Hepatocellular Carcinoma: Clinical Practice Guidelines

Clinical Practice Guidelines
Hepatocellular
carcinoma
About these slides
• These slides give a comprehensive overview of the EASL clinical

practice guidelines on the management of hepatocellular carcinoma
• The guidelines were first presented at the International Liver Congress

2018 and are published in the Journal of Hepatology
– A full copy of the publication can be downloaded from the
Clinical Practice Guidelines section of the EASL website
• Please feel free to use, adapt, and share these slides for your own
personal use; however, please acknowledge EASL as the source
About these slides
• Definitions of all abbreviations shown in these slides are provided

within the slide notes
• When you see a home symbol like this one: , you can click on
this to return to the outline or topics pages, depending on which
section you are in
These slides are intended for use as an educational resource

and should not be used in isolation to make patient
management decisions. All information included should be
verified before treating patients or using any therapies
described in these materials
• Please send any feedback to: [email protected]

Guideline panel
• Chair
– Peter R Galle
• Panel members
– Josep M Llovet, Vincenzo
Mazzaferro, Fabio Piscaglia,
Jean-Luc Raoul, Peter
Schirmacher, Valérie Vilgrain,
Alejandro Forner (EASL
Governing Board representative)
• Reviewers
– Tim Meyer, Gregory Gores,
Jean-Franҫois Dufour
EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

Outline
Methods • Grading evidence and recommendations
• Incidence of primary liver cancer

Background • Risk factors for primary liver cancer
Guidelines • Key recommendations
• Trial design and endpoints

HCC research • EASL future goals in HCC
and future goals • Unmet needs in HCC

Methods
Grading evidence and recommendations
Grading evidence and recommendations
• Grading is a simplified adaptation of the GRADE system1
Level of evidence* Confidence in the evidence

High Data derived from meta-analyses or Further research is unlikely to
systematic reviews or from (multiple) change our confidence in the
RCTs with high quality estimate of benefit and risk
Moderate Data derived from a single RCT or Further research (if performed) is
multiple non-randomized studies likely to have an impact on our
confidence in the estimate of benefit
and risk and may change the
estimate
Low Small studies, retrospective Any estimate of effect is uncertain
observational studies, registries
Grade of recommendation† (wording associated with the grade of recommendation)
Strong “Must”, “should”, or “EASL recommends”
Weak “Can”, “may”, or “EASL suggests”
*Level was downgraded if there was poor quality, strong bias or inconsistency between studies; level was upgraded if there
was a large effect size; †Recommendations were reached by consensus of the panel and included the quality of evidence,
presumed patient-important outcomes and costs
1. Guyatt GH, et al. BMJ 2008:336:924–6;
Background
Incidence of primary liver cancer
Risk factors for primary liver cancer
Background
• Liver cancer
– Fifth most common cancer
– Second most frequent cause of cancer-related death globally
• 854,000 new cases and 810,000 deaths per year
– 7% of all cancers
• HCC
– Accounts for approximately 90% of primary liver cancers
– Constitutes a major global health problem
Akinyemiju T, et al. JAMA Oncol 2017;3:1683–91 ;

Incidence of primary liver cancer in Europe
Incidence rates per 100,000

Incidence of primary liver cancer in Europe
Incidence rates per 100,000 Total number per country
Italy 10,733 The Netherlands 475

Germany 9,202 Croatia 466
France (metropolitan) 8,332 Republic of Moldova 448
Russian Federation 6,812 Slovakia 398
Spain 5,522 Belarus 327
United Kingdom 4,186 Bosnia Herzegovina 314
Romania 2,214 Denmark 311
Poland 1,998 Ireland 239
Ukraine 1,567 Slovenia 216
Greece 1,054 Norway 190
Portugal 1,004 Lithuania 175
Austria 955 Albania 171
Czech Republic, 919 Latvia 154
Switzerland 811 FYR Macedonia 135
Serbia 799 Luxembourg 68
Belgium 645 Estonia 64
Bulgaria 640 Cyprus 56
Hungary 630 Montenegro 51
Finland 620 Malta 19
Sweden 490 Iceland 10

Main risk factors for primary liver cancer worldwide*
• ~90% of HCCs are of known underlying aetiology1

– Most frequently HCV, HBV, alcohol and aflatoxin exposure
Alcohol (%) HBV (%) HCV (%) Others (%)

Europe
Western 32 13 44 10
Central 46 15 29 10
Eastern 53 15 24 8
North America 37 9 31 23
Andean Latin America 23 45 12 20
Asia
East Asia 32 41 9 18
Asia-Pacific 18 22 55 6
South-East Asia 31 26 22 21
Africa
North Africa, Middle East 13 27 44 16
Southern (sub-Saharan) 40 29 20 11
Western (sub-Saharan) 29 45 11 15
*Contribution of hepatitis B, C, alcohol and other causes on absolute liver cancer deaths, both sexes, globally and by region 2015.
Data refer to all primary liver cancers (HCC, intrahepatic CCA and liver cancer of mixed differentiation)
1. Akinyemiju T, et al. JAMA Oncol 2017;3:1683–91;
Guidelines
Key recommendations
Topics
1. Epidemiology and risk factors Click on a topic to skip

to that section
2. Prevention
3. Surveillance
4. Diagnosis
5. Recall policy
6. Staging
7. Treatment: liver resection
8. Treatment: liver transplantation
9. Treatment: systemic therapy
10. Assessment of treatment response
11. Palliative and best supportive care

Epidemiology and risk factors
• Incidence of HCC has been rising

– Driven by increases in chronic viral infections and lifestyle-related
risk factors
• Cirrhosis is an important risk factor for HCC
– Multiple causes, including viral hepatitis, chronic alcohol use, NAFLD
– Up to 90% of HCC arises on a background of cirrhosis in the
Western world1
Recommendations Level of evidence Grade of recommendation

The incidence of HCC is increasing both in Europe and worldwide;
High
it is amongst the leading causes of cancer death globally
Chronic liver disease should be treated to avoid progression High Strong
1. Forner A, et al. Lancet 2018;391:1301–1314;

Prevention
• Primary prevention of HCC can be achieved with universal

vaccination against HBV
• Progression to cirrhosis and HCC can be prevented by:
– Antiviral treatment in patients with chronic hepatitis B and C*
– Adoption of healthy lifestyle measures

Vaccination against hepatitis B reduces the risk of HCC and is
High Strong
recommended for all newborns and high-risk groups
Governmental health agencies should implement policies that:
• Prevent HBV/HCV transmission
Moderate Strong
• Counteract chronic alcohol abuse
• Promote lifestyles that prevent obesity and metabolic syndrome
In patients with chronic hepatitis, use antiviral therapies to:
• Maintain HBV suppression in chronic hepatitis B High Strong
• Maintain SVR in chronic hepatitis C
*Level of evidence high, grade of recommendation strong

HCC preventive interventions
Fujiwara N, et al. J Hepatol 2018;68:526–49

Role of DAAs for HCV in HCC
• Effect of DAAs on HCC in patients with cirrhosis is debated

– Robust conclusion impeded by retrospective assessment, absence
of HCC screening, short follow-up and loss to follow-up

Once cirrhosis is established:
• Antiviral therapy* is beneficial in preventing cirrhosis
progression and decompensation Moderate
• Successful antiviral therapy reduces but does not eliminate
the risk of HCC development
For patients with HCV-associated cirrhosis and treated HCC:
• HCC recurrence rate is high even after SVR with DAA therapy†
• Close surveillance is advised in these patients Low Strong
• The benefit of viral cure must be weighed against a potentially
higher recurrence risk
*Antiviral therapies should follow the EASL guidelines for management of chronic hepatitis B and C infection;
†
It is unclear whether this represents the inherent risk of HCC development in advanced cirrhosis, or if DAA therapy increases
recurrence rates
Impact of coffee on HCC development
• Numerous epidemiological studies have addressed the prevention

of HCC in patients with chronic liver disease
– Trials analyzing the effect of coffee consumption have shown a
consistently positive effect with regard to lowering HCC incidence

Coffee consumption has been shown to decrease the risk of HCC in
patients with chronic liver disease
Moderate Strong
In these patients, coffee consumption should be encouraged

Surveillance
• Utility of and applicability of surveillance is influenced by a number

of factors
– Incidence of HCC in target populations
– Availability of efficient diagnostic tests at acceptable costs
– Availability and effectiveness of treatments
• Definition of target populations must consider

– Incidence of HCC in subsets of patients
– Probability that effective therapies, particularly radical ones, are suitable
HCC incidence is higher in patients with more advanced cirrhosis

Probability of receiving effective therapy is lower*
Different incidence thresholds may apply to different target populations
*Because of lower applicability of surgery

Surveillance
• High rate of HCC in certain risk groups makes surveillance a

cost-effective route to reducing mortality
– Conventional threshold is US $50,000 per year of life saved*

• Implementation of screening programmes to identify at-risk
candidate populations should be improved
Low Strong
• Such programmes are a public health goal, aiming to decrease
HCC-related and overall liver-related deaths
Patients at high risk of developing HCC should be entered into
surveillance programmes. Government health policy and research Moderate Strong
agencies should address these needs
*Slightly lower (£30,000) or significantly higher levels (up to $150,000) have been proposed to account for inflation, specific
national healthcare resources and other factors
Surveillance in patients at high risk of HCC
• Surveillance is recommended in specific target populations

 Cirrhotic patients, Child–Pugh stage A and B Low Strong
 Cirrhotic patients, Child–Pugh stage C awaiting LT Low Strong
 Non-cirrhotic HBV patients at intermediate or high risk of HCC*
(according to PAGE-B† classes for Caucasian subjects, respectively Low Weak
1017 and ≥18 score points)
 Non-cirrhotic F3 patients, based on an individual risk assessment Low Weak
• Interval should be dictated by rate of tumour growth and tumour

incidence in target population
– 6-month interval is reasonable and cost-effective
• 3 months: no clinical benefit
• 12 months: fewer early stage diagnoses and shorter survival
*Patients at low HCC risk left untreated for HBV and without regular 6-month surveillance must be reassessed at latest on a yearly
basis to verify progression of HCC risk. †PAGE-B score is based on decade of age (16–29 = 0, 30–39 = 2, 40–49 = 4, 50–59 = 6,
60–69 = 8, ≥70=10), gender (M = 6, F = 0) and platelet count (≥200,000/µl = 0, 100,000–199,999µl = 1, <100,000 = 2): a total sum
of ≤9 is considered at low risk of HCC (almost 0% HCC at 5 years) a score of 10–17 at intermediate risk (3% incidence HCC at
5 years) and ≥18 is at high risk (17% HCC at 5 years)
Uncertainties in surveillance strategy
• Benefit of surveillance has not been established in all risk groups

• US remains the method of choice
– Serological tests are not currently cost-effective

Role of surveillance for patients with NAFLD without cirrhosis is
Low
unclear
Surveillance should be performed by experienced personnel in all
Moderate Strong
high-risk populations using abdominal US every 6 months
Tumour biomarkers for accurate early detection are still lacking* Low -
Patients on the waiting list for LT should undergo surveillance
for HCC
Low Strong
• To detect and manage tumour occurrence or tumour response
• To help define priority policies for transplantation
*Available data show that the biomarkers tested (i.e. AFP, AFP-L3 and DCP) are suboptimal in terms of cost-effectiveness for
routine surveillance of early HCC
Diagnosis
• Diagnosis generally relies on pathology

• Non-invasive criteria can be used in patients with cirrhosis
– Peculiar vascular derangement occurs during hepatic carcinogenesis
– High pre-test probability of HCC

Diagnosis of HCC in cirrhotic patients should be based on
High Strong
non-invasive criteria and/or pathology
In non-cirrhotic patients, diagnosis of HCC should be confirmed by
Moderate Strong
pathology
Pathological diagnosis of HCC should be based on International
Consensus recommendations1,2 using the required histological and High Strong
immunohistological analyses
1. International Consensus Group for Hepatocellular Neoplasia. Hepatology 2009;49:658–64;

2. Bosman FT, et al. WHO Classification of Tumours of the Digestive System. Fourth Edition. IARC press; 2010;
Non-invasive diagnosis
• Non-invasive diagnostic criteria for patients with cirrhosis require

particular imaging techniques
Non-invasive criteria* can only be applied to cirrhotic patients for
nodule(s) ≥1 cm, in light of the high pre-test probability, and are
High Strong
based on imaging techniques obtained by multiphasic CT, dynamic
contrast-enhanced MRI…
…or CEUS Moderate Weak
Because of their higher sensitivity and the analysis of the whole
High Strong
liver, CT or MRI should be used first
FDG PET scan is not recommended for early diagnosis of HCC
Low Strong
because of the high false-negative rate
*Diagnosis is based on the identification of the typical hallmarks of HCC, which differ according to imaging techniques or contrast
agents (APHE with washout in the portal venous or delayed phases on CT and MRI using extracellular contrast agents or
gadobenate dimeglumine, APHE with washout in the portal venous phase on MRI using gadoxetic acid, APHE with late-onset
[>60 seconds] washout of mild intensity on CEUS)
Recall policy
• Appropriate recall policy is crucial for the success of surveillance

procedures
– Defined algorithm followed when surveillance tests are abnormal

In patients at high risk of developing HCC:
• Nodule(s) <1 cm detected by US should be followed at ≤4-month
intervals in the first year Low Weak
• If no increase in size or number of nodules, surveillance can be
returned to the usual 6-month interval
In cirrhotic patients, diagnosis of HCC for nodules of ≥1 cm can
be achieved with non-invasive criteria and/or biopsy-proven High Strong
pathological confirmation
Repeated biopsy sampling is recommended in cases of:
• Inconclusive histological or discordant findings
• In cases of growth or change in enhancement pattern Low Strong
identified during follow-up, but with imaging still not diagnostic
for HCC

Algorithm for diagnosis and recall in
cirrhotic liver
Mass/nodule at imaging
<1 cm >1 cm
Repeat US at 4 months Multiphasic contrast-enhanced CT or MRI,*

or gadoxetic-enhanced MRI†
Growing/changing
Stable‡ 1 positive technique:
pattern
HCC imaging hallmarks
No Yes
‖
Biopsy unclear: Use other modality: multiphasic contrast-enhanced

Consider re-biopsy CT or MRI,* or gadoxetic-enhanced MRI,†
or contrast-enhanced ultrasound§
1 positive technique: HCC imaging hallmarks
No Yes
Non-HCC malignancy/
benign Biopsy HCC
*Using extracellular MRI contrast agents or gadobenate dimeglumine; †Diagnostic criteria: APHE and washout on the portal
venous phase; ‡Lesion <1 cm stable for 12 months (three controls after 4 months) can be shifted back to regular 6-month
surveillance; §Diagnostic criteria: APHE and mild washout after 60 seconds; ‖Optional for centre-based programmes
Staging systems and treatment allocation
• Prognostic assessment is critical in the management of HCC

– Complicated by co-existence of HCC and cirrhosis
• Staging for HCC should be based on:
– Prognostic variables from studies on natural history of HCC and cirrhosis
– Variables from evidence-based studies on therapeutic rationale

Staging systems for clinical decisions in HCC should include:
• Tumour burden
High Strong
• Liver function
• Performance status
BCLC staging system has been repeatedly validated and is High Strong
recommended for prognostic prediction and treatment allocation
• The treatment ‘stage migration’* concept applies
Patients should be discussed in multidisciplinary teams to fully
Low Strong
capture and tailor individualized treatment options
*The stage migration strategy is a therapeutic choice by which a treatment theoretically recommended for a different stage is
selected as the best first-line treatment option: usually offering the effective treatment option recommended for the subsequent
more advanced tumour stage, which occurs when patients are not suitable for their first line therapy. However in highly selected
patients, with parameters close to the thresholds, a lower-stage migration strategy could be the best option, given a
multidisciplinary decision
Modified BCLC staging system and
treatment strategy
HCC in cirrhotic liver
Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal stage (D)
Single <2 cm Solitary or Multinodular, Portal invasion/ Not transferable HCC
Prognostic Preserved liver 2–3 nodules <3 cm unresectable extrahepatic spread End-stage
stage function* Preserved liver Preserved liver Preserved liver liver function
PS 0 function* function* function* PS 3–4
PS 0 PS 0 PS1 –2
†
2–3 nodules
Solitary
≤3 cm
Optimal surgical
candidate‡
Transplant
Yes No
candidate
Yes No
Treatment§ Ablation Resection Transplant Ablation Chemoembolization Systemic therapy‖ BSC

Survival >5 years >2.5 years ≥10 months 3 months
*Child–Pugh A without ascites. Applies to all treatment options apart from LT; †PS 1; tumour-induced modification of performance
capacity; ‡Multiparametric evaluation: compensated Child–Pugh class A liver function with MELD score <10, matched with grade of
portal hypertension, acceptable amount of remaining parenchyma and possibility to adopt a laparoscopic/minimally invasive
approach; §The stage migration strategy applies; ‖Sorafenib has been shown to be effective in first line, while regorafenib is
effective in second line in case of radiological progression under sorafenib. Lenvatinib has been shown to be non-inferior to
sorafenib in first line, but no effective second-line option after lenvatinib has been explored. Cabozantinib has been demonstrated
to be superior to placebo in 2nd or 3rd line with an improvement in OS. Nivolumab has been approved in second line by FDA but
not EMA based on uncontrolled Phase 2 data. Please see notes for full details.
Treatment of HCC: liver resection
• Surgery is the mainstay of HCC treatment

– Best outcomes of any treatment in well-selected candidates
• 5-year survival of 6080%
• Liver resection and transplantation is first option with early tumours
– Extended to other stages after non-surgical tumour downstaging

Surgical resection is the treatment of choice in patients with HCC
Low Strong
arising on a non-cirrhotic liver
Indications for resection of HCC in cirrhosis should be based on:
• Multi-parametric composite assessment of liver function
• Portal hypertension
• Extent of hepatectomy and expected volume of future liver High Strong
remnant
• Performance status
• Patient co-morbidities
Peri-resection mortality in cirrhotic patients should be <3% High Strong

Assessment of post-resection risk of hepatic
decompensation
• Multi-parametric assessment
• Risk of decompensation based
on three determinants of liver
insufficiency
– Portal hypertension
– Extent of resection
– Liver function
• Likelihood of decompensation
– High: >30%
– Intermediate: <30%
– Low: 5%

Assessment of post-resection risk of hepatic
decompensation
• Multi-parametric assessment
• Risk of decompensation based
on three determinants of liver
insufficiency
– Portal hypertension
– Extent of resection
– Liver function
• Likelihood of decompensation
– High: >30%
– Intermediate: <30%
– Low: 5%

Extent of resection: anatomical vs. non-anatomical*1
A
Anatomical resection (A-A’) removes entirely the
tumour-bearing portal branches bordered by the
landmark veins, while non-anatomical resection (B-B’)
is any other type of resection in which the tumour-
bearing 3rd-order portal region is not fully removed
B
After non-anatomical resection of HCC some part
of the tumour-bearing portal region is left, which is
at high risk of tumour recurrence
Residual region of tumour-

bearing 3rd-order portal branch
at high risk of tumour recurrence
*Note that studies of newer, less invasive laparoscopic resections have questioned the superiority of anatomic liver resection in
HCC of larger size
1. Shindoh J, et al. J Hepatol 2016;65:1062–1063;
Liver resection and tumour parameters
• Indications and choice of surgical technique depend on tumour

size and location(s)

Liver resection is recommended for single HCC of any size
• In particular, for tumours >2 cm when hepatic function is Moderate Strong
preserved and sufficient remnant liver volume is maintained
In properly trained centres, liver resection should be considered
via laparoscopic/minimally invasive approaches, especially for Moderate Weak
tumours in anterolateral and superficial locations
HCC presenting with two or three nodules within Milan criteria may
be eligible for liver resection depending on:
• Performance status Low Weak
• Co-morbidities
• Preservation of liver function and remnant volume

Minimally invasive/laparoscopic resection for HCC
• Laparoscopic-robotic resection for HCC located in superficial-

peripheral positions of the liver provides optimal survival outcomes
– While minimizing complications and hospital stay
Scan detection of liver Laparoscopic treatment of the affected Removal of affected region
tumour organ through small openings Minimal signs of invasive surgery
and rapid patient recovery

Liver resection contraindications and follow-up
• A substantial proportion of patients with HCC present with

tumour-related portal vein thrombosis
– Disease at advanced stage and not amenable to curative treatment
• Tumour recurrence complicates 70% of cases at 5 years

• HCC-related macrovascular invasion is a contraindication for
liver resection
• Intervention on distal portal invasion – at segmental or Moderate
sub-segmental level – deserves investigations within
prospectively designed protocols
Neoadjuvant or adjuvant therapies are not recommended
because they have not been proven to improve the outcome of High Strong
patients treated with resection
Follow-up* after resection with curative intent is recommended
High Strong
because of high rates of treatable recurrence
*Follow-up intervals are not clearly defined. In the first year, 3–4-month intervals are practical
Treatment of HCC: liver transplantation
• Together with NAFLD/NASH, HCC is the fastest growing

indication for LT
• Milan criteria are the benchmark for selecting patients for LT
– Basis for comparison with other suggested criteria
LT is recommended as the first-line option for HCC within Milan
High Strong
criteria but unsuitable for resection
Consensus on expanded criteria for LT in HCC has not been
reached
• Patients outside Milan criteria can be considered for LT after Moderate Weak
successful downstaging to within Milan criteria, within defined
protocols
Composite criteria,* are likely to replace conventional criteria for
Low Strong
defining transplant feasibility
Tumour vascular invasion and extrahepatic metastases are an
High
absolute contraindication for LT in HCC
*That consider surrogates of tumour biology and response to neoadjuvant treatments to bridge or downstage tumours in
combination with tumour size and number of nodules: these criteria should be investigated and determined a priori, validated
prospectively and auditable at any time
Organ allocation and priority for HCC
• LT is the therapy with the highest chance of curing HCC

– Always consider unless age and co-morbidities advise against LT
• Major limiting factor is scarcity of donated organs
– Including relative priority with other LT indications
Cirrhosis HCC + cirrhosis

High pre-transplant mortality Low pre-transplant mortality
Variable post-transplant cure, depending on
High post-transplant long-term recovery
tumour stage at operation
Predictable outcome with no transplant Composite prognostic factors and variable
(MELD) biology influencing outcome
No competitive options besides Competitive options in selected patient
transplantation subgroups
↓ ↓
Urgency principle Utility principle
Focused on pre-LT risk of dying Focused on maximization of post-LT

Liver transplant prioritization
• Prioritization of cadaveric graft allocation is challenging

The use of marginal cadaveric grafts for LT in patients with HCC
Moderate
has no contraindication
Prioritizing a cadaveric graft allocation, for patients with or without
HCC, within a common waiting list, is complex:
• No system can serve all regions
• Prioritization criteria for HCC should at least include:
Moderate Strong
– Tumour burden
– Tumour biology indicators
– Waiting time
– Response to tumour treatment
Transplant benefit may need to be considered alongside the
conventional transplant principles of urgency and utility in decision Moderate Weak
making, depending on list composition and dynamics

Allocation models considered in LT
Model Definition
Focused on pre-transplant risk of dying: patients with worse outcome on the waiting list
Urgency
are given higher priority for transplantation (based on Child–Pugh or MELD score)
Based on maximization of post-transplant outcome, takes into account donor and
recipient characteristics: mainly used for HCC since the MELD score poorly predicts post-
Utility
transplant outcome in HCC due to the absence of donor factors and lack of predicting
tumour progression while waiting
Calculated by subtracting the survival achieved with LT by the survival obtained without
LT. Ranks patients according to the net survival benefit that they would derive from
Benefit
transplantation and maximizes the lifetime gained through transplantation. If applied to
HCC without adjustments, it may prioritize patients at highest risk of recurrence
Dotted lines represent different levels of survival achieved with non-transplant options
Bruix J et al. Gut 2014;63:844–55;
Pre-LT therapy and living donor options
• LT candidates with HCC waiting for a cadaveric donor can maintain

eligibility with bridging therapy
– Living donor LT may be an option in certain circumstances

In LT candidates with HCC, pre-transplant (neoadjuvant)
loco-regional therapies are recommended if feasible
Low Strong
• Reduces the risk of pre-LT drop-out
• Lowers post-LT recurrence – particularly if CR or PR is achieved
• Contribution of living donation to LT for HCC in Europe is still
marginal
• Living donor LT for HCC remains an option to be explored in
Low
selected patients and in experienced centres:
– According to waiting list time and dynamics
– Within donor-recipient double equipoise principles

Local ablation and external radiation
• Tumour ablation techniques have improved along with the imaging-

guidance tools required to ensure their successful application
Thermal ablation with radiofrequency is the standard of care for
High Strong
patients with BCLC-0 and A tumours not suitable for surgery*
In patients with very early stage HCC (BCLC-0) radiofrequency
ablation in favourable locations can be adopted as first-line Moderate Strong
therapy even in surgical patients
Microwave ablation showed promising results for local control and
Low
survival
Ethanol injection is an option in some cases where thermal
High Strong
ablation is not technically feasible, especially in tumours <2 cm
External beam radiotherapy is under investigation
• So far there is no robust evidence to support this therapeutic Low Weak
approach in the management of HCC
*Thermal ablation in single tumours 2–3 cm in size is an alternative to surgical resection based on technical factors (location of
the tumour), hepatic and extrahepatic patient conditions
Percutaneous ablation
Radiofrequency ablation Microwave ablation Cryoablation Irreversible electroporation

Active energy Active energy
Monopolar RFA deposition: few mm deposition: ~1 cm Ice ball: ~1–3 cm
Multibipolar
No touch RFA
Cell
Heat Heat Cold
membrane
diffusion diffusion diffusion
Advantages Limitations
• Well-evaluated treatment • Higher and faster temperature • Easy monitoring with imaging of • Limited risk of thermal injury to
(reference) picks reached than with RFA ice ball progression neighbouring critical structures
• Multibipolar mode: increases (less sensitive to heat sink • Unsensitive to heat sink effect
volume and effect than monopolar RFA) • Advantage of multibipolar mode
predictability (margin) of (no touch technique,
ablation zone predictability of margins)
• Thermal injury of adjacent • No reliable endpoint to set the • Cryoshock with first device • Only preliminary clinical data
structure amount of energy deposition • Limited clinical data available • General anaesthesia using
• Heat sink effect (near major with new devices curare and major analgesic
vessels) drugs is mandatory
• Multibipolar mode is less
sensitive to heat sink effect
Nault J-C, et al. J Hepatol 2018;68:783–97

Transarterial therapies
• Benefits of TACE in appropriately selected patients have been robustly

demonstrated

TACE is recommended for patients with BCLC stage B and should
High Strong
be carried out in a selective manner
The use of drug-eluting beads has shown similar benefit to
High Strong
conventional TACE and either of the two can be utilized
TACE should not be used in patients with:
• Decompensated liver disease
• Advanced liver and/or kidney dysfunction High Strong
• Macroscopic vascular invasion
• Extrahepatic spread

Transarterial therapies in development
• Potential benefits of other transarterial therapies have yet to be

sufficiently demonstrated
Recommendations Level of evidence
There is insufficient evidence to recommend bland embolization, selective

Moderate
intra-arterial chemotherapy and lipiodolization
TARE/SIRT using yttrium-90 microspheres has been investigated in:
• Patients with BCLC-A for bridging to transplantation
• Patients with BCLC-B to compare with TACE
• Patients with BCLC-C to compare with sorafenib
Current data: Moderate
• Show good safety profile and local tumour control
• Fail to show overall survival benefit compared to sorafenib in BCLC-B and
-C patients
The subgroup of patients benefitting from TARE needs to be defined
There is insufficient evidence to recommend scores that better select
Moderate
BCLC-B candidates for first TACE or for subsequent sessions

First-line systemic therapies
• VEGFR and multi-kinase inhibitors have shown survival benefits in advanced HCC
– First line: sorafenib and lenvatinib

Sorafenib is the standard first-line systemic therapy for HCC,
indicated for patients with:
• Well-preserved liver function (Child–Pugh A) and with advanced
High Strong
tumours (BCLC-C)
• Earlier stage tumours progressing upon, or unsuitable for,
loco-regional therapies
Lenvatinib is non-inferior to sorafenib and is also recommended
in first-line therapy for patients with:
• Well-preserved liver function, good performance status and
High Strong
advanced tumours (BCLC-C) without main portal vein invasion
• Tumours progressing with, or unsuitable for, loco-regional
therapies
There are no clinical or molecular biomarkers established to predict
Moderate
response to first- or second-line systemic treatments

Non-inferiority results in advanced HCC
RCTs in advanced HCC
Comparison of first-line drugs/devices vs. sorafenib
Favours tested drug Favours sorafenib

Second-line systemic therapies
• VEGFR and multi-kinase inhibitors have shown survival benefits in advanced HCC
– First line: sorafenib and lenvatinib
– Second line: regorafenib (and cabozantinib and ramucirumab*)
• Another agent that has shown some promise is the checkpoint inhibitor nivolumab
Regorafenib is recommended as second-line treatment for

patients:
• Tolerating and progressing on sorafenib High Strong
• With well-preserved liver function (Child–Pugh class A)
• With good performance status
Cabozantinib and ramucirumab* have shown survival benefits vs.
- -
placebo in this setting
Based on uncontrolled but promising data, immune therapy with
nivolumab has received FDA approval in second-line treatment,
pending Phase 3 data for conventional approval Moderate Weak
• At present, the data are not mature enough to give a clear
recommendation
*In patients with high baseline alpha-fetoprotein (> 400 ng/ml)

Systemic therapies in development
• Other systemic treatments are in development

– Have not yet demonstrated non-inferiority or clinical benefit
– Further clinical trials are required

• Treatments that failed to meet their endpoints in randomized
trials are not recommended
• Further clinical trials are needed to confirm claims of High
non-inferiority, or any trends of better outcome identified in
subgroup analysis
• Patients at BCLC D stage, who are not LT candidates, should
receive palliative support, including management of pain,
Low Strong
nutrition and psychological support
• In general, they should not be considered for clinical trials

Overview of EASL recommendations
for treatment
• *Other molecular therapies: sunitinib, linifanib, brivanib, tivantinig, erlotinib, everolimus

• Weak recommendation: more evidence needed

Assessment of response to treatment
• Different methods of response assessment are appropriate for

different treatments

Assessment of response in HCC should be based on mRECIST for
Moderate Strong
loco-regional therapies
For systemic therapies both mRECIST and RECIST1.1 are
Moderate Weak
recommended
Multiphasic contrast-enhanced CT or MRI are recommended for
assessment of response after resection, loco-regional or systemic Moderate Weak
therapies

Palliative and best supportive care
• Management of end-stage disease is only symptomatic

– No tumour-directed treatment is indicated

In HCC on cirrhosis:
• Acetaminophen ≤3 g/day to manage pain of mild intensity
• NSAIDs should be avoided whenever possible in patients with
Low Weak
underlying cirrhosis.
• Opioids to manage pain of intermediate or severe intensity
(proactively avoid constipation)
Bone metastases causing pain, or at significant risk of spontaneous
Low
secondary fracture, benefit from palliative radiotherapy

Psychological care in the palliative setting
• Psychological burden of end-stage HCC should not be neglected

or underestimated

In patients with advanced cirrhosis, use of psychoactive drugs
(particularly benzodiazepines) to treat psychological distress is
associated with an increased risk of falls, injuries, and altered
Low Strong
mental status
• Therefore, great caution should be adopted when using them in
patients with HCC and cirrhotic liver dysfunction
Psycho-oncological support and adequate nutrition is
Low Strong
recommended according to patients’ condition

HCC research and future goals
Trial design and endpoints
EASL future goals in HCC
Unmet needs in HCC
Trial design and endpoints
• Clinical trial endpoints should be chosen with care

– OS is the most important endpoint in oncology and HCC research,
and is not subject to investigator bias

Primary endpoint for Phase 3 clinical trials should be:
• OS, when testing primary treatments
Strong
• Recurrence-free survival or time to response, when testing
adjuvant therapies after resection/ablation
Endpoints for testing neoadjuvant treatments in patients on the LT
waiting list should be:
• OS Strong
• Cancer-related deaths
• Waiting list drop-out rate
• No optimal surrogate endpoints able to recapitulate OS in HCC
exist High Weak
• TTP and PFS are not suggested as primary endpoints

Response criteria in clinical trials
• Validity of response criteria can vary depending on the treatment type

studied

ORR, in particular complete response by mRECIST, correlates with OS
High
in patients treated with thermal ablation and TACE*
For Phase 2 trials testing TACE or thermal ablation, ORR and complete
Weak
response, respectively, may be considered as primary endpoints
Phase 2 studies testing systemic therapies should be randomized and
Strong
should target OS as a primary endpoint†
Use of RECIST 1.1. and mRECIST is suggested for the assessment of
Weak
response in HCC treated with systemic therapy
*Conversely, ORR and disease control rate have not been robustly shown to correlate with OS in patients receiving systemic
therapies; †ORR, TTP and recurrence-free survival can be assessed as secondary endpoints
Patient selection in clinical trials
• Careful attention to patient selection is crucial

Selection of the target population for clinical trials should use:
• BCLC staging system
Strong
• Child–Pugh class
• ECOG performance status
Stratification for prognostic factors prior to randomization is
High Strong
critical in randomized studies and is recommended
The control arm of randomized Phase 2 and 3 studies should be the
standard of care established in the current guidelines
Strong
• When no standard of care (adjuvant trials, third-line setting) a
placebo-control arm is recommended
Upfront liver biopsy and blood sampling is recommended for
Strong
clinical and diagnostic trials

EASL future goals in HCC
• The EASL HCC panel suggested focusing on the following three goals:
– Public health policies to prevent, detect, and treat chronic liver disease
– Appropriate cancer surveillance to detect HCC in a stage amenable to
curative treatment
– Link molecular subclasses in clinical trials to therapeutic response
and outcome

Unmet needs to achieve EASL future goals
• Major health policy interventions to secure:

– Universal vaccination against HBV
– Universal treatment of HCV if indicated
– Prevention of heavy alcohol intake and obesity
• Universal implementation of surveillance programmes
• New tools for early detection, including assessment of liquid biopsy
• Transition to biopsy for HCC in all instances once a tissue biomarker predicting
response is available
• Development of new therapies for improving outcome, including adjuvant
therapies, combination trials with checkpoint inhibitors and other drugs, and
modalities (TKIs, loco-regional therapies, radiation)
• Development of third-line therapies in advanced stage
• Define optimal sequencing of systemic therapy

Unmet needs to achieve EASL future goals
• Surrogate markers recapitulating OS

• Translate molecular knowledge into precision medicine, linking response rates
in trials to molecular subgroups
• Assess the role of prognostic and predictive markers in surgical and
interventional therapies within prospective investigations
• Understand the impact of minimal invasive surgery on HCC recurrence and
post-progression survival
• Define and evaluate reliable quality of life assessment tools in HCC
• Stratify patients at risk for hepatocellular carcinoma and the utilization of
chemopreventive strategies

Hepatocellular Carcinoma: Clinical Practice Guidelines

Uploaded by

Copyright:

Available Formats

Hepatocellular Carcinoma: Clinical Practice Guidelines

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Hepatocellular Carcinoma: Clinical Practice Guidelines

Uploaded by

Copyright:

Available Formats

Clinical Practice Guidelines

• These slides give a comprehensive overview of the EASL clinical

• The guidelines were first presented at the International Liver Congress

• Definitions of all abbreviations shown in these slides are provided

These slides are intended for use as an educational resource

• Please send any feedback to: [email protected]

EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

Methods • Grading evidence and recommendations

• Incidence of primary liver cancer

Guidelines • Key recommendations

• Trial design and endpoints

EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

• Grading is a simplified adaptation of the GRADE system1

Level of evidence* Confidence in the evidence

Akinyemiju T, et al. JAMA Oncol 2017;3:1683–91 ;

Incidence rates per 100,000

EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

Incidence rates per 100,000 Total number per country

Italy 10,733 The Netherlands 475

EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

• ~90% of HCCs are of known underlying aetiology1

Alcohol (%) HBV (%) HCV (%) Others (%)

1. Epidemiology and risk factors Click on a topic to skip

EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

• Incidence of HCC has been rising

Recommendations Level of evidence Grade of recommendation

1. Forner A, et al. Lancet 2018;391:1301–1314;

• Primary prevention of HCC can be achieved with universal

Recommendations Level of evidence Grade of recommendation

*Level of evidence high, grade of recommendation strong

Fujiwara N, et al. J Hepatol 2018;68:526–49

• Effect of DAAs on HCC in patients with cirrhosis is debated

Recommendations Level of evidence Grade of recommendation

• Numerous epidemiological studies have addressed the prevention

Recommendations Level of evidence Grade of recommendation

EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

• Utility of and applicability of surveillance is influenced by a number

• Definition of target populations must consider

HCC incidence is higher in patients with more advanced cirrhosis

*Because of lower applicability of surgery

• High rate of HCC in certain risk groups makes surveillance a

Recommendations Level of evidence Grade of recommendation

• Surveillance is recommended in specific target populations

• Interval should be dictated by rate of tumour growth and tumour

• Benefit of surveillance has not been established in all risk groups

Recommendations Level of evidence Grade of recommendation

• Diagnosis generally relies on pathology

Recommendations Level of evidence Grade of recommendation

1. International Consensus Group for Hepatocellular Neoplasia. Hepatology 2009;49:658–64;

• Non-invasive diagnostic criteria for patients with cirrhosis require

• Appropriate recall policy is crucial for the success of surveillance

Recommendations Level of evidence Grade of recommendation

EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

Repeat US at 4 months Multiphasic contrast-enhanced CT or MRI,*

Biopsy unclear: Use other modality: multiphasic contrast-enhanced

1 positive technique: HCC imaging hallmarks

• Prognostic assessment is critical in the management of HCC

Recommendations Level of evidence Grade of recommendation

Treatment§ Ablation Resection Transplant Ablation Chemoembolization Systemic therapy‖ BSC