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Figure 7 Barcelona Clinic Liver Cancer (BCLC) classification for HCC including estimated incidence and accepted therapeutic options, including
potential roles for RT as shown in the blue boxes. (Adapted from: Overview: Where Does Radiation Therapy Fit in the Spectrum of Liver Cancer
Local-Regional Therapies) (Shanker et al. 2021).
Is There One Etiology of HCC that Responds
Better to Immunotherapy?
Emerging data suggest that immunotherapy might be less effective for NASH-related HCC compared with other etiologies.
When data across 1656 patients from three key trials (Finn et al.
2020; Pfister et al. 2021; Yau et al. 2022) were stratified according
to underlying etiology of chronic liver disease, survival benefit of
PD-1 and PDL-1 targeted immunotherapy was reduced in those
with NASH compared with other causes (7.1 months vs 14.4
months). This has been thought to be related to the aberrant
T-cell activation that occurs in NASH leading to impaired
immune surveillance. Despite this, based on the current data, it is
not yet recommended in clinical guidelines to consider this in the
decision of treating with immunotherapy (Gordan et al. 2020).
First-line Systemic Therapy
Figure 8 Multiple areas of arterial enhancement suggestive of
multifocal HCC ( courtesy of Radiology Department, St George Hospital
Australia).
Immunotherapy (Atezolizumab and Bevacizumab)
The combination of atezolizumab (programmed death-ligand 1
antibody) and bevacizumab (anti-vascular endothelial growth
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Figure 9 Filling defect in proximal portal vein (on the left) with expansion of vessel (on the right) consistent with extension into portal vein and
associated tumor thrombus ( courtesy of Radiology Department, St George Hospital Australia).
factor) has been approved for first-line therapy of advanced
stage HCC following the phase III IM Brave trial (Bruix et al.
2021; Greten et al. 2021; Rimassa and Santoro 2009; Yau et al.
2022) (Table 6). This combination immunotherapy has shown
significant improvement in progression-free survival compared
with sorafenib monotherapy (19.2 versus 13.4 months, estimated HR for death 0.66, 95% CI 0.52–0.85). Largely based on
these data, combination atezolizumab and bevacizumab is recommended in Child-Pugh A cirrhotics in non-resectable or
advanced HCC who have not received prior systemic therapy, as
in our case patient.
Tyrosine Kinase Inhibitors (Sorafenib, Lenvatinib)
First-line tyrosine kinase inhibitors (TKI) (lenvatinib
and sorafenib) should be considered for patients that
cannot have atezolizumab and bevacizumab combination
therapy, due to contraindications (as outlined above).
Sorafenib is a multi-targeted, orally active small molecule TKI that inhibits Raf kinase and the vascular endothelial growth factor receptor (VEGFR) intra-cellular
kinase pathway. In fact, it was the first therapy to show
an increase in median overall survival (Cheng et al. 2009;
Yamashita et al. 2020).
Lenvatinib is an oral multi-kinase inhibitor that targets
vascular growth factor receptor, fibrobplast growth factors
receptor, platelet-derived growth factors receptor, RET, and
KIT. In a subsequent trial comparing lenvatinib with sorafenib,
lenvatinib was found to be non-inferior to sorafenib, and progression-free survival was significantly higher in patients
receiving lenvatinib compared to sorafenib (Yau et al. 2019).
Thus, lenvatinib can use used an alternative first-line TKI to
sorafenib.
Second-line Systemic Therapy
Second line treatment is used in patients who have had radiological or clinical disease progression on first-line treatment,
and whose performance status and liver function are adequate
to tolerate it. The choice of subsequent TKIs or immunotherapy is empiric, as there are no comparator trials in patients failing initial treatment.
Immunotherapy (Ipilimumab and Nivolumab,
Pembroluzimab)
For patients who have progressed on first-line TKI (lenvatanib,
sorafenib) with Child-Pugh A cirrhosis who have not undergone
liver transplantation, combination therapy of nivolumab
(programmed cell death 1 antibody) and ipilimumab (cytoxic
T-lymphocyte associated 4 antibody), or pembroluzimab
(programmed cell death 1 antibody) monotherapy is recommended. While second-line TKIs have been approved for this
group, immune checkpoint inhibitors have a higher objective
response rate and a more favorable side effect profile. These therapies have been approved by the FDA as second-line treatments
for sorafenib-pretreated patients based off encouraging date from
key phase II trials (Abou-Alfa et al. 2018; El-Khoueiry et al. 2017;
Scheiner et al. 2019; Zhu et al. 2018).
Tyrosine Kinase Inhibitors (Regorafenib,
Cabozantanib)
Regorafenib and cabozantanib are multi-kinase inhibitors
with a similar mechanism of action to sorafenib, blocking the
activity of multiple protein kinases involved in the angiogenesis and oncogenesis in the tumor microenvironment. In
advanced HCC patients with preserved liver function who
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Table 6
Landmark trials leading to FDA approvals for immunotherapy in advanced HCC (El-Khoury et al. 2017; Finn et al. 2020; Finn et al. 2020; Yau
et al. 2022).
Therapy Results Comment
Nivolumab
(dose-escalation vs
dose-expansion)
(Checkmate 040)
Pembrolizumab vs
placebo
KEYNOTE-240
Atezolizumab and
bevacizumab vs
sorafenib
(IMBRAVE 150)
Nivolumab vs
sorafenib
(Checkmate 459)
– Objective RR by investigator using RECIST criteria was 32%, 27% and 29% in
arms A, B (dose-escalation) and C (dose-expansion) respectively.
– Median overall survival was 22.8 months in arm A, 12.8 months in arm B, and
12.7 months in arm C.
– Median duration of response was 17.5, 22.2 and 16.6 months in arms A, B and
C respectively.
– Overall survival was 13.9 months in the pembrolizumab group compared with
10.6 months in the placebo group.
– Objective response rate was 18.3% in pembrolizumab group compared with
4.4% in placebo group
Primary endpoints
OS
1.
– At 6 months OS was 84.8% vs 72.2%
– At 12 months OS was 67.2% vs 54.6%
2. PFS was 6.8 months (54.5%) vs 4.3 months (37.2%)
Secondary endpoints
1. Objective RR was 27.3% vs 11.9%
2. Duration of response longer than 6 months was 87.6% vs 59.1%
Primary endpoint
OS was 16.4 months vs 14.7 months.
1.
Additional endpoints
1. PFS was 3.7 months vs 3.8 months
2. Objective response rate was 57% vs 26%
Arm A combination was thought to
be a reasonable second line
treatment option due to safety
profile, durable response with
significant overall response rates
in patients previously treated with
sorafenib in the first line setting.
Pembrolizumab showed
improvement in overall survival
and progression free survival over
time in patients previously treated
with sorafenib
This combination is now considered
as first line treatment option for
patients with advanced
unresectable hepatocellular
cancer if they have no
contraindications.
Nivolumab did not increase the OS
but was considered a safe
alternative in patients who had
contra-indications to TKIs and
anti-angiogenic agents.
have progressed on sorafenib, both have shown to have a
survival benefit (Brahmer et al. 2018; Kelley et al. 2017;
Rimassa and Santoro 2009). Based on this data, regorafenib
and cabozantinib have been approved as second-line treatments in patients who have progressed on sorafenib.
Side Effects of Systemic Treatment
Table 7 Side effects of systemic treatment (TKIs and immunotherapy).
Tyrosine kinase inhibitors Immunotherapy
- Hypertension - Skin toxicity
- Palmo-plantar - Colitis
erythrodysaesthesia - Endocrinopathies, pneumonitis
- Skin rash - Hepatotoxicity
- Cardiotoxicity
- Anemia, thrombocytopenia - Thromboembolic events
- Nausea, vomiting - Bleeding
- Electrolyte disturbances - Poor wound healing
- Arthralgias - Hypertension
- Pancreatic atrophy - GI perforation
- Sarcopenia - Proteinuria
Specific to VEG-F inhibitors
How Do We Manage Immunotoxicity?
The toxicity profile of immunotherapy must be considered
carefully on a case-by-case basis as it leads to a wide range of
immune-mediated adverse effects due to impaired self-tolerance (Table 7). Most immunotherapy-related adverse
effects (IRAE) are usually transient, but occasionally they
can be severe and life-threatening (Schneider et al. 2021;
Thompson et al. 2020). Overall, studies have reported less
higher grade toxicity and therefore treatment discontinuation with monotherapy (less with PD-1/PDL-1 vs CTLA-4)
compared to combination therapy (Pfister et al. 2021).
Multiple international guidelines like ASCO, ESMO, and
NCCN generally recommend a similar management plan for
treating IRAEs as mentioned below:
– Management varies according to organ system affected, in
general, ICPi treatment can be continued with close monitoring for most grade 1 toxicities, except for some of the neurologic, hematologic, and cardiac toxicities.
– ICPi therapy should most likely be suspended for most
grade 2 toxicities, with consideration of restarting treatment
when symptoms have reverted to grade 1 or less. Corticosteroids may be considered for grade 2 toxicities. For
18 THE MULTIDISCIPLINARY MANAGEMENT OF PRIMARY HEPATOCELLULAR CARCINOMA 339
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endocrinopathies immunotherapy should be withheld until
adequate hormone replacement therapy has been initiated
and treatment can be restarted after the acute symptoms have
resolved. For patients with hypophysitis or adrenal insufficiency treatment can be restarted after adequate adrenal glucocorticoid replacement.
– Grade 3 toxicities generally warrant cessation of ICPis and
the initiation of high-dose corticosteroids should not be
delayed (prednisone 1 to 2mg/kg/d or methylprednisolone 1 to
2mg/kg/d). Corticosteroids can be slowly tapered over a period
of at least 4 to 6 weeks and in some refractory cases where there
is need for ongoing corticosteroid therapy, agents like infliximab, Mycophenolate or other immunosuppressive therapies
can be considered.
– In general, permanent cessation of ICPis is recommended
with all grade 4 toxicities, except for most of the endocrinopathies that can be managed with adequate hormone replacement.
Re-treatment after previous toxicity can be considered and is
reasonably safe in most patients after having a risk benefit
discussion and the decision to retreat also depends on multiple
factors like severity of adverse effects, response to corticosteroid therapy, disease response to initial immunotherapy and
availability of other alternative treatment options (Hui et al.
2013; Schneider et al. 2021).
What Are the Challenges of Palliative Care in
HCC?
The nature of HCC necessitates the early introduction of PC.
It is a complex disease underscored by an unpredictable course
(Hope and Morrison 2011). This is largely attributable to the
fact that it frequently occurs in the context of underlying endstage liver disease (ESLD), with 85–90% of cases transpiring in
this manner (Tarao et al. 2019). Accordingly, the health trajectory of patients presenting with both is unpredictable, characterized by episodic and acute exacerbations, as well as frequent
hospitalizations and stabilizations (Befeler and Di Bisceglie
2002). Further, because of this underlying ESLD, HCC patients
suffer from the symptoms of both liver failure and cancer
(Graf and Stengel 2021). The former is characterized by the
development of jaundice, ascites, variceal hemorrhage, and
hepatic encephalopathy (Befeler and Di Bisceglie 2002), each
with its own unique management challenges and prognostic
implications. When combined with the classic constitutional
clinical plethora of HCC, encompassing symptoms such as
weight loss, anorexia, fever, and malaise (Lubel et al. 2021),
coupled with the long and protracted treatment journey (Lubel
et al. 2021), patients with this typical dual presentation are
subject to severe physical and psychological burden (Bakitas
etal. 2009).
Palliative Care
Case: A 74 year old male has a history of alcoholic ChildPugh C cirrhosis, but did not comply with HCC surveillance. He had an incidental finding of multifocal HCC with
IVC and portal vein invasion, after he presented with
abdominal pain and weight loss. Given poor underlying
liver function, he was not for surgery, locoregional treatment,
or systemic treatment, so was commenced on best supportive treatment pathway in liaison with the palliative care
team. He had worsening liver decompensation with progressive renal impairment, recurrent ascites and encephalopathy. He was transferred to a Palliative Care Unit for
symptom management given his guarded prognosis, and
passed away peacefully a week later.
Palliative care involves addressing and holistically
managing the physical, emotional, and spiritual needs of
patients and their families or carers as early in the treatment
course as possible in order to improve patient quality of life
(QoL) and to mitigate suffering (Baumann et al. 2015;
Colagrande et al. 2016; Laube et al. 2021). This goal is best
achieved in HCC through the PC multidisciplinary team,
optimally consisting of specialist PC physicians and nurses,
hepatologists, allied healthcare workers (including a social
worker, physiotherapist, speech pathologist, occupational
therapist, and dietitian), with access to chaplaincy and
bereavement counsellors (Lubel et al. 2021).
What Does Palliative Care in HCC Involve?
Importantly, palliative should be delivered congruently with
disease-modifying therapy early in the management of HCC
(Temel et al. 2010). Several randomized controlled trials (RCTs)
studying advanced cancers have supported this (Vanbutsele
et al. 2020; Woodrell et al. 2018; Zimmermann et al. 2014).
The services provided by PC fall under four main headings,
including symptom management, care coordination, psychosocial support, and decisional support. Their implementation
should extend across all stages of HCC including the early
stages, when curative treatments are still available (Table 8)
(Lubel et al. 2021).
Importantly, these four domains have a significant role in
mitigating the strenuous patient experience for those with
HCC (Tarao et al. 2019, 182). Symptom management should
include pharmacological control of pain, and choice of
analgesia should take into consideration degree of hepatic
function, and co-existent complications such as hepatic
encephalopathy or hepatorenal syndrome. Given the unpredictable course of HCC, advanced care planning should be
instituted early. Psychosocial support is important given
the severe psychological burden of HCC, and clinicians
should work to identify religious and spiritual needs of the
patient and their families, and refer to support groups when
appropriate.
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Table 8 Potential role of palliative care across all stages of HCC (Adapted from Lubel et al. 2021).
HCC stage
Early (BCLC Stage
0-A)
Single nodule <2 cm,
PST 0, Child-Pugh A
Intermediate (BCLC
Stage B)
Multinodular, PS 0,
Child-Pugh A/B
Advanced
(BCLC Stage C)
Portal invasion, N1, M1,
PS 1–2, Child-Pugh B
Late-stage/terminal
(BCLC Stage D)
PST >2, Child-Pugh C
HCC therapy
options Typical symptoms Role of palliative care in each stage
- Liver resection
- Liver transplant
- Ablation (RF/PEI)
- TACE - Adverse effects of treatment including nausea,
- Systemic
chemotherapy
(e.g. Sorafenib)
- Best supportive
care (appropriate
palliative care)
- Adverse effects of treatment including pain,
infection, fever
vomiting, pain, fever, fatigue
- Local symptoms of primary tumor
- Extrahepatic symptoms
- Adverse effects of treatment (skin reaction, diarrhea,
anorexia, fatigue)
- Local symptoms of primary tumor
- Extrahepatic symptoms
- Local symptoms of primary tumor
- Extrahepatic symptoms (fatigue, anorexia)
- Liver failure (jaundice, ascites, and encephalopathy)
- Metastatic disease (symptoms related to system of
metastases, e.g. dyspnea, pain)
Key Take Home Messages
• HCC surveillance (with liver US +/– AFP every 6 months)
recommended to be undertaken in all cirrhotics, as well as in
non-cirrhotics with chronic HBV infection who are at increased
risk of HCC.
• It is recommended that the BCLC staging should be used as
the framework for HCC management; and the management
choice should take into account the individual’s liver function,
functional status as well as psychosocial circumstances.
• The management of HCC ideally should be determined by a
multidisciplinary team to optimize patient care.
• Liver resection is a first-line therapy option in suitable patients
with HCC where there is preserved liver function, sufficient liver
remnant, and absence of significant portal hypertension.
• Liver transplantation should be considered for patients with
HCC within transplant criteria who are not suitable for curative hepatic resection or ablative therapy.
• Patients with HCC initially beyond transplant criteria may
be considered for liver transplantation after successful downstaging to within standard transplant criteria.
• Ablative therapy and SIRTEX are recommended as a curative
locoregional therapy in suitable patients with very early or early
(BCLC Stage 0 or A) HCC, or in patients who are not candidates for surgery or liver transplantation.
• SIRT or SBRT may be considered in select patients with
intermediate or locally advanced HCC for local tumor control.
- Symptom control
- Disease education
- Advanced care planning and goals of care
discussion
- Address the physical, psychosocial, and spiritual
needs of patients through symptom control,
counseling and chaplain services respectively
- Assistance with decision-making and navigation
through treatment pathways
- Symptom control
- End-of-life care
- Provision of resources (e.g. hospice unit and
community equipment)
-Family support and bereavement counseling
• Patients with advanced HCC (BCLC Stage C) or multifocal
HCC that is not amenable to curative or locoregional therapy
(BCLC Stage B) should be offered systemic therapy, with
immunotherapy or multi-kinase inhibitors (sorafenib or lenvatinib) as first-line therapy options depending on patient’s
comorbidities.
• Patients with incurable HCC should be introduced to supportive care services early in their management.
• Hepatocellular carcinoma (HCC) continues to be an
increasing indication for liver transplantation (LTx) in patients
with liver cirrhosis.
• Milan criteria remain a reference in the liver transplant
assessment of patients with HCC.
• There is an increasing role of downstaging procedures permitting transplantation in tumors exceeding Milan criteria
however no randomized data exists to support any particular
modality used in downstaging
What’s not known
• Liver allocation to patients with HCC remains a great
challenge with scoring systems being systematically updated
and refined in order to ensure a fair distribution of organs.
• Prevention of HCC recurrence after LTx continues to be a
challenge and the potential preventive role of immunosuppression with mTOR inhibitors need to be established.
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Areas for Further Research
• Further investigation is required in predicting risk of HCC
recurrence following resection, liver transplantation, and
locoregional therapies.
• Neoadjuvant or adjuvant therapies for high risk patients (for
example, with lymphovascular invasion) are still under
investigation.
• The role of radiotherapy in the neoadjuvant setting prior to
surgical resection or liver transplantation has not yet been
outlined.
• Transarterial embolization in combination with systemic
therapy is currently under investigation.
• There are no clinical or molecular biomarkers established
as of yet to predict response to first or second-line systemic
treatments. Molecular characterization of the HCC tumor
microenvironment are currently under investigation, that
may enable the development of biomarkers that can be used
in routine clinical practice to predict prognosis and treatment
response; as exists in breast and lung malignancy for example.
Trusted Websites for Further Reading
1 EASL Clinical Practice Guidelines: Liver Transplantation:
https://easl.eu/wp-content/uploads/2018/10/LiverTransplantation-English-report.pdf
2
Diagnosis, Staging, and Management of Hepatocellular
Carcinoma: 2018 Practice Guidance by the American
Association for the Study of Liver Diseases: https://www.aasld.
org/sites/default/files/2022-06/AASLD_2018_HCC_
Guidance_on_Diagnosis%2C_Staging_and_Management_
hep_29913.pdf
3 Milan criteria for liver transplantation: https://www.mdcalc.
com/calc/3900/milan-criteria-liver-transplantation
4 Scoring system for liver transplantation in Hepatocellular
Carcinoma (METROTICKET PROJECT): http://www.hcc-oltmetroticket.org
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