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18 The Multidisciplinary Management of
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Primary Hepatocellular Carcinoma
Shakira Hoque1, Christy Kim1, Mihir Desai
5
Schumacher
Suhrid Lodh
Zekry
1
2
3
4
5
6
7
8
9
10
11
12
Introduction
Hepatocellular cancer (HCC) remains one of the fastest growing
causes of cancer-related deaths in the United States and is the
leading cause of deaths overall in patients with cirrhosis
(Ioannou et al. 2007). In 2020, HCC was the sixth commonest
cancer diagnosis worldwide, with approximately 906,000 new
cases (Sung et al. 2021). In men, liver cancer was the second
most frequently occurring cancer death (Sung et al. 2021).
1,11
Department of Gastroenterology and Hepatology, St. George Hospital, Sydney, New South Wales, Australia
Department of Interventional Radiology, Prince of Wales Hospital, Sydney, New South Wales, Australia
Prince of Wales Clinical Campus, School of Clinical Medicine, University of New South Wales, New South Wales, Australia
Department of Upper Gastrointestinal and Hepatobiliary Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia
Department of Radiation Oncology, Wollongong Hospital and University of New South Wales, New South Wales, Australia
Department of Medical Oncology, St. George Hospital, Sydney, Australia
School of Medicine, University of New South Wales, Sydney, Australia
Department of Surgery, St. George Hospital Sydney and University of New South Wales, New South Wales, Australia
Department of Upper Gastrointestinal and Hepatobiliary Surgery, St. George Hospital, Sydney, Australia
Department of Interventional Radiology, Prince of Wales Hospital, Sydney, Australia
Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
, Sri Jasti6, Mostafa Abasseri
10
, Natalie Collier5, Winston Liauw
2,3
, Pram Sirimana4, Malin Katarina
1,7
, Oliver M. Fisher8, Francis Chu9,
6,11
, Piotr Milkiewicz12 & Amany
defined using the Child-Pugh classification system (Table 3).
Factors which affect prognosis include bilirubin level, presence
of portal hypertension, presence of portal vein thrombus,
presence of extrahepatic spread, presence of constitutional
symptoms, and patient’s performance status (Llovet et al.
1999b). Most of these factors are accounted for in the BCLC
staging system except performance status. The stage of HCC
and patient’s functional status (Table 4) dictate the intent and
type of treatment that should be offered.
Who Is at Risk of Developing Hepatocellular
Carcinoma?
The vast majority of HCC arises in those with underlying
chronic liver disease, including cirrhosis of any cause, chronic
viral hepatitis B, and advanced non-alcoholic fatty liver disease
with advanced fibrosis (Table 1) (Liu et al. 2019). This allows
clear identification of the at-risk population in whom screening
for HCC should be implemented.
How Do We Stage Hepatocellular Carcinoma?
The most well-recognized staging system for HCC is the
Barcelona Clinic Liver Cancer (BCLC) staging classification
(Table 2) (Llovet et al. 1999a). The BCLC staging is preferred
over the TNM staging system as it encompasses the severity of
the underlying liver disease which strongly affects prognosis,
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
Locoregional Therapy
Case: A 75-year-old male has a history of alcoholic and NASH
Child-Pugh A cirrhosis. He is independent with his mobility and
activities of daily living. His HCC surveillance prompted a multiphase CT that revealed a solitary enhancing 56mm nodule in
Segment IV (Figure 1). However, he was found to have features of
severe portal hypertension on imaging (Figure 2). His case was
discussed at an MDT meeting and it was deemed his portal
hypertension precluded surgical resection. Instead, he proceeded
to TACE of which he had two sessions, with imaging confirming
a favorable response. After re-discussion at the MDT meeting, the
interventional radiologist had concerns of a possible cystic artery
supply to the lesion, so it was decided that the patient would
benefit further from MWA to ensure treatment completion.
What Is Transarterial Embolization?
Transarterial Embolization (TAE) or Transarterial Chemoembolization (TACE) is a widely utilized therapy for the
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treatment of intermediate stage HCC who have well-preserved liver function and a large or multinodular HCC
without portal vein tumor thrombosis or extrahepatic metastasis, as outlined in the patient case seen earlier. A survival
advantage compared to best supportive care has been clearly
Table 1 Causes of liver cirrhosis.
Causes of liver cirrhosis
Non-alcoholic fatty liver disease
Alcohol related liver disease
Viral
Hepatitis B
Hepatitis C
Autoimmune
Primary biliary cholangitis
Primary sclerosing cholangitis
Autoimmune hepatitis
Infiltrative/metabolic
Haemochromatosis
Wilson’s disease
Alpha-1-antitrypsin deficiency
Granulomatous liver disease
Polycystic liver disease
Other
Medications
Hereditary hemorrhagic telangiectasia
demonstrated across a number of studies for patients receiving
TACE in this cohort (Lencioni et al. 2016; Llovet et al. 2002;
Llovet and Bruix 2003). Nearly half of all HCC patients worldwide receive TACE at some point in the course of their disease
(Lencioni et al. 2014).
There is wide heterogeneity in technique with variations
which include Conventional Transarterial Chemoembolization
(cTACE), Bland Embolization and Drug Eluting Beads TACE
(DEB-TACE).
cTACE is the most commonly performed variation. The
rationale of cTACE is to occlude the blood supply to the hypervascular HCC with an emulsion of lipidol and a chemotherapeutic agent, most commonly doxorubicin or cisplatin. As
HCC derives its vascular supply from the hepatic artery, as
opposed to the non-tumor liver parenchyma, occlusion results
in necrosis and slows tumor progression (Au and Frenette
2015; Piscaglia and Ogasawara 2018). The treatment can be
performed with a lobar, segmental, or super selective approach.
Common adverse effects include post embolization syndrome,
liver enzyme abnormalities (18.1%), fever (17.2%), abdominal
pain (11.0%), vomiting (6.0%), and nausea (1.7%) (Piscaglia
and Ogasawara 2018).
Bland embolization is performed in a small number of highly
experienced centers. Bland embolization is performed with
particles to cause ischemia by cutting off the blood supply
without a chemotherapeutic agent. Studies have indicated that
there is no survival benefit of cTACE compared to bland embo-
Table 2
Barcelona Clinic Liver Cancer (BCLC) staging system.
BCLC stage Description Child-Pugh Class Treatment
A (early stage)
A1 Single tumor with normal bilirubin A Curative resection, percutaneous
A–B
present
A3 Single tumor with raised bilirubin and portal hypertension A–B
A4 Three tumors less than 3 cm in size A–B
B (intermediate stage) Asymptomatic multinodular HCC A–B Palliative treatment
C (advanced stage) Advanced symptomatic HCC with high risk features
(vascular invasion, extrahepatic spread)
D (end-stage) End-stage widespread HCC C Best supportive care
Table 3 Child-Pugh classification system.
Clinical and lab criteria Points
1 2 3
Encephalopathy None Mild to moderate (grade 1 or 2) Severe (grade 3 or
Ascites None Mild to moderate Severe
Bilirubin (umol/L) < 34 34–50 > 50
Albumin (g/L) > 35 28–35 < 28
INR < 1.7 1.7–2.3 > 2.3
A–B Systemic palliative treatment
4)
treatment, or liver transplantationA2 Single tumor with normal bilirubin but portal hypertension
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Table 4 European Cooperative Oncology Group (ECOG) performance status classification system.
ECOG Description
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4 Completely disabled. Cannot carry on self-care. Totally confined to bed or chair.
local and low systemic drug concentrations (Sieghart et al. 2015).
In a subgroup analysis of patients with more advanced disease
such as Child-Pugh B, ECOG 1, bilobar or recurrent disease
DEB-TACE appears to outperform cTACE (Lammer et al. 2010).
What Is Transarterial Radioembolization?
Transarterial radioembolization (TARE) is a well-established
locoregional therapy which has an expanding role in the
treatment of HCC. It is a transarterial therapy which involves
radioisotope-loaded particle embolization into the liver. The
embolic particle does not occlude or alter the microvasculature
of the hepatic artery due to its small size and thus is considered
safe in portal vein thrombosis, unlike TACE. Its method of
action is via local radiotherapy with increased significance
given to its immunological effects (Chew et al. 2019). It is commonly infused via the hepatic artery into either a lobar or more
recently, in a segmental distribution.
Figure 1 Arterially enhancing 56mm nodule in segment 4 in a cirrhotic
liver.
TARE requires a comprehensive preprocedural workup
Figure 2 Dilation of portal vein
with resultant varices in right upper
quadrant, seen in portal venous
phase.
lization and this remains an area of ongoing research (Brown
et al. 2016; Maluccio et al. 2008).
Drug eluting beads (DEB) were developed to enhance the
delivery of the chemotherapeutic agent. DEBs are microspheres
which are loaded with a standardized dose of chemotherapeutic
agent (most commonly doxorubicin) that allows for a slow
release of the drug. The aim of this mechanism is to ensure high
which includes assessment of the vascular anatomy and the
hepato-pulmonary shunt. The workup involves a diagnostic
angiogram to evaluate the vascular anatomy and embolize any
extrahepatic branches which could lead to microsphere dispersion to non-target organs. In addition, the hepato-pulmonary
shunt is determined at this diagnostic angiogram through the
injection of macro aggregates of albumin (MAA) labeled with
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Tc99. MAA-Tc99 behaves similarly to the radio-embolization
microspheres and thus are used as a proxy to assess distribution
to the lungs. A large shunt can lead to rare complications such
as non-target pulmonary irradiation and radiation pneumonitis. A SPECT/CT is performed within an hour from the injection to assess the hepato-pulmonary shunt (Ilhan et al. 2015).
Contra-indications include a hepato-pulmonary shunt >20% of
the injected dose or vascular abnormalities not correctable by
embolization.
In addition, radiation lobectomy can be considered for
increasing the future liver remnant with similar volumetric
improvements to portal vein embolization with the added
benefit of local tumor control (Vouche et al. 2013). Rather than
the conventional strategy of lobar Y90 infusion, selective radio
embolization of the tumor-bearing hepatic segment has been
recently employed, termed “radiation segmentectomy.” This
method allows significantly higher radiation doses to be safely
delivered to individual segments without compromising the
non-tumor bearing liver parenchyma. Exceeding this new
threshold dose (>400 mGy) for an ablative effect results in
complete pathological necrosis of the tumor with survival outcomes similar to curative approaches such as resection and
radiofrequency ablation (Salem et al. 2021).
When Do We Use TARE Over TACE?
whereas MWA utilizes dielectric heating. Thermal ablation is
often performed percutaneously under image guidance by
inserting a probe into the tumor. Ablation may also be performed laparoscopically or via open surgery. Chemical ablation
involves injecting ethanol into a tumor to cause cell death.
MWA and RFA are the most commonly performed and clinically verified ablation techniques with well demonstrated efficacy and a safety profile (Alonzo et al. 2015; Reig et al. 2022).
Ethanol ablation should be considered where these are not feasible or safe (Reig et al. 2022). MWA is a newer modality with
advantages over RFA including a larger zone of active heating
and a more uniform necrosis within the tumor compared to
RFA (Izzo et al. 2019). Additionally as MWA is not limited by
tissue conductance, it is less susceptible to the “heat sink effect”
compared to RFA (Izzo et al. 2019). The heat sink effect is a
phenomenon where the effectiveness of hyperthermic tumor
ablation is impaired when flowing blood in a large adjacent
vessel causes a cooling effect (Goldberg et al. 1998). Whilst
there is a trend to suggest MWA may be more efficacious,
studies to date have not demonstrated a statistically significant
difference in overall survival between the two modalities (Vietti
Violi et al. 2018; Yu et al. 2017). MWA does however lead to
decreased procedure times and better tumor inactivation for
tumors 3–5 cm, adjacent to vessels and the gallbladder
(Facciorusso et al. 2016; Vietti Violi et al. 2018; Yu et al. 2017).
Compared to TACE, TARE does not demonstrate a clear
survival benefit for BCLC A/B patients; however there is
improved time to progression and reduced toxicity (Salem et al.
2016). TARE is an effective bridging therapy to liver transplantation with evidence suggesting it is more effective than TACE
(Ettorre et al. 2017; Lewandowski et al. 2009). In the newest
guidelines, TARE should now be considered for single lesions
≤8 cm in BCLC 0/A patients if surgical resection and ablation
is not technically feasible (Salem et al. 2021; Reig et al. 2022).
What Is Tumor Ablation?
Tumor ablation is a minimally invasive treatment that is commonly performed for the treatment of HCC; the primary endpoint is to obtain complete necrosis of tumors. Ablation is a
keystone in the management of HCC with proven efficacy,
especially for lesions <3 cm. It can be employed as a first line
therapy, an alternative for surgery or in association with resection in patients with a poor functional liver reserve (FLR)
(Benson et al. 2021; Izzo et al. 2019).
Most commonly thermal and chemical ablation are used for
HCC. Thermal ablation techniques include microwave ablation
(MWA) and radiofrequency ablation. Thermal ablation induces
cell death by delivering a destructive local temperature change
to the tumor to induce coagulative necrosis (Young and
Golzarian 2020). RFA employs thermo coagulation necrosis
What about Combination Therapy of
TACE-ablation?
As shown in our patient case, the combination of TACEAblation is an effective tool for 3–5 cm HCC with proven
superiority over monotherapy and for patients bridging to
transplant. There is emerging evidence that for 3–5 cm HCC, it
has comparable outcomes to surgery. TACE decreases the vascularity of the treated area and allows for a larger, more efficacious, ablation zone to be created with high rates of
histopathological necrosis (Vasnani et al. 2016; Young and
Golzarian 2020). The TACE-Ablation combination has proven
superiority compared to TACE or ablation alone in terms of
overall survival and oncological outcomes (Ni et al. 2013; Peng
et al. 2018). Additional benefits include that TACE prior to
ablation will clearly delineate the tumor margins and reveal
satellite lesions that may have been occult on preoperative
imaging (Peng et al. 2018). There is emerging data suggesting it
is comparable to surgery for overall survival and oncological
outcomes (Kim et al. 2013; Lee et al. 2019; Peng et al. 2018).
TACE-ablation is also an effective tool for bridging therapy to
transplant (Vasnani et al. 2016).
For optimal oncological outcomes, a 1 cm margin is the standard of care. Thus the TACE-ablation combination however is
dependent on a favorably located lesion due to the large ablation zone. TARE is often employed in this patient population
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however there is limited comparative data though TACEablation has been more extensively studied (Young et al. 2020).
Surgery
Case: A 56-year-old man of East Asian background is diagnosed with chronic hepatitis B after a full liver screen completed for deranged liver function tests. He is referred to a
hepatologist who commences him on an antiviral agent and
enrolls him to a HCC screen with six-monthly liver ultrasound
and serum alpha-fetoprotein (AFP) levels. He is found to have
a raised AFP level and a solitary 2-centimeter solid liver lesion
in segment VIII, which is then confirmed to be HCC on a multiphase CT abdomen with characteristic arterial enhancement
and venous washout (Figure 3). He is evaluated in a multidisciplinary meeting and undergoes curative liver resection. He
continues to follow up in the liver clinic with ongoing antiviral
therapy, monitoring of liver function tests and six-monthly
HCC screen.
How Do We Decide Who Is Eligible for
Surgery?
Many patients with HCC have underlying liver dysfunction
which makes the surgical management so challenging. The
chance of curative resection must be cautiously balanced with
the risk of precipitating hepatic failure. In early-stage disease
meeting evidence-based criteria, liver transplantation offers
the ability to not only gain local control but also treat the
underlying liver disease. However, the hindrance of graft shortages means that surgical resection remains the first-line
treatment for early-stage disease in appropriate candidates and
is safe and effective. Modern surgical approaches have achieved
mortality rates of <3% with overall morbidity rates of <30%
(Witowski et al. 2019). Most deaths are due to post-operative
liver failure. To avoid this, patient selection is paramount and
should be done using a multidisciplinary approach. Selection
involves exploring the patient, tumor and surgical factors that
may impact on peri- and post-operative outcomes. In the following section, we will explore these in turn.
The following parameters need to be taken into account in
the pre-operative assessment.
Patient Factors
General Health
Comorbid illnesses increase the risk of post-operative morbidity and mortality in patients undergoing liver surgery for
HCC (Wei et al. 2003). Therefore, thorough pre-operative evaluation of the general health of patients is a crucial aspect of
assessing their candidacy for liver resection, particularly in the
context of cirrhosis. This evaluation must incorporate assessments of all major organs, particularly cardiac, respiratory, and
renal functions. Thus, pre-operative assessment and optimization of pre-existing comorbidities and risk factors are important to minimize complications and help select patients
appropriately for surgery.
Malnutrition and Sarcopenia
Malnutrition and sarcopenia are common in patients with cirrhosis as a result of protein catabolism (Perisetti et al. 2022).
This can be compounded in patients with HCC. Patients with
malnutrition and sarcopenia undergoing liver surgery for HCC
are at a higher risk of post-operative complications, liver failure,
and longer length of stay (Huang et al. 2019; Otsuji et al. 2015).
Sarcopenia has also been associated with reduced total
functional liver volume, as well as reduced five-year overall and
recurrence-free survival (Dello et al. 2013). Nutritional therapy
given prior to liver resection has been shown to reduce sepsis,
need for treatment of ascites and overall post-operative morbidity and mortality rates (Fan et al. 1994). Identifying and
quantifying malnutrition and sarcopenia in patients being considered for liver resection is important to allow adequate preoperative nutritional optimization, aided by specialist dietetic
advice.
Figure 3 Arterially enhancing 2 cm nodule in segment 8 in a noncirrhotic liver.
Age
There is a significant age-specific increase in the development
of HCC in those aged over 75 (El-Serag and Rudolph 2007).
Liver resection in this cohort has historically been less favorable than locoregional therapies due to the perceived frailty
that accompanies advanced age, as well as the increased number
of comorbidities and likelihood of less physiological reserve to
cope with complications (Cho et al. 2019). However, a number
of retrospective studies have demonstrated similar three- or
five-year overall and disease-free survival rates between elderly
and younger patients undergoing liver resection for HCC
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