composed
of optically clear cells (by H&E) with well-defined cell borders (Fig. 7.1c) [5]. The
tumors may be interspersed with a more conventional adenocarcinoma. HCC with
clear cell features and metastasis from other anatomic sites (especially the kidney)
must be excluded by performing immunohistochemistry (clear cell carcinoma from
the kidney is PAX8 positive, CK7 negative, CK20 negative).
When a primary tumor of the liver demonstrates both glandular and squamous
differentiation, a diagnosis of adenosquamous carcinoma is made. The squamous
component is recognized by keratinization (Fig. 7.1d) and intercellular bridges
between polygonal cells [6], whereas the glandular component may also contain
mucin. At least one meta-review of prior case studies of adenosquamous carcinoma
suggests this may have a worse prognosis compared to conventional ICC [7].
7 Pathologic Assessment 97

a b

c d

e f

Fig. 7.1 (a) Typical acinar growth pattern of cholangiocarcinoma with gland formation. (b)
Mucinous adenocarcinoma with abundant extracellular mucin and cells floating in mucin. (c)
Clear cell adenocarcinoma with optically clear cytoplasm and well-defined cell borders. (d)
Squamous differentiation within an adenosquamous carcinoma demonstrating focal keratiniza-
tion. (e) Signet ring cell morphology with multiple discohesive cells, eccentric nuclei, and mucin
vacuoles. (f) Brush cytology of cholangiocarcinoma with a disorganized group of cells showing
hyperchromasia

Lymphoepithelial-like cholangiocarcinoma is a rare variant of ICC that in some

studies is related to Epstein-Barr virus (EBV) [8]. Similar to other EBV-related
carcinomas elsewhere in the body, the tumor grows as syncytial sheets of undiffer-
entiated malignant cells. Also present is an intense inflammatory reaction composed
98 B. J. Swanson

of lymphocytes and plasma cells that intermingle with the undifferentiated malig-
nant cells. The tumor will mark with keratin markers (AE1/AE3, CAM5.2, etc.) and
may show nuclear reactivity for EBV by in-situ hybridization (EBER).

Brush Cytology for Intrahepatic Cholangiocarcinoma

Cytologic and brush examination of ICC shows findings similar to other pancreati-
cobiliary adenocarcinomas such as extrahepatic cholangiocarcinoma and pancreatic
ductal adenocarcinoma. Low power examination of smear slides demonstrates a
hypercellular background. High power microscopic examination shows disorga-
nized groups of cells. The individual cells show nuclear pleomorphism, irregular
nuclear membranes, loss of nuclear polarity, and conspicuous nucleoli (Fig. 7.1f).
Brush cytology of suspicious intrahepatic bile duct strictures has excellent specific-
ity for diagnosing carcinoma, however, the sensitivity may be less than 40% [9].
When tissue is present in the cell block, immunohistochemistry can be performed to
exclude metastatic tumors.
Fluorescent in-situ hybridization (FISH) testing can be performed on brush cyto-
logic specimens of intrahepatic lesions to help diagnose ICC. Some studies have
suggested that FISH analysis of regions 1q21 (MCL1), 7p12 (EGFR), 8q24 (MYC),
and 9p21 (CDKN2A) which detect chromosomal gain and losses of the above
regions are sensitive and specific in the diagnosis of pancreaticobiliary adenocarci-
nomas [10]. These FISH probe sets are not widely available in all anatomic pathol-
ogy practices. Therefore, in our practice, we utilize FISH analysis in clinical
scenarios where the clinical suspicion for ICC is high but the brush cytology diag-
nosis is not definitive.

Differential Diagnosis of Intrahepatic Cholangiocarcinoma

It may be difficult to distinguish benign and malignant biliary tract tumors. Bile
duct adenomas are benign proliferations of bile ductules that can sometimes enter
into the differential diagnosis with ICC, especially during frozen section analysis.
The benign biology of bile duct adenomas is reflected in their histologic appear-
ance. They are composed of bland, uniform glands which lack nuclear pleomor-
phism and mitotic figures (Fig. 7.2a). They have a smooth/rounded interface with
the surrounding hepatic architecture and do not invade adjacent tissue. Bile duct
adenomas are usually small and are rarely greater in size than 2 cm. They are usu-
ally located in the subcapsule of the liver [11]. By comparison, ICC shows greater
variation in nuclear size and contour as well as conspicuous mitotic figures.
Furthermore, ICCs are usually quite large and not subcapsular. ICCs have infiltra-
tive borders with the adjacent tissue.
7 Pathologic Assessment 99

a b

c d

e f

Fig. 7.2 (a) Bile duct adenoma with bland cell morphology and a smooth interface with surround-
ing hepatocytes. (b) Hepatocellular component of combined hepatocellular-cholangiocarcinoma
with oncocytic neoplastic hepatocytes. (c) Cholangiocarcinoma component of combined
hepatocellular-­cholangiocarcinoma with gland formation. (d) Biliary intraepithelial neoplasia-3
shows severe dysplasia with loss of nuclear polarity. (e) Mucinous cystic neoplasm is composed of
mucinous epithelium with ovarian-type stroma. (f) Periductal (“onion-skin”) fibrosis of primary
sclerosing cholangitis

Whenever the diagnosis of adenocarcinoma within the liver is entertained, meta-

static tumors must be excluded. The incidence of adenocarcinomas metastatic to the
liver is greater than the incidence of primary liver tumors. Moreover, by H&E mor-
phology, ICC and metastatic adenocarcinomas can be indistinguishable. Thus, the
100 B. J. Swanson

distinction of metastasis from ICC is a very common problem in anatomic pathol-

ogy that can sometimes be difficult. Immunohistochemistry is employed to aid in
the distinction. The most common tumors to metastasize to the liver include colorec-
tal, breast, lung, pancreas, and upper gastrointestinal tract (gastric and esophageal)
[1]. Many tumors can reliably be distinguished from ICC, though pancreatic and
upper gastrointestinal tumors are more challenging.
The classic morphologic feature of colorectal adenocarcinomas is luminal necro-
sis of the glands, referred to as “dirty” necrosis, although this histologic feature is
not always present. Conversely, ICCs do not have “dirty” necrosis within central
lumens. By immunohistochemistry, colorectal adenocarcinomas are usually CK20
positive, CK7 negative, CDX2 positive, and SATB2 positive [12].
Both lobular and ductal adenocarcinomas of the breast can spread to the liver.
Ductal adenocarcinomas of the breast most closely morphologically resemble ICC
and must be excluded in women. The typical immunochemical profile of ductal
breast adenocarcinoma is CK7 positive, CK20 negative, CDX2 negative, GATA3
positive, gross cystic disease fluid protein 15 (GCDFP-15) positive, and mamma-
globin positive [13]. Furthermore, depending on the subtype of breast cancer, there
may be a variable expression of estrogen receptor, progesterone receptor, and
HER2/Neu [14].
Non-small cell carcinomas of the lung include squamous cell carcinoma, ade-
nocarcinoma, and large cell neuroendocrine carcinoma. Adenocarcinomas of the
lung can closely resemble ICC. The typical immunoprofile of lung adenocarci-
noma is CK7 positive, CK20 positive, CDX2 negative, TTF-1 positive, and Napsin
A positive [15].
Pancreatic adenocarcinomas which metastasize to the liver usually closely mimic
ICC by both morphology and immunohistochemistry. Unfortunately, there are not
reliable pathologic features that can confidently separate these entities [16]. Thus,
pathologic reports use the term pancreatobiliary to convey this ambiguity. Clinical
correlation is often needed to distinguish the two.
Upper gastrointestinal cancers (esophageal and gastric adenocarcinomas) can
similarly be impossible to distinguish from ICC by pathologic examination. Their
immunohistochemical profile closely resembles ICC: CK7 positive, CK20 variable,
CDX2 variable [17]. Furthermore, the H&E morphology of upper gastrointestinal
tract tumors is similar to ICC. Therefore, surgical pathology reports usually include
upper gastrointestinal tract tumors in the differential diagnosis.
HCC enters into the differential diagnosis of ICC when the tumor is poorly dif-
ferentiated. Histologic features, which favor ICC, include mucin production as well
as background liver that is non-cirrhotic. By comparison, H&E features which favor
poorly differentiated hepatocellular carcinoma include bile production and back-
ground liver that is cirrhotic. Immunohistochemical markers for adenocarcinoma
(MOC-31, aka Ep-CAM) and hepatocellular lesions (Hepatocyte antibody
(HepPar-1, Arginase) can be of great use in this distinction. ICCs are MOC31 posi-
tive, HepPar-1negative, Arginase negative, whereas Hepatocellular carcinomas are
MOC31 negative, HepPar-1 positive, Arginase positive [18].
7 Pathologic Assessment 101

Combined Hepatocellular-Cholangiocarcinoma is a WHO-defined tumor that

contains histologic elements of both hepatocellular carcinoma and cholangiocarci-
noma [19]. The current definition does not require a minimum amount of each com-
ponent. This tumor is thought to arise from a common progenitor cell (stem cell)
that gives rise to both the hepatocellular carcinoma component and cholangiocarci-
noma component. This tumor is associated with risk factors similar to HCC (cir-
rhosis, viral hepatitis C infection, viral hepatitis B infection). Histologically, the
hepatocellular component is identified by bile production as well as oncocytic neo-
plastic hepatocytes (Fig. 7.2b) that may show any degree of differentiation. The
hepatocellular component can also be identified by immunohistochemistry with
positive staining for HepPar-1 and Arginase. The cholangiocarcinoma component is
histologically identified by gland formation and mucin production (Fig. 7.2c).
Positivity for CK19 can help define the portions of the tumor that are cholangiocar-
cinoma. Given the theorized stem cell origin of this tumor, subtypes with stem cell
features have been recognized by the WHO: typical, cholangiocellular, and interme-
diate-cell subtypes. Immunostains which are positive in the stem cell subtypes
include CD56 and c-kit. The clinical significance of identifying the stem cell sub-
types in combined hepatocellular-­cholangiocarcinoma is unclear.
The distinction of ICC from combined hepatocellular-cholangiocarcinoma can
be very challenging on needle biopsy due to sampling limitations. Whenever a
tumor is biopsied in a patient with cirrhosis or history of viral hepatitis B/C infec-
tion, combined hepatocellular-cholangiocarcinoma should be considered in the dif-
ferential diagnosis. However, this tumor may only be definitively diagnosed after
surgical resection.

 athologic Interpretation of Surgical Resections

P
of Intrahepatic Cholangiocarcinoma

Surgical resections for ICC should be evaluated according to the College of

American Pathologists checklist for tumors of intrahepatic bile ducts (https://docu-
ments.cap.org/protocols/cp-intrahepatic-bileducts-17protocol-4000.pdf).
The growth pattern of ICC should be discerned by both gross pathologic
examination as well as H&E findings. The major growth patterns for ICC
include mass-­forming, periductal infiltrating, and a mixed mass-forming/peri-
ductal infiltrating. The growth pattern may help predict the prognosis for the
patient [20, 21].
As its name applies, the mass-forming growth pattern of ICC presents as a large
nodule that is often singular. This is the most common gross subtype of ICC. The
periductal-infiltrating subtype of ICC grows in a tree-like fashion along portal tracts.
Therefore, it is multifocal and may be more difficult to appreciate grossly.
Sometimes, a tumor may show mixed features of both mass-forming and periductal-­
infiltrating growth patterns.
102 B. J. Swanson

 recursor Lesions and Predisposing Conditions

P
for Intrahepatic Cholangiocarcinoma

Resected ICC should be pathologically evaluated for both precursor lesions and
pathologic risk factors. Precursor lesions include biliary dysplasia, intraductal pap-
illary neoplasm of bile ducts, and mucinous cystic neoplasms. Risk factors include
primary sclerosing cholangitis, hepatolithiasis (biliary stones should be mentioned
in pathology reports), liver flukes, and viral hepatitis B and C infection.
Flat dysplasia of bile ducts is thought to be a precursor for intrahepatic cholan-
giocarcinoma. The terminology has been proposed [22, 23] that these lesions are
described as biliary intraepithelial neoplasia (BilIN) similar to pancreatic intraepi-
thelial neoplasia (PanIN). Histologically, BilIN shows nuclear and architectural fea-
tures similar to cholangiocarcinoma; however, they lack invasion of the basement
membrane. A three-tiered system from low-grade dysplasia (BilIN-1) to high-­grade
dysplasia/carcinoma in-situ (BilIN-3) has been proposed. The cells of BilIN-1 dem-
onstrate mild to moderate nuclear changes (hyperchromasia, irregular nuclear mem-
branes) with maintenance of nuclear polarity. In contrast, BilIN-3 is more similar to
cholangiocarcinoma with severe nuclear atypia and frank loss of nuclear polarity
(Fig. 7.2d). BilIN-2 is reserved for lesions between BilIN-1 and BilIN-3. The pres-
ence of dysplasia/BilIN should be noted at any biliary margin of a surgical resection
specimen.
Intraductal papillary neoplasms of bile ducts (IPNB) are another potential pre-
cursor lesion to ICC. Their nomenclature, growth pattern, and risk of progression to
invasive carcinoma are similar to intraductal papillary neoplasms (IPMNs) of the
pancreas [24]. IPNB can occur in both intrahepatic and extrahepatic anatomic loca-
tions [25]. Due to their papillary and intraluminal growth pattern, IPNB will dilate
an intrahepatic bile duct to form a grossly visible cystic mass. IPNB sometimes
produce mucin, which may be evident grossly. Histologic subtypes of IPNB include
pancreatobiliary, gastric, intestinal, and oncocytic. These neoplasms may show a
mixture of each histologic subtype that can be recognized by H&E examination.
Pancreatobiliary IPNB histologically demonstrates cuboidal type epithelium with
papillary growth that lacks goblet cells. When invasive adenocarcinoma arises from
a pancreatobiliary IPNB, it is most likely to have an acinar growth pattern. Intestinal
IPNB histologically resembles colonic epithelium with innumerable goblet cells
and mucin production. Invasive mucinous cholangiocarcinoma is more likely to
occur with the intestinal subtype of IPNB. The gastric IPNB subtype demonstrates
columnar epithelium with mucin that is histologically similar to gastric foveolar
epithelium. Oncocytic IPNB has bright eosinophilic cytoplasm with a complex
arborizing papillary growth pattern. The degree of dysplasia should be documented
similar to IPMN of the pancreas with a two-tiered system of low- and high-grade
dysplasia [26].
Mucinous cystic neoplasms of the liver (also known as biliary cystadenoma) can
very rarely give rise to ICC [27]. The cyst wall lining of biliary cystadenoma is
mucinous epithelium with characteristic ovarian-type stroma (Fig. 7.2e). The
7 Pathologic Assessment 103

ovarian-­type stroma can be identified by immunohistochemical stains for CD10,

estrogen receptor, progesterone receptor, and inhibin.
Primary sclerosing cholangitis is a cholestatic disorder of the liver that affects
bile ducts anywhere in the biliary system. The etiology of the disease is not well
understood; however, it is thought that the disease may be autoimmune-related
since there is a strong correlation with inflammatory bowel disease, especially
ulcerative colitis. Pathologically, PSC shows damage of both intra- and extrahepatic
bile ducts [28]. Within the liver, the bile ducts show intraepithelial inflammation
composed predominately of lymphocytes. In addition, the bile ducts will show peri-
ductal fibrosis, also known as “onion-skin” fibrosis (Fig. 7.2f). As the inflammation
and fibrosis progress in PSC, the bile ducts will undergo senescence and atrophy. A
secondary biliary ductal proliferation around the portal tracts also occurs as the liver
progresses toward cirrhosis. Similar to other cholestatic diseases which cause cir-
rhosis, the pattern of cirrhosis in PSC is described as “jig-saw” rather than the more
common nodular pattern seen with viral hepatitis.

Molecular Assessment of Intrahepatic Cholangiocarcinoma

With the widespread use of next generation sequencing panels, clinically relevant
mutations have been identified in ICC. Common mutations in ICC include TP53,
CDKN2A/B, KRAS, and ARID1A [30]. Mutations that more frequently occur in ICC
that may have a targeted inhibitor include IDH1, IDH2, FGFR1, FGFR2, EPHA1,
and BAP1 [31]. However, this field will likely significantly change with the advent
of larger next generation sequencing panels as well as further research into the
molecular underpinnings of this cancer.
Defective DNA mismatch repair can be caused by either Lynch syndrome or may
occur sporadically. Defective mismatch repair can be pathologically assessed by
immunohistochemistry for DNA mismatch repair proteins (MLH1, MSH2, MSH6,
and PMS2) or by polymerase chain reaction (PCR) testing of mononucleotide mic-
rosatellite instability (MSI). When tumors are mismatch repair deficient or have
high-levels of microsatellite instability, they are much more likely to respond to
immune checkpoint inhibitors. Unfortunately, only approximately 1% of ICC show
defective mismatch repair [29].

Conclusion

The diagnosis of intrahepatic cholangiocarcinoma can be challenging given its sim-

ilar histopathologic appearance to other primary and metastatic liver cancers. While
morphologic and immunohistochemical assessment serves as the basis for diagnos-
ing and staging ICC, the importance of molecular testing continues to increase as
potentially targetable mutations are identified.
104 B. J. Swanson

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Chapter 8
Systemic Therapy

Ning Jin and Laith Abushahin

Introduction

Intrahepatic cholangiocarcinoma (ICC) represents the second most common

­primary liver cancer and its incidence is rising [1]. Patients with ICC have an
extremely poor prognosis, with a median survival of less than 1 year [2–5]. Only
10–15% of patients with cholangiocarcinoma are amenable to surgery [6].
Furthermore, among those who undergo surgery, the majority will have disease
recurrence [7], with the risk of recurrence being linked to nodal metastasis, tumor
size, multicentricity, and vascular invasion [8]. Adjuvant chemotherapy is, there-
fore, an important treatment approach that aims to enhance the curative potential of
resection of localized ICC. Alternatively, for patients with locally advanced or met-
astatic ICC, systemic chemotherapy with gemcitabine- or fluoropyrimidine-based
combinations in the first-line and second-line settings, respectively, may offer
improvements in quality of life and prolong the overall survival [9]. This chapter
reviews the current approaches for both adjuvant and definitive chemotherapy for
ICC and discusses novel combinations of chemotherapy with biological agents and
targeted agents used for the treatment of ICC.

N. Jin (*)
Department of Oncology, The Ohio State University Wexner Medical Center,
Columbus, OH, USA
e-mail: [email protected]
L. Abushahin
Department of Oncology, The Ohio State University Wexner Medical Center,
Columbus, OH, USA
Division of Medical Oncology, Department of Internal Medicine, Columbus, OH, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 107

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_8
108 N. Jin and L. Abushahin

Adjuvant Chemotherapy

The optimal adjuvant chemotherapy for resected ICC remains controversial for sev-
eral reasons. First, given its relative rarity, most studies have included ICC with
other biliary tract cancers (BTC) despite their unique biological and clinical fea-
tures. Second, as is the case with many uncommon cancers, the majority of cases
have been reported through retrospective series. Third, prospective trials have been
limited by significant heterogeneity in their risk for recurrence due to underlying
negative prognostic factors (e.g., margin status and lymph node status).
In one of the earliest reported series of patients with ICC undergoing hepatic
resection, Ercolani et al. reported on 72 patients of which 25 received gemcitabine-­
based adjuvant chemotherapy [10]. Although the 5-year overall survival was higher
among patients who received chemotherapy (65 vs. 40 months (p < 0.05)), the
favorable prognostic effect of adjuvant chemotherapy could not be maintained on
multivariate analysis. Two National Cancer Database (NCDB) studies have also
attempted to address this question [11, 12]. In the first study, 638 patients with ICC
who underwent surgical resection between 1998 and 2006 were identified. Among
them, 12% were treated with adjuvant chemotherapy and 23% with adjuvant chemo-
radiation. On multivariate analysis, there was a statistically significant survival ben-
efit associated with both chemotherapy and chemoradiation. After adjusting for
other prognostic factors, the improvement in survival with adjuvant therapy was
restricted to patients with positive lymph nodes and/or resection margins [11]. In the
second NCDB publication, 985 patients who underwent resection between 1998
and 2011 and who received adjuvant chemotherapy were compared to a propensity-­
matched cohort of patients who did not receive adjuvant chemotherapy. Similar to
the earlier study, a benefit with adjuvant chemotherapy was observed among patients
with nodal metastases and positive margins [12]. Of interest, 53% of patients who
received chemotherapy did not have an R0 resection indicating a large proportion of
patients with a positive margin on the cohort.
Several prospective trials have been performed to evaluate the role of adjuvant
chemotherapy for ICC, though most have included other BTCs as well. Takada et al.
randomized 436 patients with pancreatobiliary cancers, including 118 with BTCs,
to either postoperative chemotherapy with 5-fluorouracil (5-FU) and mitomycin C
(MMC) or surgery alone [13, 14]. The chemotherapy group received MMC (6 mg/
m2 intravenous (IV)) at the time of surgery and 5-FU (310 mg/m2 IV) in 2 courses
of treatment for 5 consecutive days during postoperative Weeks 1 and 3, followed
by 5-FU (100 mg/m2 rally) daily from postoperative Week 5 until disease recur-
rence. While there were no apparent differences in 5-year survival or 5-year disease-­
free rate, only 118 patients were categorized as bile duct cancers without further
classification as intrahepatic or extrahepatic cholangiocarcinoma.
While it did not specifically include ICC, the European Study Group for
Pancreatic Cancer (ESPAC)-3 was a landmark randomized controlled trial (RCT)
that evaluated the role of adjuvant chemotherapy in periampullary pancreatobiliary
cancers. Of 428 randomized patients, 96 had distal cholangiocarcinomas. ­Two-­thirds
8 Systemic Therapy 109

of the patients were randomized to either 5-FU or gemcitabine-based adjuvant che-

motherapy, while one-third underwent observation [15]. In the 5-FU arm, 143
patients received 20 mg/m2 of folinic acid via intravenous bolus injection followed
by 425 mg/m2 of 5-FU via intravenous bolus injection administered 1 to 5 days
every 28 days for 6 months. In the gemcitabine arm, 141 patients planned to receive
1000 mg/m2 of IV infusion of gemcitabine once a week for 3 of every 4 weeks for
6 months. Although adjuvant chemotherapy was associated with significantly higher
survival among all patients in the trial after adjusting for prognostic factors and
performing multiple regression analyses, the value of adjuvant chemotherapy in
cholangiocarcinoma was questionable as the median overall survival was numeri-
cally higher in the observation group compared to the chemotherapy groups
(27.2 months vs. 18.3 months in the 5-FU group and 19.5 months in the gemcitabine
group).
In a recent large RCT, the BILCAP study enrolled 447 patients with BTCs of
which 19% were ICC. Patients were randomized 1:1 to capecitabine (1250 mg/
m2 days 1–14, every 21 days, for 8 cycles) or observation. This was the first random-
ized trial to show the benefit of adjuvant therapy that was statistically significant for
the “per-protocol” cohort. Although the results of BILCAP were more in favor of
adjuvant therapy compared to the prior two randomized trials, several questions
remained to be answered including the specific effect on ICC compared to the rest
of biliary and periampullary cancers included in the trial [16].
Perhaps the most disappointing findings came from the PRODIGE 12 trial. This
was a phase III multicenter RCT evaluating adjuvant gemcitabine and oxaliplatin
(GEMOX) versus observation alone in resected biliary cancers. The study random-
ized 196 patients of which 45% had ICC. Patients were randomized, within 3 months
of R0 or R1 resection of a localized intrahepatic, perihilar, extrahepatic cholangio-
carcinoma or gallbladder cancer to receive either surveillance or 12 cycles of gem-
citabine 1000 mg/m2 and oxaliplatin 85 mg /m2 every 2 weeks. The trial results were
negative, with no difference in relapse-free survival between study arms. In addi-
tion, subgroup analysis by tumor type did not demonstrate any favorable trends
[17]. Several factors could have contributed to the lack of proven benefit of therapy
in the trial. Inclusion of cases with a lower risk of recurrence may have affected the
results as only one-third had node-positive disease and one-half the patients had
multifocal tumor. In addition, only 33% of patients in the GEMOX arm received all
six cycles of planned treatment. The results of another ongoing large randomized
trial of adjuvant chemotherapy with gemcitabine and cisplatin compared to standard
of care after curative intent resection of biliary tract cancer (ACTICCA-1) are
eagerly awaited (NCT02170090).
While the role for adjuvant systemic chemotherapy continues to be debatable,
interest in identifying a suitable adjuvant strategy remains high, given the poor
prognosis and high risk of recurrence after surgery. In the meantime, on the basis of
the BILCAP trial, adjuvant capecitabine has been established as the standard of care
for most resected BTCs including ICC. Nevertheless, all patients with resected ICC
are encouraged to enroll in clinical trials to aid our understanding of the optimal
adjuvant approach. Smarter trial designs with increased selectivity to ICC with
110 N. Jin and L. Abushahin

exploration of biologically optimized interventions are necessary. As stated earlier,

the recurrence pattern of ICC is different from other biliary cancers as it is primarily
in the form of intrahepatic or intraperitoneal recurrence [11]. This could open the
way for more anatomic focally directed interventions such as hepatic artery-based
therapies.

First-Line Palliative Chemotherapy

For patients with locally advanced or metastatic ICC, systemic chemotherapy

remains the mainstay of treatment. In particular, palliative chemotherapy for active
symptom control is vital to the management of the disease from the time of initial
diagnosis. Compared with best supportive care, palliative chemotherapy offers
improvements in quality of life and prolongs the survival for patients with BTCs,
including ICC [9]. The data for systemic therapy is limited due to the lack of large
prospective randomized clinical trials with head-to-head comparisons. Gemcitabine-
and fluoropyrimidine-based (5-FU or capecitabine) chemotherapies are the most
frequently studied combinations in phase II trials, with the exception of the combi-
nation of gemcitabine and cisplatin, which remains the standard care for the first-­
line treatment of advanced cholangiocarcinoma. In this next section, we will review
chemotherapy regimens including single-agent gemcitabine, 5-FU/capecitabine,
and gemcitabine-, fluoropyrimidine-based combinations in the first-line and second-­
line settings.
The nucleoside analog gemcitabine, as either a single agent or in combination
with other chemotherapies, has been extensively studied in patients with BTCs.
Data from phase II trials demonstrate that gemcitabine is generally well tolerated
with response rates ranging from 0% to 30% [18–21]. In one prospective phase II
trial [20], 23 chemotherapy-naïve patients with locally advanced or metastatic bili-
ary tract adenocarcinomas were enrolled and treated with gemcitabine 1000 mg/m2
on days 1 and 8, every 21 days. Six patients (26.1%) had partial response, while
eight patients (34.8%) had stable disease. The overall response rate was 26.1%
(95% CI, 22.08–30.12), the median time to disease progression was 8.1 months
(95% CI, 3.33–12.87), and the median overall survival was 13.1 months (95% CI,
1.64–24.56). Toxicities were generally mild and included grade 3–4 neutropenia
and thrombocytopenia. Treatment was well tolerated and dose omissions or reduc-
tions were rare. Overall, results suggest that gemcitabine monotherapy can be a
valid first-line treatment method for those with an Eastern Cooperative Oncology
Group (ECOG) performance status of 2.
Single-agent 5-FU is a nucleoside metabolic inhibitor that has also been assessed
in the first-line. Earlier studies used 5-FU IV bolus; however, the objective response
rates were low, and median survival was typically less than 6months [22]. In later
trials, continuous infusional 5-FU or leucovorin-modulated 5-FU were studied and
showed higher response rates (ranging from 21.4% to 32.1%), although whether
this translates into better survival is still unclear [23–27]. In the same class of
8 Systemic Therapy 111

drugs, capecitabine used as a single agent was also evaluated in patients with chol-
angiocarcinoma (n = 18) and gallbladder cancer (n = 8), given as 1000 mg/m2 twice
daily for 14 days, every 21 days. The median survival was 8.1 months (95% CI,
7.4–8.9 months) for patients with cholangiocarcinoma vs. 9.9 months (95% CI,
4.4–15.4 months) for patients with gallbladder cancer [28]. Several phase II studies
combining gemcitabine with capecitabine showed response rates of 25–31%, and
median survival of 12.7–14 months [29–31].
Multiple phase II studies have also evaluated the combination of gemcitabine
with platinum-based compounds, either cisplatin or oxaliplatin in patients with
advanced BTCs, showing response rates of 21–36%, and median survival rates of
8.4–15 months [32–35]. A pooled analysis of all published clinical trials from 1985
to 2006 concluded that the addition of oxaliplatin or cisplatin to gemcitabine
increases response rate (complete response + partial response), tumor control rate
(complete response + partial response + stable disease) and shows a trend towards
improved progression-free survival compared with fluoropyrimidine-based regi-
mens, such as 5-FU [36]. However, whether gemcitabine-based combination regi-
mens are superior to fluoropyrimidine-based regimens for advanced BTC is not
clear, as the difference in survival times are small and not significant.
In general, gemcitabine-based therapies are used for patients with good perfor-
mance status, whereas leucovorin-modulated 5-FU based therapies are reasonable
options especially for patients with borderline performance status or hyperbilirubi-
nemia in the first-line setting.

Gemcitabine with Cisplatin

The combination of gemcitabine and cisplatin compared with gemcitabine alone

was addressed in phase III ABC-02 RCT for patients with locally advanced or meta-
static cholangiocarcinoma, gallbladder cancer, or ampullary cancer. Results of this
study demonstrated improvements in both progression-free and overall survival in
patients who received gemcitabine plus cisplatin, compared to gemcitabine alone.
Patients received either cisplatin (25 mg/m2 on days 1 and 8) followed by gem-
citabine (1000 mg/m2 on days 1 and 8) every 3 weeks for eight cycles or gem-
citabine alone (1000 mg/m2 on days 1, 8 and 15) every 4 weeks for six cycles.
Median progression-free survival was 8.0 months vs. 5.0 months (HR, 0.63; 95%
CI, 0.51–0.77; P < 0.001), and median overall survival was 11.7 months vs.
8.1 months (HR, 0.64; 95% CI, 0.52–0.80; P < 0.001). Adverse events were similar
in the two groups, with the exception of neutropenia being more frequent in the
combination group [37]. This study established the gemcitabine/cisplatin combina-
tion as the standard of care in this disease. Notably, this study was supported by a
randomized phase II BT22 study of Japanese patients with BTCs, which found
median progression-free survival of 5.8 months and overall survival of 11.2 months
for gemcitabine/cisplatin, compared with 3.7 and 7.7 months for progression-free
and overall survival for gemcitabine alone [38]. A meta-analysis of these two
112 N. Jin and L. Abushahin

studies showed that the benefit of gemcitabine/cisplatin is most significant among

patients with good performance status (ECOG performance status 0–1) and results
in improved progression-free and overall survival for intra- and extrahepatic chol-
angiocarcinoma and gallbladder cancer. However, patients with a performance sta-
tus of 2 may derive the least benefit from the combination [39].

Gemcitabine with Oxaliplatin (GEMOX)

GEMOX has been evaluated in several studies, and this regimen has been well
tolerated [33, 35, 40, 41]. A phase II study of GEMOX examined a cohort of 56
patients with advanced or metastatic BTC, who were treated with gemcitabine
(1000 mg/m2 on day 1) and oxaliplatin(100 mg/m2 on day 2) every 2 weeks. The
patients were divided into two groups: Group A patients (n = 33) had the perfor-
mance status 0–2, bilirubin <2.5× normal without prior chemotherapy; Group B
patients (n = 23) had performance status >2 and/or bilirubin >2.5× normal and/
or prior chemotherapy. In Group A, the response rate was 36% and median over-
all survival duration was 15.4 months, whereas in Group B patients with perfor-
mance status >2 and prior chemotherapy, the response rate was 22% and median
survival was 7.6 months. However, the tolerability of GEMOX in Group B did
not differ significantly from that in Group A patients, indicating that this combi-
nation is safe in patients who have a poor prognosis or have received prior che-
motherapy [33]. Therefore, in patients with a concern about cisplatin toxicity
(renal or hearing impairment), oxaliplatin may be substituted for cisplatin in the
first-line setting [42].

Gemcitabine with Carboplatin

A phase II study examined a total of 48 patients with advanced BTCs (35 cholan-
giocarcinoma, 12 gallbladder and 1 ampullary cancer) in the first-line setting, who
were treated with a maximum of nine cycles of gemcitabine 1000 mg/m2 IV on days
1, 8 with carboplatin dosed at an area-under-the-curve (AUC) of 5 on day 1, every
3 weeks. A median of four cycles was administered. The overall response rate for
evaluable patients was 31.1%. Median progression-free survival and overall sur-
vival were 7.8 months and 10.6 months, respectively. The most common grade 3–4
toxicities include neutropenia and thrombocytopenia [43]. Although severe non-­
hematological toxicities were uncommon, hematological toxicities associated with
gemcitabine and carboplatin, as administered in this protocol, appeared higher com-
pared with the toxicities reported using weekly cisplatin and gemcitabine in the
ABC-02 study (Grade 3–4 anemia 12% vs. 6.3%; grade 3–4 thrombocytopenia 20%
vs. 8.2% and grade 3–4 neutropenia 37% vs. 22.6%).
8 Systemic Therapy 113

Gemcitabine with Capecitabine

In one prospective phase II study, 45 patients were enrolled (53% with cholangio-
carcinoma, 47% with gallbladder cancer) and treated with gemcitabine(1000 mg/m2
on days 1 and 8) and capecitabine (650 mg/m2 twice daily for 14 days) every
21 days. The overall objective response rate was 31%, with an additional 42% of
patients with stable disease. The median progression-free and overall survivals were
7 and 14 months, respectively [29]. This chemotherapy combination was generally
well tolerated. In another prospective phase II study, 44 patients who met at least
one of the symptoms including impaired Karnofsky performance score of 60 to 80,
analgesic consumption ≥10 mg of morphine equivalents per day, or pain score
≥20 mm/100 mm were enrolled (cholangiocarcinoma, n = 36; gallbladder cancers,
n = 8), and were treated with gemcitabine/capecitabine. The objective response rate
was 25%, the median time to progression and overall survival were 7.2 months and
13.2 months, respectively. Improved quality of life was observed in patients with a
clinical benefit response [30].

5-FU with Oxaliplatin (FOLFOX)

A retrospective cohort study has been conducted to compare the efficacy of FOLFOX
vs. gemcitabine as the first-line option in patients with advanced BTC. Twenty-two
patients were treated with FOLFOX-4 consisting of oxaliplatin (85 mg/m2, day 1),
leucovorin (200 mg/m2/day) followed by a 5-FU bolus (400 mg/m2/day) and 22-hour
infusion of 5-FU (600 mg/m2/day) for two consecutive days, every 2 weeks.
Eighteen patients received gemcitabine, 1250 mg/m2 on days 1 and 8, every 3 weeks.
In the FOLFOX-4 group, the overall response rate was 13.6% (95% CI, 4.7–33.3)
and there was a 54.5% (95% CI, 34.7–73.1) disease control rate (complete response
+ partial response + stable disease). Median overall survival was 14.1 months (95%
CI, 9.1–18.8) and median progression-free survival was 5.44 months (95% CI, 3.2–
6.3). In the gemcitabine group, there was no objective response, whereas 27.7%
(95% CI, 12.5–50.9) obtained disease control. Median overall survival was
8.3 months (95% CI, 4.7–12.9) and median progression-free survival was 3.9 months
(95% CI, 2.2–5.4). Toxicity, mainly hematological, was acceptable for both treat-
ments [21] (Table 8.1).

Second-Line Palliative Chemotherapy

There is no established second-line systemic therapy following progression after

first-line treatment. In fact, only 15–25% of patients are fit enough to receive
second-­line treatment [44]. In general, for patients who retain adequate performance
114 N. Jin and L. Abushahin

Table 8.1 Summary of first-line palliative chemotherapy studies and outcomes in patients with
intrahepatocellular cholangiocarcinoma
Treatment Response rate Overall survival (median)
Single agents
Gemcitabine [18–21, 38] 0–30% 5.2–17.3 months
5-FU [23–26] 21.4–32.1% 4.7–10 months
Capecitabine[28] 6% 8.1 months
Combination treatments
Gemcitabine + cisplatin [32, 34, 36–39] 19.5–33.3% 9.7–11.2 months
Gemcitabine + oxaliplatin (GEMOX) [33, 35, 40] 22–41% 7.6–15.4 months
Gemcitabine + carboplatin [43] 31.1% 10.6 months
Gemcitabine + capecitabine[29–31] 25–31% 12.7–14 months
5-FU + oxaliplatin (FOLFOX) [21] 13.6% 14.1 months
Note: 5-FU when given as continuous infusion or leucovorin-modulated 5-FU

status but progressed on gemcitabine with platinum regimen, FOLFOX, capecitabine

with oxaliplatin (CAPOX), 5-FU with irinotecan (FOLFIRI), or capecitabine with
irinotecan (XELIRI) can be considered.
In a Phase II study of second-line therapy, 37 patients with advanced BTC
who were refractory to gemcitabine/cisplatin chemotherapy were treated with
FOLFOX for two consecutive days, every 2 weeks: oxaliplatin (85 mg/m2, day
1), leucovorin (200 mg/m2/day) followed by a 5-FU bolus (400 mg/m2/day) and
22-hour infusion of 5-FU (600 mg/m2/day). The primary endpoint, the median
time to progression, was 3.1 months (95% CI, 2.3–3.6), while the objective
response rate was 21.6% (8 with partial response), and disease control rate was
62.2% (15 with stable disease) [45]. Another randomized phase II study evalu-
ated the efficacy and safety of second-­line capecitabine and irinotecan vs. irino-
tecan monotherapy in advanced biliary tract cancer who progressed on
gemcitabine and cisplatin. Sixty-four patients were randomized to either irino-
tecan 180 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily on days
1–10 of a 14-day cycle or single-agent irinotecan 180 mg/m2 on day 1 of a
14-day cycle. Of the 60 patients included in the analysis, the median progres-
sion-free survival was 3.7 vs. 2.4 months and median overall survival was 10.1
vs. 7.3 months for capecitabine/irinotecan and irinotecan only arms, respec-
tively. The most common grade 3 or 4 toxicities were leucopoenia and
­neutropenia [46].
A systematic review of second-line systemic chemotherapies that included 23
studies and 761 patients with advanced BTC, showed that the median overall sur-
vival was 7.2 months (95% CI, 6.2–8.2) and the median progression-free survival
was 3.2 months (95% CI, 2.7–3.7). No recommendation could be made in regard to
the most appropriate second-line regimen. These results underscore the unmet need
for prospective RCTs in this setting [47].
8 Systemic Therapy 115

Chemotherapies in Combination with Biologic Agents

With the advent of whole-exome and next generation sequencing, multiple molecular
aberrations have been identified that contribute to the multistep carcinogenesis in ICC
[48–53]. Well established genomic alterations include EGFR (epithelial growth factor
receptor) overexpression (11–27%), VEGF (vascular endothelial growth factor) overex-
pression (54%), KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation
(9–24%), and TP53 (tumor protein p53) mutation (3–36%). Results of EGFR inhibitors
or VEGF inhibitors in combination with standard chemotherapy have, in general, been
disappointing [54–58]. Most of the studies were not biomarker-driven, which may
undermine the potential benefit of targeted therapy in distinct patient populations.

Gemcitabine with EGFR Inhibitors

The EGFR family includes HER1/EGFR (human EGFR related 1/EGFR), HER2,
HER3, and HER4. EGFR is frequently implicated in the carcinogenesis of cholan-
giocarcinoma. The majority of EGFR overexpression in BTC is due to DNA copy
number gains while activating mutations in EGFR gene are rare events [48, 59]. In
a multicenter phase II trial, 44 patients with unresectable cholangiocarcinoma naïve
to chemotherapy were enrolled and treated with the EGFR inhibitor cetuximab
(400 mg/m2 at week 1, then 250 mg/m2 weekly) and gemcitabine (1000 mg/m2 on
days 1, 8 and 15), every 4 weeks. Six-month progression-free survival was 47%, and
median overall survival was 13.5 months (95% CI, 9.8–31.8 months). Nine patients
(20.4%) had partial response, and the disease control rate was 79.5%. KRAS muta-
tions were found in 7 of 27 patients and had no influence on progression-free sur-
vival. Skin toxic effect ≥grade 2 was associated with increased progression-free
survival (P = 0.05). Grade 3 or 4 treatment-related toxic effects were hematological
(52.2%), skin rash (13.6%), and fatigue (11.4%) [60]. Despite these results, ran-
domized studies have failed to demonstrate a survival benefit by combining EGFR
inhibitors with gemcitabine/oxaliplatin in advanced cholangiocarcinoma [54–56].

GEMOX with VEGF Inhibitors

VEGF overexpression has been observed in 54% of ICCs [51]. In a retrospective

study, the combination therapy of bevacizumab with GEMOX was compared to
GEMOX therapy alone in the first-line setting in metastatic BTC. Thirty-two patients
were treated with gemcitabine 1000 mg/m2 followed by 100 mg/m2oxaliplatin, plus
bevacizumab 5 mg/kg on day 1, every 2 weeks (GEMOX-bevacizumab, group A).
Twenty-five patients were treated with the GEMOX regimen only (group B). The
treatment was repeated every 2 weeks until disease progression or unacceptable
116 N. Jin and L. Abushahin

toxicity. The combination therapy of bevacizumab with GEMOX was associated with
a better progression-free survival, compared to that of GEMOX therapy (6.48 months
vs. 3.72 months, p = 0.049). However, the median overall survival was 11.31 months
and 10.34 months in Group A and B (p = 0.64), failing to demonstrate a survival ben-
efit of adding bevacizumab to the chemotherapy backbone. Specific grades 3–4 beva-
cizumab-related adverse events included hypertension (6%), cardiac ischemia (3%),
proteinuria (6%), perforation (6%), thrombosis (3%), and bleeding events (3%) [57].

Bevacizumab with Erlotinib

In a multicenter phase II study, patients (n = 53) with advanced cholangiocarcinoma

(n = 43) or gallbladder cancer (n = 10) were treated with bevacizumab 5 mg/kg
intravenously on days 1, 15 and erlotinib 150 mg by mouth daily on days 1 through
28, in a 28-day cycle. Of 49 evaluable patients, six patients (12%; 95% CI, 6% to
27%) had a confirmed partial response and 25 patients (51%) had documented sta-
ble disease. Rash was the most common grade 3 toxicity. Four patients had grade 4
toxicities, including cerebral ischemia and thrombosis. Median overall survival was
9.9 months, and time to progression was 4.4 months. In conclusion, the biologic-
only combination of bevacizumab and erlotinib has a demonstrable activity in
advanced biliary tract cancers with few grade 3 or 4 adverse events [61].

Novel Targeting Agents

A combination of whole-exome and transcriptome sequencing has been performed

to characterize a total of 260 cases of BTC, including 145 cases of ICC, 86 cases of
extrahepatic cholangiocarcinoma, and 29 cases of gallbladder cancer. Recurrent
mutations in IDH1/2 (isocitrate dehydrogenase 1/2) and BAP1 (BRCA-1 associated
protein 1), FGFR2 (fibroblast growth factor receptor 2) fusion are predominantly
found in the intrahepatic subtype, whereas ARID1B (AT-rich interactive domain-­
containing protein 1B) mutation, PRKACA (cAMP-dependent protein kinase cata-
lytic subunit alpha), and PRKACB fusion preferentially occur in extrahepatic
subtype [62], indicating that there might be distinctive molecular features among
different subtypes of cholangiocarcinoma.

FGFR2 Fusion Inhibitors

FGFR2 mitigates cell differentiation, proliferation, and apoptosis [63]. There is

marked variability in the frequency of FGFR2 fusions across studies, ranging
from 6% to 50% in ICCs. However, FGFR alterations are rarely found in
8 Systemic Therapy 117

extrahepatic cholangiocarcinomas [62, 64–66]. FGFR2 fusions are associated

with improved survival [49]. In a phase II study, BGJ398, a pan-FGFR tyrosine
kinase inhibitor, was evaluated in 61 patients with advanced or metastatic chol-
angiocarcinoma containing FGFR2 fusions or other FGFR alterations whose
disease had progressed on prior therapies. The overall response rate was 14.8%,
disease control rate was 75.4%, and estimated median progression-free survival
was 5.8 months (95% CI, 4.3 to 7.6 months). Grade 3 or 4 treatment-related
adverse events occurred in 25 patients (41%) and included hyperphosphatemia
(16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). This
study showed meaningful clinical activity against chemotherapy-refractory
cholangiocarcinoma containing FGFR2 fusions [67]. There are other FGFR
inhibitors that are under investigation (NCT02272998, NCT01752920,
NCT03278106).

IDH1/2 Inhibitors

AG-120 is an oral IDH1 inhibitor that is approved for adult patients with relapsed or
refractory acute myeloid leukemia (AML) with IDH1 mutations. In a phase I clini-
cal trial in mutated IDH1 advanced solid tumors, 73 patients with cholangiocarci-
noma were treated with AG-120 at doses ranging from 100 mg twice daily to
1200 mg once daily. AG-120 demonstrated a favorable safety profile and clinical
activity in this study [68]. Among the 72 evaluable patients, 6% (n = 4) had a con-
firmed partial response and 56% (n = 40) had stable disease. Progression-free sur-
vival rate at 6 months was 40%. Currently, a phase III, multicenter, double-blind
study (ClarIDHy) to evaluate the efficacy of AG-120 for patients with mutated
IDH1 cholangiocarcinoma is ongoing (NCT02989857).

Conclusion

ICC is a rare but aggressive cancer, with very low 5-year survival rates. While many
different chemotherapy regimens have been evaluated in cholangiocarcinoma, only
a few studies have shown promising results. For adjuvant chemotherapy, physicians
need to discuss treatment options in a multidisciplinary setting and offer the best
care to patients using a shared decision-making process. Regarding definitive che-
motherapy options for patients with locally advanced and metastatic setting, the
appropriate chemotherapies should be considered based on the patient’s perfor-
mance status and liver function. Patient participation in prospective clinical trials is
the preferred option for patients with ICC. Ongoing clinical trials will be discussed
in greater detail in a later chapter.
118 N. Jin and L. Abushahin

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68. Lowery MA, Bou-Alfa GK, Burris HA, et al. Phase I study of AG-120, an IDH1 mutant
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Chapter 9
Percutaneous Ablation

Guojun Qian, Jinglei Zhang, and Feng Shen

Introduction

Intrahepatic cholangiocarcinoma (ICC) is a primary adenocarcinoma originating

from the intrahepatic biliary tree and is the second most common primary liver
cancer after hepatocellular carcinoma (HCC) [1]. The incidence of ICC is increas-
ing worldwide according to the recent reports and its development is known to be
associated with certain predisposing genetic and environmental factors [2]. Because
ICC is often diagnosed at an advanced stage and exhibits aggressive tumor biology,
the long-term survival outcomes of patients with ICC remain poor [3]. Among pos-
sible treatments for patients with ICC, surgical resection is the only established
treatment that may provide long-term survival in well-selected patients, especially
when the tumor is completely resected with a negative surgical margin [4, 5].
However, the majority of patients are not candidates for curative-intent surgery due
to advanced disease at the time of diagnosis [6]. In addition, tumor recurrence and
metastasis are still common even among patients who are able to undergo radical
resection.
Image-guided percutaneous ablation is a minimally invasive therapy, which can
result in local destruction of multiple types of liver malignancies [7–9]. Although
ablative techniques have been well established in the treatment of HCC and isolated
liver metastases, demonstrating efficacy even in large liver tumors via stereotactic
placement of multiple radiofrequency probes [10], only limited data are currently
available on the use of ablation in ICC. In addition, for recurrent ICC after initial

G. Qian · J. Zhang
Department of Ultrasound Interventional Therapy, Eastern Hepatobiliary Surgery Hospital,
Naval Medical University, Shanghai, China
F. Shen (*)
Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital,
Naval Medical University, Shanghai, China

© Springer Nature Switzerland AG 2019 123

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_9
124 G. Qian et al.

curative resection, the use of repeat hepatectomy is usually limited by poor liver
remnant function or multifocal recurrent diseases. In addition to systemic chemo-
therapy, these patients may be treated with locoregional therapies such as external
beam radiation (XRT), radiofrequency ablation (RFA), microwave ablation (MWA),
and radioactive implants (RIs) [11, 12].
This chapter reviews the technique, mechanism of action, indications, and out-
comes of percutaneous ablation for ICC, highlighting the currently available
evidence.

Indications for Percutaneous Ablation for ICC

There is limited research for which to base guidelines on the indications for percu-
taneous ablation in ICC. In clinical practice, patients with ICC who are not suitable
for resection or who have developed relapse after resection are often considered for
percutaneous thermal ablation. However, it is not uncommon for patients with ICC
to undergo ablation based on a presumptive diagnosis of HCC, for which the use of
curative-intent ablation is more established. Since the accurate histopathological
evaluation of ablated tumors is usually not possible, this limitation must be consid-
ered when evaluating research on ablation for ICC. Percutaneous thermal ablation
is commonly used in HCC patients who have a tumor within the Milan criteria,
either as a curative-intent treatment or as a bridge to transplantation [13]. However,
some authors have reported that the indications for percutaneous ablation should be
less stringent: less than 5 nodules, each <5 cm in size, Child-Pugh class A or B liver
function, prothrombin time <17 seconds, platelet count >45 cells ×109/L, and no
evidence of macrovascular invasion and/or extrahepatic distant metastases [14].
However, treatment guidelines for the use of percutaneous thermal ablation in ICC
are not comprehensive and immature. Zhang et al. reported that ablation should be
considered based on the following criteria: histopathologically proven ICC, primary
or recurrent tumor after surgery, maximum tumor size <5 cm, tumor number <3.
Whether additional indications beyond this standard are also suitable for ablation is
unknown [15].

 herapeutic Mechanism of and Equipment for RFA

T
and WMA

Both RFA and MWA result in cytotoxic destruction of cancer cells via direct ther-
mal injury. The ablation procedures involve placing needles (electrodes/antennas)
directly into the targeted tumors. It aims to increase the temperature between 60 and
100 °C in the tumor tissues, which can lead to coagulation necrosis of the tumor
9 Percutaneous Ablation 125

while avoiding charring and vaporization of tissues [16–18]. In addition, thermal

ablation technology is designed to destroy tumors without disrupting adjacent liver
structures. These treatments have achieved acceptable outcomes in previous studies
of liver tumors [12, 14, 19].

RFA

A large body of literature exists on the use of RFA for HCC and liver metastases.
During the process of ablation, the needle is placed directly into the targeted tumor,
and one or more electrodes are deployed from the tip of the needle to the tumor tis-
sues. The heat and the friction generated by the radio energy through the ion pro-
duced by the needle generate heat and destroy the tumor tissues. A miniature
thermometer coupled to the tip of the electrode allows continuous monitoring of
tissue temperature. The power is automatically adjusted to keep the target tempera-
ture constant. As tissue temperature increases above 60 °C, cancer cell death occurs
almost instantaneously [20].
Multiple ablations can overlap to reduce the chance of residual disease and/or
local recurrence following ablation. The size of the ablated area depends mainly on
the size of the electrode needle, the temperature generated in the tissues and the
duration of the energy applied. A sharp boundary separates dead tissue and unaf-
fected surrounding tissue [20–22].

MWA

MWA is an alternative method of inducing tissue thermal coagulation. Microwave

magnetic fields make surrounding molecules rotate at high speed and frictional
heating, resulting in tissue coagulation, dehydration, and necrosis. It involves plac-
ing needle electrodes directly into the targeted tumors. Each ablation produces a
hyperechoic region surrounding the needle. Unlike RFA, MWA does not need to use
a retractable tip that results in a tendency to be more elliptical and requires more
courses of treatment for larger tumors. On the other hand, treatment sessions are
usually shorter than that for RFA because an ablation is produced in 60 seconds
with microwave therapy [23].
Currently, MWA is performed usually using a cooling shaft system that produces
a maximum power of 100 W at 2450 MHz [24], while the conventional setting for
ablation is 60–100 W output power, 120–300 seconds. If the hyperechoic micro-
bubbles produced by heat do not completely cover the entire tumor, extended micro-
wave emission is required until the desired ablative range is reached. After MWA
treatment, needle burning is needed to prevent tracking of tumor cells [12, 15, 25].
126 G. Qian et al.

Survival Outcomes after RFA for ICC

In previous studies, the technical success rate (i.e., complete ablation without local
progression for at least 1 month) defined by the Interventional Radiology Reporting
Standard [26] has been reported to be between 80% and 100% in ICC. However,
local tumor progression rate after RFA was relatively high, which was reported to
range from 8% to 50% [27–33], and the pooled rate in a meta-analysis was reported
to be 21% (95% confidence interval [CI], 13–30%) [34]. The incidence of major
complications observed after RFA was reported to be between 3.9% and 27% [14,
19, 29–32, 35].
In a meta-analysis on RFA for ICC, the pooled 1-, 3-, and 5-year survival rates
were 82% (95% CI, 72–90%), 47% (28–65%) and 24% (11–40%), respectively.
These results were comparable to the outcomes recently estimated using the
SEER database [26, 34]. Amini et al. reported that in a review of 1232 patients
who were selected from the SEER database, only 64 (5.2%) patients underwent
ablative therapy alone. Interestingly, they noted that the median survival of
patients who were treated with ablation therapy was 20 months, which was worse
than the outcomes of patients who were treated with resection but better than the
outcomes following radiation therapy alone [26]. A review from Shindoh et al.
reported that although the outcomes mentioned above were likely to be influenced
by the differences in the baseline characteristics of the patients in each group,
RFA might confer a modest survival advantage compared with other nonsurgical
treatment options [36].
More recently, an original article reported by Takahashi et al. demonstrated
that the median overall survival after ICC ablation was 23.6 months (range:
­7.4–122.5 months), and the estimated 1-, 3-, and 5-year survival rates were 95%
(95% CI: 86–100%), 40% (21–76%) and 32% (15–70%), respectively. The
median disease-­free survival was 8.2 months (range: 1.1–70.4 months) [12].
Another study reported that an increased tumor stage was associated with worse
outcomes following RFA. The use of RFA was associated with a significantly
prolonged survival compared with no local therapy in patients with stage I dis-
ease (2.1 vs. 0.7 years, P = 0.012), whereas patients with stage IV disease dem-
onstrated no survival benefit from RFA [11]. Of note, all patients who were
diagnosed as having ICC from 2004 to 2015 in the National Cancer Database
(NCDB) were analyzed in this article, and the tumor staging was according to the
seventh edition of the American Joint Committee on Cancer (AJCC)/Union for
International Cancer Control (UICC) staging system of ICC [37]. Figure 9.1
shows the features of an ICC tumor before and after ablation on contrast-
enhanced magnetic resonance imaging (MRI).
9 Percutaneous Ablation 127

a b

Fig. 9.1 A 59-year-old female patient who underwent left lateral lobectomy of the liver for a his-
topathologically proven ICC. Two years after the operation, a 1.6 cm recurrent lesion in the right
lobe was identified by MRI (a). The nonenhancing area completely enveloped the ablated tumor at
2months after the ablation (b)

RFA Versus MWA in the Treatment of ICC

Compared with RFA, MWA may have several distinct advantages including less
dependence on tissue conductivity, shorter ablation time, higher intratumoral tem-
perature, and larger ablation area and homogeneity [35, 38, 39]. Up to now, only
two original studies reported by Zhang et al. [15] and Yu et al. [25] have described
the relatively detailed procedures and outcomes of MWA in ICC. There has been no
report to compare the outcomes following RFA versus MWA within any indepen-
dent study. The comparison of outcomes of these two procedures from 5 studies
using either RFA or MWA for ICC is listed in Table 9.1.
Among these studies, a meta-analysis by Han et al. included 7 observational
studies that comprised 84 ICC patients [27–33] through a comprehensive literature
search on Ovid MEDLINE and EMBASE to identify the studies that reported data
of overall survival, local tumor progression, and complications after RFA. The
pooled 1-, 3-, and 5-year overall survival rates were 82% (95% CI: 72–90%), 47%
(28–65%) and 24% (11–40%), respectively, as above-mentioned [34]. In an article
by Zhang et al., a total of 107 patients with 171 ICC tumors (≤5 cm in size, tumor
number≤3) underwent MWA. The median follow-up after MWA was 20.1 months
(2.8–63.5 months). The median progression-free survival (PFS) after MWA was
8.9 months; and the PFS rates at 6, 12, 18, and 24 months after the treatment were
67.4%, 41.5%, 18.2%, and 8.7%, respectively. The median overall survival was
128 G. Qian et al.

Table 9.1 Reported outcomes following RFA and MWA in ICC patients
Tumor OS (%)
Authors size
(country) Treatment Study design N (cm) Indication 1-year 3-year 5-year
Carrafiello, RFA Retrospective 6 1.0–5.8 Unresectable NA – –
2010 (Italy) ICC
[28]
Giorgio, RFA Retrospective 10 2.4–5.5 Unresectable 100 83 83
2011(Italy) ICC
[40]
Han, RFA Meta-­analysis 84 0.7–10 Unresectable/ 82 47 24
2015(South recurrent ICC
Korea) [34]
Yu, MWA Retrospective 15 1.3–9.9 Unresectable 60 – –
2011(China) ICC
[25]
Zhang, 2018 MWA Retrospective 107 ≤5 Unresectable/ 93.5 39.6 7.9
(China) [15] recurrent ICC
RFA radiofrequency ablation, MWA microwave ablation; N number, OS overall survival, NA not
available

28.0 months; and the overall survival rates at 1, 3, and 5 years after the treatment
were 93.5%, 39.6%, and 7.9%, respectively [15]. In these two articles, the reported
1-year overall survival rate following RFA was lower than that after MWA, while
RFA had a higher 3- and 5-year overall survival rates than MWA.

Complications Following Percutaneous Ablation

There are fewer reports on complications associated with percutaneous thermal abla-
tion for ICC compared to HCC. In general, complications are classified as minor and
major according to the clinical practice guidelines proposed by the Society of
Interventional Radiology (SIR) [27]. Complications that require additional therapy,
cause prolonged hospital stay, lead to permanent adverse sequelae, or result in death
are evaluated as major complications. Others are considered as minor complications.
The following data are obtained by pooling 14 original studies about ICC [3, 12,
14, 15, 19, 27–33, 35, 40]. In 380 patients who were treated with percutaneous ther-
mal ablation, major complications were registered in 5% (19/380) of patients. The
mortality rate was 0.26% (1/380). Major complications included abdominal bleed-
ing (1/380, 0.26%), needle-track cancer seeding (1/380, 0.26%), large biloma
(2/380, 0.52%), biliary stricture (1/380, 0.26%), biliary fistula (1/380, 0.26%), pleu-
ral effusion with symptoms of dyspnea (3/380, 0.79%), hepatic failure (1/380,
0.26%), and liver abscess (9/380, 2.37%). One patient died of hepatic sepsis at
3.3 months after ablation despite percutaneous drainage and antibiotic therapy [29].
The minor complications included asymptomatic pleural effusion, mild bile duct
dilation with or without jaundice, gallbladder wall thickening, a small amount of
9 Percutaneous Ablation 129

pleural effusion around the ablated area, small hematomas, minimal to moderate
pain and fever, and increase in aminotransaminases. All minor complications
resolved with conservative treatment. However, since the reported overall incidence
of complications following ablation is low, percutaneous thermal ablation is gener-
ally considered safe for patients with ICC.

Ablation Versus Surgical Resection for ICC

Surgical resection is considered the first-line treatment for patients with localized
ICC. The goals of surgery include achieving a margin-negative hepatic resection
and performing a porta hepatis lymphadenectomy. However, the majority of patients
present with advanced disease at diagnosis, and only about 30% of patients may be
eligible for liver resection [41]. Surgical resection has been reported to provide a
5-year overall survival of 22–60% depending on specific clinicopathologic criteria
[3, 4]. However, tumor recurrence rates after resection are high, ranging between
44% and 70% at 5 years after surgery [42, 43].
In most previous studies, the outcomes following ablative therapies were mainly
investigated among patients who had unresectable ICC or recurrent ICC after initial
surgery [3, 12, 14, 15, 19, 23, 27–35, 40, 44]. Prognostic factors associated with abla-
tion treatment included tumor size, nodal invasion, and tumor differentiation. Given
the different indications for treatment among patients receiving surgery or ablation,
it is difficult to directly compare their long-term outcomes. There is only one original
article, which has compared the outcomes of repeat hepatic resection versus thermal
ablation for recurrent ICC [14]. Median survival time after repeated hepatic resection
and thermal ablation therapy was 20.3 and 21.3 months, respectively. The 1-, 2-, and
3-year overall survival rates were 83.8%, 38.0% and 17.1% after repeated hepatic
resection, and 69.8%, 37.3% and 20.5% after thermal ablation therapy (Table 9.2).
Overall survival rates did not differ significantly between the two groups (p = 0.996),
especially in patients with tumors less than 3 cm in size [14], suggesting that although

Table 9.2 Reported outcomes following RFA and surgical resection in ICC patients
Tumor size 3-year OS 5-year OS
Authors (country) Treatment N (cm) (%) (%)
Zhang, 2013(China) [14] RFA + MWA 77 ≤5 25 NA
Repeated HR 32 ≤5 17 NA
Wang, 2013 (China) [51] HR 367 5.5 41 35
Saiura, 2011 (Japan) [52] HR 44 5.7 56 43
Saxena, 2010 (Australia) [53] HR 40 6.5 48 28
Zhang, 2018(China) [15] MWA 107 ≤5 39.6 7.9
Kim, 2011(South Korea) [29] RFA 13 0.8–8.0 51 15
Xu, 2012(China) [19] RFA + MWA 18 1.4–6.9 30 30
HR hepatic resection, RFA radiofrequency ablation, MWA microwave ablation, N number, OS
­overall survival NA not available
130 G. Qian et al.

ablation might be effective in selected patients with recurrent ICC, its indication
should be limited according to tumor size [40].
Tumor size is an important factor associated with the therapeutic outcomes of
ablation. The length of hospital stay, treatment cost, and risk of complications tend
to be less with ablation than with hepatic resection. The incidence of major
­complications is also higher for hepatectomy compared to thermal ablation (46.9%
vs. 3.9%) [14]. Post-ablation mortality is rare, whereas the perioperative mortality
rates following resection of ICC range from 1.2% to over 7% [4, 45, 46]. Other
studies have suggested that the overall survival rate after ablation for ICC is signifi-
cantly higher compared to conservative treatments and comparable to that after
radical resection in well-selected patients [47–50]. These results suggest that abla-
tion may represent a less invasive alternative to surgical resection and is safe and
effective for patients with recurrent ICC. While additional research is needed, abla-
tion therapy may be considered a first-line treatment for selected patients with
small recurrent ICC.
An important limitation of ablative techniques is the omission of regional, lymph
node dissection. While not routinely performed for HCC, lymphadenectomy is an
important component of accurate staging and locoregional control for patients with
ICC. While less important for patients with recurrent ICC, the inability to perform
lymph node evaluation limits the current application of percutaneous ablation to
patients with otherwise resectable de novo ICC.

Combined Therapy

Because of the advanced stage at which most patients with ICC present, only a
small proportion are suitable for radical surgical resection or complete therapeutic
ablation. Combined multimodality therapy is an alternative approach to overcome
some of these limitations. Unlike HCC, ICC has poor vascularity with a fibrotic
characteristic, which leads to a limited survival benefit following transarterial che-
moembolization (TACE) [54]. On the other hand, percutaneous thermal ablation in
combination with TACE may provide improved outcomes. TACE can effectively
decrease heat dispersion during thermal ablation by occluding bloodstream and
consequently promote tumor ruin [55]. Meanwhile, thermal ablation may decrease
the required chemotherapy dose of TACE and accordingly lessen side reaction and
may also expand the ablation area and prolong progression-free survival. A study on
microwave ablation combined with TACE for ICC demonstrated improved results
compared to either TACE or ablation alone [56, 57].
Satellite lesions are often present in patients with ICC, which may preclude the
ability to perform radical resection. Local thermal ablation combined with surgical
resection is an option for patients with initially unresectable ICC. Although there is no
sufficient data about ICC specifically, several studies in HCC have reported encourag-
ing results. In a study by Choi et al., 53 patients with multifocal HCC received com-
bined intraoperative RFA with hepatic resection. The cumulative survival rates at 1, 2,
9 Percutaneous Ablation 131

3, 4, and 5 years were 87%, 83%, 80%, 68%, and 55%, respectively. Patients with
smaller resected tumors (≤5 cm) demonstrated better survival results compared with
those with larger tumor (P = 0.004). No procedure-related deaths occurred. They
reported hepatectomy-related complications in 4 patients (4/53, 8%) and RFA-related
complication only in 1 patient (1/53, 2%) [58]. However, current data on multimodal-
ity treatment in ICC, particularly percutaneous thermal ablation combined with surgi-
cal resection or other locoregional treatments are still lacking.
In clinical practice, patients with recurrent, metastatic, or unresectable ICC are
often treated with systemic chemotherapy first. This approach prioritizes early sys-
temic therapy for biologically aggressive cancer, ensures the absence of rapidly pro-
gressive disease, and potentially downsizes liver disease enabling the use of
locoregional treatments. Percutaneous ablation, like other locoregional therapies, is
most often considered in these patients who have demonstrated favorable tumor biol-
ogy in order to optimize locoregional control and facilitate chemotherapy-free time.

Summary

Although percutaneous thermal ablation for ICC has been shown to have several
distinct advantages, such as minimally invasiveness, easy to perform, repeatability,
and cost-effectiveness [19], data for its efficacy remain limited [11]. Indeed, while
the indications for ablation in HCC are well established (solitary lesion ≤5 cm, or
no more than 3 lesions and each ≤3 cm), there remain no formal guidelines for the
indications for percutaneous thermal ablation of ICC.
Based on the outcomes of retrospective data, percutaneous ablation appears safe
and associated with acceptable locoregional control and survival outcomes for
patients with recurrent or unresectable ICC. While ablation may be appropriate for
some select patients with early stage disease, the inability to perform regional lymph
node dissection prevents the wider adoption of ablation for patients with otherwise
resectable disease. Although more high-quality data are needed, including prospec-
tive multicenter trials, percutaneous ablation is an important component of the mul-
timodality treatment of patients with ICC, particularly at high-volume centers
equipped with experienced multidisciplinary teams.

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Chapter 10
Transarterial Therapies

Susan Shamimi-Noori and Michael C. Soulen

Background

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic

malignancy. The incidence of ICC and associated mortality rates are rising [1, 2].
ICC is rapidly fatal with a median overall survival (OS) of <4 months without treat-
ment [3]. The highest survival rates are observed among patients who undergo surgi-
cal resection, which increases the 5-year survival from approximately 10% to
20–40% [4]. However, only 20–40% of patients with ICC are surgical candidates [5].
Palliative systemic therapy with gemcitabine and cisplatin has become the stan-
dard of care first-line treatment based on two phase III trials of 493 patients with
locally advanced (25%) or metastatic (75%) cholangiocarcinoma from intrahepatic
(n = 108, 22%) extrahepatic (n = 149, 30%) gallbladder (n = 181, 37%) or ampul-
lary (n = 24, 5%) primaries received either intravenous cisplatin followed by gem-
citabine or gemcitabine alone. The median overall survival in the combination
therapy group was 11.6 months compared to 8 months in the gemcitabine only
group (HR 0.65, 95% CI0.54 to 0.78, P < 0.001). The median progression-free sur-
vival was also higher in the combination therapy group (8.8 months vs. 6.7 months,
HR 0.64, 95% CI 0.54–0.78, P < 0.001) [6].

S. Shamimi-Noori (*)
Division of Interventional Radiology, Department of Radiology, Hospital of the University
of Pennsylvania, Philadelphia, PA, USA
e-mail: [email protected]
M. C. Soulen
Division of Interventional Radiology, Department of Radiology, Hospital of the University
of Pennsylvania, Philadelphia, PA, USA
Department of Radiology, Abramson Cancer Center, University of Pennsylvania,
Philadelphia, PA, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 135

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_10
136 S. Shamimi-Noori and M. C. Soulen

Locoregional therapy has shown promising results for the treatment of ICC in
patients who are not surgical candidates. While percutaneous ablation may have a
role in the treatment of patients with small tumors, its efficacy in larger tumors is
less clear. Transarterial therapies have been shown to be safe and effective in the
treatment of a variety of primary and secondary hepatic malignancies [7–14]. Due
to the rarity of ICC, the available data on locoregional therapies is limited, based
only on small retrospective studies [15, 16]. Therefore, the purpose of this chapter
is to discuss the technical aspects of transarterial therapies, provide an overview of
the available literature supporting their use, and discuss triaging patients among the
available transarterial therapies.

Transarterial Therapy

While transarterial therapies can be used in a neoadjuvant approach to facilitate

downstaging [17, 18], the more common goal of treatment is to provide locore-
gional control and potentially prolong overall survival (OS), especially when com-
bined with effective systemic chemotherapy. Similar OS is observed among patients
with and without the extrahepatic disease, and the major cause of mortality from
ICC is liver failure or biliary compromise [19–21]. To that end, although high-­
quality evidence is lacking, effective locoregional treatments including transarterial
therapies may improve both the quantity and quality of life through the prevention
of local complications and reducing the burden of active disease.
The technical goal of transarterial therapy is to deliver concentrated antitumor
therapy to hepatic tumors with sparing of surrounding liver parenchyma and with
low systemic toxicity. Due to the dual blood supply of the liver, patients can undergo
selective transarterial treatments with low complication rates. More recently, selec-
tive transarterial treatments have been shown to be safe even in select patients with
portal vein thrombosis [21, 22]. Commonly used transarterial hepatic treatments for
ICC include lipiodol-based chemoembolization, drug-eluting bead chemoemboli-
zation, and radioembolization.
Lipiodol-based chemoembolization, also known as conventional chemoembo-
lization (cTACE), was described as early as 1980 for the treatment of hepatocel-
lular carcinoma [23]. One or more chemotherapeutic agents are emulsified into an
oil-­based contrast and injected into the tumor arterial bed. While there is no stan-
dardized chemotherapeutic agent combination for chemoembolization of cholan-
giocarcinoma, a combination of doxorubicin, mitomycin-C, and cisplatin (if
available) is commonly used. Gentamicin has also been used [24]. The oil-based
emulsion penetrates the tumor capillary bed maintaining a high concentration of
intratumoral chemotherapy [25]. Injection of the emulsion is followed by injec-
tion of a particulate agent such as gelatin sponge, polyvinyl alcohol, or trisacryl
gelatin microspheres. These particles devascularize the tumor resulting in isch-
emia as well as preventing washout of the previously injected chemotherapeutic
emulsion [26, 27].
10 Transarterial Therapies 137

The most common toxicity of lipiodol-based chemoembolization is post-­

embolization syndrome manifested by post-procedure pain, fevers, nausea, and
vomiting. Symptoms are usually mild and patients are often discharged home within
24 hours of treatment. Post-embolization syndrome is manageable with oral anti-­
nausea and pain medications. The rate of post-embolization syndrome after chemo-
embolization has been reported between 30% and 65% [9, 20].
Emulsions can be unstable resulting in some systemic release of chemotherapy.
Drug-eluting bead (DEB) chemoembolization (DEB-TACE) was developed with
the aim of further limiting the systemic release of chemotherapy [28]. DEBs are
microspheres loaded with chemotherapeutic agents. These beads are then injected
into the hepatic tumor arterial supply. DEBs have treatment effect via two mecha-
nisms: embolization and local controlled release of the chemotherapeutic agents.
There are multiple DEBs in clinical use which can be loaded with a variety of che-
motherapeutic agents, the most common of which are doxorubicin and irinotecan
[26]. Lammer et al. have shown an improved systemic toxicity profile of DEB-­
TACE compared to cTACE. While DEB-TACE has been shown to be safe and effec-
tive for both primary and secondary liver cancers, a survival benefit over cTACE has
not been demonstrated [29].
Transarterial radioembolization (TARE) of hepatic tumors was first described in
the 1960s, however, its use has been further developed over the last two decades [30,
31]. This form of selective internal radiation therapy is delivered by intra-arterial
injection of microspheres containing Yttrium-90, a radionuclide emitting beta radia-
tion. While the radiosensitivity of hepatic tissue limits the ability to administer sig-
nificant doses of external beam radiation, TARE allows tumoricidal radiation doses
to be given with less radiation-induced injury to the surrounding liver [32]. There is
also some embolic effect of the Yttrium-90 labeled microspheres; however, the
main therapeutic mechanism is through radiation-induced cell death. Both resin and
glass-based Yttrium-90 microspheres have been developed. Resin microspheres are
granted full premarketing Food and Drug Administration approval for the treatment
of colorectal metastases in conjunction with intrahepatic chemotherapy. Glass
microspheres are approved by the Food and Drug Administration under a humani-
tarian device exemption for the treatment of unresectable hepatocellular carcinoma
with and without portal vein occlusion in patients who can have appropriately posi-
tioned hepatic arterial catheters, and therefore, the use of glass microspheres cur-
rently requires institutional review board oversight in the United States [33].
Off-label use of both resin and glass microspheres has been studied in a variety of
primary and secondary liver cancers. Fatigue is the most common adverse event of
transarterial radioembolization and occurs in over half of patients [9].
Similar selection and exclusion criteria have been developed for all transarterial
therapies. The purpose of stringent exclusion criteria is to reduce the risk of liver
decompensation and other complications following treatment. Patient performance
status (Eastern Cooperative Oncology Group (ECOG) score ≤2) and liver function
reserve must be adequate. A serum total bilirubin level >3 is considered a contrain-
dication to transarterial hepatic therapy. Patients with portal vein thrombosis and/or
serum total bilirubin levels between 2 and 3 should be considered for selective sub-
138 S. Shamimi-Noori and M. C. Soulen

lobar or subsegmental arterial delivery of therapy. Caution is also advised in treat-

ment of patients with a Child-Pugh B score greater than 8 or those with tumor
occupying >50–70% of the total liver volume. Technical considerations such as the
presence of large arterioportal or arteriovenous shunting, renal insufficiency and
other confounding comorbidities should also be taken into account. With regards
specifically toTARE, radiation exposure to adjacent organs (e.g., heart, lungs, etc.)
and prior radiation therapies can limit the total dose administered. Planning hepatic
arteriography, arterial infusion of technetium-99m micro-aggregated albumin, and
subsequent lung and liver scintigraphy are performed as a separate procedure prior
to radioembolization to evaluate for any dosimetric or anatomic contraindications
and to calculate the appropriate treatment dose [34].

 vidence for Conventional Transarterial Chemoembolization

E
(cTACE)

A large retrospective study of patients with unresectable ICC comparing cTACE

using cisplatin (72 patients) to best supportive treatment (83 patients) showed a
median overall survival of 12.2 months in the chemoembolization group compared
to 3.3 months in the supportive care group. A statistically significant improvement
in survival was observed both in patients with and without extrahepatic disease [35].
A retrospective multi-center series of 62 patients evaluated survival aftercTACE
with triple chemotherapy (mitomycin-C, doxorubicin, cisplatin) in patients with
either ICC or poorly differentiated adenocarcinoma. Median overall survival was
15 months from initial chemoembolization and 20 months from initial diagnosis.
There was no statistically significant survival difference between patients with ICC
and patients with poorly differentiated adenocarcinoma of unknown primary.
Median OS was higher in patients who also received systemic chemotherapy com-
pared to those who did not: 28 months vs. 16 months (HR 1.94, 95%CI 1.13–3.33,
p = 0.02). Patients with extrahepatic disease had a lower median overall survival
compared to those without extrahepatic disease; however, this was not statistically
significant. Post-embolization syndrome occurred in 65% of patients and major
complication rate was reported at 3% [20].
Promising results were seen in another retrospective case series of 17 patients
with unresectable cholangiocarcinoma treated with cTACE using a triple chemo-
therapy regimen of mitomycin-C, doxorubicin, and cisplatin. Median OS from time
of diagnosis was 23 months. Two out of 17 patients with previously unresectable
disease underwent successful resection after chemoembolization. There was 1
major complication (6%) and 2 minor complications (12%) [36].
Vogl et al. sought to evaluate OS and local tumor control endpoints in patients
with unresectable cholangiocarcinoma treated with cTACE using various chemo-
therapeutic agents. In this study of 115 patients, chemotherapeutic regimens used in
a lipiodol-based emulsion included mitomycin-C alone (24 patients), gemcitabine
10 Transarterial Therapies 139

alone (8 patients), mitomycin-C combined with gemcitabine (54 patients), and the
combination of mitomycin-C, gemcitabine, and cisplatin (29 patients). No statisti-
cally significant difference was found among the different chemotherapy regimens
and median OS for the entire group was 13 months. Using RECIST criteria, 8.7%
of patients showed partial response, 57.4% showed stable disease, and 33.9%
showed progressive disease at follow up. No major complications were reported and
the rate of post-embolization syndrome was 13% [37].
Gemcitabine-based cTACE was retrospectively studied by Gusani et al. In this
42-patient study, median OS was 9.1 months from time of first treatment 45% of the
patients had extrahepatic disease. Per RECIST criteria, stable disease was seen in
48% of patients and progressive disease in 15% of patients. Tumor response in 7
patients was not evaluable. Grade 3 or higher adverse events were reported in 7
patients (16.6%). It was also noted that the median OS was statistically higher in
patients treated with gemcitabine-cisplatin and TACE compared to gemcitabine
alone (13.8 months vs. 6.3 months, p = 0.0005) [38].
Herber et al. showed that cTACE can be effective in patients with large tumors.
In a retrospective study of 15 patients with a mean tumor size of 10.8 ± 4.6 cm
(range 2–18 cm), median OS was 16.3 months after cTACE using mitomycin-C as
a single chemotherapeutic agent. According to RECIST criteria, 60% of patients
showed stable disease, 6.7% of patients showed partial response, and 26.7% of
patients showed progressive disease. There were two major complications. No
deaths or acute liver failure was reported. Forty percent of patients experienced
post-embolization syndrome [39].
Although the literature is limited to small prospective and retrospective case
series, data shows that cTACE is safe and effective in the treatment of unresectable
ICC. The most common adverse event is self-limited post-embolic syndrome.
Median OS after conventional chemoembolization is promising with data suggest-
ing improved outcomes compared to reported rates of systemic chemotherapy
alone. Evidence for the use of cTACE in treatment of ICC is summarized in
Table 10.1.

 vidence for Drug-Eluting Bead Transarterial

E
Chemoembolization (DEB-TACE)

A prospective multi-institutional study of 24 patients with unresectable ICC showed

a similar median OS among those treated with DEB-TACE versus cTACE. Median
survival was reported at 17.5 months from date of diagnosis.41.7% of patients had
extrahepatic disease. A total of 42 treatments were performed, the majority of which
used irinotecan-loaded beads. Seven treatments used doxorubicin-loaded beads.
Three patients (12.5%) underwent subsequent surgical resection. According to
RECIST criteria, at 3 months, 20 patients (83%) showed stable disease and 2
patients (8%) showed either complete or partial response. The major complication
 140

Table 10.1 Series reporting outcomes of cTACE for intrahepatic cholangiocarcinoma

# of patients in Previous # of adverse
Investigators treatment Extrahepatic systemic events Reference
(year) Study design Anticancer agents group lesions therapy (grade ≥ 3) Median OS #
Vogl et al. Prospective Mitomycin-based (± 115 Excluded – 0 13 months from [37]
(2012) cisplatin, ± initial cTACE
gemcitabine)
Park et al. Retrospective Cisplatin 72 n = 39 (54%) Excluded 26 12.2 months from [35]
(2011) diagnosis
Kiefer et al. Retrospective Mitomycin-C, 62 n = 19 (31%) n = 18 (29%) 5 15 months from [20]
(2011) doxorubicin, cisplatin initial cTACE, 20
months from
diagnosis
Gusani et al. Retrospective Gemcitabine-based (± 42 n = 19(45%) – 7 9.1 months from [38]
(2008) cisplatin, ± initial cTACE
oxaliplatin)
Burger et al. Retrospective Mitomycin-C, 17 n = 5 (29%) n = 6 (35%) 1 23 months from [36]
(2005) doxorubicin, cisplatin diagnosis
Herber et al. Retrospective Mitomycin-C 15 Excluded n = 4 (27%) 2 16.3 months from [39]
(2007) initial cTACE
S. Shamimi-Noori and M. C. Soulen
10 Transarterial Therapies 141

rate was reported at 9.5% and included hepatorenal syndrome resulting in death,
sepsis attributed to a chest port infection, and liver failure which subsequently
resolved [40].
Aliberti et al. prospectively evaluated 11 patients with unresectable ICC treated
with DEB-TACE using doxorubicin-loaded beads. There was a 100% tumor
response rate according to RECIST criteria and the median OS was reported as
13 months. All patients experienced symptoms of post embolic syndrome. One
patient developed a hepatic abscess [41].
Another prospective study including 26 patients with unresectable ICC treated
with DEB-TACE using irinotecan-eluting beads showed a similar median OS of
11.7 months. Forty-two percent of the patients had extrahepatic disease. Grade 3
or higher adverse events included post embolic syndrome, pleural empyema,
liver abscess, and cholangitis, resulting in death. At 2 months, one patient had
partial response according to RECIST criteria and was downstaged to surgery.
Forty-two percent of patients had stable disease and 50% of patients had progres-
sive disease [42].
The feasibility and safety of DEB-TACE using oxaliplatin-eluting beads in com-
bination with systemic chemotherapy were retrospectively evaluated in 9 patients
and compared to historical controls of patients treated with systemic chemotherapy
alone. There was a significantly higher median OS in the DEB-TACE group (30 vs.
12.7 months; p = 0.004). At 3 months, 4 patients (44%) showed partial response and
5 patients (56%) showed stable disease according to RECIST criteria in the DEB-­
TACE group. All patients in the historical group showed progressive disease when
reassessed between three and six cycles of treatment. Within the DEB-TACE group,
no grade 4 adverse events were observed. Grade 3 adverse events included abdomi-
nal pain, cholangitis, and a hypertensive crisis [43]. Evidence for the use of DEB-­
TACE in treatment of ICC is summarized in Table 10.2.

Evidence for Transarterial Radioembolization (TARE)

Mouli et al. retrospectively reviewed 46 patients with ICC who received 92 radio-
embolization treatments at a single institution. Stratification occurred by perfor-
mance status, solitary or multifocal tumors, tumor morphology (infiltrative or
peripheral), and the presence/absence of portal vein thrombosis. Fatigue (54%),
abdominal pain (28%), and nausea (13%) were the most common adverse events
noted. Four patients developed grade 3 albumin toxicity, three patients developed
grade 3 bilirubin toxicity, and one patient developed a gastroduodenal ulcer refrac-
tory to medical management. WHO imaging response was partial response in 11
patients (25%), stable disease in 33 patients (73%), and progressive disease in 1
patient (2%). EASL response was complete or partial response in 33 patients (73%)
and stable disease in 12 patients (27%). Survival varied based on multiple patient
and tumor characteristics. For example, the median OS was influenced by ECOG
performance status (0, 1, and 2: 14.3 months, 7.2 months, and 9.9 months,
 142

Table 10.2 Series reporting outcomes of DEB-TACE for intrahepatic cholangiocarcinoma

# of patients in Previous # of adverse
Investigators treatment Extrahepatic systemic events Reference
(year) Study design Anticancer agents group lesions therapy (grade ≥ 3) Median OS #
Kuhlmann Prospective Irinotecan 26 n = 11 (42%) n = 5 (19%) 11 11.7 months from [42]
et al. (2012) initial
DEB-TACE
Schiffman Prospective Irinotecan (35 24 n = 10 (42%) n = 20 (83%) 4 17.5 months from [40]
et al. (2011) treatments); doxorubicin diagnosis
(7 treatments)
Aliberti et al. Prospective Doxorubicin 11 – n = 11 0 13 months [41]
(2008) (100%) unspecified time
zero
Poggi et al. Retrospective Oxaliplatin 9 Excluded n = 9 (100%) 11 30 months from [43]
(2009) DEB + systemic therapy initial
DEB-TACE
S. Shamimi-Noori and M. C. Soulen
10 Transarterial Therapies 143

respectively), tumor multifocality (solitary vs. multifocal: 14.6 months and

5.7 months, respectively), prior receipt of treatment (chemotherapy naïve vs. receipt
of chemotherapy: 14.6 months and 5.7 months, respectively), absence of portal vein
thrombosis (14.4 months and 5.3 months, respectively), tumor location (peripheral
vs. infiltrative:15.6 months and 6.1 months, respectively), and disease burden
(<25% vs. 25–50% liver involvement: 14.4 months vs. 5.3 months, respectively).
Five patients were converted to resectable status [44].
In a prospective study of 25 patients with unresectable ICC treated with Y-90
resin microsphere TARE, the median OS was 9.3 months from first radioemboliza-
tion procedure. Similar to Mouli et al., the authors found improved survival in
patients with peripheral tumor type (rather than infiltrative) and in patients with
better performance status. According to RECIST criteria, 24% of patients had par-
tial response, 48% of patients had stable disease and 20% of patients had progres-
sive disease. Fatigue and self-limited abdominal pain were again the most common
clinical toxicities. Three patients developed grade 3 biochemical toxicities. One
patient developed a self-limiting duodenal ulcer [45].
Another prospective study evaluated 24 patients with unresectable ICC treated
with Y-90 glass microsphere TARE. The median OS was 14.9 months. Eight
patients had limited extrahepatic disease and 9 patients had portal vein thrombosis.
Per WHO criteria, there was a 27% partial response rate, 68% stable disease rate,
and 5% progressive disease rate. Fatigue was reported in 75% of patients and
abdominal pain reported in 42% of patients. Grade 3 or greater adverse events
included bilirubin toxicity in 1 patient and a treatment-related gastroduodenal
ulcer in 1 patient [46].
Rafi et al. prospectively evaluated 19 patients with unresectable chemorefractory
ICC treated with Y-90 resin microsphere TARE. Eleven patients had extrahepatic
disease. Median OS was 11.5 months after the first TARE. Survival was not statisti-
cally different between patients with and without extrahepatic disease. Toxicities of
fatigue and abdominal pain were similar to that reported in other studies [47].
Another prospective study of 21 patients with unresectable chemorefractory ICC
reported a median OS of 16.3 months from initial Y-90 resin microsphere
TARE. Significantly improved OS was noted in patients found to have objective
response based on modified mRECIST and EASL criteria [48].
A retrospective analysis was conducted to 33 patients treated with Y-90 resin
microspheres and assessed at three-month intervals. Twelve patients had a partial
response, 17 had stable disease, and 5 patients had disease progression after 3
months. The median time-to-progression was 9.8 months and the median OS was
22 months post-treatment. In addition, longer survival was observed in patients who
were chemotherapy naïve (14.2 months vs. 11 months). Both survival and time-to-­
progression were prolonged in patients with a tumor burden ≤25% and in patients
who had a response (partial response or stable disease) on imaging according to
RECIST criteria [49].
A systematic review of 12 studies comprising 73 patients evaluated TARE in the
treatment of unresectable ICC. The weighted median OS was 15.5 months. Tumor
response was pooled and based on reported RECIST, modified RECIST, and
144 S. Shamimi-Noori and M. C. Soulen

PERCIST criteria. At 3 months, weighted mean partial response was seen in 28% of
patients and stable disease was seen in 54% of patients. Morbidity and mortality
were reported in 8 of 12 studies. Overall, there was 1 mortality and 3 g­ astrointestinal
ulcers reported. The most common morbidities were fatigue (33%), abdominal pain
(28%), and nausea (25%). Seven patients were downstaged to surgery [50].
TARE has also shown potential in the treatment of recurrent postsurgical ICC. In
a retrospective single-center study, Sulpice et al. reported on the treatment of recur-
rent mass-forming ICC following hepatectomy in 45 patients, 25 of whom recurred
in the liver. Post recurrence, patients either had no therapy, systemic chemotherapy,
repeat hepatectomy, TARE, or a combination of the three treatments. Repeat hepa-
tectomy and TARE with Y-90 glass microspheres were associated with longer OS
following recurrence. TARE was utilized in unresectable intrahepatic recurrences
and could be used in combination with systemic chemotherapy. Median OS follow-
ing recurrence was 13 months [51].
TARE in combination with chemotherapy has been shown to be effective for
downstaging tumors to potential resection. In a retrospective study of 45 patients
with unresectable ICC, 10 patients had single large ICCs that developed in non-­
cirrhotic livers without the extrahepatic disease. After combination therapy with
TARE and systemic chemotherapy, 8 of the 10 patients underwent surgical resection
with curative intent. The 2 remaining patients had disease progression. Initial unre-
sectability was due to hepatic vein tumor involvement within the functional liver
remnant in 7 of the patients and portal vein tumor involvement within the functional
liver remnant in 1 of the patients [17]. Evidence for the use of TARE in treatment of
ICC is summarized in Table 10.3.

Triaging Patients Among Treatment Modalities

Little research is available to suggest the superiority of one transarterial therapy

over the others. Indeed, multiple studies have shown no significant difference in
long-term outcomes or radiographic tumor response, but similar toxicity rates, with
different transarterial therapies. A multi-institutional retrospective study evaluated
198 patients treated with various transarterial therapies (cTACE, DEB-TACE,
TARE, and bland arterial embolization). Median OS was 13.2 months and no sig-
nificant difference based on the type of transarterial therapy administered. Overall,
transarterial therapies were well tolerated. Complications occurred in 29.8% of
patients with a major complication rate of 8.1% [52].
In a systematic review of 20 studies evaluating a total of 929 patients with unre-
sectable cholangiocarcinoma treated with transarterial therapies, median OS was
12.4 months including was 12.5 months with TARE and 13 months with TACE [53].
Another meta-analysis of 20 studies including 657 patients treated with transar-
terial therapies for unresectable ICC also failed to show a difference in OS between
therapeutic modalities. Median OS of the cohort was 14.5 months including
13.9 months, 12.4 months, and 12.3 months for TARE, cTACE, and DEB-TACE,
 10

Table 10.3 Series reporting outcomes of TARE for intrahepatic cholangiocarcinoma

# of patients Previous
Investigators Type of Y90 in treatment Extrahepatic systemic # of adverse events Reference
Transarterial Therapies

(year) Study design microsphere group lesions therapy (grade ¾) Median OS #

Mouli et al. Retrospective Glass 46 n = 16 (35%) n = 16 8 Analysis performed based [44]
(2013) (35%) on various patient and
tumor characteristics
Hoffman et al. Retrospective Resin 33 n = 8 (24%) n = 27 0 22 months from initial [49]
(2012) (79%) TARE
Saxena et al. Prospective Resin 25 n = 12 (48%) n = 18 3 biochemical 9.3 months from initial [45]
(2010) (72%) events(clinical TARE
toxicity not graded)
Ibrahim et al. Prospective Glass 24 n = 8 (33%) n = 7 (29%) 5 biochemical 14.9 months from initial [46]
(2008) events(clinical TARE
toxicity not graded)
Camacho Prospective Resin 21 – n = 21 – 16.3 months from initial [48]
et al. (2014) (100%) TARE
Rafi et al. Prospective Resin 19 n = 11 (58%) n = 19 2 11.5 months from initial [47]
(2013) (100%) TARE
145
146 S. Shamimi-Noori and M. C. Soulen

respectively. Response rates (complete or partial response) for TARE and cTACE
were reported as 27.4% and 17.3%, respectively. Stable disease was reported as
54.8%, 46.9%, and 61.5% for TARE, cTACE, and DEB-TACE, respectively [54].
Until a large randomized controlled trial is completed, clinical decision making
among transarterial techniques will depend on specific patient characteristics, pro-
vider experience, and patient goals of care. For example, radioembolization may
have a lower immediate toxicity profile compared to chemoembolization [9].
Avoidance of severe post-embolization syndrome may be preferred in frail patients
or patients who have other immediate post-procedure obligations such as the need
to quickly return to employment or need to be a primary caregiver. The effect of
post-embolization syndrome on short-term performance status may hinder a
patient’s ability to get concomitant systemic chemotherapy. On the other hand, the
tumor response to radioembolization is usually not apparent until 3–4 months post-­
treatment, whereas the tumor response to chemoembolization is evaluated 1 month
post-treatment. Some patients and referring oncologists prefer knowing treatment
results earlier and may prefer increased short-term toxicity to a longer time to treat-
ment evaluation [15].
Therefore, decision-making should be individualized and discussed in a multi-­
disciplinary manner.
Chemoembolization should be used with caution in patients with prior biliary
interventions such as bilioenteric anastomoses, biliary stents, or sphincterotomy.
These patients are at high risk of liver abscess formation after chemoembolization,
less so following radioembolization [55, 56]. Historically, portal vein thrombus has
been a contraindication for chemoembolization; however, radioembolization has been
shown to be safe and effective in select patients with portal vein thrombosis [57].
Due to the radiosensitivity of the liver, caution must be taken when radioemboli-
zation is used in patients who have received prior radiation therapy. If underlying
liver function is within previously mentioned limits, chemoembolization is safe in
previously radiated patients [15]. Radioembolization, however, may prove to be an
efficacious treatment when used in combination with systemic chemotherapy. Certain
chemotherapies, including gemcitabine and cisplatin, have been shown to be radio-
sensitizers [58]. Multiple prospective randomized controlled trials are currently
underway which evaluate first-line therapy for unresectable cholangiocarcinoma.

Conclusion

In summary, available evidence shows that transarterial therapies are safe and effec-
tive in the palliative treatment of unresectable ICC. Specifically, evidence suggests
a benefit of transarterial therapies for local tumor control and possibly survival with
minimum impact on the quality of life. These therapies also have a role in down-
staging tumors enabling surgical resection in a small proportion of patients. Other
advantages of transarterial therapies include the high local hepatic concentration of
the delivered therapeutic agent with low systemic toxicity as well as the minimally
10 Transarterial Therapies 147

invasive nature of the treatments. Randomized controlled trials are needed to further
elucidate how to triage patients among the different types of transarterial therapies
as well as to elucidate the optimal treatment sequencing.

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Chapter 11
Radiotherapy

Florence K. Keane and Theodore S. Hong

Introduction

Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive malignancy arising

from intrahepatic biliary ducts. ICC accounted for approximately 15% of the 42,220
new diagnoses and 30,200 deaths from liver and intrahepatic bile duct cancer in the
USA in 2018 [1]. The incidence of ICC has increased in the USA over the past
40 years [2, 3], in part due to improvements in diagnostic techniques distinguishing
ICC from cancers of the unknown primary site, as well as other hepatic and bile duct
malignancies [4]. In addition to advancements in diagnostic imaging, molecular
profiling has also suggested that ICC is a distinct entity as compared with extrahe-
patic, perihilar, and gallbladder cancers [5, 6].
ICC is associated with a high risk of local tumor invasion, nodal and distant
metastases, and the majority of patients present with disease too advanced for resec-
tion. Even for those patients who undergo resection, risk of recurrence remains
high. Liver-directed radiotherapy, historically considered a palliative maneuver due
to concerns over hepatic tolerance, has emerged as a valuable treatment modality in
both the adjuvant and definitive setting. We will discuss the role of radiotherapy in
the management of ICC, with a particular focus on advanced technologies of SBRT
and charged particle therapy.

F. K. Keane · T. S. Hong (*)

Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2019 151

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_11
152 F. K. Keane and T. S. Hong

Role of Adjuvant Radiotherapy

Resection remains the optimal definitive treatment for patients with ICC. However,
outcomes after resection remain poor for the vast majority of patients. While a margin-­
negative (R0) resection is associated with 5-year overall survival as high as 63% [7], on
average 5-year OS after resection ranges from 22% to 35% [8–10]. Factors associated
with increased risk of recurrence after resection include tumor size, histologic grade,
vascular invasion, biliary invasion, positive margins, and nodal metastasis [9, 11].
Randomized data on the role of adjuvant systemic therapy are complicated by the
inclusion of patients with extrahepatic cholangiocarcinoma and gallbladder cancer in
addition to those patients with the intrahepatic disease. Due to the relative rarity of
these diagnoses, trials have also included patients with a variety of histologic features
after resection, leading to the grouping of patients with R0 resections without nodal
metastases in trials with patients with R1 resections and nodal involvement. Recently
presented randomized trials of adjuvant chemotherapy have presented conflicting
results. The BILCAP (adjuvant capecitabine for biliary tract cancer) trial [12], a ran-
domized trial of adjuvant capecitabine after resection for completely resected chol-
angiocarcinoma or gallbladder cancer, was presented in abstract form in 2017 and
showed an improvement in overall survival with the use of adjuvant capecitabine in
the intent-to-treat analysis. Of note, only 18% of patients enrolled on this trial had
intrahepatic cholangiocarcinoma, and the per-protocol analysis did not show a sig-
nificant difference in survival. By contrast, the PRODIGE 12-ACCORD 18 Phase III
trial [13] did not report an improvement in disease-free survival with adjuvant gem-
citabine and oxaliplatin. The difference in outcomes may have been driven in part by
the patient populations enrolled on each trial. The BILCAP trial included a less
favorable patient population compared with the PRODIGE 12-ACCORD 18 trial,
with lower rates of R0 resection (62% vs. 87%) and higher rates of nodal metastasis
(54% vs. 37%). Randomized trials are ongoing, including the ACTICCA-1 trial,
which will randomize patients with resected ­cholangiocarcinoma or gallbladder can-
cer to gemcitabine and cisplatin versus capecitabine alone.
There are no randomized data on adjuvant radiotherapy in biliary tract cancers,
including ICC. A meta-analysis [14] of 20 studies including 6712 patients with
intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallblad-
der cancer reported an improvement in overall survival with the use of adjuvant
therapy after resection in patients with positive margins (OR 0.36, 95% CI
­0.19–0.68) or nodal metastases (OR 0.49, 95% CI 0.30–0.80). Approximately, 27%
of patients included in this meta-analysis received some form of adjuvant therapy,
with options including chemotherapy alone, radiotherapy alone, or chemoradiother-
apy. Patients with nodal metastases most often received chemotherapy or chemora-
diotherapy, while those patients with involved margins were typically treated with
radiotherapy alone. There was a larger benefit seen with the use of adjuvant chemo-
therapy or chemoradiotherapy as compared with radiotherapy alone, with the b­ enefit
of adjuvant radiotherapy alone seemingly limited to those patients with R1 resec-
tion. Of note, only one trial in this meta-analysis included patients with intrahepatic
cholangiocarcinoma.
11 Radiotherapy 153

Retrospective single-institution series have reported a benefit with adjuvant

radiotherapy in patients with ICC. For example, Jan et al. [15] reported a series of
373 patients with peripheral ICC treated between 1977 and 2001, of whom 63
received adjuvant radiotherapy. There was a significant improvement in median
overall survival with the use of adjuvant radiotherapy (11.7 vs. 6.3 months, p = 0.02).
A series of 90 patients with regional nodal metastases reported a median overall
survival of 19.1 months with the use of adjuvant radiotherapy as compared to
9.5 months with observation alone [16].
Therefore, while there is not yet a consensus on the use of adjuvant therapy after
resection in ICC, given the high risk of recurrence after resection, the NCCN guide-
lines currently recommend consideration of adjuvant therapy, specifically chemother-
apy and/ or chemoradiotherapy, in patients with adverse risk factors including positive
margins and nodal metastases. Although SWOG S0809 [17], a phase II trial of post-
operative therapy in patients with high-risk resected extrahepatic cholangiocarcinoma
and gallbladder cancer excluded patients with ICC, it does provide encouraging
results and a potential framework for the incorporation of adjuvant therapy in the
treatment of ICC. Eligible patients included those with high-risk features such as
nodal metastases, pathologic T2–4 disease, or positive margins. Patients received four
cycles of gemcitabine and cisplatin followed by radiotherapy with concurrent
capecitabine. The at-risk nodal stations received a dose of 45 Gy, while the tumor bed
receiving 54 to 59.4 Gy. Two-year OS was 65% with this regimen. Treatment was
generally well tolerated, as 86% of patients were able to complete the full course of
treatment. There was an increased risk of local failure (30%) in patients who did not
receive radiotherapy or did not complete radiotherapy as per protocol, supporting the
use of radiotherapy in these high-risk patients. At our institution, we favor clinical trial
enrolment whenever feasible. For those patients with high-risk pathologic features
after resection, we recommend multidisciplinary evaluation, with consideration of
adjuvant chemotherapy followed by chemoradiotherapy as appropriate.

Definitive Radiotherapy

While a margin-negative resection is an optimal treatment for ICC, most patients are
unresectable at the time of diagnosis due to tumor size, vascular/ biliary invasion or
nodal metastasis [18]. Outcomes are often dismal for these patients, with median sur-
vival ranging from 3 to 9 months. Trials of both fluoropyrimidine-based and gem-
citabine-based chemotherapy regimens showed an improvement in outcomes over best
supportive care [19] and historical controls [20]. More recently, both the ABC
(advanced biliary tract cancer)-02 trial [21] and the BT (biliary tract) 22 trial [22] dem-
onstrated an improvement in survival with the use of gemcitabine and cisplatin over
gemcitabine monotherapy in patients with locally advanced or metastatic disease.
Nonetheless, despite advances in chemotherapy regimens, survival remains poor, with
a median overall survival of approximately 11 months [23]. With the development of
modern radiotherapy techniques, radiotherapy has emerged as a safe and effective
option to improve outcomes in patients with locally advanced disease (Table 11.1).
Table 11.1 Outcomes after liver-directed radiotherapy for intrahepatic cholangiocarcinoma
154

Prior Number
Pts with liver-­directed Multiple of fractions 1-year Grade ≥ 3
Study Design Modality IHCC therapies Tumor Size (range) lesions Dose (Gy) (range) LC 1-year OS toxicity
Hong et al., Phase II Proton 39 45.8% 2.2–10.9 cm 12.8% 58 GyE 15 94.1% at 46.5% at 7.7%
2015 [29] (15.1–67.5 GyE) 2 years 2 years
Tse et al., Phase I Photon, 10 50% 172 (10–465) ml ∗∗ 36 (24–54) 6 65% 58% 2 transient
2008 [34] SBRT biliary
obstruction, 2
w/ decline to
CP B
Goodman Phase I Photon, 5 NR 32.6 (0.8–146.4) ml NR 18–30 1 77%∗∗∗ 71.4%∗∗∗ None
et al., 2010 SBRT
[39]
Tao et al., Retrospective Proton or 79 NR 2.2–17 cm 39% 58.05 (35–100) 3–30 81% 87% 15.2%∗
2016 [31] IMRT
Chen et al., Retrospective Photon, 35 42.9% 7.7 ± 3.2 cm 25.7% 50 (30–60) 25 (10–33) 32.2% 38.5% 8.6%
2010 [30] 3D-­CRT
Mahadevan Retrospective Photon, 34^ 73.4% 63.8 cm3(5.9–500.1) ~23% 30 (10–45) 3 (1–5) 88% 58% Four grade 3
et al., 2015 SBRT toxicities
[54]
Ibarra et al., Retrospective Photon, 11 50% 80.2 (31.6–818.5) ml 18.2% 36–60 1–10 50% 45% 7 patients
2012 [36] SBRT
Barney Retrospective Photon, 6 83.3% 16–412.4 ml NR 55 (45–60) 3 or 5 100% 73% 1 grade 3, 1
et al., 2012 IMRT, or grade 5 due to
[55] 3D-CRT hepatic failure
Liu et al., Retrospective Photon,3D-­ 6 54∗∗∗ 8.8 (0.2–222.4) ml∗∗∗ 51%∗∗∗ 20–50 3–5 93%∗∗∗ 81.8%∗∗∗ None
2013 [32] CRT
Dewas Retrospective Photon, 6 50% 6.3 (3.6–11.2) cm 0% 45 (29–45) 3–4 100% NR NR
et al., SBRT
2012[37]
F. K. Keane and T. S. Hong
Sandler Retrospective Photon, 6 74% 2.7 cm (1–7.3) NR 40 (25–50) 5 78∗∗∗ 59%∗∗∗ 16% long
et al., 2016 SBRT term
[56]
Lanciano Retrospective Photon, 4 36.7%∗∗∗ 25.3 (0.53–316) ml∗∗∗ 26.7%∗∗∗ 36–60 3 92%∗∗∗ 73%∗∗∗ None
et al., 2012 SBRT
[57]
11 Radiotherapy

Goyal et al., Retrospective Photon, 3 100% 384 (80–818) 0% 34 (24–45) 1–3 82% at NR None
2010 [38] SBRT 8 months
Adapted from Keane et al. [58]. With permission from Elsevier
Abbreviations: Pts patients, IHCC intrahepatic cholangiocarcinoma, LC local control, OS overall survival, NR Not reported
∗Toxicities may include some redundancies, may be due to progression in some instances
∗∗All patients had tumor venous thrombosis or extrahepatic disease
∗∗∗Results include patients with other primary liver cancers included in the publication
^Includes patients with both IHCC and hilar cholangiocarcinoma
155
156 F. K. Keane and T. S. Hong

Conformal Radiotherapy

Historically, limitations in imaging, tumor localization, radiotherapy planning, and

delivery often required treatment of the entire liver, which was in turn associated
with a significant risk of hepatotoxicity and radiation-induced liver disease (RILD).
RILD, characterized by the development of anicteric hepatomegaly, ascites, and ele-
vated LFTs (often with minimal increase in bilirubin), can occur as early as 2 weeks
and as late as 4 months after hepatic radiotherapy. The risk of RILD directly corre-
lates with the dose and volume of liver irradiated. For example, retrospective series
reported a 10% rate of RILD in patients receiving 33 Gy in 1.5 Gy twice-daily frac-
tions [24] and a 44% rate of RILD in patients receiving ≥35 Gy [25]. The risk of
RILD also increases in patients with compromised hepatobiliary function [26, 27].
The development of conformal radiotherapy enabled assessment of the interac-
tion between radiotherapy dose, target volume, hepatic volume, and toxicity.
Multiple series have now demonstrated that partial hepatic tolerance to radiotherapy
is quite high and delivery of tumoricidal doses of radiotherapy with minimal toxic-
ity is feasible in carefully selected patients. Series of Phase I/II dose-escalation tri-
als [26, 28] of hyperfractionated radiotherapy with concurrent chemotherapy
conducted at the University of Michigan in patients with unresectable HCC or ICC
established key metrics regarding hepatobiliary tolerance to radiotherapy. Patients
were treated to a median dose of 58.5 Gy in twice-daily fractions (range 28.5–
90 Gy). The maximum tolerated dose for each patient was based on a maximum of
10–15% risk of RILD as determined using a normal tissue complication probability
(NTCP) model. The effective liver volume (Veff) parameter was used to facilitate
comparison of dose between different radiotherapy plans. The Phase II trial enrolled
128 patients, 44 of whom had cholangiocarcinoma. Treatment was well tolerated,
with a 4% rate of ≥3 RILD. Median overall survival was 13.3 months for patients
with ICC, far superior to historical controls. There was a particular benefit to dose-­
escalation in the overall cohort, with median OS of 23.9 months in patients treated
to ≥75 Gy versus 14.9 months in patients treated to <75 Gy (p < 0.01).
Retrospective and large-database series have also demonstrated an improvement
in outcomes with the use of radiotherapy for unresectable ICC (Table 11.1) [29–32].
A retrospective series [30] of 84 patients with ICC treated with radiotherapy, arteri-
ally directed therapy (TACE), supportive care, or a combination thereof reported an
improvement in outcomes with the use of radiotherapy as compared with TACE
alone or supportive care alone. A total of 35 patients (n = 41.7%) received radio-
therapy, of whom 15 also received TACE. Radiotherapy was associated with a sig-
nificant improvement in OS in the overall cohort (9.5 vs. 5.1 months, p = 0.003), as
well as in the subgroup of patients with central tumors (13.3 vs. 3.5 months).
A SEER analysis [33] of 3839 patients with IHCC treated between 1988 and 2003
with resection (25%), resection and adjuvant radiotherapy (7%), radiotherapy alone
(10%) or no treatment (58%) reported a 4 month improvement in median survival
with the use of radiotherapy as compared with no treatment (7 vs. 3 months,
p < 0.01). The usual limitations of large-database series, including the lack of data
11 Radiotherapy 157

on systemic therapies and comorbidities, must be considered when assessing this

study, but in the context of other series and Phase II trials, it does provide additional
support for consideration of radiotherapy for unresectable ICC.

 tereotactic Body Radiotherapy and Hypofractionated

S
Radiotherapy

Stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR)

delivers high doses of radiotherapy with rapid fall-off through the use of rigid
immobilization, precise tumor localization, and multiple conformal beams. While
there are no randomized trials of SBRT in unresectable ICC, multiple Phase II
single-­arm trials and retrospective series have demonstrated its safety and efficacy
for the treatment of primary hepatic tumors [34–39]. Of note, hypofractionated
radiotherapy employs similar rigid immobilization, localization and highly confor-
mal beam arrangements as SBRT, but fractionates treatment over a longer course,
typically 15 fractions. Given the large size of many primary hepatic tumors, hypo-
fractionated radiotherapy is often employed instead of SBRT and will also be dis-
cussed herein. As in systemic therapy, the available data often include a variety of
intrahepatic tumors, including hepatocellular carcinoma and ICC.
A Phase I dose-escalation trial of six-fraction SBRT conducted at Princess
Margaret Cancer Center [34] enrolled 41 patients with primary hepatic tumors, of
whom 10 had IHCC. Fifty percent of patients with ICC had received prior therapy,
including chemotherapy, resection, and ablative therapy. Radiotherapy dose was
selected based on the risk of toxicity as determined by the effective liver dose
parameter (Veff) and NTCP model, with a median dose of 36 Gy (range 24–54 Gy).
Treatment was well tolerated, and two patients with ICC and eight patients with
HCC developed grade 3 elevation in liver enzymes, but there were no grade 4 or 5
events. Survival was also encouraging, with a median OS of 15 months.
Retrospective series have also provided support for the role of ablative doses of
radiotherapy in the treatment of ICC, with improvements in local control and over-
all survival without significant toxicity. Tao et al. [31] published a series of 79
patients with unresectable IHCC treated with dose-escalated definitive radiotherapy
to a median dose of 58.05 Gy (range 35–100 Gy), corresponding to a median
­biologic equivalent dose of 80.5 Gy (range 43.75–180 Gy). Nearly 90% of patients
received chemotherapy prior to radiotherapy, 63% received concurrent chemother-
apy, and 47% received adjuvant chemotherapy. There was not a significant differ-
ence in the use of chemotherapy by radiotherapy dose. Patients were treated with
both photon (n = 54, 68%) and proton beam therapy (n = 25, 32%). To facilitate
dose-escalation while still meeting standard constraints for organs at risk, the
authors incorporated a simultaneous integrated boost to the gross tumor volume of
75 Gy in 15 fractions or 100 Gy in 25 fractions. There was a significant improve-
ment in 3-year overall survival with BED >80.5 Gy (73% vs. 38%, p = 0.017) and
158 F. K. Keane and T. S. Hong

3-year local control (78% vs. 45%, p = 0.04). Three patients were hospitalized
within 90 days of completion of treatment, but there were no cases of radiation-­
induced liver disease. There were seven instances of biliary stenosis (9%) but these
were thought to be due to disease progression.

Charged Particle Therapy

Charged particle therapy, including proton beam therapy and carbon ion therapy, is
characterized by rapid energy absorption and steep dose fall-off. The minimal exit
dose of proton beam therapy is particularly appealing when considering the need to
deliver a tumoricidal dose of radiotherapy while maximizing sparing of uninvolved
hepatic parenchyma. Similar to SBRT, while there are no randomized data for
charged particle therapy in primary hepatic tumors, a Phase II trial and retrospective
data have provided encouraging results regarding its efficacy and safety.
The University of Tsukuba [40] reported the largest series to date of proton ther-
apy in primary liver tumors, including 318 patients with HCC who were treated
between 2001 and 2007. There were only five grade ≥3 toxicities. While this trial
did not include patients with ICC, the safety data regarding the role of proton ther-
apy in the treatment of hepatic tumors are encouraging, particularly given the inclu-
sion of patients with Child-Pugh B cirrhosis. Overall survival was 44.6% for the
overall cohort. A retrospective series [41] of proton therapy for the treatment 28
patients with cholangiocarcinoma included six patients with ICC. Patients were
treated to a median dose of 69.2 GyE, with significant improvement in local control
with doses >70 Gy (1-year local control 82.1% vs. 22.2%).
While these retrospective data were encouraging, there were limited prospec-
tive data regarding both photon radiotherapy and charged particle therapy in
ICC. A Phase II multi-institutional trial [29] of hypofractionated, dose-escalated
proton beam therapy conducted at Massachusetts General Hospital and
M.D. Anderson Cancer Center enrolled 83 patients with localized, unresectable
HCC (n = 44), ICC (n = 37), and mixed HCC/ICC (n = 2). The majority of
patients with ICC received systemic therapy prior to trial enrollment (n = 24,
61.5%). For patients with ICC, median tumor dimension was 6.0 cm (range 2.2–
10.9 cm), 12.8% had multiple tumors, and 28.2% had tumor vascular thrombosis.
The dose was 58.05 GyE in 15 fractions for tumors within 2 cm of the porta
hepatis and 67.5 GyE in 15fractions for tumors more than 2 cm from the porta
hepatis. Doses were de-escalated as needed to ensure mean liver dose ≤24
GyE. For patients with IHCC, median radiotherapy dose was 58.05 GyE, and the
mean dose to the uninvolved liver was 21.4 GyE (range 3.2–29.5 GyE). Local
control at 2-years was 94.1% for ICC, with only two local failures. Four addi-
tional local failures occurred after 2 years. Of note, all patients with local failures
received less than 60 GyE. Median OS for ICC was 22.5 months, with 2-year OS
of 46.5%. The rate of grade 3 treatment-related toxicities was 3.6% in the overall
cohort and 7.7% in patients with IHCC. There were no grade 4 or 5 toxicities.
11 Radiotherapy 159

These impressive outcomes, particularly given the advanced disease of the

patients enrolled, demonstrate the value of radiotherapy for the treatment of
unresectable ICC.
Optimal timing of radiotherapy with systemic therapy for ICC remains an open
question. With the publication of ABC-02 and BT-22 trials, cisplatin and gem-
citabine were established as the standard of care for metastatic and locally advanced
cholangiocarcinoma. Of note, the median overall survival in the gemcitabine and
cisplatin arm on ABC-02 was 11.2 months, as compared to 22.5 months in the Phase
II trial [29] discussed above. While this difference is likely driven in part by the
significant proportion of metastatic patients included on ABC-02 (~75%), given the
excellent outcomes seen with radiotherapy in this population further study is needed.
NRG GI-001, a currently enrolling Phase III trial, will randomize patients with
unresectable ICC to systemic therapy with gemcitabine and cisplatin followed by
radiotherapy to systemic therapy alone.

Radiotherapy Treatment Planning and Delivery

Treatment of intrahepatic cholangiocarcinoma with radiotherapy is complex and

requires careful patient selection, rigid immobilization, careful delineation of tar-
gets and organs at risk, and rigorous quality assurance.
Prior to radiotherapy planning, three fiducial markers are placed in the liver
around the target lesion. These markers are critical for treatment planning and deliv-
ery and facilitate motion assessment as well as patient set-up and treatment delivery.
Biopsy can also be obtained if needed at the time of fiducial placement.
Patients are then simulated in the supine position with arms up and immobilized
with custom immobilization, which may include vacuum bags or thermoplastic
devices, with or without a body frame. The variable contrast enhancement patterns
of intrahepatic cholangiocarcinoma on CT and MRI can complicate target identifi-
cation (Figs. 11.1 and 11.2). Incorporation of multiphasic imaging with arterial,
portal venous and delayed phases is critical to ensure complete identification of the
tumor [42–45]. For example, while some tumors are characterized by arterial
enhancement and rapid venous washout, similar to HCC, other lesions have delayed
enhancement on CT [46], or are better identified with MRI. Consensus guidelines
for contouring of HCC recommend contouring the gross tumor volume (GTV)
across all phases of imaging [47]. While there are not yet consensus guidelines for
contouring of ICC, we recommend the same principle as HCC be applied here.
Technically, arterial phase images are obtained immediately after peak aortic
enhancement as determined by bolus tracking, typically 30–35 seconds after the
infusion begins. Portal venous images are obtained 70–75 seconds after the infusion
begins, and delayed phase images are obtained 3 minutes after portal venous phase
images. Of note, for those patients who are treated with proton therapy, we obtain
the 4DCT prior to the multiphasic contrast scan to avoid any impact of the increased
density of intravenous contrast on treatment planning.
160 F. K. Keane and T. S. Hong

Fig. 11.1 Intrahepatic cholangiocarcinoma with variable enhancement patterns in the arterial
phase (left) and portal venous phase (right). There is a lack of overlap with between gross tumor
volumes on arterial (red), portal venous (blue), and delayed (green phases)

Fig. 11.2 Intrahepatic cholangiocarcinoma with variable enhancement patterns in the arterial
phase (left) and portal venous phase (right). There is a lack of overlap with between gross tumor
volumes on arterial (red), portal venous (blue), and delayed (green phases)

While the use of MR-based simulation is increasing, many centers continue to

rely on CT simulation with a fusion of relevant MR sequences. Accurate fusions
of MR sequences with the planning CT is critical, as suboptimal fusions can
result in target misidentification [47]. For those centers without MR-based simu-
lation, alignment of MR-compatible fiducial markers or performing MRI in the
treatment position are two possible techniques for improving the accuracy and
ease of fusions.
A 4-dimensional (4D) CT is also performed during the simulation for assess-
ment of both target and hepatic motion [48, 49]. For those patients who do not
require respiratory gating, the average phase CT is used as the baseline CT for
planning. For those patients with significant tumor motion, respiratory gating is
employed, with treatment delivered during expiratory phases. Active breathing
11 Radiotherapy 161

control and abdominal compression have also been explored to reduce motion and
may be used based on the policy of individual treatment centers [34, 48, 50–53].
While consensus guidelines are not yet available for ICC, the ongoing protocol
NRG GI001, a randomized Phase III trial of cisplatin and gemcitabine with or with-
out hypofractionated radiotherapy, provides information on treatment planning. In
addition to the gross tumor volume (GTV), which is defined as the parenchymal and
nodal disease as seen on multiphasic CT imaging and /or MRI, an internal target
volume (ITV) must also be delineated based on the 4DCT. A clinical target volume
(CTV) may be delineated at physician preference based on clinical concerns. The
planning target volume (PTV) varies based on patient immobilization, treatment
modality (photons vs. protons), and onboard imaging. The minimum PTV, as
defined on NRG GI001, is 4 mm. When selecting the prescription dose, assessment
of the organs at risk, specifically the dose to the porta hepatis and the average dose
to the liver, is critical. Peripheral tumors, defined as >2 cm from the porta hepatis
may be treated to a maximum dose of 67.5 Gy (or GyE) in 15 fractions, assuming
that the mean liver dose is ≤22 Gy. Central tumors, within 2 cm of the porta hepatis,
may be treated to a maximum dose of 58.05 Gy (or GyE) in 15 fractions. The vol-
ume of liver receiving 10 Gy should be less than 80%, and at least 700 cc of the
uninvolved liver should be spared. Constraints are also specified for the spinal cord,
stomach, small bowel, esophagus, and kidneys.
Treatment delivery requires onboard imaging prior to and during treatment.
Onboard cone beam CT as available on linear accelerators can be used to assess
fiducial and soft tissue position prior to treatment, in-between treatment fields, and
after completion of each fraction. Fiducials may also be tracked during treatment
with onboard kV imaging, which is particularly helpful in the treatment of patients
with respiratory gating.

Future Directions

While single-arm Phase II trial and retrospective series have provided encouraging
data on the use of radiotherapy in ICC, prospective randomized trials are critical. As
discussed above, NRG GI001 is currently randomizing patients with unresectable
ICC to systemic therapy alone versus systemic therapy followed by hypofraction-
ated radiotherapy. Patients will receive their cycles of cisplatin plus gemcitabine
followed by restaging and stratification based on tumor size and number of lesions,
then randomized to an additional five cycles of chemotherapy versus one cycle of
chemotherapy, radiotherapy, then four cycles of chemotherapy. Maintenance gem-
citabine is permitted. The ABC-07 trial, a Phase II trial, will randomize patients
with advanced biliary tract cancer to cisplatin plus gemcitabine with or without
SBRT. Successful completion of these trials is critical to definitively establish the
role of liver-directed radiotherapy for biliary tract cancers.
162 F. K. Keane and T. S. Hong

Summary

The role of liver-directed radiotherapy in intrahepatic cholangiocarcinoma has

evolved from a strictly palliative treatment to a valuable component in the manage-
ment of both the adjuvant and definitive IHCC. Data on modern liver-directed radio-
therapy have demonstrated its safety and efficacy. Careful assessment of patient
comorbidities and disease extent is required to determine the optimal combination
of therapies for patients with ICC. Prospective randomized trials are needed to
determine the optimal timing of radiotherapy and integration with systemic
therapy.

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Chapter 12
Molecular Pathogenesis:
From Inflammation and Cholestasis
to a Microenvironment-Driven Tumor

Eleonora Milani, Mario Strazzabosco, Luca Fabris,

and Massimiliano Cadamuro

Introduction

Intrahepatic cholangiocarcinoma (iCCA) is a primary hepatobiliary malignancy

resulting from the neoplastic transformation of different epithelial cell types, such as
the cholangiocyte, the progenitor stem cell abutting the canals of Hering, and even
the hepatocyte. Regardless of the cell origin, a distinctive feature of this ­epithelial
cancer is the accumulation of a dense fibro-inflammatory stroma (the s­ o-­called tumor
reactive stroma, TRS) closely surrounding the tumor duct cells, encompassing

E. Milani
Department of Molecular Medicine, University of Padua, Padua, Italy
e-mail: [email protected]
M. Strazzabosco
International Center for Digestive Health (ICDH), University of Milano-Bicocca,
Milano, Italy
Section of Digestive Diseases, Department of Internal Medicine, Yale University,
New Haven, CT, USA
e-mail: [email protected]
L. Fabris (*)
Department of Molecular Medicine, University of Padua, Padua, Italy
International Center for Digestive Health (ICDH), University of Milano-Bicocca,
Milano, Italy
Section of Digestive Diseases, Department of Internal Medicine, Yale University,
New Haven, CT, USA
e-mail: [email protected]
M. Cadamuro
Department of Molecular Medicine, University of Padua, Padua, Italy
International Center for Digestive Health (ICDH), University of Milano-Bicocca,
Milano, Italy
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 167

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_12
168 E. Milani et al.

different cell populations, among which are activated fibroblasts, inflammatory cells,
immune cells, and endothelial cells [1]. Evidence is mounting that a mutual exchange
of multiple paracrine signals between the stromal and cancer cells boosts tumor
development, overgrowth, and invasion [2, 3]. Based on these findings, iCCA has
become paradigmatic of the Paget’s theory, which in the nineteenth century, first
addressed the importance of the tissue background (formerly recognized as “the
soil”) to induce and foster neoplastic transformation (behaving as “the seed”). From
this viewpoint, two fundamental pathomechanisms have been pinpointed as pivotal
triggers of the events culminating with the malignant transformation of the biliary
epithelium, including biliary/liver inflammation – often in conjunction with periduc-
tal fibrosis and cholestasis. Both chronic inflammation and cholestasis variably occur
in a number of disease conditions, not necessarily e­ volving to liver cirrhosis, which
include primary cholangiopathies, parasitic infestations, and metabolic disorders, all
known to bear an increased risk to develop iCCA. Among chronic cholangiopathies,
primary sclerosing cholangitis (PSC) and the fibropolycystic liver diseases are well-
characterized pre-malignant conditions of iCCA associated with a prominent peribil-
iary fibrotic reaction [1]. In PSC, biliary fibrosis is accompanied by a progressive bile
duct loss, while in fibropolycystic liver diseases, such as Caroli’s disease (CD) and
congenital hepatic fibrosis (CHF), progressive fibrous stroma accumulation develops
in conjunction with a dysgenetic overgrowth of the bile ducts. Chronic infestation
with liver flukes (Opisthorchis viverrini and Clonorchis sinensis), which are endemic
in Eastern Asia, correlates with cholangiocarcinogenesis through mechanical irrita-
tion and excretion of toxic metabolites for the biliary epithelium, leading to inflam-
mation, periductal fibrosis and proliferative response [4]. Recent studies have also
highlighted the strong association of iCCA with metabolic conditions. Obesity, dia-
betes and non-alcoholic fatty liver disease (NAFLD), are all conditions characterized
by a chronic, low-­grade inflammatory response caused by insulin resistance, which
is emerging as a risk factor for different epithelial malignancies [5].
In this chapter, we will first highlight the molecular underpinnings of the onco-
genic effects related to inflammation and cholestasis. We review the different path-
ways and genetic anomalies related to these pathogenetic mechanisms, which are
mostly relevant for iCCA pathogenesis. Then, we discuss the complex role of the
tumor microenvironment in sustaining iCCA invasiveness, along with a systematic
overview of the main cell types by which it is populated and the paracrine factors
mediating their deleterious interplay.

Inflammation

Malignant transformation of biliary epithelial cells generally occurs in the setting of

chronic inflammation, where high levels of a plethora of cytokines, chemokines,
growth factors, and reactive oxygen species (ROS) induce molecular changes and
dysregulation in proliferation, apoptosis, survival, and senescence signaling [1]
(Fig. 12.1). iCCA frequently develops in liver disease conditions characterized by
12 Molecular Pathogenesis: From Inflammation and Cholestasis… 169

Bile acids Proinflammatory

IL-6 HGF EGF (oxysterols) cytokines

IL-6R c-Met EGFR S1PR2 iNOS

JAK 1-2 p42/44 and PI3K-Akt ERK1/2 MAPK COX-2 ROS

p38 MAPK

Caspases
STAT3 p21 2 and 9

Proliferation

Mcl-1 Apoptosis
DNA damages

Invasiveness S100A4 S100A4

Fig. 12.1 Main intracellular pathways involved in iCCA carcinogenesis. Proliferation, apoptosis,
malignant transformation, and cancer invasiveness are driven by numerous signal pathways typi-
cally activated in chronic inflammation and cholestasis, involving pro-inflammatory cytokines
(i.e., IL-6), growth factors (i.e., EGF, and HGF), DAMP (S100A4), and bile acids. IL-6 interleu-
kin-­6, HGF hepatocyte growth factor, EGF epidermal growth factor, DAMP damage-associated
molecular patterns, S1PR2 sphingosine-1-phosphate receptor 2, iNOS inducible nitric oxide syn-
thases, IL-6R interleukin-6 receptor, MAPK mitogen-activated protein kinase, PI3K
phosphatidylinositol-­3-Kinase, ERK extracellular receptor kinase, COX cyclooxygenase, ROS
reactive oxygen species, STAT signal transducer and activator of transcription, Mcl-1 Myeloid cell
leukemia 1

different degrees of inflammation, such as intrahepatic lithiasis, intraductal parasitic

infection, PSC, and CHF/CD. As such, several inflammatory mediators play a key
role in bile ducts carcinogenesis.
Interleukin (IL)-6 is the principal cytokine of the IL-6 family and is a key media-
tor involved in the pathogenesis of CCA. IL-6 controls several pathways involved in
cell proliferation and survival acting both in an autocrine and paracrine manner [6].
This cytokine is secreted at high levels by CCA cells and its signal is transduced
through the binding to a heterodimer composed by the specific receptor IL-6R and
by a low-affinity co-receptor gp80/130. IL-6 stimulates cancer cell proliferation
through the stimulation of the mitogen-activated protein kinases (MAPK) pathway,
ERK1/2 (also known as p42/44), and p38, which in turn promotes the downregula-
tion of cyclin-dependent kinase inhibitor p21WAF1/CIP1, a major cell cycle regulator
and a typical marker of senescence [7]. IL-6 can also influence resistance to apop-
tosis in malignant cholangiocytes through the phosphorylation of the Janus kinases
170 E. Milani et al.

(JAK)-1 and -2, leading to the phosphorylation of signal transducer and activator of
transcription (STAT) proteins, in particular, of STAT3. Thus, phosphorylated STAT3
undergoes translocation into the nucleus, where it acts as a transcriptional factor
upregulating the expression of several genes, including Myeloid Cell Leukemia-1
(Mcl-1), an anti-apoptotic protein belonging to the Bcl2 family, responsible for the
resistance to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) [8].
Notably, this mechanism could be further sustained by another member of the IL-6
family, the leukemia inhibitory factor (LIF), expressed by both tumor cholangio-
cytes and inflammatory cells, that can be involved in inducing the strong chemore-
sistance typically affecting iCCA [9]. Under normal conditions, the IL-6-STAT3
signaling pathway is inhibited by suppressors of cytokine signaling 3 (SOCS-3),
whereas this negative feedback is epigenetically silenced in CCA [10].
Hepatocyte growth factor (HGF) is a multifunctional growth factor secreted by
several cell types, that could also stimulate malignant cell proliferation via its recep-
tor c-MET; c-MET is overexpressed in tumor tissues and leads to the upregulation of
a variety of signaling pathways, including phosphatidylinositol-4,5-bisphosphate
3-kinase (PI3K), STAT3, and Ras-MAPK. MET activation unfolds a broad invasive-­
growth program, that involves cell proliferation and survival, cell motility and scat-
tering, branching morphogenesis, and angiogenesis [11]. MET amplification has
been detected in 7% of iCCA and appears to be associated with poor clinical out-
come, as well as increased resistance to MET inhibitors and acquired resistance to
epidermal growth factor receptor (EGFR) and c-erb-B2/HER2 (ERBB2) inhibitors
[12]. EGFR is overexpressed in 16% of CCA, with a marked prevalence in iCCA
(around 30%), and is another factor relevant to cholangiocarcinogenesis. EGFR
phosphorylation facilitates the downstream activation of the p38 MAPK, and of
ERK1/2, responsible for the dysregulation of cell proliferation and cell-cell interac-
tions. Another member of EGFR family, ERBB2, is overexpressed by malignant
cholangiocytes (particularly ERBB2 amplifications are found to enrich in fluke-­
related CCAs) and contributes to CCA development by stimulating cancer cell pro-
liferation. Interestingly, ERBB2, together with a wide range of cytokines and
mitogens, including IL-6, HGF, EGF, and also bile acids, sustains cyclooxygenase
(COX)-2 production, which in turn is involved in the activation of IL-6 receptor
favoring a self-sustaining autocrine loop [13].
Whereas COX-1 is constitutively expressed by many cell types and regulates sev-
eral physiological responses, COX-2 and its product, prostaglandin E2(PGE2), are
increased in CCA, where these factors play a major role in shaping several malignant
features. The COX2/PGE2 axis interferes with apoptosis, either by upregulating Mcl-1
or by inhibiting caspase-2 and -9, two effectors of the pro-apoptotic cascade.
Furthermore, the role of COX2 in cholangiocarcinogenesis is further confirmed by
studying the effects on CCA growth of celecoxib, a selective COX2 inhibitor. Upon
celecoxib treatment, CCA cells show an arrest at the G1-S checkpoint in the cell cycle
progression, while increasing the expression levels of the cdk inhibitors p21 and p27
[14]. In chronic cholangiopathies, COX2 activation is also stimulated by the ex-novo
expression of inducible nitric oxide synthase (iNOS). This results in the accumulation
12 Molecular Pathogenesis: From Inflammation and Cholestasis… 171

of high local concentrations of nitric oxide (NO) and of reactive nitrogen oxide spe-
cies (RNOS), responsible for the accumulation of DNA damages due to the genera-
tion of mutagenic compounds such as 8-oxo-7,8-dihydro-­ 2′-deoxyguanosine
(8-oxo-dG) and 8-nitro guanine. Moreover, mutagenic effects caused by RNOS accu-
mulation depend on the inactivation DNA repair enzyme, such as 8-oxo-deoxygua-
nine DNA glycosylase 1 (hOGG1), through the nitrosylation of tyrosine and cysteine
residues [15]. Several genetic mutations involving driver oncogenes (i.e., KRAS),
tumor suppressor (i.e., p53, p16INK4a, SMAD4, and APC) and chromatin-remodeling
genes (i.e., ARID1A, PBRM1, and BAP1) have been reported in iCCA by next gen-
eration sequencing. Of note, inactivation of p53, a tumor suppressor gene regulating
the balance between cell proliferation and apoptosis, is the most frequent genetic
abnormality detected in iCCA (21.7–76%), while KRAS mutations are less common
(9–17% of iCCA) [16]. Furthermore, a variety of fibroblast growth factor receptor 2
(FGFR2) gene fusion products have been noted in 10–16% of iCCA, highlighting the
paramount importance of FGFR pathways in cholangiocarcinogenesis. Epigenetic
modifications are inflammatory-related conditions of growing interest in the develop-
ment of CCA; in particular, somatic mutations in isocitrate dehydrogenases (IDH)-1
and -2 have been detected in up to 25% of iCCA and their pro-oncogenic effects
depend on the production of the oncometabolite 2-hydroxyglutarate (2-HG) which
increases DNA methylation, thereby perturbing gene expression[17]. About 7% of
iCCA are characterized by genetic inactivation of ARID1A that interacts with the
switching defective/sucrose non-­fermenting (SWI/SNF) chromatin-remodeling com-
plex to inhibit the nuclear activity of the highly related transcriptional regulators yes-
associated protein (YAP) and its transcriptional coactivator with PDZ-binding motif
(TAZ). This inhibitory interaction is an alternative to YAP/TAZ association with
TEAD leading to transcription of genes controlling cell fate plasticity, gain of stem-
ness properties, and tumorigenesis [18]. Interestingly, the association between
ARID1A–SWI/SNF and YAP/TAZ is influenced by mechanical stress derived from
the cell microenvironment and may represent the molecular link by which an abnor-
mally remodeled extracellular matrix (ECM) may exert pro-tumorigenic effects (see
below) (Table 12.1).
Another protein recently found to be critically involved in CCA progression is
S100A4 (also known as fibroblast-specific protein-1), a cytoskeletal calcium-­
binding protein, whose nuclear expression in malignant cholangiocytes has been
shown to enhance tumor invasiveness and metastasis [19]. Usually localized in the
cytoplasm of mesenchymal cells, following stimulation with IL1β, S100A4 may
enter into the nucleus by undergoing SUMOylation, a post-translational mechanism
similar to ubiquitination involved in multiple processes, among which gene tran-
scription regulation, as demonstrated in human chondrocytes, or nuclear transloca-
tion. S100A4 nuclearization leads to the activation of the small GTPase Cdc-42 and
Rho-A, the secretion of active matrix metalloproteinase (MMP)-9, and the expres-
sion of transmembrane metalloproteases MT-1-MMP, responsible for the formation
of invadopodia (dynamic actin-based protrusions that degrade extracellular matrix)
and thus enabling tumor cell invasion into the stromal microenvironment [20].
172 E. Milani et al.

Table 12.1 List of gene mutations and signaling perturbations featuring iCCA
Gene/pathway alteration Functional role
IL-6/IL-6R (gp130) overexpression Cell proliferation, apoptosis resistance
HGF/c-MET amplification Cell proliferation, survival, motility
EGFR overexpression Cell proliferation, cell adhesion
HER2 amplification Cell morphogenesis, development, and proliferation
KRAS mutations Cell proliferation
BRAF mutations Cell proliferation, secretion and differentiation
COX-2 overexpression Cell proliferation, survival
Mcl-1 downregulation Apoptosis
SWI-SNF complex inactivation Cell differentiation
YAP/TAZ overexpression Cell proliferation, survival, adhesion, migration
Hedgehog (Hh) overexpression Development, cell migration
Notch overexpression Cell proliferation, survival, migration, angiogenesis
p53 mutations Cell cycle arrest, apoptosis, senescence, DNA repair
p21 WAF1/CIP1and p27KIP1downregulation Negative cell cycle regulation
p16INK4a, DPC4/Smad4 and APC Cell cycle deceleration, cell attachment
inactivation
FGFR2 rearrangements Cell proliferation, differentiation and angiogenesis
IDH1–2 mutations Altered methylation status and survival
MMP overexpression ECM remodeling, cell migration
VEGF overexpression Angiogenesis and lymphangiogenesis
PDGF-D overexpression Lymphangiogenesis
IL interleukin, HGF hepatocyte growth factor, EGF epidermal growth factor, HER human epider-
mal growth factor receptor 2, COX cyclooxygenase, YAP yes-associated protein, TAZ transcrip-
tional coactivator with PDZ-binding motif, FGFR fibroblast growth factor receptor, IDH Isocitrate
dehydrogenase, MMP metalloproteinase, VEGF vascular endothelial growth factor, PDGF
platelet-­derived growth factor

Cholestasis

Cholestasis is another well-established risk factor for iCCA development along

with chronic inflammation. The conjugated bile acids (CBA) and oxysterols, con-
tained in the bile in high concentrations, stimulate production and secretion of
several growth factors. CBAs promote tumorigenesis by acting as pro-proliferative
agents, as well as by interfering with apoptosis. CBAs interact with sphingosine
1-phosphate receptor 2 (S1PR2) to activate ERK1/2 and Akt signaling; this modu-
latory axis activates the transcription factor nuclear factor kappa B (NF-kB) that
unleashes IL-6 and COX-2 production. Moreover, CBAs may activate EGFR via a
TNFα-dependent mechanism resulting in a mitogenic effect of cholangiocytes.
CCA overgrowth is also promoted by the CBA-induced downregulation of the bile
acid receptor farnesoid X-activated receptor (FXR), which instead, is upregulated
by free bile acids [21]. Increased intracellular concentrations of CBAs contribute
to resistance to apoptosis by inducing the overexpression of Mcl-1, which blocks
the activation of the pro-apoptotic caspase cascade [22]. In contrast, increased
12 Molecular Pathogenesis: From Inflammation and Cholestasis… 173

levels of oxysterols, a product of cholesterol oxidation, promote carcinogenesis,

and recently, oxysterols activate the developmental pathway of Hedgehog (Hh) by
binding the extracellular domain of Smoothened, a G protein-coupled receptor
transducing Hh signals [23]. The Sonic Hh variant is overexpressed by human
CCA cells, whereby it modulates the cell cycle checkpoints and the migratory
capabilities of malignant cells [24]. This interesting observation links cholestasis
with a corruption of morphogenetic signaling ultimately leading to cancer as a
perturbed developmental process.
Besides Hh, other morphogenetic pathways critically involved in liver embryo-
genesis and liver repair are often dysregulated in malignant cholangiocytes and
have been implicated as fundamental players for cholangiocarcinogenesis. Recent
studies have demonstrated that Notch1 orchestrates a pathologic transdifferentia-
tion of hepatocytes into neoplastic cholangiocyte-like cells precursors of
iCCA. Notch1 is overexpressed in iCCA tissue, and it is activated by its interaction
with Jagged1 and Jagged2 ligands through a cell-cell contact. Upon ligand bind-
ing, Notch receptor undergoes two proteolytic cleavages operated by the metallo-
endopeptidase containing a disintegrin and metalloprotease (ADAM) and
γ-secretase leading to release of the Notch intracellular domain (NICD). NICD
enters the nucleus and acts as transcriptional factor for many developmental genes,
among which hairy and enhancer of split (Hes)-1, Hes-5, and Hairy/enhancer of
split related with YRPW motif (Hey)-1, involved in cell fate determination, prolif-
eration, migration, apoptosis, and angiogenesis [25]. In experimental cholestasis
(3,5-diethoxycarbonyl-1,4-dihydrocollidine, DDC treatment), Notch activation is
instrumental for biliary repair [26]. Moreover, using a mouse model of iCCA gen-
erated by the hydrodynamic transfection of the active form of Notch1 (NICD) and
of the oncogene K-RasV12D, combined with cell-­fate tracing techniques, iCCA orig-
inates from transdifferentiating hepatocytes. Treatment with different MEK inhibi-
tors (U0126, PD901, and Selumetinib) induces iCCA regression by reducing
proliferation and stimulating apoptosis [27]. Taking a similar approach, in which
Notch2flox/flox mice were transfected with active forms of AKT and YAP, the absence
of Notch2 prevents the neoplastic transformation of hepatocytes to iCCA generat-
ing in turn, hepatocellular adenoma-like lesions [28]. Overall, these findings sug-
gest that persistent activation of both Hh and Notch signaling occurring in chronic
cholestasis can exert potent oncogenic effects on the biliary epithelium.

 ole of the Tumor Microenvironment in Inducing

R
iCCA Invasiveness

The exuberant generation of a desmoplastic stroma, the TRS, is a characteristic

trait of iCCA. TRS is composed of several cell elements lying in strict contact with
each other, encompassing cancer-associated fibroblasts (CAF), tumor-associated
macrophages (TAM), immune cells, lymphatic endothelial cells (LEC), assembled
within an abnormal remodeled ECM consisting of collagen, glycoproteins, and
174 E. Milani et al.

CAF

Neuropilin-1 CXCL14 VEGF-C

MMP1-2-9 FGF1-2 SDF-1 VEGF-D
Cathepsin HGF HB-EGF
TGFβ PDGF-BB
PDGF-DD

VEGFR3
Lyve+
Tenascin C PROX1
ECM Periostin
Osteopontin
iCCA cells
MCP-1
TNFa
CCL3-4-5-8
IL-6
MIF
WNT
M-CSF

MMP-9 LEC
TAM

Fig. 12.2 Paracrine and autocrine factors mediating the complex interplay between neoplastic and
stromal compartment in iCCA. Within the tumor microenvironment, multiple cell types densely sur-
round the neoplastic bile ducts and provide them with several peptides stimulating the main malig-
nant properties of CCA. On the other hand, malignant cholangiocytes are main drivers involved in the
recruitment and activation of cells populating the TRS (CAF, TAM, and LEC, among others). iCCA
intrahepatic cholangiocarcinoma, CAF cancer-associated fibroblast, TAM tumor-associated macro-
phage, LEC lymphatic endothelial cell, ECM extracellular matrix, FGF fibroblast growth factor, TGF
transforming growth factor, HGF hepatocyte growth factor, MCP1 monocyte chemoattractant protein
1, MIF macrophage migration inhibitory factor, M-CSF monocyte colony stimulating factor, TNF
tumor necrosis factor, IL interleukin, SDF stromal cell-derived factor, MMP metalloproteinase,
VEGF vascular endothelial growth factor, PDGF platelet-derived growth factor

proteoglycans [29]. An intense cross talk mediated by a multitude of autocrine and

paracrine cues occurs between the malignant and the stromal component and con-
tribute to the acquisition of the hallmarks of cancer (Fig. 12.2).

CAFs

CAFs are the most represented cell population within the TRS. CAFs are a type of
perpetually activated myofibroblasts, characterized by the expression of α-smooth
muscle actin (SMA), vimentin, S1000A4, and fibroblasts activation protein (FAP)
12 Molecular Pathogenesis: From Inflammation and Cholestasis… 175

and are supposed to originate from different cell sources, including hepatic stellate
cells (HSC), portal fibroblasts (PF), or bone marrow-derived mesenchymal cells.
Once attracted nearby the malignant ducts, CAFs are activated by a broad range of
cytokines, chemokines and growth factors largely produced from both CCA and
inflammatory cells [30–32]. The most prominent are C-C motif chemokine ligand 2
(CCL2), C-X-C motif chemokine 14 (CXCL14), stromal cell-derived factor (SDF-­
1) fibroblast growth factor (FGF) 1-2, transforming growth factor (TGF)-β, insulin-­
like growth factor (IGF)-1, HGF, granulocyte-macrophage colony stimulating factor
(GM-CSF)-1, and platelet-derived growth factors (PDGF). A stand-alone role is
played by PDGF-DD. PDGF-DD is, in fact, overexpressed by neoplastic cholangio-
cytes under hypoxic conditions and binds to its cognate receptor, PDGFRβ,
expressed by CAF, to activate both a proliferative ERK1/2-dependent pathway and
a pro-migratory cascade, mediated by the activation of Rho-GTPases (in particular,
Rac-1 and Cdc42) and by the phosphorylation of JNK [33]. Once within the tumor
microenvironment, CAFs sustain cancer progression by releasing a plethora of
cues, in particular, SDF-1, PDGF-BB, heparin-binding (HB)-EGF, and TGFβ,
which molds the malignant behavior of tumor cholangiocytes by affecting their pro-
liferation, survival, migration, and invasiveness.
SDF-1, also known as CXCL12, is a chemokine that, working in concert with the
HGF/c-MET axis, binds to its specific receptor CXCR4 expressed by malignant
cholangiocytes to activate ERK1/2 and PI3K/Akt pathways, providing them with a
proliferative advantage. Notably, tumor cholangiocytes are hyper-responsive to
SDF-1, as they overexpress CXCR4 upon the joint effect of TNFα secreted by TAM
and HGF derived from the CAF themselves [30]. SDF-1 confers also a survival
advantage to CCA cells by upregulating the expression of the anti-apoptotic protein
Bcl-2 [34]. PDGF-BB is another member of the PDGF family suffice to stimulate
pro-migratory and proliferative functions in CCA cells, together with an enhanced
resistance to apoptosis. PDGF-BB is also able to inhibit the release of TRAIL, a
regulator of apoptotic cellular responses, by activating the Hh signaling. Specifically,
the interaction between PDGF-BB and its receptor PDGFRβ (also expressed by
CCA cells) results in increased intracellular levels of cyclic adenosine monophos-
phate (cAMP), which stimulate the PKA-dependent translocation of Smoothened to
the plasma membrane, followed by glioma-associated oncogene (GLI) activation,
ultimately responsible for Hh stimulation [35].
HB-EGF is a growth factor copiously produced by CAF that supports tumor
growth and metastasization through a paracrine loop. HB-EGF is a ligand for EGFR,
whose activation is one of the most frequent phenotypic changes underlying CCA
development. Activation of the HB-EGF/EGFR axis on one side stimulates the
ERK1/2 and STAT3 pathways, while on the other, unfolds a β-catenin-mediated
transcriptional program, proficient in cell migration and invasion. Of note, EGFR
expression promotes TGFβ production by CCA cells, which further stimulates
HB-EGF synthesis, in a self-perpetuating autocrine loop [36].
Moreover, CAFs act on the tumor microenvironment by displaying strong ECM
modifying capabilities mediated by the production of multiple proteins, encompass-
ing neuropilin-1, several MMPs (MMP-1, MMP-2, and MMP-9), cathepsins, and
176 E. Milani et al.

plasminogen activators, which remodel qualitatively and quantitatively the ECM

scaffold through the modulation of integrin expression and changes in the collagen
composition. This pathological remodeling results in an increased ECM stiffness
that is essential for the activation of intracellular mechanosensors by which cells
decipher structural changes of their microenvironment to assume a more aggressive
malignant phenotype. In fact, a stiffer ECM activates YAP/TAZ [37] to induce a
range of pro-oncogenic effects, such as cell proliferation, gain of stem cell-like
properties, and invasive functions [29].
ECM ability to support cancer aggressiveness is also sustained by the aberrant
deposition by CAFs and by other inflammatory cells of tenascin-C and periostin,
two structural proteins acting as modulators of integrin-mediated pathways, which
impinge upon CCA cell proliferation and invasion [30]. Besides effects on tumor
cells and ECM, CAF favor TRS crowding by recruiting other stromal cell ele-
ments, in particular, inflammatory cells and endothelial cells, ultimately aiding the
tumor spread.

TAMs

TAMs are the most represented immune cell population within the CCA microenvi-
ronment. TAMs mainly originate from circulating monocytes and are engaged nearby
the tumor area by a variety of soluble factors secreted by either neoplastic or stromal
cells, such as monocyte chemoattractant protein (MCP)-1, CCL3, CCL4, CCL5,
CCL8, macrophage migration inhibitory protein-1α, vascular endothelial growth
factor (VEGF), and M-CSF [31]. Once recruited into the TRS, monocytes can trans-
differentiate prevalently into M2 macrophages, characterized by the constitutive
expression of CCL17, CCL18, IL1α, IL6, IL10, and Arginase-1 under the control of
PGE2, IL-2, IL-10, and TGFβ [29]. In CCA, TAMs closely cooperate with CAF to
generate a milieu tolerant to tumor growth and invasion, both by suppressing anti-
tumor functions exerted by T cells and M1 macrophages, and by promoting tumor
cell proliferation, migration, and apoptosis resistance, ECM remodeling, and angio-
genesis. Several soluble factors underpin pro-tumorigenic effects of TAMs, includ-
ing TNFα, IL6, and MMP-9. TNFα is in fact abundantly produced by
lipopolysaccharide (LPS)-activated macrophages located at the tumor edge, and fos-
ter epithelial-to-mesenchymal-transition (EMT)-like phenotypic changes in CCA
cells, resulting in the downregulation of epithelial markers, such as cytokeratin (K) 7
and 19, E-cadherin, and EpCAM, and upregulation of mesenchymal markers, such
as N-cadherin, and vimentin, via a Snail and ZEB2-mediated processes [38].
Moreover, the activation of the TNFα-specific receptor TNFR2 stimulates the pro-
duction by macrophages of MMPs, in particular, of MMP-9. MMP-9 secretion is
stimulated by the activation of NF-kB, Akt, and MAPK signaling responsible for the
activation of COX2 that, through PGE2, acts as a trigger for MMP-9 secretion and
activation [39]. MMPs secreted by TAMs are fundamental for the breakdown of the
basement membrane, mainly composed by laminin, and of the surrounding matrix
12 Molecular Pathogenesis: From Inflammation and Cholestasis… 177

favoring intravasation of neoplastic cells and their metastatization. In addition, TAMs

are a source of IL-6 and may activate morphogenetic pathways, such as the WNT/β-­-
catenin signaling. In particular, Wnt3 produced by LPS-activated macrophages binds
to its receptor Frizzle, whose stimulation leads to nuclear translocation of β-catenin,
where it can regulate expression of oncogenes, such as c-Myc and cyclin D1 [40].

Immune Cells

During cancer growth, tumor cells progressively develop skills to avoid immune
surveillance by activating a range of stratagems, including the expression of tumor-­
specific antigens, upregulation of immune checkpoint molecules, or secretory abil-
ities to suppress proliferation of CD4+ and CD8+ lymphocyte proliferation [41].
Antagonizing mechanisms regulating escape from tumor immune response has
become one of the most promising approaches for the treatment of malignancies
with strong resistance to conventional chemotherapeutic agents or without alterna-
tive treatments, as the case of CCA. The blockade of the programmed-death cell
protein (PD) receptor and ligand (PD-1/PD-L1) axis is one of the most valuable
strategies in this context, as shown in both hematologic and solid neoplasms,
including Hodgkin’s lymphoma, non-small-cell lung cancer (NSCLC), renal cell
carcinoma (RCC), and bladder cancer. Under physiological conditions, the interac-
tion between PD-1, expressed on activated T and B cells, and PD-L1, expressed by
macrophages and lymphocytes, induces CD8+ cell exhaustion, controls tolerance,
and attenuates immune response, reducing T cell activation and empowering the
immunosuppressive functions of regulatory T cells (Tregs). In the tumor microen-
vironment, persistent overexpression of PD-1/PD-L1 correlates with poor disease
outcome [42]. Cytokines, such as IFNγ and TNFα, abundantly released in the
tumor microenvironment, upregulate PD-L1 expression not only on T, B, and
endothelial cells but also on tumor cells, leading to PD-1 activation. PD-1 is usu-
ally expressed by tumor-infiltrating lymphocytes (TIL) to induce T cell exhaustion,
and consequently loss of their ability to produce pro-inflammatory cytokines and
cytolitic molecules [43]. Noteworthy, effectiveness of PD-L1 antibodies, such as
pembrolizumab, has been tested in several clinical trials for patients with advanced
iCCA and histological evidence of a dense TIL accumulation, with encouraging
results [44].

LECs

Another structural component that is crucial for the TRS functions is the lymphatic
network that develops in and around the neoplastic scar, and importantly, its extent
correlates with a worse outcome and a shorter disease-free and overall survival in
iCCA [45]. On a physiological ground, the function of the lymphatic system is to
178 E. Milani et al.

regulate fluid homeostasis, facilitate interstitial protein transport, and sustain immu-
nological functions. Lymphatic vessels are composed by a thin layer of LEC, sur-
rounded by a discontinuous wall of αSMA+ mural cells, equipped with fenestrations,
enabling immune cell migration, and with valves, to direct progression of the lym-
phatic fluid flux. LECs are characterized by the expression of several specific pro-
teins, among which lymphatic vessel endothelial hyaluronan receptor-1 (Lyve-­1),
the sialoprotein podoplanin (PDPN), and the transcription factor prospero homeo-
box 1 (PROX1), together with VEGFR3, the cognate receptor for the main pro-
lymphangiogenic growth factors, VEGF-C and VEGF-D, and by the co-­receptor
neuropilin-1. Besides, LECs express major histocompatibility complex class (MCH)
I and II, sharing with professional antigen-presenting cells (APC) the ability to dic-
tate self-tolerance [46]. In addition, LECs are a source of chemokines (i.e., CCL-19
and CCL-21) and express adhesion molecules, i.e. macrophage mannose receptor
(MR), and common lymphatic endothelial and vascular endothelial receptor-1
(CLEVER-1), which facilitate leukocyte trafficking and transmigration [47].
Unfortunately, the flipside of this vast expression of adhesion molecules enabling
cell trafficking is that they may favor tumor cell intravasation and thus, lymphatic
metastasis. Similar to what happens with other solid cancer types, including mela-
noma, lung, colon, and breast cancer, lymphatic dissemination is the major route for
tumor spread in iCCA, and the assessment of lymph node involvement is a critical
step towards tumor staging and therapeutic patient stratification. In contrast with
hepatocellular carcinoma (HCC) associated with a rich, newly formed blood vessel
bed, which is a diagnostic hallmark, iCCA is characterized by a prominent tumor-­
associated lymphangiogenesis, which correlates with tumor progression (45).
Among the main lymphangiogenic growth factors, VEGF-C is the most extensively
studied. Upon VEGF-C stimulation, VEGFR-3 leads to the activation of PI3K/Akt
and ERK pathways, which promote LEC proliferation, survival, and vascular
assembly and sprouting. Of note, PI3K, the upstream activator of Akt, has been
shown to interact directly with VEGFR-3 and to elicit LEC tube formation and
migration, via a Rho GTPase Rac1-mediated pathway [48]. Angiopoietins (Ang-1
and Ang-2), and their cognate receptor Tie-2, are a further lymphangiogenic system
regulating the endothelial layer stability, but with opposite roles. Whereas Ang-1
stimulates vascular stabilization and maturation in a paracrine manner, Ang-2 acts
through an autocrine loop to induce vessel destabilization and disruption as prereq-
uisite for vascular sprouting [49]. Different PDGF family members, as shown in
CCA for PDGF-D, strongly cooperate to tumor-associated lymphangiogenesis.
Besides promoting CAF migration and activation [33], tumor cell-derived PDGF-D
enables CAF to produce VEGF-A and VEGF-C. In turn, VEGF-A and VEGF-C, by
interacting with their receptors VEGFR-2 and VEGFR-3 expressed by LECs, kindle
LEC migration and gathering into highly branched vascular structures, where they
also enhance the endothelial permeability to make lymphatic vessels proficient to
cancer cell invasion [50]. Tumor-associated lymphangiogenesis is a research area
worth being further explored in order to identify new therapeutic avenues aimed at
preventing iCCA spread.
12 Molecular Pathogenesis: From Inflammation and Cholestasis… 179

Conclusion

In the last few years, increasing efforts have been made to unravel the complex
landscape of molecular mechanisms promoting iCCA development, growth, and
dissemination. Based on these findings, it is becoming clear that chronic inflamma-
tion and cholestasis occurring in several pre-malignant liver disease conditions are
often associated with a perturbation of intracellular pathways controlled by driver
oncogenes found to be strongly associated with iCCA. Beyond tumorigenesis, a
critical component driving tumor progression is then the development of a highly
dynamic TRS, acting as an engine that oversees and enhances numerous pro-­
invasive features of malignant cholangiocytes. Inside this multicellular compart-
ment, where cell interactions are supported by an abnormally remodeled ECM,
CAF work in concert with innate and adaptive immune cells, including TAM and
TIL, to shape a microenvironment with a proclivity to cancer spread. In this setting,
lymphatic vessels behave as a preferential route of dissemination. Given the wide
heterogeneity of the tumor microenvironment in iCCA, it represents a challenge to
derive relevant populations for basic research and drug discovery and may serve as
a model that can be translated also to other epithelial tumors characterized by abun-
dant desmoplasia, such as pancreatic or breast carcinomas.

Acknowledgments M.C. was supported by Fondazione Cariplo, Grant No. 2014-1099; L.F. was
supported by the University of Padua, Progetti di Ricerca di Dipartimento (PRID) 2017.

Conflict of Interest Statement Authors have nothing to disclose.

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Chapter 13
Clinical Trials and Novel/Emerging
Treatment

Jonathan D. Mizrahi, Reham Abdel-Wahab, and Milind Javle

Introduction

Intrahepatic cholangiocarcinoma (ICC) is increasing in incidence and presents a

therapeutic challenge, as most patients present at an advanced unresectable stage
and face an adverse prognosis. Recent next-generation sequencing studies indicate
that these tumors are enriched with several actionable mutations, perhaps more than
other gastrointestinal cancers. Morphologically, these tumors are diverse and may
be mass-forming, intraductal or periductal [1]. Therefore, the traditional, “one-size-­
fits-all” approach is not ideal for this cancer. Historically, liver-directed approaches
have been more commonly used in hepatocellular cancer, while systemic chemo-
therapy remains the primary approach for the advanced stage of ICC. This paradigm
has fortunately begun to change, and patients with ICC now have multiple treatment
options including liver-directed and targeted therapies based on underlying muta-
tional profile.

J. D. Mizrahi
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center,
Houston, TX, USA
e-mail: [email protected]
R. Abdel-Wahab
Department of Gastrointestinal Medical Oncology, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA
Clinical Oncology Department, Faculty of Medicine, Assiut University, Asyut, Egypt
e-mail: [email protected]
M. Javle (*)
Department of Gastrointestinal Medical Oncology, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 183

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1_13
184 J. D. Mizrahi et al.

Liver-Directed Locoregional Therapies

Over two-thirds of ICC patients have unresectable disease at diagnosis and 71% of
patients who undergo curative-intent resection develop postoperative disease
recurrence. Local or regional recurrence after surgery occurs in 85% of the patients
[2]. The role of locoregional therapies in ICC, including transarterial chemoembo-
lization (TACE), transarterial radioembolization, hepatic artery infusion (HAI),
radiation therapy, and radiofrequency (RFA), is still controversial and have not
been evaluated in prospective randomized control trials. These therapies are
reviewed below.

Radiation Therapy

With the remarkable advances in the radiotherapy technology, radiation therapy is

now safe and effective for patients with ICC, particularly for those with an adequate
liver reserve and without advanced primary sclerosing cholangitis (PSC). The use of
radiotherapy for ICC can be in the adjuvant or advanced disease setting. Given the
positive results of the adjuvant therapy for biliary cancer (BILCAP) trial, which
showed improved overall survival with capecitabine as compared with placebo, che-
motherapy after surgical resection of ICC is preferred [3]. A large retrospective
review of 3839 ICC patients from the Surveillance, Epidemiology, and End Results
(SEER) indicated however that surgery followed by adjuvant radiotherapy results in
a significantly higher overall survival (OS) compared with surgery alone (P = 0.01).
Similarly, patients treated with definitive radiotherapy (without resection) had a
higher OS than patients who did not receive any radiation in this study [4]. Zheng
et al. compared the treatment outcome of ICC treated with hepatectomy with post-
operative radiotherapy for close margin (group A), hepatectomy without adjuvant
radiotherapy for close margin (group B), and hepatectomy with a wide margin. This
study showed that adjuvant radiotherapy for close surgical margin improved the
3-year OS, progression-free survival (PFS) and extrahepatic recurrence (55%, 44%,
and 43%, respectively) as compared with 20%, 10%, and 65% in group B (P = 0.01,
0.03, and 0.007, respectively) [5]. Additionally, a meta-analysis of 11 studies with
226 unresectable or recurrent CCA patients was performed to evaluate the role of
stereotactic body radiation therapy (SBRT). The median OS was 13.6 months with
53.8% pooled 1-year OS, 81.8% 1-year local recurrence rate, <10% grade 3 acute
toxicity, and 10–20% late toxicity [6]. Studies investigating the role of radiation in
ICC are summarized in Table 13.1 [7–12]. High doses of radiation can be safely
delivered safely for ICC and in a study conducted at MD Anderson Cancer Center,
dose correlated with longer OS and higher local control rate. Doses more than
80.5 Gy result in the median OS of 30 months and a 3-year OS with local control
rate of 73% and 78%, respectively [13]. Novel approaches including high-dose
hypofractionated proton therapy may be another promising modality for ICC. In a
Table 13.1 Clinical studies of locoregional therapy of unresectable ICC
Patients Treatment sessions Median OS 1-year OS
Authors Year Country N = () median (range) Therapeutic agents (months) rate (%) DCR N = (%)
cTACE
Burger et al. [31] 2005 USA 17 2 (1–4) Cisplatin 23 NA NA
Herber et al. [29] 2007 Germany 15 3.9 (1–15) Mitomycin-C 21.1 51.3% 10 (66.7%)
Gusani et al. [30] 2008 USA 42 3.5 (1–16) Gemcitabine (n = 18) Overall (9.1) NA 20 (571%)a
Gemcitabine/cisplatin Gemcitabine
(n = 14) (6.3)
Gemciatbine/cisplatin Gemcitabine/
followed by oxaliplatin cisplatin (13.8)
(n = 4)
Gemcitabine followed by
oxaliplatin (n = 4)
Gemcitabine followed by
cisplatin (n = 2)
13 Clinical Trials and Novel/Emerging Treatment

Kim et al. [27] 2008 Republic of 49 3 (1–17) Cisplatin 10 46% 42 (55%)

Korea
Park et al. [26] 2011 Republic of 72 2.5 (1–17) Cisplatin 12.2 51% 59 (89.4%)b
Korea
Kiefer et al. [28] 2011 USA 62 2 (1–4) Cisplatin/doxorubicin/ 15 61% 34 (75.6%)c
mitomycin-C
Vogl et al. [25] 2012 Germany 115 7.1 (3–30) Gemcitabine (n = 8) 13 52% 76 (66.1%)
Mitomycin-C (n = 24)
Gemcitabine/mitomycin-C
(n = 54)
Gemcitabine/mitomycin-C/
cisplatin (n = 29)
(continued)
185
Table 13.1 (continued)
186

Patients Treatment sessions Median OS 1-year OS

Authors Year Country N = () median (range) Therapeutic agents (months) rate (%) DCR N = (%)
DEB-TACE
Poggi et al. [33] 2009 Italy 9 NA Oxaliplatin eluting 30 NA 9 (100%)
microspheres
Schiffman et al. [32] 2011 USA 24 NA Doxorubicin (n = 7 17.5 NA 22 (92%)
sessions)
Irinotecan (n = 35 sessions)
Aliberti et al. [34] 2017 Italy 127 NA DEB doxorubicin (n = 109) DEBDOX: 14.3 NA All: 120 (95%)
LIF doxorubicin (n = 18) LIFDOX: 13 DEBDOX: 103
(95%)
LIFDOX: 15
(85%)
Y-90 radioembolization
Ibrahim et al. [42] 2008 USA 24 1–2 – 14.9 NA 21 (95.5%)d
Saxena et al. [40] 2010 Australia 25 1–2 – 9.3 40% 17 (72%)e
Hoffmann et al. [43] 2012 Germany 33 1–2 – 22 NA 29 (87.9%)
Soydal et al. [38] 2016 Turkey 16 1–2 – 9.6 NA NA
Shaker et al. [39] 2018 USA 17 1–2 – 33.6 NA NA
Reimer et al. [41] 2018 Germany 21 1–2 – 15 NA 10 (47.6%)
Hepatic artery infusion
Tanaka et al. [48] 2002 Japan 11 51 (12–84) Fluorouracil 26 91% 9 (82%)
Shitara et al. [45] 2008 Japan 20 8 (2–46) Mitomycin-C/degradable 14.1 NA 18 (90%)
starch microspheres
Jarnagin et al. [46] 2009 USA 26 7 (2–25) Floxuridine NA NA 25 (96.1%)
Inaba et al. [47] 2011 Japan 13 NA Gemcitabine 12.8 NA 1 (7.7%)
Ghiringhelli et al. 2013 France 12 7 (2–15) Gemcitabine/oxaliplatin 20.3 NA 11 (91.7%)
[50]
J. D. Mizrahi et al.

Massani et al. [49] 2015 Italy 11 6 Fluorouracil/oxaliplatin 17.6 NA 7 (63.6%)

 Radiation therapy (Rth)
Jiang et al. [8] 2010 China 90 50 Gy (34–60) Surgery + adjuvant Rth Rth: 19.1 Rth: 68.8% Rth: 18 (65%)
(n = 24) Surgery alone: Surgery
Surgery alone (n = 66) 9.5 alone:
43.2%
Barney et al. [11] 2012 USA 10 45-60Gy SBRT NA 73% 10 (100%)
Jia et al. [7] 2015 China 38 56.8 Gy (50–60) Surgery + adjuvant IMRT IMRT group: NA NA
(n = 14) 21.8
Surgery alone (n = 24) Surgery alone
group: 15
Mahadevan et al. 2015 USA 34 30 Gy (10–45) SBRT 17 58% NA
[10]
Liu et al. [9] 2017 Taiwan 15 45 Gy (25–60) SBRT 12.6 50.3% 12 (80%)
Shen et al. [12] 2017 China 28 45 Gy (36–54) SBRT 15 57.1% 25 (89.3%)
Radiofrequency
Kim et al. 2011 Republic of 20 1–2 RFA 27.4 70% –
13 Clinical Trials and Novel/Emerging Treatment

Korea recurrent
Kim et al. 2011 Republic of 13 1ry 1–2 RFA 38.5 85% –
Korea lesions
Haidu et al. 2011 Austria 11 1–2 Stereotactic RFA 60 91% –
Giorgio et al. [63] 2011 Italy 10 NA RFA NA 100% –
Xu et al. 2012 Shanghai 18 NA RFA 8.8 36.3% –
Fu et al. 2012 China 17 1–2 RFA 33 84.6% –
Butros et al. 2014 USA 7 1–2 RFA 38.5 100% –
a
Response was not evaluated in 7 patients
b
Response was not evaluated in 6 patients
c
Response was not evaluated in 17 patients
d
Response was not evaluated in 1 patient
e
Response was not evaluated in 3 patients
187
188 J. D. Mizrahi et al.

single-arm, phase II, multi-institutional study, 92 patients with hepatocellular can-

cer or ICC received 15 fractions of proton therapy to a maximum total dose of
67.5 Gy equivalent [14]. With a median follow-up among survivors of 20 months,
the local control rate at 2 years was 94.1% for ICC with an OS rate at 2 years of
46.5%. These studies indicate that radiation therapy is an attractive option for
patients with ICC, both as adjuvant therapy for margin-positive and for locally
advanced unresectable cases.

Liver Transplantation

While surgical resection of early-stage ICC remains the consensus treatment of

choice, the role of liver transplantation in the management of this malignancy
remains controversial. The potential benefits of transplant include replacement of
underlying hepatobiliary pathology such as primary sclerosing cholangitis and
cirrhosis with a healthy liver. The Mayo Clinic developed a protocol for the treat-
ment of small extrahepatic and hilar cholangiocarcinoma involving neoadjuvant
chemoradiation followed by liver transplantation, which is now the standard of
care for a subset of extrahepatic CCA [15]. Five-year survival rates among these
highly selected patients who treated per protocol were reported to be as high as
65–70% [16]. Unfortunately, most of the reported outcomes of patients with ICC
undergoing liver transplant have been less encouraging with high recurrence rates
and low OS.
Goldstein et al. reported a single institution study of liver transplantation with
adjuvant radiation therapy and chemotherapy [17]. Fourteen patients were con-
firmed to have cholangiocarcinoma on post-transplant pathology, 8 of whom had
ICC. The 1-year survival rate was reported to be 53% with a disease-free survival of
40% and 33% at 1 year and 2 years, respectively. In a larger retrospective analysis,
the 1-year and 5-year survival rates of European patients who underwent liver trans-
plantation between 1968 and 2000 for ICC were reported as 58% and 29%, respec-
tively [18]. More recently, Becker et al. analyzed 280 patients in the United Network
for Organ Sharing/Organ Procurement and Transplantation Network patient data-
base who underwent liver transplantation for a diagnosis of cholangiocarcinoma
[19]. They found a 5-year survival rate of 38% in patients who were transplanted
after the year 2000. In the subgroup of patients who were known to have cholangio-
carcinoma prior to liver transplantation, the authors reported a 5-year survival rate
of 68%. This analysis did not assess outcomes by tumor location (i.e., intrahepatic
vs. extrahepatic). In 2016, a retrospective international multicenter study evaluated
patients with cirrhosis who received a liver transplant and were incidentally noted
on explant to have ICC [20]. Of the patients who were considered to have “very
early” ICC (single lesion ≤2 cm in size), 5-year cumulative recurrence risk was
18%, compared to 61% of patients with more advanced ICC. Notably, almost half
of patients found to have ICC on explant did not have any suspicious hepatic lesions
prior to surgery.
13 Clinical Trials and Novel/Emerging Treatment 189

Whether these outcomes can be improved with better patient selection is an

essential question regarding the future role of liver transplantation in the treatment
of ICC. Hong et al. described the experience at the University of California Los
Angeles with transplant in patients with cholangiocarcinoma who would otherwise
not be eligible by the standards set by the Mayo Clinic [21]. Twenty-five patients
underwent liver transplantation for ICC compared with 12 patients who underwent
partial hepatectomy. On multivariate analysis, risk factors for reduced overall sur-
vival included partial hepatectomy rather than transplant, perineural invasion, hilar
rather than intrahepatic tumor and multifocal tumors. Interestingly, tumor size,
defined as ≥5 cm for ICC, was not found to be associated with worsened survival.
The same authors used their experience with liver transplantation in cholangiocar-
cinoma to create a predictive scoring model of recurrence risk [22]. The 5-year
recurrence-free survival was 78%, 19%, and 0% for patients in the low-risk,
intermediate-­risk, and high-risk groups, respectively.
Recently, our group investigated the role of a liver transplant for ICC in patients
who had experienced disease response or stability for 6 months or more with sys-
temic chemotherapy. Twenty-one patients were referred for evaluation and 12
patients were accepted, of whom six patients have undergone liver transplantation
for ICC. Three patients received livers from extended criteria deceased donors that
would otherwise have been discarded, two from domino living donors and one from
a standard criteria liver donor. The median duration from diagnosis to transplanta-
tion was 26 months and median follow-up from transplantation was 36 months. All
patients received neoadjuvant chemotherapy while awaiting liver transplantation.
Overall survival was 100% at 1 year, 83% at 3 and 5 years. Three patients developed
the recurrent disease at a median of 7·6 months after transplantation, with 50%
recurrence-free survival at 5 years [23, 24].
In summary, the role of liver transplantation in the treatment of patients with
unresectable ICC remains unclear. However, the above data suggest there may be a
role for neoadjuvant therapy in improving outcomes of patients receiving liver
transplantation.

Transarterial Chemoembolization (TACE)

Although TACE is ideally used for hypervascular tumors like hepatocellular carci-
noma (HCC), hepatobiliary angiography identified that ICCs are relatively hypervas-
cular tumors as compared to the normal liver parenchyma. The concept of conventional
TACE (cTACE) is to deliver chemotherapeutic agents directly into the tumor feeding
artery. Several studies have evaluated the efficacy and safety of cTACE in the treat-
ment of CCA [25–31]. All trials included locally advanced unresectable CCA patients
with ECOG PS ≤ 1. The range of median overall survival was 9–23 months and the
procedure was tolerable. Although the results were promising, these studies included
both ICC and extrahepatic CCA, making the evaluation of cTACE efficacy in ICC
challenging. (Table 13.1) Moreover, drug-eluting bead TACE (DEB-TACE) is similar
190 J. D. Mizrahi et al.

to cTACE but allows delivery of a higher dose of chemotherapeutic agents directly

inside the tumor with less systemic toxicity and more tumor necrosis. Experience with
DEB-TACE in ICC is limited but supports its efficacy and safety [32–34]. (Table 13.1)
A retrospective review of three independent prospective studies compared the efficacy
and safety of cTACE with mitomycin-­C (n = 10), DEB-TACE with irinotecan (n = 26),
and systemic therapy with gemcitabine and oxaliplatin (n = 31) for ICC. This study
showed that the PFS and OS with DEB-TACE (3.9 and 11.7 months, respectively)
were higher when compared with cTACE (1.8 and 5.7 months, respectively).
Furthermore, this survival outcome was similar to that with systemic chemotherapy
(6.2 and 11 months, respectively) [35].
Furthermore, due to a high rate of postoperative recurrence, the role of adjuvant
TACE has been evaluated. Wu et al. retrospectively reviewed 114 ICC surgically
resected patients of whom 75 were treated with adjuvant TACE. The study results
showed that adjuvant TACE significantly improved the OS rate in patients who had
poor prognostic factors including tumor size ≥5 cm and advanced stage [36].

Radioembolization

Radioembolization represents internal radiation therapy using Yttrium-90 (Y-90)

microspheres, which emits a high dose of lethal beta radiations up to 120 Gy. While,
both TACE and Y-90 delivered through the hepatic artery, Y-90, unlike TACE, is a
non-occlusive procedure and its effect depends upon free radical release that can
lead to apoptosis. While TACE is contraindicated in the presence of portal vein
thrombosis, radioembolization can be safely performed in this setting. Moreover,
radioembolization can be used for bilobar disease but each lobe is treated separately
with at least 4 weeks gap between sessions [37]. Recent studies regarding the role
of Y-90 in ICC are summarized in Table 13.1 [38–43]. A systematic review of 7
prospective case series and 5 retrospective cohort studies, which included 298 unre-
sectable ICC patients concluded that the median OS in patients treated with Y-90 is
15.5 months with 82% overall response rate (ORR) [44]. This survival rate is simi-
lar to the reported survival rate of systemic chemotherapy and TACE. Thus, radio-
embolization should be considered one of the treatment approaches for ICC.

Hepatic Artery Infusion

Hepatic arterial infusion (HAI) chemotherapy is feasible in ICC and has followed
the experience of treating colorectal cancer liver metastases. Although several che-
motherapeutic agents can be infused through the hepatic artery, floxuridine is the
most commonly used drug due to its short half-life, 95% extraction rate during the
“first-pass” through the liver, low toxicity when combined with dexamethasone and
extensive multicenter experience [45–50]. (Table 13.1) A meta-analysis of 20
13 Clinical Trials and Novel/Emerging Treatment 191

studies included 657 unresectable ICC patients and compared the treatment out-
come of HAI (n = 62), TACE (n = 431), DEB-TACE (n = 37), and yttrium-90 radio-
embolization (n = 127). The OS among HAI treated group was 22.8 months as
compared with 13.9 months with Y-90, 12.4 months with cTACE and 12.3 months
with DEB-­TACE. The ORR was 56.9%, 27.4%, and 17.3% with HAI, Y-90, and
TACE, respectively. While 61.5% of DEB-TACE treated patients had SD, none
experienced CR or PR [51].
A retrospective analysis of 525 ICC patients revealed that HAI combined with
systemic chemotherapy led to a higher OS benefit over chemotherapy alone (30.8
vs. 18.4 months, respectively) (P < 0.001) and the difference was maintained in
patients with lymph node involvement [52]. Prospective trials of HAI are limited
but suggest the feasibility of this approach along with systemic therapies [53].

Radiofrequency Ablation

Radiofrequency ablation is an effective locoregional treatment approach that can be

used for the treatment of small ICC with 80–100% reported success rates [54]. A
systematic review and a meta-analysis of 7 observational studies included 84 ICC
patients showed that RFA associated with 1-, 3-, and 5-year OS rates of 82%, 47%,
and 24%, respectively [55]. A previous study showed that complete ablation could
be achieved with RFA session in lesions ≤3.4 cm in size. However, modern stereo-
tactic RFA allows complete ablation of larger tumors with one session. Recently,
stereotactic RFA used for treating 52 unresectable ICC lesions in 17 patients.
Lesions up to 10 cm were completely ablated within one session with a median OS
of 60 months [56]. A summary of the previously published studies of RFA in ICC
has been summarized in Table 13.1 [57–63]. However, the majority of these studies
included both primary and recurrent ICC lesions.
In summary, the concept of using liver-directed therapies for ICC is attractive as
can provide effective locoregional control without systemic toxicities. However,
majority of the evidence in this regard is retrospective and future multicenter ran-
domized clinical trials are warranted to examine the efficacy of different modalities.
Institutional expertise, tumor location, vascularity, and underlying liver function
play a key role in the selection of the optimal approach.

Systemic and Targeted Therapy

Systemic Chemotherapy

Patients with advanced cholangiocarcinoma (CCA) have limited chemotherapeutic

options. Gemcitabine and cisplatin is currently the worldwide standard first-line
therapy for advanced CCA based on the randomized, controlled, phase III ABC-02
192 J. D. Mizrahi et al.

study, which enrolled 410 patients with locally advanced or metastatic biliary tract
cancer, of those 241 patients (58.8%) were cholangiocarcinoma. In this trial, the
median OS with the combination therapy was 11.7 months as compared with
8.1 months with gemcitabine alone Hazard ratio (HR) = 0.64, P < 0.001. Also, the
PFS was 8 and 5 months, respectively (HR = 0.63, P < 0.001) [64]. A meta-analysis
of 104 trials comprising 2810 biliary tract cancer (BTC) patients confirms the supe-
riority of gemcitabine and platinum-based chemotherapy over other chemothera-
peutic agents [65]. Recently, Shroff et al. reported the phase II study results of
gemcitabine, cisplatin, and nab-paclitaxel for advanced BTC. Among the 60 treated
patients, 38 had advanced unresectable ICC. Median follow-up was 12.2 months
and median PFS 11.8 months. Partial response and disease control rates were 43%
and 84%, respectively. Median OS was 19.2 months (95% CI, 13.2 to not estima-
ble). Grade ≥ 3 toxicities occurred in 57% of patients, and 18% withdrew owing to
toxicities. Neutropenia was the most common toxicity (32%).
Second-line systemic approaches for this disease with gemcitabine or
fluoropyrimidine-­based regimens including gemcitabine plus capecitabine, gem-
citabine plus oxaliplatin, gemcitabine plus fluoropyrimidine, fluoropyrimidine with
cisplatin, or oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), or single-agent gem-
citabine, fluorouracil, or capecitabine have limited efficacy with an average PFS of
3 months [66]. A systematic review of 14 phase II clinical trials, 9 retrospective
cohort studies, and two case reports has been pooled and analyzed to identify the
best second-line therapy for BTC and they concluded that there is no strong evi-
dence to support one regimen over others [67]. This raises the great unmet need for
prospective randomized controlled trials to explore a better combination treatment
approaches for this cancer.

Targeted Therapy

Recently, next-generation sequencing (NGS) has indicated that ICC is enriched

with a relatively high number of actionable mutations and has been a focus of inten-
sive drug development. Promising anti-tumor activity has been noted with novel
targeted therapies directed against fibroblast growth factor receptor 2 fusion
(FGFR), isocitrate dehydrogenase-1 (IDH1) and IDH2, BAP1, BRAF V600E muta-
tions, and Her2/neu amplification. A summary of the targeted therapy clinical trials
is depicted in Table 13.2 [68–107].

IDH-1 and IDH-2 Pathway

Mutations in IDH1 and 2 have been identified in approximately 10–40% of ICC

patients as compared with 3–4% of extrahepatic CCA [108, 109]. The prognostic
significance of IDH mutations remains controversial. Majority of the retrospective
data do not show any significant correlation between IDH mutations and patient
Table 13.2 Clinical studies of novel targeted therapies for advanced and metastatic Cholangiocarcinoma
Patients Line of OS PFS RR
Author Year (N) Agents Trial phase therapy Study arms (months) (months) (%)
FGFR
BGJ398
Javle et al. [74] 2018 61 Alone II Second Single NA 5.8 14.8
IDH
AG-120
Burris et al. [69] 2015 20 Alone I NA Single 5 NA 5
EGFR
Cetuximab
Borbath et al. [68] 2013 44 With GEM II First Single 13.5 NA 20.4
Gruenberger et al. 2010 30 With GEMOX Single 15.2 88 63
[72]
Malka et al. [78] 2014 150 I: GEMOX I: 12.4 I: 5.3 I: 29
13 Clinical Trials and Novel/Emerging Treatment

II: GEMOX + II: 11 II: 6 II: 23

cetuximab
Chen et al. [70] 2015 122 I: GEMOX I: 9.8 I:4.1 I:15
II: GEMOX + II: 10.6 II:6.7 II:27
cetuximab
Paule et al. [79] 2007 9 Second Single 7 4 22
Rubovszky et al. 2013 34 With GEMCAP Any line Single 15.7 8.6 17.6
[81]
(continued)
193
Table 13.2 (continued)
194

Patients Line of OS PFS RR

Author Year (N) Agents Trial phase therapy Study arms (months) (months) (%)
Panitumumab
Hezel et al. [73] 2014 31 With GEMOX II First Single in KRAS wild 20.3 10.6 45
type
Leone et al. [77] 2016 89 I: GEMOX I: 10.2 I: 4.4 I:18.2
II: GEMCOX + II: 9.9 II: 5.3 II:
panitumumab 26.7
In KRAS wild type
Sohal et al. [82] 2013 35 With GEM-IRINO Single in KRAS wild 12.9 9.7 31.4
type
Vogel et al. [83] 2015 93 With GEMCIS I: GEMCIS I: 21.4 I: 8.2 I: 39
II: GEMCIS + II: 12.8 II: 6.7 II: 45
panitumumab
In KRAS wild type
Jensen et al. [75] 2012 46 With GEMOX-CAP Any line Single 10 8.3 33
Erlotinib
Lee et al. [76] 2012 268 With GEMOX III First I: GEMOX I: 9.5 I: 4.2 I: 16
II: GEMOX + II: 9.5 II: 5.8 II: 30
erlotinib
Chiorean et al. [71] 2012 11 With docetaxel II Single 5.7 NA NA
Philip et al. [80] 2006 42 Alone Any line Single 7.5 2.6 8
HER2
Lapatinib
Ramanathan et al. 2009 17 Alone II Any line Single 5.2 1.8 0
[90]
J. D. Mizrahi et al.
Afatinib
Moehler et al. [87] 2015 9 With GEMCIS I First Single 7.7 5.2 NA
VGFR
Bevacizumab
Lyer et al. [99] 2018 50 With GEMCAP II First Single 10.2 8.1 72
Zhu et al. [93] 2010 35 With GEMOX Any line Single 12.7 7 40
Sorafenib
Luo et al. [106] 2017 44 Alone Prospective Single 5.7 3.2 53.9
El-Khoureiry et al. 2012 31 Alone II First Single 9 3 0
[85]
Moehler et al. [88] 2014 102 With GEM I: GEM + sorafenib I: 8.4 I: 3 I: 8
II: GEM II: 11.2 II: 4.9 II: 6
Lee et al. [86] 2013 39 With GEMCIS Single 14.4 6.5 12a
Bengala et al. [84] 2010 46 Alone Second Single 4.4 2.3 32.6
Sunitinib
13 Clinical Trials and Novel/Emerging Treatment

Yi et al. [92] 2012 56 Alone I Second Single 4.8 1.7 9

Neuzillet et al. [89] 2017 53 Alone II Single 9.6 5.2 15
Vanderanib
Santoro et al. [91] 2015 173 Alone II First Single 7.5 3.4 4
Cediranib
Valle et al. [100] 2015 124 With GEMCIS II/III First I: GEMCIS + I: 14.1 I: 8 I: 44
cediranib II: 11.9 II: 7.4 II: 19
II: GEMCIS
Regorafenib
Sun et al. [105] 2017 37 Alone II Second Single 5.6 3.6 10.7
Other less recognized pathways
MAPK
(continued)
195
Table 13.2 (continued)
196

Patients Line of OS PFS RR

Author Year (N) Agents Trial phase therapy Study arms (months) (months) (%)
Selumetinib
Bridgewater et al. 2016 12 With GEMCIS I First Single NA 6.4 37.5b
[96]
Bekaii-Saab et al. 2011 28 Alone II Any line Single 9.8 3.7 12
[95]
Trametinib
Loka et al. [98]. 2015 20 Alone II Second Single NA 2.4 5
Binimetinib
Lowery et al. [107] 2015 12 With GEMCIS I First Single 9.1 6.4 50
MK-2206
Ahn et al. [94] 2015 8 Alone II Second Single 3.5 1.7 0
c-MET
Cabozanitib
Goyal et al. [97] 2017 19 Alone II Second Single 5.2 1.8 0
Combined targeted therapy
Lubner et al. [103] 2010 49 Bevacizumab + erlotinib II First Single 9.9 4.4 12c
El-Khoueiry et al. 2014 34 Sorafenib + erlotinib Single 6 2 6
[101]
Jensen et al. [102] 2015 88 Gemox-CAP + panitumumab I: Gemox-CAP + I: 9.5 I: 6.1 I: 46
versus bevacizumab panitumumab II: 12.3 II: 8.2 II: 18
II: Gemox-CAP +
bevacizumab
Shroff et al. [104] 2017 25 Pazopanib + trametinib Ib Second Single 6.4 3.6 5d
a
Response was not evaluated in 6 patients
b
Response was not evaluated in 4 patients
c
Response was not evaluated in 4 patients
J. D. Mizrahi et al.

d
Response was not evaluated in 5 patients
13 Clinical Trials and Novel/Emerging Treatment 197

survival [110–112]. Burris et al. [69] conducted a phase I dose escalation and expan-
sion clinical trial to assess safety and tolerability to AG-120 in IDH1 mutant
ICC. Among 73 enrolled patients, 6% had partial response, 56% had stable disease,
with 40% 6-months PFS [113]. This agent is now being investigated in a placebo-­
controlled phase III trial.

DNA Repair Gene Pathway

DNA repair mechanisms are essential for maintaining genomic stability.

Dysregulation of DNA repair pathway is often associated with the accumulation of
several GAs and higher tumor mutational burden (TMB). In a recent report on 422
BTCs who underwent mutational profiling, DNA repair genes mutations occurred
in 45.2% ICC. In this trial, DNA repair genes were defined as ‘direct’ DNA repair
genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6,
PALB2, POLD1, POLE, PRKDC, RAD50, and SLX4) and “caretaker” genes (BAP1,
CDK12, KMT2C/MLL3, TP53, and BLM). Direct DNA repair gene alterations were
associated with a high tumor mutation burden (TMB) [114].
Poly (ADP-ribose) polymerases (PARPs), a family of proteins including PARP1
and PARP2, are activated by DNA damage and facilitate DNA repair [115]. PARP
inhibition (PARPi) has been an effective therapeutic strategy against tumors associ-
ated with DNA repair genes mutations. The preliminary results of a phase I study of
PARPi (veliparib) in combination with capecitabine and oxaliplatin for 17 solid
tumor patients included 6 cholangiocarcinoma patients of whom 3 (50%) experi-
enced stable disease [116].
Preclinical and clinical studies noted that highly mutated tumors harbor neo-
antigens, which make them more responsive to immune checkpoint inhibitors
[117–119]. PARP inhibitors alone or with checkpoint inhibitors are being inves-
tigated in ICC.

Fibroblast Growth Factor Receptor Pathway

FGFR is a complex pathway that consists of 4 FGFR transmembrane receptors

(FGFR1, FGFR2, FGFR3, and FGFR4) and 18 FGF ligands. Dysregulation of the
FGFR pathway including fusion, amplification, and mutation has been reported in
ICC, with a relatively high incidence of FGFR2 fusions in ICC (10–16%). FGFR
mutated ICC may represent a specific disease phenotype, with a younger patient
population and having a relatively indolent disease course [110]. Currently, several
FGFR-specific targeted agents are being investigated in ICC including infigratinib
(BGJ398), TAS-120, ARQ087, pemigatinib (INCB54828), JNJ425756493, and
PRN1371. Sixty-one patients with FGFR2 fusion (n = 48), mutation (n = 8), or
amplification (n = 3) were treated with infigratinib [74]. The overall response rate
was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3%
FGFR2 fusions only), and the estimated median progression-free survival was
198 J. D. Mizrahi et al.

5.8 months. Grade 3 or 4 treatment-related adverse events occurred in 25 patients

(41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-­
plantar erythrodysesthesia (4.9%).

EGFR and BRAF Mutations

Genetic aberrations in Epidermal Growth Factor Receptor (EGFR), BRAF, and

Her2/neu have been identified in BTC and are relatively uncommon in ICC (0–2%).
EGFR overexpression, on the other hand, has been reported in 11–27% of ICC
[120]. EGFR inhibitors including erlotinib, cetuximab, and panitumumab alone or
in combination with systemic chemotherapy have been investigated in several phase
II trials [68–83]. One phase III trial that investigated the addition of erlotinib to
gemcitabine and oxaliplatin showed an improved response rate without a survival
benefit. However, subgroup analysis showed that the improvement in response cor-
related with tumor KRAS status, only KRAS wt benefited from erlotinib [121].
Dabrafenib, a BRAF V600E mutation blockade, has been administrated in combina-
tion with trametinib, MEK inhibitor, for BRAF V600E mutated patients with a
promising response [122, 123]. Currently, there is an ongoing trial to study the
efficacy of this combination on rare tumors including BTC (NCT02034110) [124].

Vascular Endothelial Growth Factor Pathway

Prior studies showed that 54% of ICC patients have VEGF overexpression and this
may be an important target in this cancer. However, single-agent VGFR inhibitors
including sorafenib, sunitinib, and vandetanib failed to show any encouraging sur-
vival benefit in BTC patients. Recently, ABC-03 trial compared the efficacy of gem-
citabine and cisplatin with and without cediranib, a VGFR 1–3 inhibitor. The
addition of cediranib improved the overall response rate (44% vs. 19%, P = 0.004)
without any survival benefit. Further studies are required to identify predictive bio-
markers for VEGF inhibitors for better patient allocation in clinical trials [120].
Lubner et al. treated 53 eligible patients with BTC in a multicenter trial of bevaci-
zumab with erlotinib [103]. Of 49 evaluable patients, six (12%) had a confirmed
partial response. Stable disease was documented in another 25 patients (51%). Rash
was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median
OS was 9.9 months, and time to treatment progression was 4.4 months indicating
that VEGFR-directed therapies have potential benefit in this cancer.

Chromatin Remolding Pathway

Genetic aberrations in chromatin remolding genes comprising BAP1, ARID1A,

PBRM, and MLL have been noted in ICC [110]. BAP1 mutation in cholangiocarci-
noma associated with aggressive disease and poor response to standard systemic
13 Clinical Trials and Novel/Emerging Treatment 199

therapy and exploring BAP-1 targeted agents such as EZH2 inhibitors may have
therapeutic value [125]. Preclinical studies have indicated the efficacy of histone
deacetylase inhibitors such as vorinostat in CCA models although clinical efficacy
has yet to be demonstrated [126].

Immunotherapy

The role of immunotherapy in cancer treatment continues to progress and enormous

strides have been made in melanoma, renal cell carcinoma, urothelial cancer and
non-small cell lung cancer [127, 128]. Therapeutic strategies across various tumor
types that harness patient innate and acquired immune systems have included
immune checkpoint inhibitors, vaccines, and cytotoxic T lymphocyte therapy.
Immune checkpoint inhibitors, including anti-PD-(L)1 and anti-CTLA-4 antibod-
ies, have been particularly exciting in their propensities to lead to prolonged, dura-
ble responses in a subset of patients [129]. Predictive factors include TMB, PDL-1
expression and tumor immune infiltration [130].
Among BTCs, ICCs have fewer CD8+ T lymphocytes than extrahepatic CCAs
and gallbladder cancers [131]. Higher levels of infiltrating CD8+ T lymphocytes
have been shown to portend a more favorable prognosis in patients with colorectal
cancer and pancreatic cancer [132, 133]. A meta-analysis of 12 studies with over
2300 patients by Wang et al. did note a positive association between intraepithelial
CD8+, CD4+, and Foxp3+ T lymphocytes and OS in BTC patients, though this data
was not broken down by disease subtype [134].
In addition to the prognostic value of the immune infiltrate of malignancy, there
is also a predictive value in regards to response to checkpoint inhibition. In particu-
lar, tumors that possess what has been termed an “immune-inflamed phenotype” are
characterized by numerous infiltrating immune cells and a higher likelihood of
response to checkpoint inhibition [135]. Conversely, there is evidence that patients
whose tumors have fewer infiltrating CD8+ T lymphocytes do not respond as well
to checkpoint inhibition [136].
In May 2017, the FDA granted accelerated approval to pembrolizumab for the
treatment of patients with cancers who harbor high microsatellite instability (MSI-­
H) or mismatch repair deficiency (dMMR) in the metastatic, pre-treated setting.
While this approval indeed applies to patients with cholangiocarcinoma, the inci-
dence of MSI-H or dMMR in this population is very low, having been reported as
low as 1% and as high as 10% [137, 138]. The KEYNOTE-158 trial assessed
response to pembrolizumab among 21 patients with non-colorectal MSI-H tumors,
of whom 3 had cholangiocarcinomas. The overall response rate among the non-­
colorectal tumor patients was 42.9% with a disease control rate of 66.7% [139].
Recently, at the European Society of Medical Oncology (ESMO) annual meet-
ing, KEYNOTE-158 was presented. A total of 104 patients with BTC were treated
with single-agent pembrolizumab. The overall response rate was 5.8%: 17 pts.
(16%) had stable disease and the median PFS was 2.0 months while the median OS
was 9.1 months. The available data suggest that treatment with single-agent check-
200 J. D. Mizrahi et al.

point inhibitors in patients with advanced cholangiocarcinoma have very modest

clinical efficacy in an unselected population and should not be considered in the
absence of MSI-H or outside a clinical trial setting.
The role of vaccine therapy and adoptive immunotherapy with cytotoxic T lym-
phocytes (CTLs) for cholangiocarcinoma constitute alternative avenues of immuno-
therapy with heavy research interest. Peptide and dendritic cell vaccines rely on the
patient’s intrinsic immune system to activate an anti-tumor response, while adoptive
immunotherapy strategies, including CTLs, aim to expand reactive T-cells in the
laboratory prior to re-infusion into the patient.
A number of peptide and dendritic cell vaccines targeting antigens such as WT1
and MUC1 among others have been developed and studied in phase I and II trials.
Aruga et al. performed a phase I trial utilizing a four-peptide vaccine developed
from cancer-testis antigens that are commonly expressed in cholangiocarcinoma
[140]. The vaccine was administered weekly until disease progression in nine
patients with advanced, pre-treated BTC. It was well tolerated with median PFS and
OS similar to what is seen with cytotoxic chemotherapy. Notably, seven of the nine
patients were found to have peptide-specific T-cell responses as assessed by analysis
of peripheral T-cells. Early phase trials combining vaccines with chemotherapy in
either the metastatic or adjuvant setting have yielded mixed results [141, 142]. Kida
et al. analyzed tumor and peripheral blood samples from patients with BTCs, nine
of whom had ICCs, in order to assess the best candidates for tumor-associated anti-
gens as targets for immunotherapy [143]. By studying the tumor-infiltrating lym-
phocytes and peripheral lymphocytes from the patient samples and comparing these
to controls without BTCs, the authors found a number of potential epitopes that may
be suitable for vaccine therapy. Furthermore, they concluded that patients with high
peripheral blood lymphocyte counts, indicating a robust baseline immune system,
were the ones who benefited most from immunotherapy.
The efficacy of adoptive immunotherapy in ICC with ex-vivo expansion of cyto-
toxic T lymphocytes and subsequent re-introduction to the patient has been studied
in the setting of adjuvant therapy after surgical resection [142]. Shimizu et al. found
that combination of this adoptive immunotherapy approach combined with postop-
erative dendritic cell vaccine yielded a median PFS increase from 7.7 months to
18.3 months and a median OS increase from 17.4 months to 31.9 months when
compared to surgery alone. An ongoing clinical trial at the National Cancer Institute
is assessing the efficacy of infusing tumor-infiltrating cytotoxic T lymphocytes
expanded ex vivo with or without pembrolizumab in a variety of advanced solid
tumors including cholangiocarcinoma (ClinicalTrials.gov ID: NCT01174121).
While immunotherapy has revolutionized the treatment of many advanced malig-
nancies over the past several years, the jury is still out in regards to its future role for
patients with ICC. Adoptive immunity strategies involving infusing cytotoxic
tumor-infiltrating lymphocytes may offer some value, though more data are needed
to confirm this. Thus far, peptide and dendritic cell vaccines have yet to demonstrate
significant efficacy. Although the early results of single-agent checkpoint inhibitors
in cholangiocarcinoma have been fairly disappointing, combinatorial strategies
13 Clinical Trials and Novel/Emerging Treatment 201

Fig. 13.1 Unresectable

intrahepatic
cholangiocarcinoma
NGS
Localized Disseminated

Liver-directed Systemic
therapy + consider Chemotherapy
systemic
chemotherapy

Progressive disease:
Add targeted agents based on
molecular phenotype

with multiple checkpoint inhibitors and checkpoint inhibitors with targeted thera-
pies are the next frontier of investigation and hold considerable promise.
In the past decade, there has been an abundance of therapeutic options for ICC
and a rational, multidisciplinary, sequential approach is indicated (Fig. 13.1) Liver-­
directed therapies, systemic chemotherapy, and targeted therapies are changing the
treatment paradigm of ICC and offer considerable promise towards improving the
clinical outcome of this cancer.

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Index

A Antagonizing mechanisms, 177

ACTICCA-1 trial, 152 Anti-angiogenic therapy, 46
Adjuvant capecitabine for biliary tract cancer,
152
Adjuvant chemotherapy, 108, 109 B
Adjuvant systemic therapy BILCAP trial, 72, 109, 152, 184
ACTICCA-1 trial, 152 Bile duct adenomas, 98, 99
at-risk nodal stations, 153 Bile duct cysts, 6, 7
BILCAP trial, 152 Bile duct tumors, 5
biliary tract cancers, 152 Bile ducts carcinogenesis, 169
complications, 152 Biliary cystadenoma, see Mucinous cystic
gemcitabine and cisplatin, 153 neoplasms of the liver
local failure, 153 Biliary epithelial cells, 168
multi-disciplinary evaluation, 153 Biliary intraepithelial neoplasia (BilIN), 5, 99,
with positive margins or nodal metastases, 102
152 Biliary tract cancer (BTC), 11–13, 16, 68,
PRODIGE 12-ACCORD18 Phase III trial, 71–73, 77, 114, 116, 152, 153, 161
152 Bolus tracking technique, 54
Adjuvant therapy, 71, 72 Brush cytology, 97, 98
Adoptive immunotherapy, 200
Advanced Biliary Cancer (ABC)-02 trial, 46
AJCC 7th edition staging system, 27, 30 C
AJCC 8th edition staging system, 30–32 CA 19-9, 13, 14
AJCC/UICC 6thed TMN liver cancer staging Cancer-associated fibroblasts (CAF), 174–176
system, 24 Carcinoembryonic antigen (CEA), 14
AJCC/UICC 7thedition staging sytem, 33 Caroli’s disease, see Type V bile duct cysts
AJCC/UICC 8thedition staging sytem, 33 Central fibrous stroma, 16
Alcohol, 8 Charged particle therapy, 158, 159
American Joint Committee on Cancer/Union Chemoembolization, 146
for International Cancer Control Cholestasis, 11, 168, 169, 172, 173
(AJCC/UICC) TMN staging Chromatin remolding pathway, 198
system, 22, 23, 25–26 Cirrhosis, 7

© Springer Nature Switzerland AG 2019 209

T. M. Pawlik et al. (eds.), Intrahepatic Cholangiocarcinoma,
https://doi.org/10.1007/978-3-030-22258-1
210 Index

Clinical diagnosis DNA repair gene pathway, 197

contrast-enhanced US, 14, 15 Doxorubicin eluting beads-transarterial
C-tissue diagnosis, 17, 18 chemoembolization (DEB-TACE),
CT scan, 16, 17 46, 137, 139–142
(18) F-fluorodeoxyglucose positron
emission tomography, 16
liver function tests and tumor markers, 13 E
magnetic resonance imaging, 16, 17 EGFR and BRAF mutations, 198
ultrasonography, 14 Epidemiology, 1–3, 12
Clinical presentation, 13 Epigenetic modifications, 171
Clonorchiasis, 5, 8
Colorectal cancer, 14, 190, 199
Combined hepatocellular-cholangiocarcinoma, F
7, 99, 101 Falciform ligament, 86
Combined multimodality therapy, 130 Fat suppression, 54
Common lymphatic endothelial and vascular Fibroblast growth factor receptor 2 (FGFR2)
endothelial receptor-1 fusion inhibitors, 116, 117
(CLEVER-1), 178 gene fusion products, 171
Computed tomography (CT) pathway, 197
arterial phase, 54 Fibroblast specific protein-1, 171
delayed phase, 54 Fibrous stroma, 14–16, 18, 54, 57, 58, 168
intraductal growing cholangiocarcinoma, 62 First-line palliative chemotherapy
intrahepatic cholangiocarcinoma, 54 5-FU with oxaliplatin (FOLFOX), 113
mass-forming cholangiocarcinoma, 56, 57 gemcitabine and cisplatin, 111, 112
periductal-infiltrating cholangiocarcinoma, gemcitabine with capecitabine, 113
59, 60 gemcitabine with carboplatin, 112
portal venous phase, 54 GEMOX, 112
Conformal radiotherapy, 156 Flat dysplasia, 102
Conjugated bile acids (CBAs), 172 Fluorescent in-situ hybridization (FISH)
Conventional transarterial chemoembolization testing, 98
(cTACE), 138–140, 189, 190 (18) F-fluorodeoxyglucose positron emission
See also Lipiodol-based tomography (FDG-PET), 16
chemoembolization Future liver remnant (FLR), 68
Cox proportional hazard model, 23 5-FU with oxaliplatin (FOLFOX), 113
Cyclooxygenase (COX)-2 production, 170

G
D Gemcitabine with oxaliplatin (GEMOX), 112
D drug-eluting bead TACE (DEB-TACE), 189, Glucose transporter type 1 (GLUT-1), 56
190
Deep lymphatic drainage, 86
Defective DNA mismatch repair, 103 H
Definitive radiotherapy Hepatocellular carcinoma (HCC), 12, 14, 16,
charged particle therapy, 158, 159 21, 23, 30, 58, 77, 79, 95, 96, 100,
conformal radiotherapy, 156 101, 123–125, 130, 131, 158, 159
normal tissue complication probability Hepatic arterial infusion (HAI) chemotherapy,
model, 156 46, 190, 191
outcomes, 153–156 Hepatic artery chain, 86
stereotactic ablative radiotherapy, 157 Hepatobiliary phase imaging, 55
stereotactic body radiotherapy, 157 Hepatocyte growth factor (HGF), 170
Delayed enhancement pattern, 16 Hepatolithiasis, 6
Diaphragmatic lymphatic plexus, 86 Hepatotoxicity, 156
Distal (dCCA) cholangiocarcinoma (dCCA), 11 Heterogeneous hyperenhancement, 15
Index 211

Heterogeneous hypoenhancement, 15 J
Hilar periductal-infiltrating Japanese staging systems, 22
cholangiocarcinoma, 59
Homogeneous hyperenhancement, 15
Hypovascular mass with progressive K
concentric filling, 16 Klatskin tumor, 3

I L
ICC staging system, 22 Lipiodol-based chemoembolization, 136, 137
laparoscopy, 38 Liver Cancer Study Group of Japan (LCSGJ)
lymphadenectomy, 32, 35–38 staging system, 22, 24
tumor markers, 39–41 Liver directed loco-regional therapies
IDH-1 and IDH-2 pathway, 192 hepatic arterial infusion chemotherapy,
IDH1/2 inhibitor, 117 190, 191
IL-6-STAT3 signaling pathway, 170 liver transplantation, 188, 189
Immune cells, 168, 177, 179, 199 radiation therapy, 184, 188
Immune checkpoint inhibitors, 199 radioembolization, 190
Immune-inflamed phenotype, 199 radiofrequency ablation, 191
Immunotherapy, 199, 200 trans-arterial chemoembolization, 189, 190
Inducible nitric oxide synthase (iNOS), 170 Liver flukes, 3, 5
Inflammation Liver transplantation, 188, 189
bile ducts carcinogenesis, 169 Liver-directed radiotherapy, 151
biliary epithelial cells, 168 adjuvant systemic therapy
cyclooxygenase (COX)-2 production, 170 ACTICCA-1 trial, 152
epigenetic modifications, 171 at-risk nodal stations, 153
ERK1/2, 169 BILCAP trial, 152
FGFR2 gene fusion products, 171 biliary tract cancers, 152
gene mutations, 171, 172 complications, 152
hepatocyte growth factor, 170 gemcitabine and cisplatin, 153
IL-6-STAT3 signaling pathway, 170 local failure, 153
inducible nitric oxide synthase, 170 multi-disciplinary evaluation, 153
interleukin (IL)-6, 169 PRODIGE 12-ACCORD18 Phase III
MET activation, 170 trial, 152
MET amplification, 170 PRODIGE12-ACCORD 18 trial, 152
mitogen-activated protein kinases (MAPK) with positive margins or nodal
pathway, 169 metastases, 152
p38, 169 definitive radiotherapy
S100A4, 171 charged particle therapy, 158, 159
signaling perturbations, 171, 172 conformal radiotherapy, 156
Interleukin (IL)-6, 169 normal tissue complication probability
International Classification of Disease for model, 156
Oncology (ICD-O), 2–3 outcomes, 153–156
Intraductal calculi, 54 stereotactic ablative radiotherapy, 157
Intraductal growing cholangiocarcinoma stereotactic body radiotherapy, 157
computed tomography, 62 future aspects, 161
magnetic resonance treatment delivery, 161
cholangiopancreatography, 62 treatment planning, 159–161
ultrasonographic manifestation, 62 Locoregional therapy, 136
Intraductal growth sub-type, 41–43 Logarithm of the ratio of the number of
Intraductal papillary neoplasm of the bile duct metastatic lymph nodes and the
(IPNB), 5, 6, 102 number of negative lymph nodes
Intraductal papillary neoplasms (IPMNs), 102 (LODDS), 92
212 Index

Lymph node chains, 86 therapeutic mechanism, 125

Lymph node drainage, 34, 86 vs. RFA, 127, 128
Lymph node metastasis, 68 Mild peripheral rim enhancement with central
Lymph node ratio (LNR), 27, 92 hypodensity, 16
Lymphadenectomy, 32, 35–38 Mitogen-activated protein kinases (MAPK)
extension, 90, 91 pathway, 169
factor, 88 Molecular pathogenesis
heterogeneous outcomes, 88 cholestasis, 172, 173
in ICC patients with cirrhosis, 90, 91 inflammation
lymph-nodal evaluation, 88 bile ducts carcinogenesis, 169
radiological assessment, 89 biliary epithelial cells, 168
timing, 88 cyclooxygenase (COX)-2 production,
Lymphatic endothelial cells (LEC), 177–178 170
Lymphoepithelial-like cholangiocarcinoma, 97 epigenetic modifications, 171
ERK1/2, 169
FGFR2 gene fusion products, 171
M gene mutations, 171, 172
Macrophage mannose receptor (MR), 178 hepatocyte growth factor, 170
Magnetic resonance cholangiopancreatography IL-6-STAT3 signaling pathway, 170
(MRCP) inducible nitric oxide synthase, 170
biliary system, 55 interleukin (IL)-6, 169
DWI, 55 MET activation, 170
intraductal growing cholangiocarcinoma, MET amplification, 170
62 mitogen-activated protein kinases
mass-forming cholangiocarcinoma, 58 (MAPK) pathway, 169
periductal-infiltrating cholangiocarcinoma, p38, 169
61 S100A4, 171
slow-moving fluids, 55 signaling perturbations, 171, 172
Magnetic resonance imaging (MRI) multiple paracrine signals, 168
bolus tracking technique, 54 tumor microenvironment
diffusion weighted imaging, 54 CAF, 174–176
fat suppression, 54 immune cells, 177
hepatobiliary contrast agents, 55 LECs, 177–178
intraductal growing cholangiocarcinoma, TAMs, 176, 177
62 Mucinous cystic neoplasms of the liver, 99,
mass-forming cholangiocarcinoma, 57, 58 102
periductal-infiltrating cholangiocarcinoma, Multiple peribiliary stem cell niches, 11
61
T1-weighted sequence, 54
T2-weighted sequence, 54 N
Major vascular invasion, 75 National Cancer Center of Japan (NCCJ)
Mass forming type, 41–43 staging system, 22
Mass-forming intrahepatic Neoadjuvant therapy, 77–79
cholangiocarcinoma Nodal basin
with capsular retraction, 63 classification, 87
with central enhancement, 63 ESMO recommendation, 87
computed tomography, 56, 57 harvesting, 89
magnetic resonance imaging, 57, 58 LODDS and LNR, 92
positron emission tomography, 59 lymph node drainage, 86
ultrasonographic manifestation, 56, 57 lymphadenectomy
MET amplification, 170 extension, 90, 91
Microwave ablation (MWA) factor, 88
Index 213

heterogeneous outcomes, 88 Percutaneous ablation

in ICC patients with cirrhosis, 90, 91 combined multimodality therapy, 130
lymph-nodal evaluation, 88 complications, 128–130
radiological assessment, 89 indications, 124
timing, 88 limitation, 130
staging systems, 87, 88 MWA
Non-alcoholic fatty liver disease (NAFLD), 8, therapeutic mechanism, 125
12, 168 vs. RFA, 127, 128
Normal tissue complication probability outcomes, 129
(NTCP) model, 156 overall survival rate, 130
Notch intracellular domain (NICD), 173 Prognosticpfactors, 129
RFA
therapeutic mechanism, 125
O vs. MWA, 127, 128
Obesity, 3, 7, 8 survival outcomes, 126
Oil-based emulsion, 136, 137 tumor size, 130
“Onion-skin” fibrosis, 103 vs. surgical resection, 129
Orthotopic liver transplantation (OLT), 79 Periductal infiltrating (PI) type, 41–43
Periductal-infiltrating cholangiocarcinoma
computed tomography, 59, 60
P magnetic resonance imaging, 61
Paget’s theory, 168 ultrasonographic manifestation, 59
Pancreatic adenocarcinomas, 100 Perihilar cholangiocarcinoma (pCCA), 3, 11
Pancreatic intraepithelial neoplasia (PanIN), Peripheral irregular rim-like enhancement, 15
102 Portal lymph node dissection, 32, 34
Pathogenetic mechanisms, 168 Portal lymphadenectomy, 72
Pathologic assessment Portal vein embolization (PVE), 68
clear cell ICC, 96, 97 Portal vein invasion, 61
cytologic and brush examination, 97, 98 Positron emission tomography (PET)
differential diagnosis distant metastasis, 56
bile duct adenomas, 98, 99 glucose transporter type 1, 56
colorectal adenocarcinomas, 100 glucose utilization, 55
combined hepatocellular-­ mass-forming cholangiocarcinoma, 59
cholangiocarcinoma, 99, 101 Post embolic syndrome, 137, 146
HCC, 100 Posterior periportal chain, 86
lobular and ductal adenocarcinomas, Primary liver cancer, 1
100 Primary sclerosing cholangitis (PSC), 6,
non-small cell carcinomas, 100 103, 184
pancreatic adenocarcinomas, 100 PRODIGE 12-ACCORD18 Phase III trial, 152
upper gastrointestinal cancers, 100 Prognosis
glandular and squamous differentiation, intraductal growth sub-type, 41–43
96, 97 locally advanced unresectable and
lymphoepithelial-like cholangiocarcinoma, 97 metastatic ICC, 46
molecular assessment, 103 margin status, 44
mucinous morphology, 96, 97 mass forming type, 41–43
precursor lesions, 102, 103 nomograms, 46, 47
risk factors, 102 periductal infiltrating type, 41–43
signet ring cell morphology, 96, 97 periductal-infiltrating type, 42
surgical resections, 101 progression free survival, 46
tubular or acinar growth pattern, 96, 97 recurrences, 44, 45
typical immunohistochemical staining Programmed-death cell protein (PD) receptor
pattern, 96 and ligand (PD-1/PD-L1), 177
214 Index

R tumor size and multifocal disease, 73–75

Radiation therapy, 184, 188 Surveillance, Epidemiology and End Results
Radiation-induced liver disease (RILD), 156 (SEER) database study, 22, 24
Radioembolization, 146, 190 Systemic chemotherapy, 191, 192
Radiofrequency ablation (RFA), 191 Systemic therapy, 135
therapeutic mechanism, 125 adjuvant chemotherapy, 108, 109
vs. MWA, 127, 128 FGFR2 fusion inhibitors, 116, 117
Resectability, 68 first-line palliative chemotherapy
Rim-like enhancement pattern, 16 5-FU with oxaliplatin (FOLFOX), 113
Risk factors, 12 gemcitabine and cisplatin, 111, 112
gemcitabine with capecitabine, 113
gemcitabine with carboplatin, 112
S GEMOX, 112
S100A4, 171 IDH1/2 inhibitor, 117
Satellite lesions, 74, 130 second line palliative chemotherapy
Second line palliative chemotherapy bevacizumab with erlotinib, 116
bevacizumab with erlotinib, 116 in combination with biologic
in combination with biologic agents, 115 agents, 115
gemcitabine with EGFR inhibitors, 115 gemcitabine with EGFR inhibitors, 115
GEMOX with VEGF inhibitors, 115–116 GEMOX with VEGF Inhibitors,
Selective internal radiation therapy, 137 115–116
Serum alpha-fetoprotein (AFP), 14
Signet ring cell morphology, 96, 97
Smoking, 8 T
Sonic Hh variant, 173 Targeted therapy
Staging laparoscopy, 38 chromatin remolding pathway, 198
Stereotactic ablative radiotherapy DNA repair gene pathway, 197
(SABR), 157 EGFR and BRAF mutations, 198
Stereotactic body radiation therapy (SBRT), fibroblast growth factor receptor
72, 157, 184 pathway, 197
Superficial lymphatic pathway, 86 IDH-1 and IDH-2 pathway, 192
Surgical treatment immunotherapy, 199, 200
future liver remnant, 68 vascular endothelial growth factor
laparoscopic intraoperative ultrasound, 68 pathway, 198
liver transplantation, 79 Trans-arterial chemoembolization (TACE), 46,
long-term outcomes 63, 64, 130, 189, 190
conditional survival, 77 Transarterial radioembolization (TARE), 137,
intrahepatic recurrence, 76–77 141, 143–145
long term survivors, 77 Transarterial therapy
overall survival, 76 conventional transarterial
repeat hepatectomy, 76 chemoembolization, 138–140
major vascular invasion, 75 drug-eluting bead chemoembolization, 137
neoadjuvant therapy, 77–79 drug-eluting bead transarterial
nodal disease, 72–73 chemoembolization, 139–142
patient selection, 68 goal of, 136
portal vein embolization, 68 lipiodol-based chemoembolization, 136,
resectability, 68 137
surgical margin status long term outcomes/radiographic tumor
adjuvant therapy, 71, 72 response, 144
vs. extent of resection, 71 neoadjuvant approach, 136
nodal disease, 71 off label use, 137
R0 vs R1, 69 oil-based emulsion, 136, 137
width of negative margin, 69, 71 quantity and quality of life, 136
Index 215

radioembolization, 146 intraoperative, 54

selection and exclusion criteria, 137 with jaundice or right upper quadrant pain,
selective transarterial treatments, 136 54
technical considerations, 138 mass-forming cholangiocarcinoma, 56, 57
transarterial radioembolization, 137, 141, periductal-infiltrating cholangiocarcinoma,
143–145 59
Tubular/acinar growth pattern, 96, 97 Univariate and multivariate hazard ratios,
Tumor markers, 39–41 27–29
Tumor reactive stroma (TRS), 167 Unresectable intrahepatic cholangiocarcinoma,
Tumor-associated lymphangiogenesis, 178 63, 64, 201
Tumor-associated macrophages (TAM), 176, Upper gastrointestinal cancers, 100
177
Type V bile duct cysts, 7
Typical immunohistochemical staining pattern, V
96 Vaccine therapy, 200
Vascular endothelial growth factor pathway,
115, 198
U Viral hepatitis, 7, 8, 101
Ultrasonography
free of radiation risk, 54
intraductal growing cholangiocarcinoma, Y
62 Yttrium-90 labeled microspheres, 137