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Part IX
Interventional Oncology
Transarterial Chemoembolization
PaulHaste andMatthewS.Johnson
34
Pathophysiology
Liver cancer can be either primary or metastatic. Metastatic
disease is more common than primary liver cancer; the most
common metastatic tumors are breast, lung, and colon/rectum [1]. Transarterial embolization (TAE) and chemoembolization (TACE) play a larger role in the treatment of primary
liver cancer than they do treating hypervascular metastatic
disease such as neuroendocrine tumor, metastatic renal cell
carcinoma, and rarely pancreatic and colon cancer. This
chapter will focus on primary liver cancer.
Hepatocellular carcinoma (HCC) accounts for 70–90% of
all primary liver cancer worldwide with the remainder being
either cholangiocarcinoma (CCA) or mixed HCC/CCA.
Primary liver cancer is one of the ve most frequently diagnosed cancers in the world and is the second leading cause of
cancer death worldwide [2]. It is estimated that there will be
nearly 41,000 new cases of primary liver cancer diagnosed in
the USA in 2017 with the total number of deaths related to
liver cancer close to 29,000. The incidence has more than
tripled since 1980 [3]. HCC most often occurs in the setting
of chronic liver disease. The most common risk factors are
shown in Table34.1 [4].
Key Point
Hepatitis B virus infection and aatoxin exposure can
lead to HCC without the presence of cirrhosis.
P. Haste
Indiana University School of Medicine, Department of Radiology,
Indianapolis, IN, USA
e-mail: phaste@iupui.edu
M. S. Johnson (
Indiana University School of Medicine, Department of Radiology,
Indianapolis, IN, USA
Indiana University School of Medicine, Department of Radiology
and Imaging Sciences, Indianapolis, IN, USA
e-mail: matjohns@iupui.edu
*)
Clinical Indications
HCC is often asymptomatic, which may lead to late diagnosis. For this reason, the American Association for the Study
of Liver Disease (AASLD) and the European Association
for the Study of Liver Disease (EASL) recommend routine surveillance screening for high-risk patients [5, 6].
The AASLD recommends abdominal sonography every
6–12months [5]. Institutional or regional preference may
favor multiphase contrast-enhanced CT or MRI of the
abdomen over ultrasound [7]. Alpha-fetoprotein (AFP) is a
serum tumor marker that may be elevated in patients with
HCC and can be useful for surveillance and response monitoring. However, many HCCs do not express elevated AFP;
thus the AASLD does not recommend its routine isolated
use for surveillance [5].
HCC does not have a single characteristic appearance at
US.The tumor is more likely to be hypoechoic but can be
hyperechoic or has mixed echogenicity. Suspicious masses
require further work-up with multiphase contrast-enhanced
CT or MRI [8]. A diagnosis of HCC can be established without tissue biopsy when a mass demonstrates the characteristic features of HCC on CT or MRI. Those characteristics
include arterial phase hyperenhancement (Fig. 34.1) with
washout (tumor darker than background liver) during the
portal venous or delayed imaging (Fig.34.2). In 2011, the
American College of Radiology ofcially launched the
LI-RADS (Liver Imaging Reporting and Data System)
reporting system for interpreting CT and MRI for patients at
risk for HCC [9]. A summary of the updated 2014 LI-RADS
algorithm is shown in Fig.34.3.
Multiple HCC treatment algorithms exist. The Barcelona
Clinic Liver Cancer (BCLC) staging system is the most
widely accepted staging system, and its treatment algorithm is the one most commonly used in the Western hemisphere [11]. It takes into account performance status,
Child-Pugh score, tumor size, number of tumors, vascular
invasion, lymph node spread, and/or metastatic disease
(Fig.34.4).
© Springer International Publishing AG, part of Springer Nature 2018
N. A. Keefe et al. (eds.), IR Playbook, https://doi.org/10.1007/978-3-319-71300-7_34
381
382
P. Haste and M. S. Johnson
Table 34.1 Risk factors for HCC
Risk factor Key points
Hepatitis B virus Leading risk factor worldwide, accounting for
Hepatitis C virus In the USA, chronic HCV infection is the
Nonalcoholic fatty
liver disease
(NAFLD)
Alcohol Heavy alcohol intake increases the risk of HCC
Aatoxin Carcinogens produced by Aspergillus are
50% of cases of HCC
leading cause of HCC
Leading cause of chronic liver disease in the
USA.NAFLD can lead to nonalcoholic
steatohepatitis (NASH), which can cause
cirrhosis, putting patients at risk for HCC
through the development of cirrhosis
thought to mutate tumor suppressor gene p53.
Most cases are seen in sub-Saharan Africa and
eastern Asia
Key Point
Child-Pugh score is based on ve clinical measures
(higher score, most severe derangement):
• Total bilirubin
• Serum albumin
• Prothrombin time
• Ascites
• Hepatic encephalopathy
Conventional Therapy
Medical Management
Historically, most systemic therapies have been ineffective in the
treatment of HCC [12]. Sorafenib and regorafenib (oral multikinase inhibitors) are the only systemic medications approved for
the treatment of HCC.In controlled trials, sorafenib has shown a
nearly 3-month improvement in overall survival (OS) when
compared to placebo [13]. Sorafenib is usually reserved for
patients with advanced state disease (BCLC C) given the relatively minor survival benet and moderate side effect prole.
Immunotherapy for HCC is currently being evaluated in multiple
studies. Nivolumab, an immune checkpoint inhibitor, has shown
promising results in both phase I and phase II clinical trials [14].
Fig. 34.1 Axial image from the arterial phase of a contrast-enhanced
CT scan demonstrating a circumscribed enhancing tumor (white arrow)
Fig. 34.2 Delayed-phase contrast-enhanced CT scan demonstrating
washout (i.e., darker than background) of the arterial phase-enhancing
tumor. These characteristic imaging ndings allow a diagnosis of HCC
without tissue biopsy
Surgical Management
Surgery plays a vital role in the management of HCC as resection and liver transplantation are considered curative therapies
for this disease. Surgical resection is the rst-line, potentially
curative treatment for small HCC (<3cm) in patients with preserved liver function. Child-Pugh class A patients with small
HCC may have a 70% 5-year overall survival rate after surgical resection [15]. Unlike transplantation, these patients
require continued surveillance because of a sustained lifelong
risk of recurrence. Liver transplantation has emerged as a
curative option for select patients with HCC [16].
Transplantation is an ideal treatment for HCC because it
removes the tumor and also replaces the underlying damaged
liver with healthy tissue. Early results for transplantation
yielded unacceptable rates for posttransplant recurrence leading to [17] the development of the Milan criteria. These allow
Key Point
Milan criteria for liver transplantation:
1. Single HCC not exceeding 5cm
2. Up to three tumors with the largest not exceeding 3cm
3. No macrovascular invasion (i.e., portal vein
involvement)
34 Transarterial Chemoembolization
383
Observation in high-risk patient
Treated observation
Definitely
benign
ALGORITHM
“Washout”
“Capsule”
Threshold growth
Untreated observation
Probably
benign
Neither definitely nor
probably benign
Diameter (mm):
None:
One:
≥ Two:
Probable malignancy, not specific for HCC
Arterial phase
hypo- or iso-
enhancement
≥ 20 ≥ 20
< 20
LR-3
LR-3 LR-4 LR-4
LR-4
LR-3 LR-3 LR-3
< 10 10-19
LR-4LR-4
Tumor in vein
Arterial phase
hyper-
enhancement
LR-4
LR-5
LR-5
LR-MLR-Treated LR-1 LR-2
LR-5V
LR-4
LR-5
LR-5
Apply ancillary features and then tie-breaking rules to adjust category
LR-4
Observations in this cell are categorized LR-4 except as follows:
LR-5
LR-5g, if there is Ï 50% diameter increase in £ 6 months. These observations are equivalent to OPTN 5A-g.
LR-5us, if there is both “washout” and visibility as discrete nodules at antecedent surveillance ultrasound, per AASLD HCC criteria.
Fig. 34.3 LI-RADS 2014 diagnostic algorithm (Adapted from ACR LI-RADS content at http://www.acr.org/Quality-Safety/Resources/LIRADS
[10])
HCC
Very Early Stage (0)
Single <2 cm
Child-Pugh A, PS 0
Early Stage (A)
Single or ≤3 nodules <3 cm
Child-Pugh A-B, PS 0
Intermediate Stage (B)
Large multinodular
Child-Pugh A-B, PS 0
Advanced Stage (C)
Portal Invasion
Extrahepatic spread
Child-Pugh A-B, PS 1-2
Potential candidate
for liver
Single
≤ 3 nodules
transplantation
Yes
Portal pressure
bilirubin
No
Normal Increased
Associated
diseases
No Yes
Ablation Ablation TACE Sorafenib
Resection Transplant
Terminal Stage (D)
Child-Pugh C, PS 3-4
Best supportive
care
Fig. 34.4 Barcelona Clinic Liver Cancer staging for hepatocellular carcinoma treatment (Adapted from Ref. [11])
384
P. Haste and M. S. Johnson
for appropriate selection of HCC patients who will have the
best outcomes following transplantation [18]. Other guidelines have been described, such as the UCSF criteria; however
the Milan criteria are the most utilized.
Interventional Therapy
The majority of the liver’s blood supply is via the portal vein
(~75%) with the remainder (~25%) coming from the hepatic
artery. Liver tumor(s) will predominantly derive their blood
supply from the hepatic artery. Transarterial embolization
(TAE) and chemoembolization (TACE) are image-guided
procedures wherein embolic agents with or without chemotherapeutic drugs are injected directly into the arteries supplying the tumor(s). The unique dual blood supply in the
liver allows arterial embolization to selectively injure the
tumors, while the portal vein supplies surrounding unaffected parenchyma. This unique vascular anatomy led to the
use of bland, i.e., no chemo, hepatic artery embolization in
the 1980s, demonstrating improved outcomes when compared to systemic therapies [19, 20].
TACE was rst described in the early 1980s in Japan.
Early studies evaluated intra-arterial delivery of a chemotherapeutic agent (Mitomycin C) combined with a watersoluble encasing agent (ethyl cellulose) to multiple different
tumor types [21]. The theory behind TACE is that the chemotherapy drug can be administered directly into the artery supplying the tumor, lessening systemic levels of the drug.
In 2002, Llovet etal. and Lo etal. independently published
randomized control trials (RCTs) demonstrating improved overall survival in patients with intermediate-state HCC (BCLC B)
when using TACE versus best supportive care [22, 23]. A 2002
meta-analysis of existing RCTs concluded that TACE signicantly improved 2-year overall survival when compared to conservative management [24, 25]. A recent controlled trial showed
equivalent outcomes of TACE versus TAE in HCC patients [25].
Table 34.2 Example of TACE regimen
Conventional TACE (cTACE)
Chemotherapy
25–50mg of
doxorubicin with
or without
10mg of
Mitomycin C (and
cisplatin)
Table 34.3 Pre-procedure imaging and labs
Imaging Laboratory data
1. Multiphase contrastenhanced CT or MRI
(refer to Fig.34.2)
Embolic
agent Chemotherapy Embolic agent
Lipiodol
(2:1 mixture
with
chemo)
Drug-eluting embolic TACE
(DEE-TACE)
50–75mg of
doxorubicin (per
vial)
1. CBC (particular focus on platelets
and WBC)
2. CMP (particular focus on AST,
ALT, total bilirubin, albumin, and
creatinine)
3. INR
4. Alpha-fetoprotein (helpful to have as a
baseline to help understand response.
Will not be elevated in all cases)
2 vial of
40–300μ
microspheres
Multiple studies have compared the two different options. In
2010 the PRECISION V study, an international, multicenter
RCT, demonstrated DEE-TACE to be safe, effective, and
equivalent to cTACE.It showed a signicant decrease in systemic side effects when using DEE-TACE [26]. A 2013 metaanalysis concluded comparable safety proles with improved
response and 1-year and 2-year survival for DEE-TACE [27,
28]. The choice of treatment is based on operator preference
and determined on a case-by- case basis (Table34.2).
Most patients with HCC have some level of underlying
liver disease. Understanding the patient’s baseline liver function is very important as poor liver function may necessitate
decreased chemotherapy dose or preclude treatment altogether. The specic regimen changes in higher-risk patients
are institutionally dependent and usually based on performance status and total bilirubin, white blood cell count, and
other serum measures (Table34.3).
Key Point
Indications to treat HCC with TACE:
1. Downstage for transplant (i.e., shrink the tumor so
the patient falls within transplant criteria).
2. Keep patients within transplant criteria while awaiting transplant.
3. Palliative treatment for those who are not transplant
candidates.
TACE is generally administered in one of two ways: (1)
conventional TACE (cTACE) in which chemotherapy and
iodized oil are infused followed by a temporary or permanent
embolic agent or (2) drug-eluting embolic TACE (DEE- TACE)
wherein chemotherapy such as doxorubicin or epirubicin is
slowly released from microspheres injected into the tumor.
The How To
At most institutions, the patient’s imaging will be
reviewed at a multidisciplinary tumor board, with collaborative effort between IR, oncology, and hepatobiliary transplant surgery in order to devise the best
treatment plan for each individual patient. Once the
decision to treat with transarterial embolotherapy has
been made, here is what you expect to see when you
walk into the procedure suite.
1. Most TACE will be performed through a right
transfemoral artery approach. Some institutions
prefer a transradial artery approach, particularly in
2. The Seldinger approach is used to access the artery
of choice under ultrasound guidance. (Refer to
Chap. 8 for more information.)
(continued)
34 Transarterial Chemoembolization
385
3.
catheter are advanced through a vascular sheath to
selectively catheterize the celiac artery. These steps
can be made easier by prior review of pre-procedure
CT or MRI with special attention to anatomic variants and vascular stenoses. (Refer to Chap. 6 for
more information.)
4. Celiac and common hepatic arteriograms are
performed to delineate downstream anatomy and
34.5) the potentially hypervascu-
lar tumor(s).
5. A coaxial microcatheter and wire will advanced
through the base catheter into the desired arteries
supplying the tumor(s). Multiple arteriograms in
different obliquities are often performed to outline
34.6).
Roadmap guidance may be used.
6. Most modern angiographic systems can perform
cone beam CT imaging; this creates an intra-procedural CT image during arterial contrast injection
and potential for detecting tumors with higher sensitivities than MRI or conventional CT [28].
7. The embolic mixture is slowly injected under con-
physicians may add Gelfoam (a temporary embolic
agent) or permanent microspheres after administra-
-
34.7).
8. All catheters are removed and disposed of in a special
chemotherapy bin. The access sheath is then removed,
and hemostasis is achieved at the arteriotomy site
using a closure device or manual compression.
Fig. 34.5 Common hepatic arteriogram of a 63-year-old man with a right hepatic lobe HCC.Early phase (a) delineating the hepatic arterial
anatomy. Later phase (b) beginning to show circumscribed enhancement of the right lobe HCC (white arrow)
Fig. 34.6 Selective right hepatic arteriography through the microcatheter
demonstrates the right hepatic lobe HCC.Misregistration artifact explains
why the single catheter “appears” twice (in black and white). Early phase
(a) demonstrating the microcatheter (black arrow) in the artery supplying
the tumor with early lling of the tumor (white arrow) and late phase (b)
with persistent arterial enhancement of the tumor (red arrow)
386
P. Haste and M. S. Johnson
Fig. 34.7 Completion arteriogram after embolization. (a) Angiography
demonstrates selective devascularization of the tumor (red arrow) and its
supplying arteries (white arrow) with preservation of uninvolved arteries
Key Point
The degree of selectivity (i.e., how far out in the artery
you get) is often inuenced by the tumor burden and
liver function. If someone has multiple tumors in one
lobe and good liver function, it may make more sense
to administer the chemotherapy proximally (not selective). However, in patients with a solitary tumor and/or
poor liver function, chemotherapy should be administered as distally as possible (super-selective).
Post-procedure
Upon embolization, patients are monitored in a recovery area
on bed rest for femoral artery punctures or seated for transradial punctures. Patients may be discharged later that day or
admitted overnight for observation. Nearly all patients experience some degree of post-embolization syndrome which
includes fever, pain, nausea, vomiting, and malaise [29].
Symptoms are controlled with oral or intravenous antiinammatory, pain, and antiemetic medications [30]. In select
patients, morning CBC and CMP can be obtained to evaluate
for post-procedural toxicities. Discharge medications include
prescriptions for pain, nausea, and potentially antibiotics.
Follow-up protocols vary among institutions; typical follow- up includes a clinic visit 2–4weeks after TACE with the
option for early imaging at 1month. The results of surveillance imaging will determine whether repeat embolization,
ablation, or systemic therapy is appropriate to treat residual
(blue arrows). (b) A later image shows persistent density throughout the
tumor (black arrow) due to Lipiodol deposition. Diffuse Lipiodol within
the tumor has been correlated with good tumor response.
or new disease. (Refer to Chap. 36 for liver ablation.)
Patients’ continued management is best discussed within the
multidisciplinary conference [31].
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Transarterial Radioembolization (TARE)
RyanHickey, RobertJ.Lewandowski, andRiadSalem
Introduction
Transarterial radioembolization (TARE) refers to the delivery of radioactive microspheres directly into an artery that
perfuses a tumor or tumor-bearing tissue. In current clinical
practice, radioembolization is employed almost exclusively
for liver tumors. The radioactive microspheres become
lodged within and around the tumor and cause tumor cell
death through the effects of radiation.
Pathophysiology
Primary liver cancer is one of the most common malignancies
worldwide and the second leading cause of cancer death.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, followed by cholangiocarcinoma.
HCC most commonly arises in the setting of chronic liver
diseases including but not limited to viral hepatitis, alcoholinduced liver disease, nonalcoholic steatohepatitis, and hemochromatosis [1]. Intrahepatic cholangiocarcinoma is a cancer
of the intrahepatic bile ducts of the liver that represents
10–15% of primary hepatobiliary cancers. In the majority of
cases, no underlying risk factor is identied; however, patients
with a history of chronic inammatory processes of the bile
ducts, such as primary sclerosing cholangitis, bropolycystic
diseases of the biliary system including choledochal cysts and
Caroli’s disease, and liver uke infestation, are at increased
R. Hickey
New York University Langone School of Medicine, Department of
Radiology, Division of Vascular & Interventional Radiology,
New York, NY, USA
e-mail: ryan.hickey@nyumc.org
R. J. Lewandowski (
Northwestern University, Feinberg School of Medicine,
Department of Radiology, Division of Vascular and Interventional
Radiology, Chicago, IL, USA
e-mail: r-lewandowski@northwestern.edu; rsalem1@nm.org
*) · R. Salem
35
risk [2]. Furthermore, the liver is the most common location
for metastatic disease due to its dual blood supply; the most
common primary tumors to metastasize to the liver originate
from the GI tract, breast, ovaries, bronchus, and kidney.
Treatment of these complex patients requires a multidisciplinary approach. Based on location, extent of disease, and
patients underlying hepatic function, treatments can include
medical therapy, surgical resection, transplantation and
interventional options of transarterial embolization (TAE),
chemoembolization (TACE), radioembolization (TARE),
and local ablative therapies. Hepatic tumors amenable to
treatment with TARE include primary liver tumors as well as
hypervascular hepatic metastases of primary malignancies
such as colorectal carcinoma, neuroendocrine tumors, and
ocular melanoma, among others [3–5].
Clinical Indication
Eligibility for TARE requires assessment of the patient’s disease
burden, biochemical parameters of liver function, and performance status. Patients should have liver-only or liver-dominant
primary or metastatic disease with a tumor burden involving less
than 50% of the liver. A bilirubin level≤2mg/dL, albumin >3g/
dL, and normal international normalized ratio (INR) have been
used as indicators of adequate hepatic reserve and synthetic
function. Cancer- related symptoms should be minimal. The
Eastern Cooperative Oncology Group (ECOG) score is a commonly used scoring system that rates the effects of cancer-related
symptoms on the activities of daily living (Table35.1). Patients
being considered for TARE should have an ECOG score of 0–2.
Key Point
Indicators of adequate hepatic reserve:
• Total bilirubin ≤2mg/dL
• Albumin >3g/cL
• Normal INR
© Springer International Publishing AG, part of Springer Nature 2018
N. A. Keefe et al. (eds.), IR Playbook, https://doi.org/10.1007/978-3-319-71300-7_35
389
390
R. Hickey et al.
Table 35.1 Eastern Cooperative Oncology Group performance status
score. Patient should have an ECOG score<3 to qualify for TARE
ECOG performance status
Grade Performance
0 Fully active, no restrictions
1 Restricted by strenuous activity, able to carry out light work
2 Ambulatory >50% of waking hours, able to care for self,
cannot carry out any work activities
3 Conned to bed/chair >50% of waking hours, limited
self-care
4 Conned to bed or chair 100% of time, completely disabled,
cannot care for self
5 Dead
Portal vein thrombus (PVT) includes portal vein tumor
thrombus (PVTT) due to direct tumor invasion into the portal
vein and bland thrombus, which can occur in patients with
cirrhosis. Because hepatic arterial embolization procedures
typically occlude the arterial supply to a portion of liver, the
presence of PVT has been considered a relative contraindication to hepatic arterial embolization procedures due to the
higher-risk of liver infarction or decompensation resulting
from a loss of both arterial and portal venous inow. However,
TARE, likely due to its microembolic nature, has been shown
to be safe and effective in the setting of PVT [6, 7].
Patients who have had an intervention or surgery involving the ampulla of Vater, such as patients with biliary stents,
sphincterotomies, or direct biliary-enteric anastomoses, have
an increased risk of hepatic abscesses following TARE.These
patients require special consideration including unique antibiotic protocols to reduce this risk.
Conventional Therapy
Treatment of hepatocellular carcinoma depends on the severity of underlying liver disease and extent of tumor involvement. The Barcelona Clinic Liver Cancer (BCLC) algorithm
is currently the most accepted staging and treatment algorithm for hepatocellular carcinoma in Europe and in the
United States (refer to Chap. 34 for more information) [8, 9].
Systemic chemotherapy is often the foundation of treatment
for intrahepatic cholangiocarcinoma as well as hepatic
metastases of primary cancers [10–12].
Surgery plays a vital role in the management of primary
and metastatic hepatic tumors. Surgical resection such as a
wedge resection or segmentectomy can be performed in
patients without evidence of vascular invasion and in those
patients who will be able to maintain adequate liver reserve
post-resection. Patients with underlying hepatic dysfunction
have a higher perioperative mortality compared to patients
with normal hepatic function. Liver transplantation is the
only curative treatment for HCC with candidacy based on the
Milan criteria (refer to Chap. 34 for more information).
Interventional Therapy
TARE relies on differences in the perfusion of hepatic tumors
compared to the normal liver parenchyma. Whereas the
normal liver parenchyma derives the majority of its blood
supply from the portal vein (~75%), tumors that arise in the
liver, particularly hypervascular tumors such as hepatocellular
carcinoma and certain metastases, derive the majority of
their blood supply from the hepatic arteries [13, 14]. Infusion
of microspheres into the hepatic arteries that perfuse liver
tumors results in preferential deposition of the microspheres
in the tumors compared to the non-tumor-bearing liver
parenchyma, providing higher radiation doses to the tumor
tissue and relative sparing of the liver parenchyma.
Key Point
Hepatic tumors derive the majority of the blood supply
from the hepatic artery, as opposed to the liver parenchyma, which receives approximately 75% of its blood
supply from the portal vein.
The use of traditional external beam radiation therapy for
the treatment of primary and metastatic liver tumors has generally been limited by the radiosensitive nature of the liver
tissue. However, the principles of radioembolization allow
for the safe administration of high and therapeutic doses of
radiation [15–18].
The microspheres used for radioembolization are comprised of either glass or resin and are loaded with the radioisotope
90
yttrium. The microspheres range in size from 20μm
to 30μm (glass) or 20μm to 60μm (resin). 90Yttrium is an
isotope that emits only beta radiation with a tissue penetration of 2.5–11 mm. The half-life of 90yttrium is 64.2 h.
Because the source of radiation is implanted and internal,
TARE is classied as a brachytherapy.
Clinical Outcomes withTARE
Primary Liver Cancers
The use of TARE for hepatocellular carcinoma (HCC) has
been described for patients with early-, intermediate-, and
advanced-stage HCC. Outcomes from the largest studies
evaluating the use of TARE for the treatment of HCC are
summarized in Tables 35.2 and 35.3.
In 2011, Salem etal. published level 1 evidence from the
PREMIER study, in which patients with early or intermediate
stage HCC were randomized to receive either transarterial