JOURNAL
OF HEPATOLOGY

Clinical Practice Guidelines

EASL Clinical Practice Guidelines: Management
of hepatocellular carcinomaq
European Association for the Study of the Liver ⇑

Summary
Liver cancer is the fifth most common cancer and the second
most frequent cause of cancer-related death globally. Hepatocellular carcinoma represents about 90% of primary liver cancers and constitutes a major global health problem. The
following Clinical Practice Guidelines will give up-to-date
advice for the clinical management of patients with hepatocellular carcinoma, as well as providing an in-depth review of all
the relevant data leading to the conclusions herein.
Ó 2018 European Association for the Study of the Liver. Published by
Elsevier B.V. All rights reserved.

Introduction
In 2012, the previous guidelines for the management of hepatocellular carcinoma (HCC) were published as a result of a joint
effort by the European Association for the Study of the Liver
(EASL) and the European Organisation for Research and Treatment of Cancer (EORTC).1 Since then several clinical and scientific advances have been achieved. Thus, an updated version of
the document is needed.

Objectives of the guideline
These EASL Clinical Practice Guidelines (CPGs) are the current
update to the previous EASL-EORTC CPGs.1 These EASL CPGs
define the use of surveillance, diagnosis and therapeutic strategies recommended for patients with HCC.
The purpose of this document is to assist physicians,
patients, healthcare providers and health-policy makers from
Europe and worldwide in the decision making process, based
on the currently available evidence. Users of these guidelines
should be aware that the recommendations are intended to
guide clinical practice in circumstances where all possible
resources and therapies are available. Thus, they should adapt
the recommendations to their local regulations and/or team

q
Clinical practice guideline panel: Peter R. Galle (chair), Alejandro Forner (EASL
governing board representative), Josep M. Llovet, Vincenzo Mazzaferro, Fabio
Piscaglia, Jean-Luc Raoul, Peter Schirmacher, Valérie Vilgrain.
⇑ Corresponding author. Address: European Association for the Study of the Liver
(EASL), The EASL Building – Home of Hepatology, 7 rue Daubin, CH 1203 Geneva,
Switzerland. Tel.: +41 (0) 22 807 03 60; fax: +41 (0) 22 328 07 24.
E-mail address: easloffice@easloffice.eu.

capacities, infrastructure and cost-benefit strategies. Finally,
this document sets out some recommendations that should be
instrumental to advancing the research and knowledge of this
disease, and ultimately contributing to improved patient care.

Methodology
Composition of the guidelines group
The guideline development group (GDG) of this guideline project is composed of international experts in the field of HCC,
comprising the areas of hepatology (PRG, AF, JL, FP), surgery
(VM), radiology (VV), oncology (JLR) and pathology (PS). Initially, the EASL governing board nominated a chair (PRG)
and a governing board member (AF) to propose a panel of
experts and finally nominated the above GDG, Additionally,
a guideline methodologist was appointed to support the
GDG (MF).
Funding and management of conflict of interests
This guideline project has kindly been supported by EASL. The
financial support did not influence the development of this
guideline. Key questions to be answered and outcomes were
chosen in accordance with the consensus of the expert panel.
Recommendations were reached by consensus of the expert
panel and based on clinical expertise and existing evidence.
A declaration of conflicts of interest was required to participate in the guideline development. The ethical committee of
EASL assessed the individual interests and decided that there
were no substantial conflicts of interest.
Generation of recommendations
In a first step the panel identified, prioritised and selected relevant topics and agreed on key questions to be answered. These
questions were clustered and distributed according to the
defined working groups, which are reflected in the different
chapters.
According to the key questions, a literature search was
performed. The studies identified and included were assessed
and assigned to categories related to study design and
strength of evidence according to endpoints. Based on this
evidence, the drafts for recommendation and chapters were
created.
Consent was provided for all recommendations during the
consensus conference, moderated by Markus Follmann, MD
MPH MSc, a certified moderator for the German Association of
Scientific Medical Societies (AWMF). Formal consensus

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methodology (nominal group technique) was used to agree
upon the recommendations. All expert panel members participated in person and were entitled to vote on the recommendations. The consensus conference was performed as a personal
meeting over two days (in June and September 2017). When
evaluating the evidence, the balance of benefits and harms,
and the quality of the evidence were taken into consideration.
Expert opinion and experience was included, particularly, if
the body of evidence was insufficient and if further aspects such
as time and costs, additional side effects, quality of life, resource
use, etc. had to be considered.
To simplify the identification of consented recommendations, all consented recommendations are highlighted throughout the guidelines documents (Tables). In order to avoid
ambiguity, a standardised language was used to classify the
direction and strength of each recommendation.
These EASL CPGs on the management of HCC provides recommendations (strong or weak) based on the level of evidence
(low, moderate, high) according to a simplified adaptation of the
GRADE system2 (Table 1).
Peer review
The final version of these CPGs was subject to peer review.
Update process
Because of the increasing number of publications, guidelines
need to be continually updated to reflect the recent state of evidence. After 2023, these guidelines will expire. Should important changes occur in the meantime, such as newly available
interventions, new important evidence or withdrawal of drug
licensing, the information contained in the guidelines will be
outdated earlier. In these cases, an update issue of the guidelines is needed earlier. EASL (cpg@easloffice.eu) will decide if
an earlier initiation of an update is required.

Table 1. Level of Evidence and Grade of Recommendations (adapted from
GRADE system).
Level of evidence*

Confidence in the evidence

High

Further research is unlikely to
change our confidence in the
estimate of benefit and risk.

Moderate

Low

Data derived from metaanalyses or systematic
reviews or from (multiple)
randomized trials with high
quality.
Data derived from a single
RCT or multiple nonrandomized studies.

Small studies, retrospective
observational studies,
registries.

Recommendationsy
Grade
strong
weak

Further research (if
performed) is likely to have
an impact on our confidence
in the estimate of benefit and
risk and may change the
estimate.
Any estimate of effect is
uncertain.

Wording associated with the
grade of recommendation
‘‘must”, ‘‘should”, or ‘‘EASL
recommends”
‘‘can”, ‘‘may”, or ‘‘EASL
suggests”

*
Level was graded down if there is a poor quality, strong bias or inconsistency
between studies; Level was graded up if there is a large effect size.
y
Recommendations were reached by consensus of the panel and included the
quality of evidence, presumed patient important outcomes and costs.

Epidemiology, risk factors and prevention
Recommendations
  The incidence of HCC is increasing both in Europe and
worldwide; it is amongst the leading causes of cancer
death globally (evidence high).
  Vaccination against hepatitis B reduces the risk of HCC
and is recommended for all new-borns and high-risk
groups (evidence high; recommendation strong).
  Governmental health agencies should implement policies to prevent HCV/HBV transmission, counteract
chronic alcohol abuse, and encourage life styles that prevent obesity and metabolic syndrome (evidence moderate; recommendation strong).
  In general, chronic liver disease should be treated to
avoid progression of liver disease (evidence high;
recommendation strong).
  In patients with chronic hepatitis, antiviral therapies
leading to maintained HBV suppression in chronic hepatitis B and sustained viral response in hepatitis C are
recommended, since they have been shown to prevent
progression to cirrhosis and HCC development (evidence
high; recommendation strong).
  Once cirrhosis is established, antiviral therapy is beneficial in preventing cirrhosis progression and decompensation. Furthermore, successful antiviral therapy
reduces but does not eliminate the risk of HCC development (evidence moderate). Antiviral therapies should
follow the EASL guidelines for management of chronic
hepatitis B and C infection.
  Patients with HCV-associated cirrhosis and HCC treated
with curative intent, maintain a high rate of HCC recurrence even after subsequent DAA therapy resulting in
sustained viral response. It is presently unclear whether
this represents the inherent risk of HCC development in
advanced cirrhosis, or if DAA therapy increases recurrence rates. Thus, further research is encouraged. Currently, close surveillance is advised in these patients.
The benefit of viral cure must be weighed against a
potentially higher recurrence risk (evidence low;
recommendation strong).
  Coffee consumption has been shown to decrease the risk
of HCC in patients with chronic liver disease. In these
patients, coffee consumption should be encouraged
(evidence moderate; recommendation strong).

Epidemiology
Liver cancer is the fifth most common cancer and the second
most frequent cause of cancer-related death globally, with
854,000 new cases and 810,000 deaths per year, accounting
for 7% of all cancers.3 Hepatocellular carcinoma (HCC) represents about 90% of primary liver cancers and constitutes a major
global health problem. The incidence of HCC increases progressively with advancing age in all populations, reaching a peak at
70 years.4,5 In Chinese and black African populations the mean

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 Clinical Practice Guidelines

Population numbers
Italy
Germany
France (metropolitan)
Russian Federation
Spain
United Kingdom
Romania
Poland
Ukraine
Greece
Portugal
Austria
Czech Republic
Switzerland
Serbia
Belgium
Bulgaria
Hungary
Finland
Sweden

Liver cancer
6.0+
4.8-6.0
3.4-4.8
2.7-3.4
<2.7
No data

10,733
9,202
8,332
6,812
5,522
4,186
2,214
1,998
1,567
1,054
1,004
955
919
811
799
645
640
630
620
490

The Netherlands
Croatia
Republic of Moldova
Slovakia
Belarus
Bosnia Herzegovina
Denmark
Ireland
Slovenia
Norway
Lithuania
Albania
Latvia
FYR Macedonia
Luxembourg
Estonia
Cyprus
Montenegro
Malta
Iceland

475
466
448
398
327
314
311
239
216
190
175
171
154
135
68
64
56
51
19
10

Fig. 1. Incidence rates of primary liver cancer according to geographical distribution in Europe. Total numbers per country and age-adjusted incidence
rates per 100,000 of liver cancer in Europe in 2012. The colour intensity is proportional to the magnitude of incidence. Available from: http://globocan.iarc.fr.
Data refer to all primary liver cancers (hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver cancer of mixed differentiation). Source:
GLOBOCAN 2012, IARC -29.11.2017

age of patients with the tumour is appreciably younger. This is
in sharp contrast to Japan, where the incidence of HCC is highest
in the cohort of men aged 70 to 79 years.6,7 HCC has a strong
male preponderance, with a male to female ratio estimated to
be 2–2.5:1.8
The pattern of HCC occurrence shows a significant geographical imbalance, with the highest incidence rates in East Asia
(more than 50% of the cases occurring in China) and sub-Saharan Africa, together accounting for about 85% of all cases.8 In
Europe, the incidence is lower with the exception of Southern
Europe, where the incidence in men (10.5 age-standardised
incidence rates per 100,000) is significantly higher9 (Fig. 1).
HCC incidence has been growing on a global scale. Between
1990 and 2015 newly diagnosed HCC cases increased by 75%,
mainly due to changing age structures and population growth.
Age-standardised incidence rates have increased in many high
socio-demographic index countries like the USA, Canada, Australia, New Zealand and most European countries; conversely,
some countries with high incidence rates like China and Eastern
Sub-Saharan Africa have experienced a decrease by more than
20%.3
Annual incidence and mortality rates were 65,000 and
60,240 cases in Europe and 21,000 and 18,400 cases in the
USA in 2008, respectively. It is estimated that by 2020 the number of cases will reach 78,000 and 27,000, respectively.8 In Europe, hepatitis C virus (HCV) infection during 1940–60 and in the
USA one decade later led to the current increase in HCC incidence. In Europe, the incidence and mortality rates reported
are heterogeneous. During the last decades HCC mortality
increased in males in most countries (i.e. Austria, Denmark, Germany, Greece, Ireland, Portugal, Norway, Spain, Switzerland,
and United Kingdom), but decreased in some others (Finland,
France, Italy, Netherlands, and Sweden).9 In the USA, the rate
of HCC deaths appears to have increased by about 40% from
1990 to 2004, in contrast to the overall rate of cancer deaths,
which declined by about 18% during the same period.10 This
growth in incidence was due to the emergence of chronic liver
disease, mainly chronic hepatitis C, but also to an increase in
hepatitis B virus (HBV)-related HCC, particularly among immigrants from countries with endemic HBV infection, and the
184

increasing incidence of non-alcoholic fatty liver disease
(NAFLD). Projections of cancer incidence and deaths in the
USA estimate that, in 2030, liver cancer will be the third leading
cause of cancer-related deaths, surpassing breast, colorectal,
and prostate cancers.11,12 Conversely, in Japan, a country where
the impact of HCV-related HCC was first noticed after World
War II, a decline in HCC incidence has been noted for the first
time since 1990.6,7 Finally, the impact of universal infant vaccination against HBV has decreased the rate of HBV-related HCC
in endemic countries, as reported for children and younger
adults in Taiwan.13,14
Aetiology and risk factors
Approximately 90% of HCCs are associated with a known underlying aetiology3 (Table 2), most frequently chronic viral hepatitis (B and C), alcohol intake and aflatoxin exposure. In Africa and
East Asia, the largest attributable fraction is caused by hepatitis
B (60%), whereas in the Western world only 20% of cases can be
attributed to HBV infection, while chronic hepatitis C appears to
be the major risk factor.3 Worldwide, approximately 54% of
cases can be attributed to HBV infection (which affects 400 million people globally) while 31% can be attributed to HCV infection (which affects 170 million people), leaving approximately
15% associated with other causes. However, these calculations
are rough estimates which do not reflect co-morbidities and
are likely to underestimate the impact of non-alcoholic steatohepatitis/metabolic syndrome.3
Cirrhosis is an important risk factor for HCC, and may be
caused by chronic viral hepatitis, chronic alcohol abuse acquired
and inherited metabolic diseases, such as NAFLD, as well as
genetic haemochromatosis, or in some cases alpha-1-antitrypsin deficiency. All aetiologic forms of cirrhosis may be complicated by tumour formation, but the risk is higher in patients
with chronic viral hepatitis. Overall, one-third of cirrhotic
patients will develop HCC during their lifetime.15 Long-term follow-up studies have found that approximately 1–8% of patients
with cirrhosis develop HCC per year (e.g. 2% in HBV-infected cirrhotic patients and 3–8% in HCV-infected cirrhotic patients).16
In general, features of liver disease severity (low platelet count
of less than 100x109/L, presence of oesophageal varices) in

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Table 2. Geographical distribution of main risk factors for primary liver
cancer world-wide.
Europe
Western
Central
Eastern
North America
Andean Latin America
Asia
East Asia
Asia-Pacific
South-East Asia
Africa
North Africa, Middle East
Southern (sub-Saharan)
Western (sub-Saharan)

Alcohol (%)

HBV (%)

HCV (%)

Others (%)

32
46
53
37
23

13
15
15
9
45

44
29
24
31
12

10
10
8
23
20

32
18
31

41
22
26

9
55
22

18
6
21

13
40
29

27
29
45

44
20
11

16
11
15

Contribution of hepatitis B, C, alcohol and other causes on absolute liver cancer
deaths, both sexes, globally and by region 2015 (3). Data refer to all primary liver
cancers (hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver cancer of mixed differentiation). HBV, hepatitis B virus; HCV, hepatitis C virus.

addition to older age and male gender correlate with development of HCC among patients with cirrhosis.17 Recent studies
have shown that liver cancer incidence increases in parallel to
portal pressure, measured directly18 or linked to the degree of
liver stiffness as measured by transient elastography.19–24
Several studies have identified HBV-related factors as key
predictors of HCC development in patients with chronic hepatitis B infection. Hepatitis B virus e antigen seropositivity,25 high
viral load,26 and genotype C27 are independent predictors of
HCC development. In addition, hepatitis B viral load correlates
with the risk of progression to cirrhosis.28 Similarly, recent
meta-analyses claimed that the risk of HCC development is
increased in patients with HCV genotype 1b29 or genotype 3.30
Dietary exposure to aflatoxin B1 is an important co-factor for
HCC development in parts of Africa and Asia. Aflatoxin B1 exposure originates from fungal contaminations of staple foodstuffs
preferentially in tropical and subtropical regions. Epidemiologic
and molecular studies have shown a strong correlation between
aflatoxin B1 exposure, TP53 mutations (codon 249) and incidence of HCC, specifically in HBV-infected individuals.31
For patients with alcoholic liver cirrhosis, an increased risk of
developing HCC has been reported for most parts of the world
(with the exception of Northern Europe), including France32
and Spain.33 Regarding other risk factors, patients with
haemochromatosis develop HCC in up to 45% of cases,34 almost
exclusively in stage III of the disease (cirrhosis).35 HCC is more
frequent in patients affected with acute hepatic porphyria36
and porphyria cutanea tarda,37 as well as being a well-documented complication of cirrhosis associated with alpha-1-antitrypsin deficiency.38
Growing evidence from retrospective investigations suggests
an increased HCC incidence in patients with NAFLD associated
with metabolic syndrome, diabetes,39,40 and obesity.41 Moreover, metabolic syndrome has an additive risk effect in those
patients with chronic viral hepatitis.42,43 Overall, NAFLD is
becoming a relevant cause of HCC in developed regions44–46
and it is estimated that in the USA between 500,000 and
900,000 new cases of HCC may develop as a result of the high
prevalence of metabolic syndrome and NAFLD.47 In NAFLD,
the reported HCC incidence is very heterogeneous, ranging from
0.25% to 7.6%.48 Furthermore, in a relevant proportion of

patients, HCC develops in non-cirrhotic livers.49,50 NAFLD may
overlap with alcohol-related liver disease and future epidemiologic studies should address the relevance of this aspect of comorbidity.49 Epidemiologic evidence of a link between cigarette
smoking and the occurrence of HCC was traditionally conflicting, but recent evidence supports that smoking is a significant
co-factor.51,52 The incidence of HCC is higher among patients
with HIV infection than controls in the general population,
and HIV appears to be an additive co-factor, increasing the risk
of HCC in patients with chronic viral hepatitis.53
Prevention
Primary prevention of HCC can be achieved with universal vaccination against HBV infection.14 Vaccination against hepatitis B
is recommended by the World Health Organization for all newborns and high-risk groups.54 Since perinatal or early postnatal
transmission is an important cause of chronic HBV infections
globally, the first dose of hepatitis B vaccine should be given
as soon as possible after birth even in low-endemic countries
(those with prevalence of hepatitis B surface antigen carriers
<2%). Vaccination is also recommended in age-specific cohorts
(young adolescents) and people with risk factors for acquiring
HBV infection (i.e. health workers, travellers to areas where
HBV infection is endemic, injecting drug users, and people with
multiple sex partners).
Antiviral treatment for patients with chronic hepatitis B and
C infection should follow the recommendations of existing
European Association for the Study of the Liver guidelines.55,56
Pegylated interferon alfa, lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir disoproxil fumarate and tenofovir
alafenamide are now available for HBV treatment, but longterm follow-up data assessing their efficacy in secondary
prevention of HCC are only available for interferon, lamivudine
entecavir, and tenofovir disoproxil fumarate treatment. Observational studies assessing the effect of interferon showed a
potential effect in reduction of HCC incidence,57 and long-term
therapy with nucleotide or nucleoside analogues appears to
favourably impact HCC incidence when data from randomised
or matched controlled studies are considered.58,59 After the first
five years of entecavir or tenofovir disoproxil fumarate therapy,
recent data suggest that HCC incidence is decreasing further,
with the decrease more evident in patients with baseline
cirrhosis.60,61
In hepatitis C viral infection, all-cause mortality and the risk
of HCC is reduced among patients with HCV who achieve a sustained virological response (SVR) with interferon-based antiviral therapy.62 Meta-analyses of interferon-based therapies
showed a more than 70% reduction in HCC incidence (absolute
risk reduction: 4.6%) after SVR,63 independently of the grade
of fibrosis. Patients with liver cirrhosis acquire a reduced
HCC incidence after SVR, however, a relevant risk (<1.5%
[0.3–2.4%]) remains.64,65 Based on these data, SVR after HCV
treatment leads to reduced HCC incidence, but surveillance of
cirrhotic patients for HCC after SVR should be maintained as
outlined below.56,66 The advent of the new direct-acting antivirals (DAA) has been a major breakthrough because of their high
efficacy, and their adequate safety profile which enabled their
use in patients with advanced liver disease, in whom interferon-based regimens were not recommended. Based on previous studies assessing the benefits of interferon-based
treatments, HCV eradication was expected to translate into a
reduced incidence of de novo tumours in patients with HCV.

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Furthermore, recurrence of HCC after initial anti-tumour treatment was also hoped to be reduced through HCV cure. However,
some recent reports claimed that the HCC risk may remain
higher in patients after DAA therapy than after interferon-based
treatment. An alarm signal was released about a potentially
increased risk of early tumour recurrence in successfully treated
patients with HCC who received DAA therapy.67,68 In addition,
this appeared to be associated with a more aggressive tumour
behaviour after therapy.69 These observations were suggested
to be related to the immune distortion associated with the rapid
decrease in viral load, leading to changes in the inflammatory
profile. This could translate into impaired immune surveillance,
favouring the growth of already existing preclinical cancer
clones. Another, more simplistic explanation could come from
the broader spectrum of patients receiving antiviral therapy in
the DAA era: more patients with a higher risk of developing
HCC are treated, since DAA therapy can be offered to patients
with more advanced liver disease who would not have been
considered suitable for interferon treatment.
These studies led to several groups around the world publishing their experiences, but the limitations in several key
aspects of the studies (retrospective assessment, absence of
HCC screening, short follow-up and an excessive number lost
to follow-up) impedes a robust conclusion.70–76 Very recently,
a meta-analysis concluded that there is no evidence that HCC
occurrence or recurrence is different between patients receiving
DAA or IFN therapy, but its strength is limited because of the
inclusion of significantly heterogeneous studies without adequate follow-up for detecting HCC.77 Another large retrospective cohort study of hepatitis C virus patients (n = 22,500) who
were treated with DAA examining in the VA population demonstrated a reduction in the incidence of hepatocellular carcinoma
in patients achieving a SVR.78
To adequately assess the risk of HCC recurrence/development, it is essential to determine if treated patients were properly screened for HCC before DAA initiation, how and for how
long follow-up screening was performed and finally, if the incidence of HCC during follow-up was one of the endpoints of retrospective analysis.79 Regrettably, in most of the previous
studies these variables were not registered, limiting the
strength of their conclusions. Therefore, further information
about the HCC incidence after viral cure is still needed.
It is of great clinical relevance to point out that patients with
HCV-associated cirrhosis and HCC treated with curative intent
maintain a high rate of HCC recurrence even after subsequent
DAA therapy. In these patients, close surveillance (tertiary prevention) is advised and the benefit of viral cure must be
weighed against a potentially higher recurrence risk. The follow-up after HCC treatment with curative intent and subsequent successful DAA treatment implies 3–4-month imaging
intervals for the first two years that can be extended to sixmonth intervals thereafter.
Numerous epidemiological studies have addressed the prevention of HCC in patients with chronic liver disease. Among
these, only trials analysing the effect of coffee consumption
have shown a consistently positive effect with regard to lowering HCC incidence. A large-scale population-based Japanese
cohort study showed an association between coffee drinking
and reduced risk of liver cancer. Individuals who consumed coffee on a daily basis had a lower HCC risk than those who almost
never drank coffee (hazard ratio 0.49; 95% CI 0.36–0.66); this
inverse association was confirmed in patients with chronic hep-

186

atitis C.80 Similarly, a reduced HCC risk independent of its aetiology was found in Italy in a hospital-based case-control study81
and confirmed in a meta-analysis of case-control studies and
cohort studies from Japan and Southern Europe.82,83 Recently,
in the European Prospective Investigation into Cancer and
Nutrition, a nested case-control study confirmed an inverse
relationship between coffee intake and HCC (risk ratio of having
four or more cups vs. less than two cups was 0.25; 95% CI 0.11–
0.62).84 The benefit of coffee consumption in liver disease is not
limited to HCC; in the US Multi-ethnic Cohort (more than
215,000 people) high levels of coffee consumption were associated not only with reduced HCC incidence, but also with lower
chronic liver disease mortality.85 None of the studies have
reported adverse hepatic effects of coffee consumption. Therefore, for the first time the panel has seen sufficient evidence
to encourage patients with chronic liver diseases to drink coffee
in order to decrease liver-related mortality and HCC development. A clear dose recommendation can currently not be given.

Surveillance
Recommendations
  Implementation of screening programmes to identify atrisk candidate populations should be improved. Such
programmes are a public health goal, aiming to decrease
HCC-related and overall liver-related deaths (evidence
low; recommendation strong).
  Patients at high risk of developing HCC should be
entered into surveillance programmes. Government
health policy and research agencies should address these
needs. Groups at high risk are depicted (Table 3) (evidence moderate; recommendation strong).
  The role of surveillance for patients with NAFLD without
cirrhosis is unclear (evidence low).
  Surveillance should be performed by experienced personnel in all high-risk populations using abdominal
ultrasound every six months (evidence moderate; recommendation strong)
  Tumour biomarkers for accurate early detection are still
lacking. The data available 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 (evidence low).
  Patients on the waiting list for liver transplantation
should be surveilled for HCC in order to detect and manage tumour occurrence or tumour response, and to help
define priority policies for transplantation (evidence
low; recommendation strong).

Surveillance consists of the periodic application of a diagnostic test to individuals at specific risk of developing a given disease. Its usefulness and applicability are influenced by several
factors, such as the incidence of the surveyed disease in the target population, the availability of efficient diagnostic test(s) at
bearable costs and acceptability for the target population, and
the availability of treatments and their effectiveness.86 The

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aim of surveillance is to obtain a reduction in disease-related
mortality. This is usually achieved through a diagnosis of the
disease at the early stage that, in turn, enhances the applicability and improves cost-effectiveness of therapies.
In the Western world, hepatocellular carcinoma (HCC) arises
in a cirrhotic background in up to 90% of cases.87 Cirrhosis not
only hampers the application of tumour therapies, but it is itself
a progressive disease that affects patient survival. A reduction in
overall mortality represents the most appropriate endpoint to
assess the efficacy of surveillance.
At present, there is insufficient evidence to modify the previously established definition of at-risk patients, but grey areas
exist, requiring specific evidence. In particular, exact estimation
of the HCC development risk in non-cirrhotic patients with nonalcoholic fatty liver disease (NAFLD) and in cirrhotic patients
with long standing removal of the aetiological factors remains
an unmet need, to be addressed by future research.
Ultrasound (US) is the method of choice and is often applied
beyond HCC surveillance to monitor other conditions, such as
the development of portal hypertension, including the onset of
ascites or portal vein thrombosis, although its use in this setting
has not been well defined.
Target populations
According to the general principles of surveillance, factors
affecting the definition of the target population must consider
the incidence of HCC in a specific set of patients and the probability that effective therapies, particularly radical ones, are suitable for these patients. Notably, in the setting of HCC, the
incidence is higher in more advanced liver disease, but the probability of receiving radical (mainly surgical) therapies becomes
lower, because of lower applicability of surgery, thus different
incidence thresholds may apply to different target populations.
In fact, decision analysis and cost-effectiveness models suggest that an intervention is considered cost-effective if it provides life expectancy increases of at least three months with a
cost below an established threshold. Conventionally the threshold adopted by most agencies in the last couple of decades has
been US $50,000 per year of life saved,88 although either 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.89,90
Cirrhotic patients
Cost-effectiveness studies indicate that an incidence of 1.5%/
year or greater would warrant surveillance of HCC in cirrhotic
patients,91 irrespective of its aetiology.92,93 However, the presence of cirrhosis with advanced liver failure (Child-Pugh class
C) or decompensation in the Child-Pugh class B (with large
ascites, hepato-renal syndrome or clinical jaundice) prevents
effective HCC therapies from being employed when transplantation is not an option. Accordingly, surveillance for HCC is not
cost-effective in these patients,94 but must instead be carried
out for patients on the waiting list for transplantation for
cirrhosis, as HCC onset may modify both priority on the list
and transplantability. Finally, although it seems intuitive that
surveillance might not be cost-effective above a certain age
cut-off, the lack of data prevents adoption of any specific recommendation: therefore, patients’ conditions and the consequently
estimated life expectancy should support the choice, rather than
age alone.

Non-cirrhotic individuals
Patients with chronic hepatitis B virus (HBV) infection are at
risk of HCC development even in the absence of cirrhosis, but
the exact degree of risk is ill-defined and appears influenced
by geographical region (higher in Asia and Africa than in Western Countries,95,96 higher levels of HBV replication,97,98 age
and gender (males higher than female). These patients are at
higher risk than the general population and at lower than
patients with established HBV cirrhosis, but they are also more
suitable for surgical treatments. Thus, cost-benefit modelling is
needed in this scenario and expert opinion indicates that
surveillance would be warranted if HCC incidence is at least
0.2%/year.92,93,99 Therefore, even though regular six-month
surveillance may not be indicated at initial observation, it may
be recommended at a later time. Therefore, such patients should
be regularly reassessed even though standard surveillance is not
yet warranted. Additionally, fibrosis tends to progress to cirrhosis over time in untreated patients, but may benefit instead
from antiviral therapies leaving a potential space of uncertainty
in deciding upon start and continuation of surveillance and further claiming for HCC risk stratification.99 Therefore, some prognostic models have been proposed to assess the risk of
developing HCC, but none of the studies have universal applicability. Concerning immigrants to Europe from areas where HBV
is endemic an individual risk assessment is required as the
impact of migration on HCC risk has not been thoroughly
investigated.
Patients with chronic hepatitis C and bridging fibrosis in the
absence of cirrhosis (Metavir F3) are also at risk of being understaged and thus at significant risk of HCC.17 Additionally, the
fact that the transition from advanced fibrosis and cirrhosis cannot be accurately defined, led the European Association for the
Study of the Liver to recommend surveillance for patients with
bridging fibrosis. This panel continues to endorse such a policy.
In this respect, transient elastography appears to be a promising
tool that is able to stratify patients with active viral replication
at different HCC risks.19–24
Information about the incidence of HCC in patients with nonviral chronic liver disease without cirrhosis, such as alcoholic
and non-alcoholic steatohepatitis (NASH), autoimmune liver
disease, genetic haemochromatosis, alpha-1-antitrypsin deficiency, and Wilson’s disease is limited.34–38 However, available
evidence suggests that HCC usually arises in these contexts once
cirrhosis is established.87
It is estimated that half of the cases of NASH-induced HCC
arise in non-cirrhotic patients.50,100 However, the incidence of
HCC in these non-advanced patients is expected to be insufficiently high to deserve universal surveillance, given the large
prevalence of NAFLD in the general population. However, it is
important that patients at risk in the future are identified, in
order to categorise those who should be screened for HCC.
The obesity of these patients is another challenge, as it makes
US screening more difficult. Radiological methods, such as computed tomography (CT) scans or magnetic resonance imaging
(MRI), are available, but the surveillance programme would no
longer be cost-effective. There is a clear need to prospectively
acquire information on cohorts of patients with NASH, in order
to define high-risk patients who should undergo surveillance.101
Moreover, such patients are also more prone to obesity and cardiovascular disease, which may hamper a surgical approach.
Therefore, no evidence-based recommendation about imple-

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Table 3. Recommendations for HCC surveillance: Categories of adult
patients in whom surveillance is recommended.
  Cirrhotic patients, Child-Pugh stage A and B (evidence low; recommendation strong)
  Cirrhotic patients, Child-Pugh stage C awaiting liver transplantation
(evidence low; recommendation strong)
  Non-cirrhotic HBV patients at intermediate or high risk of HCC* (according to PAGE-By classes for Caucasian subjects, respectively 10–17 and ≥18
score points) (evidence low; recommendation weak)
  Non-cirrhotic F3 patients, regardless of aetiology may be considered for
surveillance based on an individual risk assessment (evidence low;
recommendation weak)
*
Patients at low HCC risk left untreated for HBV and without regular six months
surveillance must be reassessed at least yearly to verify progression of HCC risk.
y
PAGE-B (Platelet, Age, Gender, hepatitis 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/ll = 0, 100,000–199,999/ll = 1, <100,000/ll = 2): a total
sum of ≤9 is considered at low risk of HCC (almost 0% HCC at five years) a score of
10–17 at intermediate risk (3% incidence HCC at five years) and ≥18 is at high risk
(17% HCC at five years).114

mentation of surveillance programmes in this setting can be
made.
Some factors are associated with a higher risk of severe/
fibrosis cirrhosis and HCC occurrence, such as the presence of
diabetes mellitus, older age102 and concurrent alcohol intake.103
Furthermore, simple laboratory scores help identify patients at
greater risk of severe fibrosis warranting more in-depth assessment. Studies of genetic factors suggested the PNPLA3 148 M
variant at rs738409 to be associated with HCC development in
obese individuals104 and in patients with histologically proven
NAFLD.105 Whether a combination of these or other parameters
may identify individuals at a risk of HCC high enough to deserve
specific surveillance is still a matter of investigation. To summarise, patients with metabolic syndrome or NASH identified
to be affected by severe fibrosis or cirrhosis either by histology
or elastography should undergo surveillance,106 in keeping with
the general recommendation reported above, whereas the risk
of HCC development is insufficiently established in individuals
without severe fibrosis/cirrhosis to deserver universal surveillance for HCC.
Treated viral chronic hepatitis
Recent advances in therapy have led to relatively high rates of
viral clearance or suppression among those being treated for
chronic hepatitis B or C. Successful treatment leading to sustained virological response (SVR) in chronic hepatitis C, and
hepatitis B e antigen seroconversion or sustained HBV-DNA suppression in chronic hepatitis B, decreases, but does not eliminate the risk of HCC.58,63,107,108 Surveillance should be offered
to treated patients with chronic hepatitis B who remain at risk
of HCC development because of baseline factors, or those with
hepatitis C virus (HCV)-induced advanced fibrosis or cirrhosis,
even after achieving SVR. The value of shear wave elastography
to identify patients with chronic hepatitis at greater risk of HCC
has been proven in replicating HCV, but has been insufficiently
validated in patients who achieved SVR after HCV eradication. In
particular, the stiffness thresholds associated with sustained
higher risk of HCC development, after achieving SVR with
PegIFN-based therapies, ranged from 6.5 to 12.0 kPa.109–111
Therefore, given the current knowledge there is no evidence
for a timing or stiffness threshold to stop surveillance in
patients who were included in surveillance programmes prior

188

to interferon-based anti-HCV therapy. There is even less information in patients achieving SVR after direct-acting antiviral
(DAA) therapies, therefore, there is no evidence to change the
indication for surveillance. The limited data produced so far
showed that HCC occurrence is not eliminated in patients at
risk, at least in the short/mid-term after SVR of HCV with
DAA, mandating continued surveillance.68,112–114
In connection with patients infected with HBV, one HCC risk
stratification model includes also specific stratification of risks
in Caucasian patients respectively starting nucleos(t)ide analogues (NUC) antiviral therapy or continuing long-term treatment beyond five years.60,115 Data showed that Caucasian
patients with cirrhosis at the time of initiating NUC therapy
benefit from a decrease in HCC yearly incidence between the
first five and second five years of treatment, specifically from
3.22% to 1.57%.60 However, even the latter incidence remains
higher than the recommended threshold for receiving surveillance. Therefore, these data confirm that surveillance is to be
maintained in patients infected with HBV who have reached
the stage of cirrhosis for no less than 10 years, regardless of
receiving effective antiviral treatment. In connection with
NUC-treated non-cirrhotic patients, the global incidence rate
of HCC was shown to be lower than in cirrhotic patients, as
expected,60,115 but does not appear to decrease overall after five
years of therapy (0.49% in the first five years vs. 0.47% in years 5
to 10),60 remaining slightly higher than the recommended
threshold for initiating HCC surveillance. However, this global
incidence of HCC, only slightly higher than the surveillance
threshold, can be further stratified into at least three different
patient groups in Caucasian individuals (low, intermediate, high
risk of HCC) according to the PAGE-B classification.115 Patients
in the low HCC risk class (PAGE-B score ≤9, Table 3), which represent about one-fourth of large case series of patients infected
with HBV115 hardly developed HCC up to 10 years after starting
NUC60,115 and therefore do not overcome the 0.2%/y threshold
for starting surveillance. The PAGE-B score has not yet been validated in Asia, but other scores have been produced in this geographical region, such as the GAG-HCC,116 CUHCC116 and
REACH-B117 systems, which tend to include similar prognostic
variables as the PAGE-B, but whose validation appeared suboptimal in Caucasian patients. Hence, only locally produced HCC
risk stratification scores in HBV are to be applied in specific geographical regions, to reliably avoid surveillance treated HBV
non-cirrhotic patients at low risk of HCC.99
Surveillance tests
Tests that can be used in HCC surveillance include serological
and imaging examinations. The imaging test most widely used
for surveillance is US, which has an acceptable diagnostic accuracy when used as a surveillance test (sensitivity ranging from
58 to 89%; specificity greater than 90%).118 A meta-analysis
including 19 studies showed that US surveillance detected the
majority of HCC tumours before they presented clinically, with
a pooled sensitivity of 94%. However, US was less effective for
detecting early-stage HCC, with a sensitivity of only 63%.119
The widespread popularity of US also relies on the absence of
risks, non-invasiveness, good acceptance by patients and relatively moderate cost, and its capacity to detect the onset of
other complications of cirrhosis early, such as subclinical ascites
or portal vein thrombosis, which may also require prompt
treatment. Nonetheless, US detection of HCC on a cirrhotic

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background is a challenging issue, particularly in the instance of
very coarse liver echotexture on US, which may impair identification of small tumours. Because of these limitations, the performance of US in early detection of HCC is highly dependent
on the expertise of the operator and the quality of the equipment. Thus, special training is recommended. The use of pure
blood pool US contrast agents (commonly utilised in Europe)
has not proven to increase the ability of US to detect small
HCC tumours.120
Multidetector CT or dynamic MR imaging are not cost-effective for surveillance in general, because of the considerable rate
of false-positive findings and the need to use contrast agents to
achieve adequate sensitivity.121 Practical experience suggests
that the rate of false-positive results that will trigger further
investigation is very high and non-cost-effective. These circumstances are overcome in the setting of the waiting list for liver
transplantation, where CT scan or MRI are alternatives to US.
These techniques should also be considered when obesity,
intestinal gas, and chest wall deformity prevent an adequate
US assessment. Even in these circumstances, radiation risk due
to repeated exposure to CT scan and the high cost of MR and
the need for contrast injection with the associated risks of allergic reaction and the recent reported brain accumulation of
gadolinium122 make their use in long-term surveillance highly
debatable.
Serological tests that have been investigated or are under
investigation for early diagnosis of HCC include alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP) -also known
as prothrombin induced by vitamin K absence II (PIVKA II)- the
ratio of glycosylated AFP (L3 fraction) to total AFP, alpha-fucosidase, and glypican.123–125 AFP is the most widely tested biomarker in HCC. It is known that persistently elevated AFP levels are
a risk factor for HCC development and can be used to help define
at-risk populations.126 Notably, AFP has mostly been tested in
the diagnostic mode rather than for surveillance. This is relevant, since its performance as a diagnostic test cannot be
extrapolated to the surveillance setting. As a serological test
for surveillance, AFP has a suboptimal performance. One randomised study127 and one population-based observational
study128 reached opposite results. The latter study provides a
rationale for testing AFP in special populations or healthcare
environments when US is not readily available.128 However,
when combined with US, AFP levels are only able to provide
additional detection in 6–8% of cases not previously identified
by US, also confirmed more recently.129 Reasons for the suboptimal performance of AFP as a serological test in the surveillance
mode are twofold. Firstly, fluctuating levels of AFP in patients
with cirrhosis might reflect flares of HBV or HCV infection, exacerbation of underlying liver disease or HCC development.130
Secondly, only a small proportion of tumours at an early stage
(10–20%) present with abnormal AFP serum levels, a fact that
has recently been correlated with a molecular subclass of
aggressive HCCs (S2 class, EpCAM positive).131–133 When used
as a diagnostic test, AFP levels at a value of 20 ng/ml show good
sensitivity but low specificity, whereas at higher cut-offs of 200
ng/ml the sensitivity drops to 22% with high specificity.134 However, such information was mostly obtained in viraemic
patients, in whom active hepatitis may act as a confounding factor. When such a factor is removed by pharmacological treatment, the diagnostic accuracy of AFP significantly increased
because of the reduction of false-positive cases at lower AFP
thresholds (as low as 12–20 ng/ml)135–139 Despite great interest

in these results suggesting a potential for AFP at least in this setting, there is still insufficient evidence to calculate the costeffectiveness of AFP in the surveillance of patients with hepatitis
B virus at risk of HCC in Western countries and whether this
oncomarker has any additional role and impact on survival in
comparison to US alone. Hence, research efforts to this end
are highly warranted. Similar analyses have not yet been provided for patients with hepatitis C virus, because of the very
recent introduction of direct-acting antivirals able to effectively
eradicate HCV in large populations of cirrhotic patients.
Specific evidence about the utility of AFP for early tumour
detection when used to complement US surveillance in patients
with unsatisfactory liver US explorability does not exist and
thus no recommendation can be made.
All other serum markers have usually been evaluated, alone
or in combination, in a diagnostic or prognostic, rather than
surveillance setting. Moreover, their diagnostic performance
has often been assessed at an HCC prevalence remarkably
higher than that expected in the context of surveillance.140 In
addition, DCP levels have been associated with portal vein invasion and advanced tumoural stage, a fact that prevents the
usage of this marker for early detection.141 A similar situation
occurs with AFP-L3 fraction levels.142 At present, none of these
tests can be recommended for surveillance of patients at risk of
developing de novo HCC.
In conclusion, US can be seen as the most appropriate test
to perform surveillance. The combination with AFP is not recommended in patients with active liver inflammation, as the
6–8% gain in the detection rate does not counterbalance the
increase in false-positive results, ultimately leading to an
approximately 80% increase in the cost of each small HCC
diagnosed.119,143 It is worth remarking that insufficient data
are available regarding the diagnostic accuracy of AFP in
patients with adequate treatment of the aetiological cause
of liver disease (effective antivirals, abstinence from alcohol,
etc.), making any calculation of the cost-effectiveness impossible to date.
Surveillance efficacy
Only one randomised controlled trial was published on HCC
surveillance with US. This was a population-based study with
cluster randomisation (randomising entire villages) comparing
US and AFP measurements every six months vs. no surveillance
in a population of Chinese patients with chronic hepatitis B
infection regardless of the presence of cirrhosis.144 Despite suboptimal adherence to the surveillance programme (55%), HCCrelated mortality was reduced by 37% in the surveillance arm
because of increased applicability of resection in detected cases.
Other types of evidence include population and non-population-based cohorts and cost-effectiveness analysis which mostly
reinforce the benefits of regular US schemes.94,119,145–151 However, these studies are heterogeneous as far as stage and aetiology of liver disease, and surveillance protocols. Moreover,
almost all suffer from methodological biases such as lead-time
bias (apparent improvement of survival because of an anticipated diagnosis) and length time bias (over-representation of
slower-growing tumours). While the latter is unavoidable in
this type of study, lead-time bias can be minimised using correction formulas. Nonetheless, in a recent retrospective
case-control study from Italy, lead-time bias accounted for
most of the surveillance benefit, but only until the third year
of follow-up after HCC diagnosis.152 Moreover, after

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lead-time adjustment, estimated in 6.5 months, semi-annual
surveillance maintained a survival benefit over symptomatic
diagnosis.152
Surveillance interval
The ideal interval of surveillance for HCC should be dictated by
two main features: rate of tumour growth up to the limit of its
detectability, and tumour incidence in the target population.
Based on the available knowledge on mean HCC volume doubling time;145,146,148 a six-month interval represents a reasonable choice, since a shorter interval of three months did not
translate into any clinical benefit149 and a longer interval of
12 months appears cost-effective, but with fewer early-stage
HCC diagnoses153 and shorter survival.150
Finally, cost-effectiveness studies have shown that semiannual US-based surveillance improves quality-adjusted life
expectancy at a reasonable cost.154 In light of available knowledge, a six-month scheduled surveillance is the preferable
choice. Further trials in this setting would be difficult to
implement.

Diagnosis
Recommendations
  Diagnosis of HCC in cirrhotic patients should be based on
non-invasive criteria and/or pathology (evidence high;
recommendation strong).
  In non-cirrhotic patients, diagnosis of HCC should be
confirmed by pathology (evidence moderate; recommendation strong).
  Pathological diagnosis of HCC should be based on the
International Consensus recommendations using the
required histological and immunohistological analyses
(evidence high; recommendation strong).
  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 based on imaging techniques
obtained by multiphasic CT, dynamic contrast-enhanced
MRI (evidence high; recommendation strong) or CEUS
(evidence moderate; recommendation weak). 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 s) washout
of mild intensity on CEUS).
  Because of their higher sensitivity and the analysis of the
whole liver, CT or MRI should be used first (evidence
high; recommendation strong).
  FDG PET-scan is not recommended for early diagnosis of
HCC because of the high rate of false negative cases (evidence low; recommendation strong).

190

Imaging-based diagnosis
Imaging is an essential part of hepatocellular carcinoma (HCC)
diagnosis, contributing to primary liver tumour typing and
HCC staging. Non-invasive imaging diagnosis of HCC in the setting of a cirrhotic liver was accepted in 2001, when dynamic
imaging explorations demonstrated the typical diagnostic pattern155 (updated in 2005156). Imaging-based diagnosis relies
on the peculiar vascular derangement occurring during hepatic
carcinogenesis157 and of the high pre-test probability of HCC in
the setting of cirrhosis,158–161 although the frequency of intrahepatic cholangiocarcinoma (CC) and combined HCC/CC is also
increased in cirrhosis.162 The higher pre-test probability is also
the reason why a non-invasive diagnosis is only accepted by the
European Association for the Study of the Liver (EASL) in cirrhotic patients, appreciating that there are non-cirrhotic
patients at significant risk of developing HCC. Contrastenhanced imaging methods are necessary for the diagnosis of
HCC and are based on vascular phases (lesion appearance in
the late arterial phase, in the portal venous phase, and in the
delayed phase).159,161,163 The typical hallmark is the combination of hypervascularity in late arterial phase (defined as arterial
phase hyperenhancement [APHE] according to LI-RADS [Liver
Imaging Reporting and Data System] classification) and washout on portal venous and/or delayed phases, which reflects
the vascular derangement occurring during hepatocarcinogenesis.157 The previous EASL-European Organisation for Research
and Treatment of Cancer (EORTC) guidelines have raised concerns focussed particularly on two aspects of HCC diagnosis:
the diagnostic criteria according to tumour size and the imaging
modality. As studies have shown a dramatic drop in sensitivity
when two coincidental imaging techniques were required in
HCCs between 10 and 20 mm,159 the 2012 EASL-EORTC guidelines have proposed one conclusive imaging in centres of excellence with high-end radiological equipment. In these centres,
the use of a sequential algorithm maintained high specificity
while increasing the sensitivity for nodules of 1–2 cm.161 Concerning the contrast-enhanced imaging techniques, only multiphasic computed tomography (CT) and magnetic resonance
imaging (MRI) were recommended. As the biodistribution of
the ultrasound (US) contrast agent available in Europe (confined
to the intravascular space) differs from the iodinated contrastCT and extracellular gadolinium-based MRI contrast agent,
tumours other than HCC (such as cholangiocarcinoma) may display homogeneous contrast enhancement in the arterial phase
followed by washout on contrast-enhanced US (CEUS).164,165
Diagnostic performance of CT and MRI
Since the previous EASL/EORTC guidelines, many studies and
several meta-analyses have assessed the diagnostic performance of multiphasic contrast-enhanced CT and MRI.166–168 In
most studies, there was a trend towards higher sensitivity of
MRI compared to CT, with specificity ranging between 85%
and 100%.167 Indeed, results vary according to HCC size, with
MRI performing better than CT particularly in small lesions
(sensitivity of 48% and 62% for CT and MRI, respectively, in
tumours smaller than 20 mm vs. 92% and 95% for CT and MRI,
respectively, in tumours equal or larger than 20 mm).168
Sensitivities are even lower when explanted liver is used as
the reference standard and in prospective studies.168 A recent
prospective multicentric study, including 381 patients with

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544 nodules, shows a sensitivity and specificity of 72.3% and
89.4% for MRI using extracellular contrast agents, and 71.6%
and 93.6% for CT in lesions between 20–30 mm, respectively.169
In lesions of 10–20 mm size, sensitivities and specificities were
70.6% and 83.2% for MRI using extracellular contrast agents, and
67.9% and 76.8% for CT, respectively.169 In lesions of 10–20 mm
in size, the combination of CT and MRI had a specificity of 100%,
but a sensitivity of 55.1%.169 These results reinforce the imaging
hallmark for the non-invasive diagnosis of HCC, with a slight
decrease in specificity for small nodules with either CT or
MRI. These results do not support the use of coincidental imaging in small lesions.
Many other imaging findings have been described in HCCs at
CT and at MRI and occur more commonly in HCCs than in regenerative or dysplastic nodules: hyperintensity on T2-weighted
MRI, hyperintensity on diffusion-weighted MRI, intra-lesional
fat, lesional iron sparing, corona enhancement, presence of capsule, mosaic architecture, nodule-in-nodule architecture,
intralesional haemorrhage.170 Indeed, they increase the likelihood of a lesion being an HCC. However, they do not have a
specificity approaching 100% and therefore do not allow a conclusive diagnosis of HCC.
Comparison of CT vs. contrast-enhanced MRI using
hepatobiliary contrast agents
Multiple studies have compared the diagnostic performance of
multiphasic CT with gadoxetic acid-enhanced MRI.171–179 They
have all shown gadoxetic acid-enhanced MRI to have higher
sensitivity than multiphasic CT and similar specificity, the difference being significant in small lesions.166,180–182 Only one
prospective study compared multiphasic CT with gadobenate
dimeglumine-enhanced MRI using dynamic and dynamic plus
hepatobiliary phases.183 Here, dynamic plus hepatobiliary phase
MRI had a higher sensitivity and negative predictive value than
multiphasic CT and dynamic phase MRI alone.
Comparison between extracellular MR agents and gadoxetic
acid or gadobenate dimeglumine
Large prospective comparisons of diagnostic performance for
HCC between extracellular MRI and either gadoxetic-enhanced
MRI or gadobenate dimeglumine MRI are missing.184 Several
meta-analyses have looked at the sensitivity of MRI using extracellular or hepatobiliary contrast agents (gadoxetic acid or
gadobenate dimeglumine).166,168,185 All have found MRI using
hepatobiliary contrast agents to be associated with higher sensitivity than with extracellular agents, particularly in small
HCCs, but large, prospective, head-to-head comparative studies
are still lacking.
Specific issue with gadoxetic-enhanced MRI
Gadoxetic acid is unique in that approximately 50% of the
administrated dose is taken up by the hepatocytes and excreted
into the bile ducts, while the other half is excreted by the kidneys, allowing for functional evaluation of the hepatocytes. Such
biokinetics have several consequences for diagnostic issues:
firstly, the classically late dynamic phase obtained at 3 min
should be renamed the transitional phase, as signal intensity is
a combination of extracellular and hepatocellular concentrations
and lesion hypo-intensity on that phase is not synonymous with
a washout; secondly, hypo-intensity on hepatobiliary phase is
related to a decrease in membrane transporters and is again

not a washout phenomenon. Therefore, on gadoxetic acidenhanced MRI, washout can only be diagnosed on portal venous
phase and hypo-intensity on hepatobiliary phase is regarded as
an ancillary finding favouring malignancy, either primary or secondary. As most HCCs (80%–90%) are hypo-intense in the hepatobiliary phase, this feature may contribute to the differentiation
of HCC from benign nodules developed on chronic liver diseases.186,187 When hypo-intensity on the transitional phase
and/or the hepatobiliary phase is used as an alternative to
washout, the sensitivity for diagnosis of HCC is increased, but
unfortunately the specificity is decreased.168,188–191 Remarkably,
gadoxetic acid-enhanced MRI has advantages over extracellular
contrast agents. Despite the lower specificity for HCC diagnosis,
gadoxetic acid-enhanced MRI has a higher sensitivity for detecting nodules that are either HCC not displaying the typical features of imaging hallmarks or high-grade dysplastic nodules.
This increased sensitivity for detecting lesions/HCCs may be of
particular value in patients thought to harbour single HCC,
finally improving patient management. The increased sensitivity
in lesion detection was reported to translate into a reduction in
the risk of disease recurrence.192 Lesion signal intensity on
hepatobiliary phase is also a prognostic factor.193 Lastly, nonhypervascular, non-HCC nodules that are hypo-intense on hepatobiliary phase have a higher risk of progression to typical HCC
than iso- or hyper-intense nodules.194 Regrettably, most data
about the usefulness of gadoxetic acid come from Eastern countries, where most HCCs arise in patients chronically infected
with hepatitis B virus, with relatively well-preserved liver function. Confirmatory studies in the West including more advanced
liver disease secondary to alcohol abuse, NAFLD and hepatitis C
virus infection are awaited.
The injection of gadoxetic acid was claimed to be associated
with an increased risk of transient respiratory motion artefacts
in the arterial phase that could reduce image quality. The presence of such artefacts has been reported in a wide range of
patients depending on the case series (from 2.4% to 18%).195–197
Whether these artefacts hamper the detection of lesion vascularity on arterial phase has not been not clearly established yet.
Contrast-enhanced ultrasound
The usage of CEUS was questioned in the previous EASL guideline because of the potential risk of misdiagnosis in the
instance of CC, which appeared to occur at a rate of 2–5% of
all new nodules in cirrhosis.164,165,198 Indeed, the pattern of
global APHE followed by washout at CEUS is not specific for
HCC and occurs in about 50% of mass-forming CC in cirrhosis,
leading to a risk of misdiagnosis of around 1% of nodules arising in cirrhosis.164,165 However, following these reports, subsequent studies demonstrated that the onset of washout takes
place earlier than 60 s after contrast injection in the vast
majority of CCs (50 to 85%),199–204 while this is rarely observed
in HCC, and that the intensity of washout in the portal phase is
more marked in CC than in HCC.205 This has led to a refinement
of the definition of the typical hallmark for HCC at CEUS, which
therefore would be APHE followed by late (>60 s) washout of
mild degree.206,207 This definition improves the capacity of
CEUS to identify malignant lesions such as CC (which are often
not identified as definitively malignant by CT and MRI using
the conventional vascular criteria.208–210 This new CEUS criteria for HCC has already been adopted in Italy (Italian Association for the Study of the Liver211 and by the American

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College of Radiology in the USA.206,212 A very recent large retrospective study in more than 1,000 lesions in cirrhosis,
showed this new definition of the typical HCC pattern (corresponding to the LR5 classification according to LI-RADS for
CEUS) has a positive predictive value for HCC of almost 99%
(higher than the one achieved using the previous EASL and
American Association for the Study of Liver Diseases (AASLD)
criteria, corresponding to 94%) and positive likelihood ratio of
15.5, with no case of misdiagnosis with intrahepatic CC.198
Such improvement in diagnostic capacity was associated with
only a slight decrease in sensitivity in comparison to the previous EASL and AASLD criteria (from 67% to 62%).198 Furthermore, in a recent prospective multicentric study, in the 10–
20 mm nodules, CEUS had a specificity of 92.9% vs. 76.8% and
83.2% for CT and MRI, respectively.169 Also, in the 10–20 mm
nodules, the positive likelihood ratio of CEUS for diagnosing
HCC was 5.6 while it was 2.9 and 4.2 with CT and MRI, respectively.169 Finally, after a first inconclusive CT or MRI, CEUS as a
second imaging technique had the highest specificity with only
a slight drop in sensitivity for the 10–20 mm nodules and the
highest sensitivity and specificity for 20–30 mm nodules.169
However, when CEUS is compared with either CT or MRI, its
sensitivity is significantly lower, especially in nodules of 10
to 20 mm because of a lower detection rate of washout than
with CT or MRI.159,213–215 Accordingly, CEUS can be effectively
utilised to characterise lesions in cirrhosis. However, CEUS with
pure blood pool contrast agents, such as those containing sulfur hexafluoride or octafluoropropane with a phospholipid
shell, utilised in Europe and North America for liver investigations, is not a panoramic technique, because the arterial phase
is too short to allow adequate exploration of the entire liver
and deeply seated lesions may be difficult to visualise. Consequently, it was reported to miss around 13% of HCC visible
on CT or MRI.213 CEUS, can be utilised to characterise one or
very few nodules visible at conventional baseline US. CEUS also
suffers from the difficulty of reviewing images acquired in
another centre, unlike CT or MRI. Furthermore, it is not recommended as a first-line imaging technique or for recall strategies
in terms of cost-effectiveness, because CT or MRI will be
needed for staging, but it can be utilised when both CT and
MRI are contraindicated or are inconclusive for the HCC diagnosis.214,215 Notably, if MR or CT suggest a malignant lesion
other than HCC, this panel recommends obtaining a pathological confirmation.

Lesion size
The radiological hallmarks of HCC only occur in a minority of
patients with small tumours (<2 cm),216 regardless of which
imaging modality is utilised. HCC not showing APHE on imaging
cannot be regarded as less aggressive than typical HCC.217
Therefore, postponing other diagnostic modalities to the
expected six-month surveillance interval, after a first inconclusive imaging technique, without attempting to reach a definitive
diagnosis is contraindicated, even in very small lesions.
Delaying a definitive diagnosis of a suspicious lesion until it
exceeds 2 cm in diameter leads to increased treatment failures
or recurrences, regardless of whether the lesion is ablated or
resected,218 since the development of satellite nodules and
microscopic vascular invasion increases exponentially beyond
this size cut-off.219 Therefore, it is crucial to provide reliable
diagnostic tools for a final diagnosis below the size of 2 cm.

192

Although nodules <10 mm should not prompt the start of the
recall strategy, they may be found on imaging performed for
other nodules ≥10 mm in size. When these small nodules do
not display the typical imaging hallmarks of HCC, their presence
should not affect the treatment strategy planned, although they
cannot be ignored in the case of surgical resection or ablative
treatment. The optimal management for nodules <1 cm showing the typical HCC pattern has not yet been clarified. According
to the LI-RADS classification, which endorses a conservative
approach, a definitive diagnosis of HCC cannot be established,
but they must be considered as probable HCC.220 A clear recommendation cannot be given and the EASL panel recommends
local multidisciplinary board discussion for the management
of patients found to host such tiny apparently typical lesions.
Despite advances in contrast-enhanced imaging and particularly MRI, at present, the EASL panel does not endorse imaging
options to predict any diagnosis apart from definitive HCC
(e.g. low-/high-grade dysplastic nodule or large regenerative
nodules, etc.). In connection with this issue, the EASL panel
highlights that the diagnosis of HCC using the ACR LI-RADS system220 differs from the EASL guidelines when CT or MRI are considered. The LI-RADS system also integrates the use of imaging
features not related to tumour enhancement, such as the presence of tumour capsule or significant tumour growth over time,
which have not been prospectively validated and are not
accepted by EASL. Conversely, the diagnosis of HCC by CEUS is
coincident when using the current EASL or LI-RADS criteria.
Additionally, the LR2, LR3 and LR4 LI-RADS classes might be
helpful to further stratify the risk of HCC in individual nodules
(corresponding respectively to low, intermediate or high probability of HCC), but none of these classes rule out the presence of
HCC,221 thus a biopsy should be performed whenever technically feasible, at least in the dominant nodule. One interesting
aspect of the LI-RADS system is the standardisation of the
reporting and data collection of imaging techniques that
improves communication and understanding between imaging
operators and clinicians. Further efforts are warranted to adopt
standardised and unique definitions worldwide for the diagnosis of HCC207 and to harmonise different systems.
Characterisation of portal vein thrombosis
Macrovascular invasion (mostly observed in the portal vein) is a
major prognostic factor frequently seen in large HCC, but sometimes present in oligo-nodular small HCC as well. Cirrhotic
patients also tend to develop portal vein thrombosis, with a
yearly incidence as high as 16% in Child-Pugh B-C patients.222
Therefore, portal vein thrombosis may also complicate diagnosis of cirrhotic livers harbouring HCC, causing a burning diagnostic challenge to differentiate portal vein thrombosis from
tumour portal vein invasion, which has prognostic and therapeutic implications.
Contrast-enhanced imaging techniques can distinguish portal vein thrombosis from tumourous portal vein invasion with
high accuracy. Two imaging findings are quite specific for
tumour portal invasion: presence of APHE and high signal intensity within the obstructed vessel on diffusion-weighted MRI
with high b-values.223–226
Value of FDG-PET in HCC diagnosis
HCC is not a very avid tumour for FDG-PET as uptake is
observed in less than 40% of the cases,227 and most well differentiated HCCs are 18F-FDG PET negative. Some other tracers

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have been suggested such as 11C-choline. However, the overall
detection rate of PET/CT with these tracers cannot compare with
contrast-enhanced CT and MRI.228 Yet, uptake on 18F-FDG-PET
seems to be of potential prognostic value. It is associated with
poor prognosis, increased serum alpha-fetoprotein and vascular
invasion. Therefore, it may facilitate the selection of patients for
surgical resection or liver transplantation.229,230
Diagnosis of HCC in a non-cirrhotic liver
Imaging features of HCC developing in a non-cirrhotic liver are
not different from those in cirrhosis. HCC in non-cirrhotic livers
tend to be larger at diagnosis as patients are not enrolled in
surveillance programmes. Yet, the specificity of the imaging
hallmarks (AHPE and washout on portal venous and/or delayed
phases) is lower than in cirrhosis as alternative diagnoses are
seen more commonly (e.g. hepatocellular adenoma, and hypervascular metastases). Therefore, the diagnosis of HCC requires
pathologic proof in non-cirrhotic livers.
Pathological diagnosis
As classification of liver cancer is based on morphological
parameters, pathohistological diagnosis is the gold standard in
defining HCC and its differential diagnoses. Pathohistological
diagnosis of HCC is based on the criteria of the World Health
Organization (WHO) classification231 and the International Consensus Group for Hepatocellular Neoplasia.232 Morphological
staging of HCC in resection and transplantation specimens relies
on accurate macroscopic and histological assessment of the
tumourous lesions and has to be performed according to the
valid TNM-classification including resection margin assessment.233 Usually grading of the tumour is provided, although
there is no worldwide uniform agreement on which grading
scheme to use and data on the independent prognostic value
of grading in HCC are inconclusive.
Pathologic differential diagnostic assessment of focal liver
lesions in cirrhosis includes distinction of HCC from other primary (intrahepatic cholangiocarcinoma, combined HCC/CC)
and secondary malignancies of the liver (especially neuroendocrine tumours, squamous cell carcinoma metastases, lung
cancer metastases). Usually differential diagnosis can be made
on the basis of regular and special histological stains. Especially
in cases of poorly differentiated, solid growing carcinomas or
tumours of presumed mixed/intermediate/precursor cell differentiation (combined HCC/CC) immunohistological markers
(especially for lineage differentiation) can be helpful to support
or define the diagnosis. While differential diagnosis of HCC and
intrahepatic CC is expected to be conclusive on the basis of
these diagnostic measures, differential diagnosis of HCC from
combined HCC/CC is not clear cut and may leave uncertainty
in a few cases. Generally, clear cut CC differentiation of any size
or unequivocal signs of mixed/intermediate differentiation in
more than 10% of the tumour should induce the diagnosis of
combined HCC/CC.
Recently, HCC subtypes that can be defined by morphomolecular analyses and that display specific biological behaviour have been identified, such as fibrolamellar and chromophobe subtypes.234,235 Currently, HCC subtyping has no major
impact on clinical decision making, however, most clinical trials
exclude the fibrolamellar subtype.

Histological assessment is also essential for the distinction of
benign and premalignant precursor lesions from (mostly highly
differentiated) HCC. This is relevant for the distinction of premalignant dysplastic nodules from highly differentiated HCC,
mostly in the instance of background cirrhosis and the question
of malignant transformation of ß-Catenin mutated hepatocellular adenoma. Distinction of dysplastic nodules from HCC
involves absolute (vascular and interstitial invasion) and several
relative parameters (trabecular disarray, increased nuclear/cytoplasmic ratio), and should be supplemented by immunohistological markers (see below). Especially hepatocellular adenomas
with ß-catenin mutations in exon 3 carry a high risk of transformation into HCC and need to be identified.234,236 Beside morphological parameters of malignancy (see above) analysis for
human telomerase reverse transcription (hTERT) mutations
may help to diagnose existing malignant transformation.237
Diagnosis and management of hepatocellular adenoma are
described extensively elsewhere in another EASL guideline.237
Specificity of liver biopsy based diagnosis of HCC has been
reported to reach up to 100%,238 although in routine diagnostics
these numbers may not be reached because of the differential
diagnostic challenges in highly differentiated hepatocellular
tumours. Sensitivity of liver biopsy-based diagnosis of HCC
depends on location, differentiation, and size of the lesion, as
well as the expertise of the person performing the biopsy and
the pathologist, it is reportedly in the range of 90% for all
tumour sizes. Pathological diagnosis is generally more challenging for nodules <2 cm in size,239 since these lesions often represent well differentiated tumours. In a prospective study, the first
biopsy was reported positive in  60% of cases for tumours less
than 2 cm.159
Since the histopathological criteria of malignancy in hepatocellular tumours, namely significant cytological and histological atypia and interstitial and vascular invasion, can be
missed by biopsy specimens,159 the diagnosis of early and well
differentiated HCC should be further supplemented by
immunohistological analyses for markers linked to malignant
transformation of hepatocytes. A combination of three different
immunomarkers –HSP70 (HSPA7), glypican 3 (GPC3), and glutamine synthetase (GS) — has been shown to further support
the diagnosis of highly differentiated HCC in surgically resected
specimens (sensitivity and specificity of 72% and 100%, respectively),240 and its specificity was externally validated in samples obtained by percutaneous biopsy241–243 although its use
does not significantly increase the sensitivity of HCC diagnosis
in an expert setting.243 Both, the International Consensus
Group of Hepatocellular Neoplasia and the WHO have adopted
this three-marker panel in their recommendations.231,232 There
is still a need to increase the sensitivity of these panels by
defining new markers correlating with malignant transformation. Staining for neovascularisation may provide additional
help. In addition, immunohistological markers may help to
identify HCCs with poorer prognosis (cytokeratin 19
[CK19]).244 Furthermore, it should be emphasised that diagnostic accuracy in difficult biopsy cases can be increased by sending formalin-fixed paraffin-embedded tissue blocks or slides to
expert liver pathologists for a second opinion.
Several gene expression signatures have been proposed to
support diagnosis, and to subtype HCCs with a potential for

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prognostic assessment.245–247 However, the clinical usefulness
of such analyses has not been proven and has not entered routine diagnostics, so far. Molecular markers have been assessed
on HCC tissues for their predictive potential and have been used
as inclusion criteria in clinical trials.248 As the number of clinical
trials increases, the availability of HCC tissue has become more
relevant for including patients. Although always an individual
decision integrating clinical (palliative vs. curative) and patient
specific factors (age, etc.), several centres have introduced more
active biopsy strategies into their policies.
Potential risks of liver tumour biopsy are bleeding and needle track seeding. In a meta-analysis, the risk of tumour seeding
after liver biopsy was reported to be 2.7% with a median time
interval between biopsy and seeding of 17 months,249 but this
study probably suffers from publication bias and even lower
rates are expected in experienced centres. It has further been
reported that needle track seeding can be treated well, e.g. by
excision or radiation and does not affect outcome of oncological
treatment250 and overall survival.249 In a meta-analysis of the
bleeding risk of liver tumour biopsies, mild bleeding complications range around 3–4%, while severe bleeding complications
requiring transfusions are reported in 0.5% of cases.251 In conclusion, it is now widely accepted that the potential risks, bleeding and needle track seeding, are infrequent, manageable and do
not affect the course of the disease or overall survival. In gen-

eral, they should not be seen as a reason to abstain from diagnostic liver biopsy.
Synthesis of radiological and histopathological diagnosis/
synopsis
Diagnostic assessment of hepatic lesions suspected of being
HCC in a specific patient is influenced by the size and location
of the lesion, the state of the non-tumourous liver, the clinical
status of the patient, the imaging patterns, the expertise of
the diagnostic physicians, the extent of therapeutic options,
and general conditions of the respective healthcare system.
Generally proposed diagnostic algorithms may not be able to
address all parameters. The certainty of diagnosis represents a
high priority; its impact is rising with extent and effectiveness
of therapy in HCC and its differential diagnoses.
In cirrhotic patients, the diagnosis of HCC is often based on
contrast-enhanced imaging as shown in the diagnostic algorithm (Fig. 2). Biopsy of the lesion is indicated when the imaging-based diagnosis remains inconclusive, especially in lesions
smaller than 2 cm in diameter where the diagnostic performance of contrast-enhanced imaging is lower. Considering a
degree of uncertainty with imaging-based HCC diagnosis
(around 5–10%), even when classical diagnostic parameters
are fulfilled, biopsy has to be considered if a higher level of certainty is required. Furthermore, several centres have introduced

Mass/nodule at imaging

<1 cm

>1 cm

Repeat US at 4 mo

Multiphasic contrast-enhanced CT, or
multiphasic contrast-enhanced MRI*, or
gadoxetic-enhanced MRI**

Stable****

Growing/changing
pattern

1 positive technique:
HCC imaging hallmarks

Yes

No
*****
Use the other modality multiphasic
contrast-enhanced CT, or
multiphasic contrast-enhanced MRI*, or
gadoxetic-enhanced MRI**, or
contrast-enhanced ultrasound***

Biopsy unclear:
Consider re-biopsy

1 positive technique:
HCC imaging hallmarks

- Non-HCC malignancy
- Benign

No

Yes

Biopsy

HCC

Fig. 2. Diagnostic algorithm and recall policy in cirrhotic liver. ⁄Using extracellular MR contrast agents or gadobenate dimeglumine. ⁄⁄Using the following
diagnostic criteria: arterial phase hyperenhancement (APHE) and washout on the portal venous phase. ⁄⁄⁄Using the following diagnostic criteria: arterial phase
hyperenhancement (APHE) and mild washout after 60 s. ⁄⁄⁄⁄Lesion <1 cm stable for 12 months (three controls after four months) can be shifted back to regular
six months surveillance. ⁄⁄⁄⁄⁄Optional for centre-based programmes.

194

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a more active biopsy strategy in order to address different trial
and experimental treatment options, especially for systemic
therapies. Potential complications of liver biopsy are rare and
manageable and do not justify abstaining from diagnostic
biopsy. Broader availability of liver biopsy in HCC has the potential to provide suitable patients access to more clinical trials,
enlarging the treatment options and supporting research measures expected to improve the therapeutic situation in liver cancer in the future.
In non-cirrhotic liver, imaging alone is not considered sufficient and histological assessment is required to establish the
diagnosis of HCC. It must be acknowledged that the diagnosis
of liver cirrhosis might be difficult in some cases; therefore,
the diagnostic process for HCC in patients where cirrhosis is
uncertain should be carried out as in non-cirrhotic patients.
Therefore, liver biopsy is recommended and has the additional
advantage of providing further information regarding the nontumourous liver tissue.

Recall policy

follow-up is a reasonable approach in these cases (Fig. 2). An
accepted rule is to consider any nodule larger than about 1 cm
as an abnormal screening result, warranting further investigation. These new nodules should trigger the recall strategy for
diagnosis with non-invasive or invasive (biopsy) criteria, as
described in the section on diagnosis. If a definitive diagnosis
cannot be reached with non-invasive radiological criteria
because of a lack of the typical radiographic hallmarks of HCC,
then biopsy is recommended. If even biopsy does not show
malignancy (or very rarely a definitive haemangioma), then at
least strict follow-up every 3–4 months is recommended. However, repeat bioptic sampling is directly recommended in cases
of inconclusive histological findings or when apparently conclusive non-malignant histological findings are overtly discordant
with the suggested imaging diagnosis (e.g. histological finding
of cirrhosis in the instance of a well demarcated focal lesion
with arterial hyperenhancement) since percutaneous biopsy
bears the risk of false negative results.159 A new biopsy is also
recommended in case of growth or change in the enhancement
pattern identified during follow-up, but with imaging still not
diagnostic for HCC. Upon detection of a suspicious nodule, the
recommended policy is to evaluate the patient in a referral centre with appropriate human and technical resources.

Recommendations
  In patients at high risk of developing HCC, nodule(s) less
than 1 cm in diameter detected by ultrasound should be
followed at ≤4-month intervals in the first year. If there
is no increase in the size or number of nodules, surveillance could be returned to the usual six-month interval
thereafter (evidence weak; recommendation weak).
  In cirrhotic patients, diagnosis of HCC for nodules of ≥1
cm in diameter can be achieved with non-invasive criteria and/or biopsy-proven pathological confirmation (evidence strong; recommendation strong).
  Repeated bioptic sampling is recommended in cases of
inconclusive histological or discordant findings, or in
cases of growth or change in enhancement pattern identified during follow-up, but with imaging still not diagnostic for HCC (evidence low; recommendation
strong).

Recall policy is crucial for the success of surveillance procedures. It consists of a defined algorithm to be followed when
surveillance tests show an abnormal result. This definition must
take into account the ideal target of surveillance, i.e. the identification of hepatocellular carcinoma (HCC) at a very early stage
(2 cm or less), when radical treatments can be applied with the
highest probability of long-term cure.87 In the case of HCC
surveillance, abnormal ultrasound results are either a newly
detected focal lesion or a known hepatic lesion that enlarges
and/or changes its echo pattern.252
Pathological and radiological studies show that the majority
of nodules smaller than 1 cm that can be detected in a cirrhotic
liver are not malignant159,219 and adequate bioptic sampling of
such tiny lesions is challenging. Moreover, the initial growth is
usually only of slow expansion in the early phases, even in the
instance of HCC, and complete response to therapy is almost
always achievable in lesions up to 2 cm.253,254 Thus, a strict

Staging systems and treatment allocation
Recommendations
  Staging systems for clinical decision making in HCC
should include tumour burden, liver function and performance status (evidence high; recommendation
strong).
  The BCLC staging system (Fig. 3) has been repeatedly validated and is recommended for prognostic prediction
and treatment allocation (evidence high; recommendation strong). The levels of evidence for treatments
according to strength and magnitude of benefit are summarised (Fig. 9).
  Treatment stage migration concept applies.
  Refinement of BCLC classes (particularly B and C) by clinical data, molecular classes or biomarker tools should
further facilitate understanding of outcome data, treatment allocation and trial stratification. This needs to be
validated in a clinical setting.
  Patients should be discussed in multidisciplinary teams
to fully capture and tailor individualised treatment
options (evidence low; recommendation strong).

Staging systems
Once the diagnosis is established, prognostic assessment is a
critical step in the management of hepatocellular carcinoma
(HCC). Cancer classification is intended to establish prognosis
and enable the selection of the adequate treatment for the best
candidates. In addition, it helps researchers to exchange information and design clinical trials with comparable criteria. In
patients with HCC, unlike most solid tumours, the co-existence
of two life-threatening conditions, such as cancer and cirrhosis,

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HCC in cirrhotic liver

Prognostic
stage

Very early stage (0)
Single <2 cm
Preserved liver function1,
PS 0

Early stage (A)
Single or 2-3 nodules <3 cm
Preserved liver function1, PS 0

Intermediate stage (B)
Multinodular,
unresectable
Preserved liver function1,
PS 0

Advanced stage (C)
Portal invasion/
extrahepatic spread
Preserved liver function1,
PS 12-2

Chemoembolization

Systemic therapy5

>2.5 years

≥10 months

Terminal stage (D)
Not transplantable HCC
End-stage liver function
PS 3-4

2-3 nodules
≤3 cm

Solitary
Optimal surgical
candidate3

No

Transplant
candidate

Yes

No

Transplant

Ablation

Yes

Treatment4
Survival

Ablation

Resection

>5 years

BSC
3 months

Fig. 3. Modified BCLC staging system and treatment strategy. 1‘‘Preserved liver function” refers to Child-Pugh A without any ascites, considered conditions
to obtain optimal outcomes. This prerequisite applies to all treatment options apart from transplantation, that is instead addressed primarily to patients with
decompensated or end-stage liver function. 2PS 1 refers to tumour induced (as per physician opinion) modification of performance capacity. 3Optimal surgical
candidacy is based on a multiparametric evaluation including compensated Child-Pugh class A liver function with MELD score <10, to be matched with grade of
portal hypertension, acceptable amount of remaining parenchyma and possibility to adopt a laparoscopic/minimally invasive approach. The combination of the
previous factors should lead to an expected perioperative mortality <3% and morbidity <20% including a postsurgical severe liver failure incidence <5%. 4The
stage migration strategy is a therapeutic choice by which a treatment theoretically recommended for a different stage is selected as best 1st line treatment
option. Usually it is applied with a left to right direction in the scheme (i.e. offering the effective treatment option recommended for the subsequent more
advanced tumour stage rather than that forecasted for that specific stage). This occurs when patients are not suitable for their first line therapy. However, in
highly selected patients, with parameters close to the thresholds defining the previous stage, a right to left migration strategy (i.e. a therapy recommended for
earlier stages) could be anyhow the best opportunity, pending multidisciplinary decision. 5As of 2017 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 of OS from eight months (placebo) to 10.2 months (ASCO GI 2018). Nivolumab has been approved in second line by FDA but not EMA
based on uncontrolled phase II data. ASCO, American Society of Clinical Oncology; BCLC, Barcelona Clinic Liver Cancer; EMA, European Medicines Agency; FDA,
Food and Drug Administration; MELD, model for end-stage liver disease; PS, performace status; OS, overall survival. Modified with permission from87.

complicates prognostic assessments.87,255 In addition, the presence of cancer-related symptoms has consistently shown an
impact on survival. Finally, any system aimed at being clinically
meaningful should link prognostic prediction to treatment
indication.
Staging systems for HCC should be designed with data from
two sources. Firstly, prognostic variables obtained from studies
describing the natural history of cancer and cirrhosis. Secondly,
treatment-dependent variables obtained from evidence-based
studies providing the rationale for assigning a given therapy
to patients in a given subclass.
The main clinical prognostic factors in patients with HCC,
based on studies reporting the natural history of the disease,
are related to tumour status (defined by number and size of
nodules, presence of vascular invasion, extrahepatic spread),
liver function (defined by Child-Pugh’s class, bilirubin, albumin,
clinically relevant portal hypertension, ascites) and general
tumour-related health status (defined by the Eastern Cooperative Oncology Group [ECOG] classification and presence of
symptoms).256–260 Aetiology has not been identified as an independent prognostic factor.260
Several staging systems have been proposed to provide a
clinical classification of HCC. In oncology, the standard classification of cancer is based on the TNM staging. In HCC, the 8th
196

TNM edition in accordance with the American Joint Committee
on Cancer,233 which was obtained from the analysis of a series
of patients undergoing resection, has several limitations.261,262
Firstly, pathological information is required to assess microvascular invasion, which is only available in patients treated by surgery ( 20%). In addition, it does not capture information
regarding liver functional status or health status. Finally, its
prognostic value in non-early tumours is limited.262 Among
more comprehensive staging systems, six have been broadly
tested, three European (the French classification,263 the Cancer
of the Liver Italian Program [CLIP] classification,257 and the Barcelona-Clínic Liver Cancer [BCLC] staging system87,264) and
three Asian (the Chinese University Prognostic Index [CUPI]
score,265 the Hong-Kong Liver Cancer [HKLC] staging system266
and the Japan Integrated Staging [JIS], which was refined including biomarkers (alpha-fetoprotein [AFP], des-c-carboxyprothrombin [DCP] AFP-L3) (bm-JIS)267). CUPI and the CLIP scores
largely sub-classify patients at advanced stages, with a small
number of effectively treated patients. Overall, most of these
systems or scores have been externally validated, but only three
include the three types of prognostic variables (BCLC, CUPI, and
HKLC) and only two assign treatment allocation to specific prognostic subclasses (BCLC and HKLC). HKLC was derived from a
large cohort of patients (n = 3,927, mostly HBV-related), and

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identifies nine stages and sub-stages. Regrettably, this proposal
has some limitations: survival among different stages overlaps,
there is no external validation in Western countries evaluating
its performance in a population including all stages of the disease,268 and the population used for developing the HKLC staging was already treated and the outcome retrospectively
analysed, introducing an unintentional selection bias against
transarterial chemoembolisation (TACE) in comparison to
resection.269
The current European Association for the Study of the Liver
Clinical Practice Guidelines endorse the BCLC classification for
several reasons. It includes prognostic variables related to
tumour status, liver function and health performance status
along with treatment-dependent variables obtained from
cohort studies and randomised trials. It has been externally validated in different clinical settings260,270–273 and is an evolving
system that links tumour stage with treatment strategy in a
dynamic manner, enabling the incorporation of novel advances
in the understanding of the prognosis or management of HCC. In
this regard, the seminal classification reported in 1999264 was
updated with the incorporation of stage 0 (very early HCC)
and chemoembolisation for intermediate HCC in 2003,274 further modified in 2008 to incorporate sorafenib as a first-line
treatment option in advanced tumours,275 the consideration of
ablation as first-line treatment in selected patients with solitary
HCC smaller than 2 cm,276 and finally included other systemic
therapies and the elimination of the Child-Pugh score as a tool
for evaluating liver function.87 As discussed later, further refinements in class stratification (for instance to incorporate
biomarkers) or treatment allocation resulting from positive
high-end trials are expected in the coming years.
Tissue and serum biomarkers predicting prognosis have been
less explored in patients with HCC. Strict rules for incorporating
prognostic or predictive markers into clinical practice have been
published.277 According to these rules, acceptable biomarkers
should be obtained from randomised investigations, as is the
case with RAS status and response to cetuximab in colon cancer.
Only in particularly compelling circumstances can prognostic or
predictive markers tested in cohort studies be adopted in clinical practice. The panel recommends incorporating biomarkers
for the management of HCC when the following requirements
are met: i) Demonstrate prognostic prediction in properly powered randomised studies or in training and validation sets from
cohort studies; ii) Demonstrate independent prognostic value in
multivariate analysis including known clinico-pathological predictive variables; iii) Confirm results using the same technology
in an external cohort reported by independent investigators.
None of the biomarkers tested so far fulfil these criteria in
HCC.278
There is room for further refinement of prognosis evaluation.
Liver function has traditionally been assessed through the
Child-Pugh classification, which is known to have limited predictive power as temporary events not fully captured (renal failure, spontaneous bacterial peritonitis, hyponatremia, recurrent
encephalopathy or malnutrition) may indicate end-stage liver
disease, requiring transplant. If a transplant is not feasible,
HCC should be categorised as terminal stage (BCLC D) and best
supportive care should be offered. Furthermore, the assessment
of Child-Pugh score includes some subjective variables (for
instance, ascites detected by imaging) that might impair its clinical applicability. The combination of albumin and bilirubin
(ALBI score) has been shown to stratify patients across BCLC

stages279 and allows subgrouping of Child-Pugh A patients,
but its role in clinical decision making or stratification in
research trials is not defined. Both parameters are already
included in the evaluation of patients and hence, while statistically significant it may be clinically irrelevant.280
Regarding serum markers, increased AFP is associated with
poorer prognosis. Elevated AFP levels have been shown to predict risk of tumour recurrence after resection,281,282 risk of
drop-out in patients on the waiting list for liver transplantation,283–285 survival and risk of tumour recurrence after liver
transplantation,286–290 response to loco-regional therapies,291–
293
and survival in advanced HCC.294,295 Other markers such
as vascular endothelial growth factor (VEGF) and angiopoietin
2 (Ang2) have been shown to have independent prognostic
value in large cohorts of untreated advanced tumours.294 The
heterogeneity of the above studies prevents the formulation of
a clear recommendation, but it is advised that AFP levels >200
and/or >400 ng/ml be tested as prognostic factors of poor outcome in research investigations.
Outcome prediction and treatment allocation
The treatment allocation recommended in these guidelines is
modified from the BCLC classification and is summarised
(Fig. 3). Patients with HCC are classified into five stages (0, A,
B, C and D) according to pre-established prognostic variables,
and therapies are allocated according to treatment-related status. Prognosis prediction is defined by variables related to
tumour status (size, number, vascular invasion, N1, M1), liver
function (bilirubin, portal hypertension, liver function preservation) and health status (ECOG). Treatment allocation incorporates treatment dependant variables, which have been shown
to influence therapeutic outcome, such as bilirubin, portal
hypertension or presence of symptoms-ECOG.
Very early HCC (BCLC stage 0) is defined as the presence of a
single tumour <2 cm in diameter without vascular invasion/
satellites in patients with good health status (ECOG-0) and
well-preserved liver function (Child-Pugh A class). Nowadays,
5–10% of patients in the West are diagnosed at this stage, while
in Japan the figure is almost 30% because of the widespread
implementation of surveillance programmes.296 From pathological studies, though, two subclasses of tumours have been
defined: vaguely nodular-type – size around 12 mm without
local invasiveness - and the distinctly nodular-type – mean size
16 mm which might show local invasiveness. Vaguely nodular
types are very well differentiated HCCs that contain bile ducts
and portal veins, have ill-defined nodular appearance and, by
definition, do not have invaded structures. Distinctly nodulartype show local metastases surrounding the nodule in 10% of
cases, and microscopic portal invasion in up to 25%.239 Therefore, some tumours smaller than 2 cm are prone to disseminate
locally, but others behave as carcinoma in situ and those are
defined as stage 0. Recent data have shown a five-year survival
in 80–90% of patients with solitary HCC smaller than 2 cm treated with resection.297,298 Since radiofrequency ablation (RFA) is
able to offer a complete tumour necrosis with a safe margin in
the majority of cases, it is likely that resection and RFA are similar in terms of outcome. A recent Markov model for very early
tumours (BCLC 0) created to simulate a randomised trial
between resection vs. RFA followed by resection for cases with
initial local failure, concluded that both approaches were nearly
identical in terms of survival.299 A systematic review and metaanalysis including seventeen studies (3,996 patients treated

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with resection and 4,424 patients treated with ablation) with an
associated cost-effectiveness analysis using a Markov model
concluded that, for very early HCC (single nodule <2 cm) in
Child-Pugh class A patients, RFA provided similar life expectancy and quality-adjusted life expectancy at a lower cost.218
Finally, several cohort studies have reported five-year survival
beyond 70% after RFA in well-selected patients with very early
HCC.253 The only advantage of surgical resection would be the
opportunity to assess the risk of early recurrence by pathology
(microvascular invasion, poor differentiation or presence of
satellites). If a high risk of recurrence is detected in the specimen, liver transplant might be indicated (the so-called ‘‘ab initio”
indication).300,301 If a patient is not a candidate for liver transplant, the availability of the pathology characteristics will not
change the treatment strategy and thus, RFA might become
the first-line option (see chapter ‘resection’), leaving surgery
for those patients with nodules not suitable for RFA, or who fail
treatment.276,302 Regrettably, no randomised controlled trial
addressing this issue has been reported so far and comparison
of cohort studies suffers from selection bias favouring surgical
resection.
Early HCC (BCLC stage A) is defined in patients presenting
with single tumours >2 cm or three nodules <3 cm in diameter,
ECOG-0 and preserved liver function. Median survival of
patients with early HCC reaches 50% to 70% at five years after
resection, liver transplantation or local ablation in selected candidates. The natural outcome of these cases is ill-defined
because of the scarcity of data reported, but median survival
is estimated to be around 36 months.303 An improvement in
survival is universal when applying the so-called treatmentdependent variables to the selection of candidates.
Tumour status is defined by the size of the main nodule and
multi-centricity (single lesion, three nodules ≤3 cm), each of
these categories showing significantly different outcomes. As
discussed below, for single tumours beyond 5 cm surgical resection is still considered as a first option, because if modern MRI is
applied in preoperative staging, the fact that solitary large
tumours remain single and have no macrovascular involvement
- which might be common in HBV-related HCC - reflects a more
benign biological behaviour.
Variables related to liver function are relevant for candidates
considered for resection. Absence of clinically relevant portal
hypertension (defined as HVPG ≤10 mmHg) and normal bilirubin are key predictors of survival in patients with single
tumours undergoing resection.304–306 Similarly, Child-Pugh
class A is the strongest prognostic variable in patients undergoing local ablation,292,297,307,308 along with tumour size and
response to treatment.309 Since liver transplantation may
potentially cure both the tumour and the underlying liver disease, variables mostly related with HCC have been clearly established as prognostic factors (single tumours ≤5 cm or three
nodules ≤3 cm), defining the so-called Milan criteria.
Intermediate HCC (BCLC stage B): Median survival for
untreated patients at an intermediate-stage (BCLC-B – multinodular asymptomatic tumours without vascular invasion or
extrahepatic spread) is 16 months,310,311 or 49% at two years.260
According to the positive results in terms of survival benefit of
two randomised controlled trials,312,313 and a cumulative
meta-analysis,310 TACE is considered the first-line treatment,

198

while recent cohort studies have reported a median survival
of around 40 months in well-selected candidates with a state
of the art technique and a super-selective approach.293,314,315
The current intermediate HCC definition includes a wide
range of patients according to liver function and tumour burden.
This has triggered a major controversy and willingness to further stratify the BCLC-B category according to tumour burden
and liver function.316,317 Some of these proposals classify large
solitary HCC beyond 5 cm with an expansive growth as intermediate-stage, although vascular invasion or tumour dissemination has been excluded after proper imaging evaluation.
However, if technically feasible they may benefit from surgical
resection, and these patients should be classified as BCLCA.1,87,318 Another rare subgroup are patients with large multifocal HCC affecting both lobes, without vascular invasion or extrahepatic spread, as major tumour burden is usually associated
with cancer-related symptoms and thus, these patients correspond to a more evolved tumour stage either C or D instead of
a poor prognostic subclass of intermediate-stage. Finally,
Child-Pugh A-B may include patients with refractory ascites,
and events such as spontaneous bacterial peritonitis, hyponatremia or recurrent encephalopathy, which predict poor outcome in the absence of transplantation.255,319 In such
instances, liver transplantation should be considered and if
HCC exceeds the accepted criteria for the patient to be listed,
then the patient must be classified as BCLC D. While studies
analysing the natural history and prognostic factors may
include such patients,316 therapeutic trials usually exclude them
because of their high short-term mortality.
Advanced HCC (BCLC stage C): Patients with cancer-related
symptoms (symptomatic tumours, ECOG 1-2), macrovascular
invasion (either segmental or portal invasion) or extrahepatic
spread (lymph node involvement or metastases) bear a poor
prognosis, with expected median survival times of 6–8
months,260,310,311 or 25% at one year.260 Nonetheless, it is obvious that this outcome varies according to liver functional status
and other variables. In the last decade, major advancements
have occurred in the field of advanced HCC. Until 2007, there
was no FDA-approved first-line treatment for patients with
advanced HCC. This scenario has changed as a result of data
showing survival benefits in patients receiving sorafenib – a
multi-tyrosine kinase inhibitor - in advanced cases.320,321 The
results of these randomised controlled trials represented a
breakthrough in the management of HCC, as it is discussed in
the systemic therapies section of this document, impacting on
the survival of patients with advanced disease. The positive
results of sorafenib opened the door for evaluation of other targeted agents. Regrettably, all subsequent phase III trials evaluating new agents alone or in combination with sorafenib, in firstline or in second-line treatment, failed to demonstrate a survival benefit. Only very recently, regorafenib, an oral multikinase inhibitor with a similar mechanism of action to sorafenib, demonstrated an impact on survival in a phase III trial in
patients with HCC who progressed but were tolerant to sorafenib and had Child-Pugh A liver function and performance status
0 or 1.322 According to this study, regorafenib is recommended
in second-line in those patients who progressed but were tolerant to sorafenib. Very recently, lenvatinib, an inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth

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factor receptors 1–4, platelet-derived growth factor receptor a,
RET, and KIT, demonstrated non-inferior survival to sorafenib in
an open-label, multicentre, non-inferiority, randomised trial.323
Finally, cabozantinib, a MET, VEGFR2 and RET inhibitor
approved for thyroid and renal cancer, has shown survival benefit compared to placebo in second-line.324
End-stage HCC: Patients with end-stage disease are characterised by very poor performance status (Eastern Cooperative
Oncology Group 3–4) that reflects a severe tumour-related disability. Their median survival is 3–4 months or 11% at one
year.260 Similarly, Child-Pugh C patients with tumours beyond
the transplantation threshold also have a very poor prognosis.
Concept of treatment stage migration
A proportion of patients in each stage do not fulfil all the criteria
for the treatment allocation. In these cases, the patient should
be offered the next most suitable option within the same stage
or the next prognostic stage. For instance, patients at BCLC-A
failing local ablation should be offered chemoembolisation.
Similarly, patients at BCLC-B stage with contraindications or
with untreatable progression on chemoembolisation,325,326
should be offered sorafenib, as reported in the SHARP trial.320
Refinement of BCLC classification
Some studies challenged the capacity of BCLC to precisely stratify patients for trial design. These studies mostly included
patients at BCLC-C stage of the disease.268,327 The panel of
experts acknowledges that the range of survival reported for
patients at BCLC-B and -C warrants consideration. Further stratification of patients within each class according to liver function
(Child-Pugh A vs. B, ascites, ALBI score, etc.), prognostic molecular biomarkers, or evolutionary events (pattern of progression,
development of side effects during systemic therapy, etc.)
should be explored.

Liver resection
Recommendations
  Surgical resection is recommended as treatment of
choice in patients with HCC arising on a non-cirrhotic
liver (evidence low; recommendation strong).
  Indications for resection of HCC in cirrhosis should be
based on multi-parametric composite assessment of
liver function, portal hypertension, extent of hepatectomy, expected volume of the future liver remnant, performance status and patients’ co-morbidities (evidence
high; recommendation strong).
  Perioperative mortality of liver resection in cirrhotic
patients should be less than 3% (evidence high; recommendation strong).
  LR is recommended for single HCC of any size and in particular for tumours >2 cm, when hepatic function is preserved, and sufficient remnant liver volume is
maintained (evidence moderate; recommendation
strong).
  In properly trained centres, LR should be considered via
laparoscopic/minimally invasive approaches, especially
for tumours in anterolateral and superficial locations
(evidence moderate; recommendation weak).
  HCC presenting with two or three nodules within Milan
criteria may be eligible for LR according to patient performance status, co-morbidities and preservation of liver
function and remnant volume (evidence low; recommendation weak).
  HCC-related macrovascular invasion is a contraindication for LR. Intervention on distal portal invasion – at
segmental or sub-segmental level – deserves investigations within prospectively designed protocols (evidence
moderate).

Response assessment
Recommendations
  Assessment of response in HCC should be based on mRECIST for loco-regional therapies (evidence moderate;
recommendation strong). For systemic therapies both
mRECIST and RECIST1.1 are recommended (evidence
moderate; recommendation weak). The use of changes
in serum biomarker levels for assessment of response
(i.e. AFP levels) is under investigation.
  Multiphasic contrast-enhanced CT or MRI are recommended for assessment of response after resection,
loco-regional or systemic therapies (evidence moderate; recommendation weak). Follow-up strategies for
detection of recurrence after different treatments are
outlined in the specific treatment sections.

For details see the chapter Trial design and endpoints (paragraphs response rate and response assessment tools, objective
response in loco-regional therapies and objective response in
systemic therapies).

  Neoadjuvant or adjuvant therapies are not recommended because they have not been proven to improve
the outcome of patients treated with resection (evidence high; recommendation strong). Further clinical
trials with new agents are encouraged.
  Follow-up after resection with curative intent is recommended because of high rates of treatable recurrence
(evidence high; recommendation strong). Follow-up
intervals are not clearly defined. In the first year, 3–4
month intervals are practical.

Surgery is the mainstay of hepatocellular carcinoma (HCC)
treatment, leading to the best outcomes of any treatment available in well-selected candidates (five-year survival of 60–80%).
Liver resection (LR) and liver transplantation (LT) represent
the first option in patients with early tumours on an intention-to-treat perspective. Surgical interventions can often be
extended to other stages of HCC, once effective tumour downstaging is achieved by non-surgical means.

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Several technical and methodological updates in HCC resection and transplantation have been implemented in the last five
years. In the updated guidelines, a comprehensive review of the
current standards of surgery in patients with HCC has been
undertaken, with special focus on innovations and selection criteria that bear a demonstrable impact on patient outcomes, providing availability and access of the proposed refinements to the
whole community of health providers dealing with HCC.
Liver resection in non-cirrhotic liver
Hepatic resection is the treatment of choice for HCC in non-cirrhotic patients (5% of cases in the West, 40% in Asia),328 where
even major resections can be performed with low rates of lifethreatening complications and acceptable outcome. Definition
of HCC in normal liver may vary and can be challenging at times.
In the elusive field of non-cirrhotic liver the emerging indication
for LR is represented by resection of HCC in non-alcoholic fatty
liver disease (NAFLD) and metabolic syndrome, in which HCC
may in fact occur in the absence of cirrhosis or severe fibrosis.50,100,329 Results of LR in patients with NAFLD and metabolic
syndrome are burdened by a significant rate of severe complications, ranging from 13 to 20%, although post-surgical mortality
in this group is contained within 2%. Therefore, LR in NAFLD and
metabolic syndrome is a surgical procedure with a risk profile
closer to cirrhotic rather than to truly normal livers. Curative
potential of LR for HCC-related to NAFLD/metabolic conditions
(i.e. long-term survival) seems to be higher than that observed
in hepatitis virus-related tumours.330,331 However, co-morbidities such as dyslipidemia, hypertension, diabetes, obesity, heart
and lung chronic dysfunction are commonly observed in these
patients and play a significant and negative prognostic role.
Liver resection in cirrhotic liver
Several refinements in techniques, perioperative management
and case selection have improved surgical interventions for liver
cancer in patients with chronic liver disease and cirrhosis. Since
no single surgical modality fits all HCC presentations, a multidisciplinary approach to surgical intervention is mandatory.
This should be focussed on the key conditions affecting decision
making in the area of surgical HCC, resulting in a multi-parametric approach to cancer and non-cancer components in the
single patient. Criteria presented in the previous European Association for the Study of the Liver (EASL)/European Organisation
for Research and Treatment of Cancer (EORTC) Clinical Practice
Guidelines in 20121 (i.e. solitary tumours and very well-preserved liver function, hepatic vein to portal system gradient
≤10 mmHg or platelet count ≥100,000/ml) describe the ‘‘ideal”
candidates for LR in cirrhosis. Such prescription remains confirmed, especially in a non-experienced context.
However, in the last few years patients exceeding one or
more of the described criteria have been approached with LR
in experienced centres, providing accurate balance of the relative weight of each determinant of prognosis. This has been
enabled by general optimisation of surgical technique, preresection imaging planning, ultrasonic and bipolar dissector
devices, intermittent hilar clamping (Pringle manoeuvre), low
central venous pressure maintenance, mini-invasive approaches
and intensive post-operative management. Indirect confirmation of improved perioperative management of the surgical
patient emerges from the reported decrease in blood transfusion during LR in cirrhosis, from 80% to 90% to less than 10%
in two decades.332 Overall, outcome results achieved in patients
200

undergoing LR in experienced centres (i.e. post-operative mortality and severe post-surgical morbidity of <3% and <30%,
respectively) seem to favour the use of extended criteria for
LR, namely of HCCs in which one or more conventional selection
criteria for LR summarised in the 2012 EASL/EORTC Guidelines
are not satisfied.
A consensus on ‘‘extended criteria” for LR in cirrhosis has not
been reached, even though any expansion in patients’ selection
criteria should consider, measure and combine at least three
groups of variables:
1. Liver function assessment
Although liver function determined by Child-Pugh stage333,334
remains the most practiced method for measuring liver reserve
– with stage A allowing LR within safe limits – other parameters
such as model for end-stage liver disease (MELD) or MELD-Na
score, indocyanine green kinetics, liver stiffness measurement
(LSM) and cholinesterase/bilirubin ratio, have shown a significant role in improving patient selection, especially in those with
borderline liver function.335–339 Non-invasive comprehensive
assessment of fibrosis grade by LSM with transient elastography, and dynamic liver function determination by means of
the hepatic indocyanine green kinetic (ICG test), are additional
very informative tools for LR planning. Significant risk of posthepatectomy liver failure340 can be predicted by liver stiffness
above 12–14 kPa.336,341,342 LSM can also be used to estimate a
safe liver remnant volume.343 A retention rate of ICG at 15
min (ICGR15) after i.v. administration of 0.5 mg/kg body weight
of such an inert, water-soluble fluorescent substance can be
measured at bedside with non-invasive pulse dye densitometry
devices. Various cut-offs of ICGR15 can be part of the decision
making algorithm for liver resective procedures in cirrhotic
patients, limiting resection and segmentectomy to patients with
ICGR15 below 20–25% and 30–35%, respectively.344,345
2. Portal hypertension
Although clinically relevant portal hypertension (CRPH;
(defined as HVPG >10 mmHg) is a significant prognostic factor
affecting survival in both surgical and medical patients with
HCC in cirrhosis,306 its relevance as an independent determinant
of post-surgical outcomes has been questioned.305 As limited
resection in patients with preserved liver function and moderate CRPH yields competitive survival outcomes,346,347 the role
of portal hypertension in decision making for eligibility to resection of HCC should be always balanced with the extent of hepatectomy and liver function indicators, such as the MELD
score348 and the availability and predicted effectiveness of alternative HCC therapies. Simplified decisional algorithms, like the
one presented (Fig. 4) are of help in predicting the risk of
post-surgical decompensation in cirrhotic patients on the basis
of pre-surgical, non-invasive, objective parameters. Such algorithms can also be applied in the Western context.
3. Extent of hepatectomy and surgical invasiveness
According to tumour size, number of detectable tumour satellites, intrahepatic tumour location at intraoperative ultrasound
and the available surgical experience, LR can be performed by
conventional means (i.e. open: laparotomic) or through minimally invasive operations (i.e. close: laparoscopic-robotic). Furthermore, LR can be anatomic (i.e. providing systematic removal
of the tumour-bearing portal territories, with exposure of the
landmark veins framing the segmental territory) or non-ana-

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OF HEPATOLOGY
Portal hypertension
No

Yes

Extension of
hepatectomy

Extension of
hepatectomy

Minor

Major

Minor

Major

(<3 segment)

(≥3 segment)

(<3 segment)

(≥3 segment)

MELD score
≤9

>9

Low risk
5% risk of liver
decompensation

Intermediate risk
<30% risk of liver
decompensation

High risk
>30% of liver
decompensation

Liver-related mortality: 0.5%

Liver-related mortality: 9%

Liver-related mortality: 25%

Yes

MELD score >9
No

Portal hypertension

Extension of hepatectomy
Major
Minor

MELD score ≤9

Fig. 4. Multi-parametric assessment of the risk of liver decompensation
after LR for HCC in cirrhosis. Simplified decisional algorithm identifying high
(red), intermediate (yellow) and low (green) risk of liver decompensation,
according to a hierarchic interaction of the three main determinants of liver
insufficiency: portal hypertension, extent of resection and liver function. HCC,
hepatocellular carcinoma; LR, liver resection. Adapted from348 with
permission.

tomic (Fig. 5). The extent and precise definition of LR (hepatectomies) should be correctly reported according to international
terminology.349
The extent of LR can be accurately planned ahead of surgery
by means of CT/MRI volume calculation of the removed and the
remnant parts of the liver, to be adjusted on liver function,
grade of portal hypertension and body weight (see above). Retrospective studies linking anatomic resections and better outcome should be interpreted with caution, because of the
propensity to perform wider interventions in patients with
well-preserved liver function. With respect to size, anatomic
resections should be preferred for HCC nodules of at least 2
cm in size,350 with a very large retrospective series351 and
newer less invasive laparoscopic-resections questioning the
superiority of anatomic LR in HCC of larger size.352–354 Limited
resections conducted through laparoscopic-robotic techniques
in large volume centres are feasible and indicated for curative
LR in selected groups of HCC with borderline liver conditions
(i.e. Child B7, moderate PH or bilirubin around 2 mg/dl) and several studies have demonstrated that laparoscopic-robotic resections of HCC in cirrhosis are associated with reduced risk of

post-operative liver decompensation.298,355,356 That widens
the curative perspective offered by modern LR approaches, particularly in hepatitis C virus (HCV)-related cirrhotic patients in
which pre/post-resection treatment with direct-acting antivirals (DAAs) may optimise liver function control.
On top of the previous considerations, LR for HCC – as with
any surgical procedure –patients’ general condition, performance status and co-morbidities must be considered ahead of
any intervention. Age should not be a contraindication per se,
if adequate performance status and no major co-morbidities
are confirmed in patients undergoing LR for HCC. In particular,
post-surgical survivals compared to age-sex-matched reference
populations suggest that LR can be offered in patients >70 years
old, who are in fact exposed to a smaller loss of their individual
lifespan in comparison with their younger counterparts.357
When liver-preservation principles are met, and patient’s
general conditions have been scrutinised as permissive for surgical intervention, LR should be tailored on HCC characteristics
and presentation. In this respect, at least four major considerations should contribute to decide the best approach to LR in case
of single HCC in cirrhosis:
a. Tumour size and intrahepatic tumour location influence decision
on surgical approach. For single HCCs ≤2 cm deeply/centrally
located, radiofrequency ablation (RFA) offers competitive
results with respect to LR (see paragraph on local ablation). Conversely, laparoscopic-robotic LR for HCC located in superficialperipheral positions of the liver provides optimal survival outcomes while minimising complications and hospital stay
(Fig. 6);
b. LR can be offered to single HCC regardless of its size. Although
patients with a single HCC of any size can be offered LR with a
definitive survival advantage over other treatments – especially
for tumour >5 cm – surgical feasibility may vary according to the
liver volume and function-preservation principles summarised
previously. However, studies have confirmed that post-resection
outcome decreases as tumour size increases. It is worth noting
that while HCCs beyond 5 cm still qualify as an early stage eligible for LR – if technically feasible, according to Barcelona Clinic
Liver Cancer (BCLC) classification – the 5 cm cut-off defines
tumours trespassing into the intermediate-stage in other classifications266 and also defines the limit in size for which an HCC is
excluded from liver transplantation according to conventional
criteria. In practice, tumours >5 cm are surgically actionable as
early HCC (BCLC-A), but appear to bear a worse prognosis than
BCLC-A <5 cm HCC. Some authors have suggested designating
this subgroup as BCLC-AB stage.358
c. Minimal invasive LR can be an effective option in very early
(≤2 cm) and early HCC. Although ablation is the first-line treatment for the majority of tumours ≤2 cm because of its higher
cost-effectiveness218 and of milder liver function impact, especially for deeply/centrally located tumours, studies demonstrate
that patients treated with laparoscopic-robotic LR for very early
and early HCC mainly located in superficial or antero-lateral
liver positions suffer less complications and shorter hospital
stays, with respect to traditional open resection, while achieving
competitive oncologic outcome with respect to ablation.359–362
No differences in operative time, blood loss, intraoperative

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complications, hospital stay, and morbidity were found in
laparoscopic LR for cirrhotics compared with non-cirrhotics
and in fact a laparoscopic approach appears to reduce the incidence of post-operative ascites, liver failure and morbidity with
no difference in overall or disease-free survival at two years.363
In selected patients with suboptimal/difficult indications for a
percutaneous approach, or in cases of concomitant minimally
invasive liver procedures, laparoscopic tumour ablation should
be considered a doable option. Although three randomised
controlled trials (RCTs) did not show superiority of LR over
RFA for tumours up to 4–5 cm364–366 other studies367 and
meta-analyses368,369 emphasised superior results of LR – either
open or minimally invasive – on local tumour control and on
subsequent patient survival. A more objective model based on
a large data set showed LR to be progressively superior to percutaneous ablation, as the maximal tumour size increased from
2 cm.370 Reported morbidity and mortality in major laparoscopic-robotic LR series collected in very early and early HCC
are 10–15% (including laparotomic conversions) and 1%,
respectively.371,372
d. For single HCC >3 cm LR is cost-effective. When the perspectives
on treatment effectiveness and cost are combined and metaanalysed to replace the absence of RCTs in patients receiving
resection or ablation for early tumours, LR prevails over ablation
in single HCC above 3 cm, while uncertainty still remains for
nodules 2–3 cm in size.218 Also, from the perspective of interventional radiology, competitive local control and long-term
patient outcome favour LR – provided the maintenance of the
liver preservation principles and absence of co-morbidities
described above are considered – in patients with HCC above
the 3 cm threshold.373
If patient performance status and co-morbidities allow surgical consideration, and if liver function and remnant liver volume-preserving principles are met, HCCs presenting with
multiple nodules are not a contraindication per se for surgical
intervention. In particular, HCC with multiple nodules within
Milan criteria (≤3 nodules, each ≤3 cm in size) belong to the
early-stage category (Fig. 3) and thus, at least in theory, could
be approached with LR, if eligibility for ablation and liver transplant is suboptimal or excluded. There is a lack of research comparing LR with the large span of therapeutic alternatives usually
proposed for multifocal HCC.211,374,375 However, LR applied to
multifocal HCC achieves competitive survival rates in several
studies211,376 and compared to TACE.377,378 While in large
groups of Western patients a net survival benefit in favour of
LR with respect to non-surgical loco-regional treatments has
been observed across all stages of tumour presentation.358
Regrettably, these retrospective comparisons were almost certainly associated with selection bias, as the patients who were
selected for resection over TACE probably had clinical characteristics that gave the surgeon confidence of a good outcome,
whereas those selected for TACE likely lacked such features,
immediately introducing a bias against TACE. In BCLC-A patients
with multifocal tumour within Milan criteria, LR might be
effective if sufficient liver function (Child-Pugh A and MELD
≤9) and good performance status (Eastern Cooperative Oncology
Group 0–1) were present, and its efficacy compared to available
loco-regional therapies should be evaluated in prospective
studies.

202

HCC-related portal vein invasion
A substantial proportion of patients with HCC present with
tumour-related portal vein thrombosis (PVTT) either at onset
of disease or as result of HCC recurrence or progression, leading
the disease to an advanced stage not amenable to curative treatments.379 The observed increase in PVTT detection rate may be
related to technical improvements in imaging techniques over
time. Similarly, the better outcomes reported for resected HCC
in recent years might be explained by the exclusion of patients
that in the past were not diagnosed as PVTT, especially at segmental and sub-segmental level. Patients with HCC and PVTT
may present as asymptomatic and within Child-Pugh stage A,
although in most instances have a significant degree of synthetic dysfunction and an impending liver decompensation that
precludes any attempt at surgical cure. PVTT can be graded as
PV1 (segmentary), PV2 (secondary order branch), PV3 (firstorder branch), PV4 (main trunk/contralateral branch).380 The
extension of PVTT is known to directly affect patients prognosis
whatever treatment is attempted,381,382 including LR, especially
in the presence of elevated alpha-fetoprotein and large tumours.
Propensity matched-cohorts analysis by the Liver Cancer Study
Group of Japan demonstrated, however, that as long as the PVTT
is limited to the first-order branch (PV1), LR can offer a longer
survival outcome than non-surgical treatment,383,384 offering
median survival intervals exceeding four years. Also, in Western
series, a remarkable prognosis after LR for patients with HCC
and PVTT has been demonstrated.385–388 Nonetheless, no
prospective comparison of LR vs. systemic treatments or
radioembolization has ever been reported, thus how much the
remarkable survival was related to a super-selection of the population remains unclear. Therefore, LR can only be considered
for PV1/2 extension of HCC, and only then as an option to be
tested within research settings and not to be considered a standard of practice.
Neoadjuvant or adjuvant therapies
Tumour recurrence complicates 70% of cases at five years,
reflecting either intrahepatic metastases (true recurrences) or
the development of de novo tumours. No clinical definition of
both entities has been established, but the cut-off of two years
has been adopted to grossly classify early and late recurrences.275 Several strategies to prevent and treat recurrence
have been tested in the setting of randomised studies. In the
past decade, before the advent of DAAs for treatment of HCV
infection, different meta-analyses evaluated the effect of interferon in improving recurrence-free survival and late recurrence
of HCC after LR.389,390 Other strategies tested, including
chemotherapy, chemoembolisation, internal radiation and retinoids, did not provide any benefit in terms of prevention of
relapse.391 Adoptive immunotherapy reduced HCC recurrence,
whilst increasing recurrence-free survival392 and overall survival after curative treatment,393 which is of interest in light
of future studies on modern therapies with immune checkpoint
inhibitors, including the CTLA-4, PD-1, and PD-L1 inhibitory
pathways and other checkpoint proteins. A randomised controlled trial (RCT) testing sorafenib vs. placebo as adjuvant therapy after LR or ablation failed to demonstrate any positive
effect.394 Considering the currently available information, the
panel does not recommend adjuvant therapy after LR, and
prospective studies in this setting are strongly encouraged.

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OF HEPATOLOGY
Liver transplantation

A

B

A

B’
A’

sm for
A-A’

Recommendations
  LT is recommended as the first-line option for HCC
within Milan criteria but unsuitable for resection (evidence high; recommendation strong). Milan criteria
are the benchmark for selection of patients with HCC
for LT and the basis for comparison with other suggested
criteria.
  Consensus on expanded criteria for LT in HCC has not
been reached. Patients beyond the Milan criteria can be
considered for LT after successful downstaging to within
Milan criteria, within defined protocols (evidence moderate; recommendation weak).
  Composite criteria that consider surrogates of tumour
biology – among which AFP is the most relevant – and
response to neoadjuvant treatments – to bridge or
downstage tumours – in combination with tumour size
and number of nodules, are likely to replace conventional criteria for defining transplantability. Composite
criteria should be investigated and determined a priori,
validated prospectively and auditable at any time (evidence low; recommendation strong).
  Tumour vascular invasion and extrahepatic metastases
are an absolute contraindication for LT in HCC (evidence
high).
  The use of marginal cadaveric grafts for LT in patients
with HCC has no contraindication (evidence moderate).
Prioritising a cadaveric graft allocation, for patients with
or without HCC, within a common waiting list, is complex and no system can serve all regions. Prioritisation
criteria for HCC should at least include tumour burden,
tumour biology indicators, waiting time and response
to tumour treatment (evidence moderate; recommendation strong).
  Transplant benefit may need to be considered alongside
the conventional transplant principles of urgency and
utility in decision making, regarding patient selection
and prioritisation, depending on list composition and
dynamics (evidence moderate; recommendation
weak)
  In LT candidates with HCC, the use of pre-transplant
(neoadjuvant) loco-regional therapies is recommended
if feasible, as it reduces the risk of pre-LT drop-out and
aims at lowering post-LT recurrence – particularly when
complete or partial tumour response are achieved (evidence low; recommendation strong).
  Although the 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 selected patients
and in experienced centres, according to waiting list
time and dynamics, and within donor-recipient double
equipoise principles (evidence low).

T

sm for
B-B’

V8i
MHV

P8v
P8d
RHV

B

PRPM
B’

B

A’

T

P8v
P8d
RHV

PRPM

MHV
Residual region of tumor
bearing 3rd-order portal
branch
at high risk of tumor
recurrence

Fig. 5. Principles of anatomic vs. non-anatomic liver resection for HCC. (A)
Anatomic resection (A-A1) removes entirely the tumour-bearing portal
branches bordered by the landmark veins, while non-anatomic resection (BB1) is any other type of resection in which the tumour-bearing 3rd order
portal region is not fully removed. (B) After non-anatomic resection of HCC
some part of the tumour-bearing portal region is left, which is at high risk of
tumour recurrence This picture is reproduced from Shindoh J et al. J Hepatol
2016 (with permission). HCC, hepatocellular carcinoma; MHV, middle hepatic
vein; P8v, ventral branch of P8; P8d, dorsal branch of P8; PRPM, right paramedian pedicle; RHV, right hepatic vein; V8i, intermediate vein for segment
VIII.

Hepatocellular carcinoma (HCC) is the only generally
accepted indication for solid organ transplantation in cancer
and yet, liver transplantation (LT) for HCC represents a prototype for other transplant indications in various cancer conditions affecting the liver.395,396
Four areas have been addressed by the panel in the context
of LT for patients with HCC: i) Patient selection; ii) Organ allocation and priority for patients with HCC with respect to nonHCC candidates; iii) Neoadjuvant therapies and their impact
on LT for HCC; (4) Living donor LT for HCC.
Patient selection
Currently, patients with HCC in cirrhosis represent about 30%–
35% of the waiting list population in Europe, with large variations from northern to southern Europe (Scandinavian Countries: 15%–18%, Mediterranean Countries up to 40%–44%). HCC
is the fastest growing indication for LT worldwide, together
with NASH/NAFLD liver insufficiency.397
The expected five-year survival rates of LT for HCC meeting
conventional Milan criteria (single tumour ≤5 cm or multiple
tumours ≤3 nodules ≤3 cm in size, without vascular invasion)398
are 65%–80%, and patients meeting the Milan criteria have a significant survival advantage (hazard ratio 1.68) over patients
beyond the criteria.399,400 The Milan criteria works as the most

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Scan detection of liver tumor

Laparoscopic treatment of the affected organ
through small openings

Removal of affected region.
Minimal signs of invasive surgery and rapid
patient recovery

Fig. 6. Principles of mini-invasive/laparoscopic liver resection for HCC. HCC, hepatocellular carcinoma.

reliable border for transplantability in case of HCC both in Western and Eastern guidelines. Patients within Organ Procurement
and Transplantation Network (OPTN) T2 stage (Milan) criteria
are considered eligible for LT, while those beyond Milan can
be offered LT only after successful downstaging into Milan
criteria.401
Expanded criteria
Prospective trials comparing different criteria for LT in HCC are
unlikely to be conducted.
Criteria beyond Milan that have claimed non-significant differences compared to the Milan criteria in terms of post-LT survival, and that have been externally validated are: UCSF criteria
(i.e.: single nodule ≤6.5 cm or 2–3 nodules ≤4.5 cm and total
tumour diameter ≤8 cm,402,403 Up-to-7 criteria (i.e.: those HCCs
having the number 7 as the sum of the size (cm) of the largest
tumour and the number of tumours,404 Total tumour volume
(TTV) criteria + alpha-fetoprotein (AFP) (i.e.: total tumour volume
<115 cm3 and AFP <400 ng/ml,288,405 and the AFP-French model
(i.e.: points system based on tumour size, number of tumours
and AFP cut-off levels at 100 ng/ml and 1,000 ng/ml.286 Among
other expanded criteria from the East (Asian criteria) originally
developed for living donor LT, only the Hangzhou criteria406 and
the Seoul criteria407 consider AFP level (below 400 ng/ml)
among the variables contributing to eligibility for LT, similarly
to the prospective downstaging criteria tested in the Bologna
centre.408
In fact, several AFP cut-offs have been proposed for incorporation into transplant criteria: 100 ng/ml,286,409,410 200 ng/
ml,230 400 ng/ml,288,408,411 1,000 ng/ml286,412,413 but no consensus has been reached on how to combine them with the morphological characteristics of HCC. When treated as continuous
variables, AFP and variations in tumour morphology may be
used to estimate post-LT survival probability, within an individualised incremental risk of death after LT. Using a calculator
available at the address: www.hcc-olt-metroticket.org the individual post-transplant outcome of any patient with HCC considered for listing can be calculated on radiology parameters
collected at any time, as well as after receiving neoadjuvant/downstaging treatment.290
Notably, in published criteria and in prediction models the
size of HCC rather than the number of tumour nodules has
the major prognostic role,404,405 with nodules <1 cm usually
204

not considered in the calculations of number of active tumours.
It has been proposed that when predicting post-LT outcome in
patients with HCC treated with neoadjuvant therapies, each
tumour nodule should be defined as active if showing at
dynamic radiological imaging (contrast-enhanced CT scan or
MRI) an enhancement in the arterial phase with venous washout, even if this is only a part of an otherwise necrotic nodule.290
In other words, for the specific prediction of post-LT outcome in
HCC, each tumour nodule should be measured as totally vital
(i.e., including in the tumour size calculation any concomitant
necrotic area) even if a partial enhancement is detectable after
neoadjuvant/downstaging treatment. Conversely, fully necrotic
HCC should count zero in such a prognostic computation
(Fig. 7). Whatever criteria are applied, data on ten-year survival

4.5 cm
AFP serum level
150 ng/ml

3 cm
A
B
2.5 cm

45 ng/ml
C

Selection criteria
Milan
UCSF
TTV + AFP
Up-to-7
French model
HALT-HCC score
Metroticket 2.0

Pre-treatment
OUT
OUT
IN
OUT
OUT (3 points)
High risk (score 21)
55% at 5 yr
(if HCV-negative)

Post-treatment
OUT
IN
IN
IN
IN (1 point)
Low risk (score 17)
70% at 5 yr
(if HCV-negative)

Fig. 7. Computation of HCC nodules treated with neo-adjuvant therapies
in light of liver transplantation. Post-treatment stage migration of this HCC
according to commonly used criteria for transplant selection is indicated (see
also text). HCC, hepatocellular carcinoma. Example of multifocal (three
nodules) HCC presented for transplant consideration after neo-adjuvant
treatments (downstaging). On last pre-LT imaging, tumour nodules are
considered as fully necrotic (black) or still vital if presenting even minimal
amount of enhanced tumour tissue (white). For transplant consideration this
case should be rated as a two nodules HCC of 4.5 cm and 2.5 cm in size, with
decrease in AFP from 150 to 45 ng/ml.

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is scarce, and the panel endorses the practice of reporting these
figures for transplantation in HCC, in order to better discriminate differences in outcome and in benefit of transplant with
respect to non-transplant therapies.
Extrahepatic tumour spread cannot be cured by an extreme
loco-regional treatment such as LT and represents a clear contraindication for LT.
Macrovascular tumour invasion – either at portal vein or
hepatic veins level – is an absolute contraindication for LT, since
it is the most important and independent risk factor for
post-transplant HCC recurrence and for significant decrease in
survival.414 As for liver resection, tumour invasion of distal
portal branch at sub-segmental level remains a debated issue,
since peripheral tumour invasion can be detected today more
frequently than in the past – because of improved imaging. Segmental/sub-segmental portal thrombosis with partial/complete
regression after loco-regional/systemic treatments is not currently an indication for LT, but may be considered as part of
dedicated prospective investigations.
Marginal cadaveric grafts
Meta-analyses have confirmed LT as the therapy with the highest chances of curing HCC.415 Therefore, LT should be considered
in any HCC treatment strategy whenever possible, unless age
and co-morbidities advise against transplant. The major limiting
factor of LT in HCC is the scarcity of donated organs, with the
additional problem of balancing the distribution of available
organs equally among cancer vs. non-cancer indications. With
the aim of enlarging the available organ pool to meet the growing demand of transplantation in patients with HCC, several
surgical techniques have been developed. All these techniques
produce the so-called ‘‘marginal graft” (also defined as
‘‘extended criteria livers”).416,417
Marginal grafts definition includes: i) living donor right lobe
graft, cadaveric split livers (in which an organ from cadaveric
donors is divided and made available for two recipients of different size), ii) organs with severe steatosis, iii) organs recovered
not only from donation after brain death (DBD donors) but also
after circulatory death (DCD donors).
As patients with HCC frequently show better liver function
and lower model for end-stage liver disease (MELD) scores in
comparison to patients undergoing LT for advanced cirrhosis,
marginal grafts are preferentially proposed for HCC recipients
according to the donor-recipient match principle, aimed at
balancing the risks of organ and LT failures. Although initially
concerns were raised regarding the use of marginal grafts for
patients with HCC, recent reports have confirmed that marginal
livers are currently used in up to 60% of HCC European recipients.418,419 With respect to the use of donors after circulatory
death, it has been recently shown that recipients who are transplanted with a good quality DCD liver do no worse than those
transplanted with livers from DBD donors.420 Notably, the
DCD experience and results are improving, thanks to a new generation of resuscitation/recondition perfusion machines.
Although a retrospective study with competing-risk regression analysis has demonstrated that donor-related factors of
poor quality livers, such as donor >60 years old, body mass
index >35, diabetes and severe steatosis are associated with
an increased rate of HCC recurrence after liver transplant,421
the risk-benefit ratio of post-LT survival remains in favour of
the use of marginal donors for patients with HCC.

Organ allocation and priority for HCC
Objective decisions on organ allocation within common waiting
lists (prioritisation policies between HCC vs. non-HCC patients)
are driven by various factors, whose relative weight is frequently modified according to local/regional contexts.417
The most frequent drivers of a balanced organ distribution
among different transplant indications are based on exception
points. Exception points assignment for patients with HCC listed
for LT are currently based on:
  Tumour burden and presentation (see selection criteria paragraph above);
  Point progression over time (with/out cap and stand-by period before some categories of HCC receive points);422–424
  MELD score and MELD-combined scores such as HCCMELD,425 deMELD;285 MELDEQ;408,426
  Response to loco-therapies against the tumour, based on
bridging or downstaging aims.427–430
Several studies have demonstrated that response to locoregional therapies for HCCs while waiting for transplantation
is correlated to post-LT cancer recurrence and can be used as
a surrogate of tumour biology in outcome predictions.431
Novel MELD exception point systems for HCC, based on
tumour characteristics and dynamics have been implemented
in Europe and America, because of differential post-treatment
responses and a risk of drop-out over time.432,433 This evolution
in HCC priority systems, together with the predicted relative
increase in cadaveric graft availability due to a reduction in hepatitis C virus (HCV)-related diseases because of direct-acting
antiviral treatment, are likely to increase the number of HCC
considered for LT in the near future.434–436 The issue must be
considered and prospective protocol investigations on HCC
transplant patients with HCV are required.
Any outcome prediction of LT in HCC must deal with the
double and differential prognosis of cirrhosis and cancer. Main
drivers for decision making in this contest are based on Urgency
(i.e., focussed on pre-transplant risk of dying without transplant)
and Utility principles (i.e., focussed on maximisation of posttransplant outcome). Those principles apply differently whether
or not HCC appears on top of liver cirrhosis,437 as summarised
(Table 4).
Studies have shown that additional specificities must be
considered at the time of LT listing for HCC, as competitive
non-transplant options exist for the large majority of patients
with well-preserved liver function.437,438 Particularly, transplant benefit (TB) considerations should be added to the conventional principles of urgency and utility when decisions on
patients with HCC are made. TB is the net benefit in survival
achieved by subtracting the survival that could be achieved
by non-transplant options from the absolute post-LT survival439 (Fig. 8). According to a pure transplant benefit
approach, the LT indication in HCC may be counterintuitive,
serving more effectively intermediate/advanced stages of
HCC.440 Also, the use of TB is limited by the fact that is difficult to be properly quantified ahead of transplant. However, it
has been demonstrated that TB plays a strong important role
in prioritising at least four conditions involving patients with
HCC:292,427,441,442
  Decompensated cirrhosis (MELD >15–20) or non-cancerrelated MELD exceptions with HCC within conventional
Milan criteria (see above);

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Table 4. Application of urgency and utility principles in liver transplantation for cirrhosis with or without HCC.
Cirrhosis

HCC + cirrhosis

High pre-transplant mortality
High post-transplant long-term recovery
Predictable outcome with no transplant (MELD)
No competitive options besides transplantation
;
Urgency principle
Focussed on pre-transplant risk of dying without transplant

Low pre-transplant mortality
Variable post-transplant cure, depending on tumour stage at operation
Composite prognostic factors and variable biology influencing outcome
Competitive options in selected patients subgroups
;
Utility principle
Focussed on maximisation of post-transplant outcome

HCC, hepatocellular carcinoma.

Different
post-treatment
survival achieved
with nontransplant options

Different
levels of
transplant
benefit

Time
Allocation models considered for liver transplantation
Model
Urgency

Definition
Focused on pretransplant risk of dying: patients with worse
outcome on the waiting list are given higher priority for
transplantation (based on Child or MELD score)

Utility

Based on maximisation of post-transplant outcome, takes into
account donor and recipient characteristics: mainly used for
HCC since the MELD score poorly predicts post-transplant
outcome in HCC due to the absence of donor factors and lack
of predicting tumour progression while waiting

Benefit

Calculated by subtracting to the survival achieved with LT the
survival obtained without LT. Ranks patients according to the
net survival benefit that they would derive from transplantation
and maximise the lifetime gained through transplantation. If
applied to HCC without adjustments, it may prioritise patients
at highest risk of recurrence.

Fig. 8. Models governing decision-making on prioritisation of liver
transplant candidates with cirrhosis and HCC. HCC, hepatocellular carcinoma. Adapted from,437 with permission.

  Barcelona Clinic Liver Cancer B patients (multifocal HCC)
within validated expanded criteria (see above) and with disease control after having achieved objective response with
downstaging treatment (Fig. 7) and not eligible for further
treatments;39
  Recurrent/persistent HCC after potentially curative treatment (liver resection or ablation), if the persistent/recurrent
tumour burden remains within conventional LT criteria (i.e.:
the so-called ‘‘salvage LT”301,443,444);
  Patients within Milan criteria who are untreatable with liver
resection or loco-regional therapies.
Notably, TB principles tends to prevail when cancer-related
risk of drop-out and response to loco-regional treatments are
taken into account. In fact, waiting list candidates slightly
beyond the accepted limits of transplantability are significantly
more likely to die or be removed from the waiting list than less
advanced candidates (Milan Criteria) but – if prioritised and
transplanted early by means of exception points – show similar
survival in comparison to less advanced HCC.428 As response to

206

pre-LT treatment influences the risks of drop-out, LT eligibility
and priority for HCC may not be determined completely up
front, but come into focus after the best available therapy has
been applied and discussed, within an adaptive approach also
based on TB considerations.430,432,433
Neoadjuvant therapies in LT and downstaging within Milan
criteria
LT candidates with HCC – if not treated – are inherently at risk
of cancer progression while waiting, with an incremental risk of
tumour progression and post-transplant cancer-related mortality related to HCC presentation and AFP variation over
time.290,404,445,446 Several studies and meta-analyses on locoregional treatment have demonstrated significant advantages
of neoadjuvant therapies in reducing the drop-out risk due to
tumour progression.412,422,447–449 Neoadjuvant protocols are
very heterogeneous among centres, but hierarchic use of ablation and transarterial therapies in various combinations is
almost universal, especially when expected waiting time is
above six months.450,451
When defining neoadjuvant treatments, ‘‘bridging” describes
treatment of accepted transplant candidates within Milan criteria while on the waiting list, while ‘‘downstaging” describes
treatment used to bring patients whose tumour burden is outside accepted criteria for transplantation to within acceptable
criteria. Acceptable criteria are defined as those criteria achieving an expected survival after LT equal to patients who meet
transplant criteria without downstaging.399 In the large majority of studies, patients are accepted as LT candidates when their
HCC, presenting at an intermediate/advanced stage, is successfully down-staged to within the Milan criteria.412,452,453 The
consensus on the Milan criteria as an endpoint for downstaging
protocols is influenced by the current MELD system, that assigns
additional exception points to patients down-staged to within
Milan criteria.
Response to bridging and downstaging treatments significantly influences not just drop-outs, but also the rate of posttransplantation tumour recurrences.412,444 Interestingly, good
response to downstaging is frequently related to the presence
of histology markers of good prognosis in the treated HCC
(i.e.: absence of microvascular invasion and satellites, low
tumour grading), similarly to patients receiving LT within Milan
criteria at presentation.400,412 Thus, response to downstaging
has an important role in predicting tumour aggressiveness. Ultimately, response to downstaging represents a selection tool for
defining eligibility for transplant and refining priority in
patients with different HCC presentations.454–457
As downstaging designates a selection strategy, its applicability depends on the context in which it is applied and on
whether more restrictive vs. more relaxed criteria are defined

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•
•
•
•
•

High

Adjuvant therapy after resection/ablation
Chemotherapy
Other molecular therapies*
Hormonal compounds
Y90-radiation (1st line)

Sorafenib, lenvatinib (1st line) •
Regorafenib, cabozantinib (2nd line) •
Chemoembolization •
Radiofrequency ablation PEI (<2 cm)
LT/LDLT-Milan

Levels of
evidence
Moderate

Y90-radiation (BCLC B)

Low

External beam radiation

• Nivolumab
• Down-staging to Milan
• LT/LDTL validated extended

Resection •
MW ablation •

Resection in non-cirrhotic liver •
Neo-adjuvant therapy on waiting list

Strong

Weak

Strong

Negative <

Recommendation

> Positive

*Other molecular therapies (sunitinib, linifanib, brivanib, tivantinig, erlotinib, everolimus)
Weak recommendation: more evidence needed

Fig. 9. Representation of EASL recommendations for treatment according to levels of evidence and strength of recommendation (adaptation of the
GRADE system). LDLT, living donor liver transplantation; LT, orthotopic liver transplantation; MW, microwave; PEI, percutaneous ethanol injection; RF,
radiofrequency ablation.

RCT in advanced HCC-first line
Comparing drugs/devices vs. standard of care, sorafenib
Upper limit for
non-inferiority

Illustrative
scenarios
Superior

Lenvatinib 0.92 (0.79-1.06)

Non-inferior

Linifanib 1.04 (0.89-1.20)
Brivanib 1.07 (0.94-1.23)

Inferior/
inconclusive

Y90 1.15 (0.94-1.41)*

Estimated HR

0.87

0.94

Favors tested drug

1.00
1.08
Estimated HR

lesion >5 cm but ≤6 cm, or 2 lesions ≤5 cm with total tumour
diameter of ≤8 cm, or 4–5 nodules ≤4 cm with total tumour
diameter ≤12 cm, plus AFP <400 ng/dl408 or b): single lesion
≤8 cm, or 2–3 lesions ≤5 cm with total tumour diameter of ≤8
cm, or 4–5 nodules all ≤3 cm with total tumour diameter ≤8
cm, plus AFP <1,000 ng/ml.412 With those restrictions, the
drop-out rate from the protocols was limited to 10% and
34.7% respectively, namely within a much lower range compared to those studies in which more liberal access to downstaging was allowed, and in which the drop-out rate from the
downstaging strategy itself was 44%–76%.458,459 Therefore,
restricting eligibility for downstaging protocols is recommended, in order to limit futile treatments and improve the success rate of the strategy. Prospective studies to address this
issue are suggested.

1.40

Favors sorafenib

Fig. 10. Understanding non-inferiority results in advanced HCC. It is
estimated that RCT testing drugs head-to-head to sorafenib in first line might
have three potential results a) drug is superior to sorafenib if the HR (95% CI)
boundaries do not cross the unity (no example so far). b) The drugs are noninferior compared to sorafenib, if the HR (95% CI) boundaries fall between 1
and 1.08 (lenvatinib case), and C) the drug is inferior to sorafenib if the HR
(95% CI) boundaries cross the 1.08 upper limit for non-inferiority (linifanib
and brivanib cases). Also, the negative results of Y-90 vs. sorafenib are shown.
To claim non-inferiority a specific trial needs to be conducted. (Modified from
Llovet, CCR 2014). ⁄These treatments are inferior or inconclusive. If the RCT
have been designed for superiority (i.e. Y90 vs. sorafenib) a specific RCT with
non-inferiority design is needed to claim non-inferiority. HCC, hepatocellular
carcinoma; HR, hazard ratio; RCT, randomised controlled trial.

for starting and ending the strategy itself. The choice of Milan
criteria as the endpoint for downstaging has been influenced
by the MELD system that assigns additional exception points
to patients down-staged to within Milan criteria. Incidentally,
only two studies have determined upfront selection criteria
for starting downstaging in patients carrying HCC beyond Milan
Criteria. In those studies, HCCs eligible for downstaging were
defined by the following size-and-number parameters: a) single

Living donor LT for HCC
Living donor liver transplantation (LDLT) is the elective procedure for liver replacement in large parts of Asia, because of a
shortage of deceased organ donation and higher incidence of
HCC, possibly due to a higher frequency of viral hepatitis. In
Europe LDLT still represents a debated second-line option, if
cadaveric donation is not feasible or waiting time is prohibitively prolonged, with the procedure reserved to very experienced resection and transplantation centres. One may notice
that after about 20 years of practice, LDLT in Europe has not
been fully embraced and in some countries even abandoned.
Currently LDLT represent 6–7% of the total number of LT performed yearly in Europe (data from ELTR and Eurotransplant
2017). The reasons for that are multifactorial and attain to
donor risk, technical challenges both in the donor and the recipient operation, suboptimal cultural acceptance of possible failures, introduction of the MELD score and increased utilisation
of marginal donors.460 The risks and benefits of LDLT should
be accurately evaluated in both donor and recipient, a concept
known as double equipoise.399,461
Although there are no reasons to maintain substantial differences in donor source for HCC recipients, selection criteria for

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cadaveric LT vs. LDLT differ and so does the rate of reported survival at five years. Overall, tumour size and number of tumour
nodules considered suitable for LT are less restrictive for LDLT.
This causes on average a reduction in expected survival that,
however, is recognised as acceptable when the donation process
is treated as a personal gift, rather than a resource to be distributed in the community. In Asia patients with LDLT beyond
Milan criteria, including far advanced HCC, accounted for about
30% to 40% of total LDLT,462 with exceptions also offered to
patients with macrovascular invasion.463 Notably, no prospective study on extended indications or transplant benefit advantages have been produced in this population. In Europe, LDLT
remains a challenging transplant alternative in selected cases
of HCC in which extended transplant indications may be
explored.

Local ablation and external radiation
Recommendations
  Thermal ablation with radiofrequency is the standard of
care for patients with BCLC 0 and A tumours not suitable
for surgery (evidence high; recommendation strong).
Thermal ablation in single tumours 2 to 3 cm in size is
an alternative to surgical resection based on technical
factors (location of the tumour), hepatic and extrahepatic patient conditions.
  In patients with very early stage HCC (BCLC-0) radiofrequency ablation in favourable locations can be adopted
as first-line therapy even in surgical patients (evidence
moderate; recommendation strong).
  Microwave ablation showed promising results for local
control and survival (evidence low). Other ablative therapies are under investigation.
  Ethanol injection is an option in some cases where thermal ablation is not technically feasible, especially in
tumours <2 cm (evidence high; recommendation
strong)
  External beam radiotherapy is under investigation. So far
there is no robust evidence to support this therapeutic
approach in the management of HCC (evidence low;
recommendation weak).

Over the past 30 years, several methods for chemical or thermal tumour destruction have been developed and clinically
tested.373 The seminal technique was percutaneous ethanol
injection (PEI), which induces coagulative necrosis of the lesion
as a result of cellular dehydration, protein denaturation, and
chemical occlusion of small tumour vessels. Subsequently, thermal ablative therapies emerged, and are classified as either
hyper-thermic treatments (heating of tissue at 60°–100 °C) –
including radiofrequency ablation (RFA), microwave ablation
(MWA), and laser ablation – or cryoablation (freezing of tissue
at  20 °C and  60 °C). Most procedures are performed using a
percutaneous approach, although in some instances ablation
with laparoscopy is recommended.

208

In parallel to the improvements in tumour ablation techniques, the efficacy of imaging-guidance tools, important for
the procedures technical success, has recently been shown.
Indeed, the accurate placement of an electrode or an applicator
in the tumour is essential for achieving complete tumour control. According to personal experience, ultrasound, computed
tomography (CT), and Cone-beam CT are the modalities of
choice for guidance and immediate assessment. Fusion imaging
enables the overlay of multiple imaging, such as real-time ultrasound and CT. It is most helpful in tumours barely visible on
ultrasound and has been shown to decrease the risk of mistargeting.464 Electromagnetic tracking guiding systems allow faster electrode placement into the target than conventional
methods and could reduce the risk of bleeding complications.465
Indeed, controlling the presence and volume of tumour necrosis
at the end of the procedure is of the utmost importance in order
to achieve complete ablation. This can be done with administration of IV contrast agents using ultrasound, Cone-beam CT, CT or
magnetic resonance imaging (MRI).466,467
Percutaneous ethanol injection is a well-established technique for the treatment of nodular-type HCC that leads to complete necrosis in 90% of tumours <2 cm.291,309 Yet, PEI is
associated with incomplete necrosis in most HCCs >2 cm and
suffers a high local recurrence rate, which may reach 49% in
lesions exceeding 2 cm.468 The distribution of alcohol inside
the lesion cannot be well governed and usually does not extend
beyond the cirrhotic fibrous tissue surrounding the tumour.
Accordingly, all meta-analyses that have included randomised
controlled trials that compared PEI with RFA have favoured
RFA over PEI in terms of overall survival (OS), disease-free survival, and recurrence.469–471 Another chemical ablation technique, percutaneous acetic acid injection, has not offered
substantial advantages to PEI.472,473
The mechanisms of cell death in RFA are based on the frictional heat generated using high-frequency alternating current.
Heat produces coagulative necrosis of the tumour and allows
extension of the necrosis to a ‘‘safety ring” in the peri-tumoural
tissue, which might eliminate small-undetected satellites. RFA
has been evaluated as first-line therapy in early HCCs. In a series
of 162 patients with cirrhosis, the OS and recurrence-free survival, were 67.9% and 25.9%, respectively.474 A meta-analysis
showed OS of 76% at three years for single HCCs <3 cm, with
recurrence-free rates of 46%.218 Significant predictors of poor
OS are Child-Pugh class B, elevated serum alpha-fetoprotein
level, and presence of portosystemic collaterals.253,309,474 The
only significant predictive factor of local tumour progression,
which is approximately 30% at three years, is tumour size with
a clear threshold at 2 cm in diameter.253,307–309,474 OS in very
early HCC (<2 cm) treated by RFA was demonstrated to be at
least equal to surgical treatment in a Markov model299 and in
a cost-effective analysis based on data from a systematic
review.218
Sub-capsular HCCs
Tumour location has been a matter of debate in RFA for two reasons: firstly, the technical success (whether a sub-capsular location is a risk factor of reduced effectiveness and local tumour
progression) and secondly the risk of complications that could
be higher in superficial tumours. Since the release of previous
guidelines, a large study using propensity score matching has
compared the long-term outcome of RFA in subcapsular or

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non-subcapsular HCCs.475 Various authors have shown that
there were no significant differences in OS, local tumour progression, and major complication rates between the two
groups.475,476 It is worth remembering that some tumour location issues could be overcome by use of artificial ascites or by
performing laparoscopy assisted ablation. However, in some
instances a safe ablation of subcapsular tumours is unfeasible,
depending on the location (e.g. close to the gallbladder or in
cases of previous abdominal surgery preventing detaching of
liver capsule from bowel loops, etc.). Clearly, the retrospective
nature of the above studies suffers from inclusion bias, excluding subcapsular lesions considered at excessive risk of
complications.
Intermediate HCCs
Selected patients with tumours larger than 3 cm, oligo-nodular
multiple (>3 nodules <3 cm) tumours or advanced compensated
liver failure (Child-Pugh B not clinically decompensated) can be
reasonably treated with RFA on an individual basis or with a
combination of two treatment modalities. Although these treatments provide good results, they are unable to achieve response
rates and outcomes comparable to those observed in small
HCCs. Yet, the large tumours benefit from improvements in
tumour ablation technique and especially the multipolar
approach.477–479 In large HCC, another approach is to combine
RFA with transarterial chemoembolisation. Recent meta-analyses have shown that the combination of RFA with transarterial
chemoembolisation significantly increases OS and recurrencefree survival, without a significant difference in major
complications, but the combination is technically and resource
demanding, and external validation in Western countries is
awaited.480–482
RFA vs. surgery
There have been several studies, trials and meta-analyses that
have compared RFA with surgical resection as a first-line treatment for patients with small, solitary HCC,482 as well as a recent
Cochrane review.483 The Cochrane review included four trials,
representing 574 patients, comparing RFA to surgery in patients
with early resectable HCC. The authors did not find evidence of a
difference in mortality at maximal follow-up between the two
treatments. The proportion of patients with HCC recurrence in
the liver was lower in the surgery group than in the RFA group,
while the number of serious adverse events and any adverse
events was lower in the RFA group than in the surgery group.
The length of hospital stay was shorter in the RFA group than
in the surgery group. None of the trials reported health-related
quality of life. Finally, on the basis of a systemic review of the
literature, RFA was shown to be the most cost-effective therapeutic strategy in very early HCC (single nodule <2 cm) and in
the presence of two or three nodules ≤3 cm.218 When deciding
between surgery and ablation, it must be considered that similar prognostic factors affect RFA and surgery, namely liver dysfunction and tumour size, but with significantly different
weightings and rates of progression between the two treatment
modalities. Prognosis after surgery is more heavily affected by
the progression of liver dysfunction (as expressed by the model
for end-stage liver disease score) than RFA, even in compensated patients in Child-Pugh A, whereas RFA suffers a more

abrupt drop in effectiveness with increasing tumour size than
surgery.370 Additionally, in daily practice, tumour location has
highly important consequences on the choice between thermal
ablation or surgery, as only a limited number of cases are
equally suitable for both techniques.484
RFA vs. microwave ablation
In RFA, an electric current in the RF range is delivered through
one or several needle electrodes (monopolar or multipolar) producing heat-based thermal cytotoxicity. MWA uses electromagnetic energy that heats the tissue and is less prone to heat sink
effect, meaning that treatment efficacy is less affected by vessels
located in the proximity of the tumour. In the previous EASL/
EORTC guidelines, MWA microwave was under investigation.
Since 2011, we have found 15 articles, which have compared
RFA with MWA (Table S1). All but one are retrospective, most
of them were percutaneous procedures, and the number of
patients included varies from 35 to 879 patients. In all series,
OS was not significantly different between RFA and MWA. The
rate of complete response was not significantly different. In 10
studies that evaluated the rate of local recurrence, MWA
showed a significant decrease in local recurrence in four studies,
while results were not different between the two techniques in
the other six studies. The rate of complications was not
different.
Similarly, recent meta-analyses indicate a similar efficacy
between the two percutaneous techniques, with one study
showing possible superiority of MWA in larger HCCs.485,486 It
is worth pointing out that different devices with single RF electrodes (e.g. cool tip vs. various hooked needles) were shown to
produce similar rates of adverse events and similar necrosis volumes,487 whereas different MWA devices seem to produce substantially different ablation volumes and shapes.488
Treatments under investigation
Laser ablation and cryoablation have been proposed for local
ablation in HCC. Since the previous guidelines, only one randomised trial has compared RFA with laser ablation in patients
with HCC, within Milan criteria, with a non-inferiority design.
Laser ablation results were not inferior to RFA in complete
tumour ablation, time to local progression, and OS.489 However,
laser ablation requires higher operator skills than RFA or MWA
because of the need to position multiple fibres inside the same
tumour, with adequate spatial distribution, although it might be
safer in difficult locations.490
So far one randomised controlled trial has compared cryoablation with RFA in 360 patients with HCC. No differences were
observed between the two techniques concerning OS, and
tumour-free survival. Local tumour progression was significantly lower in the cryoablation group than the RFA group.491
Yet the complication rate is not negligible, particularly because
of the risk of ‘‘cryoshock”, a life-threatening condition resulting
in multi-organ failure, severe coagulopathy and disseminated
intravascular coagulation following cryoablation.
Irreversible electroporation (IRE) is a novel form of tissue
ablation that uses high-current electrical pulses to induce pore
formation of the cell lipid bilayer, leading to cell death. It is
not affected by heat sink and may result in less collateral damage based on its mechanism of action. In a short series of

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patients with HCC who underwent liver transplantation, most
tumours showed complete pathologic necrosis without any
viable tumour cells, with preservation of bile ducts within the
treatment area.492,493 However, delivery of IRE requires general
anaesthesia with deep muscular blockade, given the muscular
contraction induced by IRE stimuli, making its performance
more demanding than RFA/MWA, and making it costlier in
terms of resources.
The other non-chemical non-thermal ablation techniques are
still undergoing clinical investigation. High-intensity focussed
ultrasound is a novel ablative approach reported in cohorts of
patients with small tumours, but no randomised studies are
available.494,495
External radiation therapy
Many series and some trials have been reported on the efficacy
and tolerability of different techniques of external beam radiotherapy in different stages of HCC,496 but we do not have any
well conducted prospective trial to consider radiotherapy as
an efficient and proven option.
Most trials and series tested the interesting combination of
external beam radiotherapy with TACE or other intra-arterial
treatments. A systematic review and meta-analysis focussed
on trials comparing TACE with or without radiotherapy497
reported 25 trials (including 11 randomised controlled trials)
involving 2,577 patients and concluded that patients receiving
the combined treatment had a better survival and response rate
than those treated with TACE alone, at the price of more gastroduodenal ulcers and transient increases in aminotransferases
and bilirubin. But in a systematic review of randomised studies,
comparing TACE alone vs. TACE plus external beam radiotherapy, all trials were rated as low to very low quality.498
Results of a planned interim analysis (analysing 69 patients)
of an ongoing prospective randomised trial comparing TACE to
proton beam radiation therapy in patients within Milan or San
Francisco transplant criteria,499 showed a trend toward
improved local control and progression-free survival with
radiotherapy.
Many other therapeutic areas have been tested including
radiotherapy in first-line treatment, particularly in Korea.500
Patients with portal vein thrombosis were considered as a good
target,501 with some cases of secondary liver transplantation.502,503 A Surveillance Epidemiology End Results (SEER)
database analysis comparing ablative techniques and external
radiation in solitary nodules,504 showed significantly better
results for ablative techniques in nodules over 3 cm in diameter,
for those under 3 cm there was no significant difference, but
there was a major trend in favour of ablative techniques. Stereotactic body radiotherapy was safely used as a bridge to liver
transplantation in patients with HCC in a large Canadian series,
with comparable drop-out rates and survival to TACE and RFA,
from time of listing.505
The consensus of experts and a recent review506,507 concluded that despite signs of efficacy and safety, there was a
compelling need for large prospective studies and particularly
randomised phase III trials evaluating the role of radiotherapy.
Notably, a recent phase II clinical trial, mostly in patients with
HCC (69/90), tested ‘individualised adaptive stereotactic body
radiotherapy’ in patients at high risk of liver damage based on
indocyanin green retention at 15 min (assessed at different
phases of the treatment). This new strategy needs further evaluation, but its tolerability seems very good.508
210

Transarterial therapies
Recommendations
  TACE is recommended for patients with BCLC stage B
and should be carried out in a selective manner (evidence high; recommendation strong). The use of
drug-eluting beads has shown similar benefit to conventional TACE (cTACE; gelfoam-LipiodolÒ particles) and
either of the two can be utilised (evidence high; recommendation strong). TACE should not be used in patients
with decompensated liver disease, advanced liver and/or
kidney dysfunction, macroscopic vascular invasion or
extrahepatic spread (evidence high; recommendation
strong). There is insufficient evidence to recommend
bland embolisation, selective intra-arterial chemotherapy and lipiodolisation (evidence moderate).
  TARE/SIRT using yttrium-90 microspheres has been
investigated in patients with BCLC-A for bridging to
transplantation, in patients with BCLC-B to compare
with TACE, and in patients with BCLC-C to compare with
sorafenib. Current data show a good safety profile and
local tumour control but 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 (evidence moderate).
  There is insufficient evidence to recommend scores that
better select BCLC-B candidates for first TACE or for subsequent sessions (evidence moderate).

Transarterial chemoembolisation
Transarterial chemoembolisation (TACE) is the most widely
used primary treatment for unresectable HCC,325,509 and was
the recommended first-line therapy for patients with intermediate-stage disease in the previous guidelines.1 HCC exhibits
intense arterial neo-angiogenic activity during its progression.
The rationale for TACE is that the intra-arterial infusion of a
cytotoxic agent followed by embolisation of the tumour-feeding
blood vessels will result in a strong cytotoxic and ischaemic
effect targeted to the tumour since this tends to become entirely
fed by arterial inflow, unlike the surrounding parenchyma
which receives the majority of inflow through the portal system.
TACE should be distinguished from chemo-lipiodolisation,
which involves the delivery of an emulsion of chemotherapy
mixed with LipiodolÒ, bland transcatheter embolisation (TAE),
where no chemotherapeutic agent is delivered, and intra-arterial chemotherapy, where no embolisation is performed. Details
on the distinct types and definitions of image-guided transcatheter embolisation have been reviewed elsewhere.510,511
Conventional TACE
This procedure is also called Lipiodol TACE. It involves transcatheter delivery of chemotherapy emulsioned with Lipiodol,
followed by vascular stagnation achieved with particle embolisation. The combination of Lipiodol drug emulsion followed by
particle embolisation demonstrates a better pharmacokinetic
effect over Lipiodol/drug emulsion without particle embolisation or drug alone and induces substantially greater tumour
necrosis compared to injection of Lipiodol alone or as a drug

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emulsion without particle embolisation.512 Moreover, the combination of Lipiodol/drug emulsion with particles also demonstrates better long-term survival than injection of
Lipiodol/drug emulsion without particles.513 Retention of Lipiodol can also be regarded as an additional imaging
biomarker.512
The most common drugs used during conventional TACE,
either as single agents or in combination regimens, are doxorubicin or epirubicin, cisplatin or miriplatin.514 These anticancer
drugs have been tested amongst others on three human HCC
cell lines. The most effective drug was idarubicin which is currently under evaluation in clinical trials.515,516
Survival benefits of TACE compared to best supportive care
were demonstrated by two randomised controlled trials,312,313
one of which identified treatment response as an independent
predictor of survival,312 and several meta-analyses.310,517 As a
result of these investigations, TACE is the standard of care for
patients who meet the criteria for the intermediate-stage of
the BCLC staging system, i.e. those with multinodular and/or
large HCC, absence of cancer-related symptoms and no evidence
of vascular invasion or extrahepatic spread. In 2011, a metaanalysis by Cochrane investigators challenged the efficacy of
TACE.518 Several biases contained in this assessment, including
the use of trials with inappropriate control arms or target populations leading to poor outcomes, call into question the impact
of this investigation.
Recently, a systematic review on conventional TACE has
included 101 articles, with a total of 10,108 patients.514 The
objective response rate was 52.5% (95% CI 43.6–61.5), and the
overall survival (OS) was 70.3% at one year, 51.8% at two years,
40.4% at three years, and 32.4% at five years with a median OS of
19.4 months (95% CI 16.2–22.6). The five most common adverse
events were liver enzyme abnormalities (18.1%), fever (17.2%),
haematological/bone marrow toxicity (13.5%), pain (11%), and
vomiting (6%), which are related to the occurrence of postembolization syndrome. Overall mortality rate was 0.6% and the
most common cause of death was related to acute liver insufficiency. Very recently, an RCT suggested that the combination of
intravenous steroids with antiemetics for three days at the time
of TACE reduce the incidence of the postembolization syndrome
in comparison to antiemetics alone,519 with a good safety profile, but external validation is required before any such policy
can be endorsed.
TACE with drug-eluting beads
Strategies to improve anti-tumoural activity and clinical benefits with chemoembolisation have been launched. The ideal
TACE scheme should allow maximum and sustained intratumoural concentration of the chemotherapeutic agent with minimal systemic exposure, along with calibrated tumour vessel
obstruction.
Embolic microspheres have the ability to sequester
chemotherapeutic agents and release them in a controlled mode
over a one-week period. TACE with drug-eluting beads (TACEDEB) using calibrated doxorubicin-carrying microspheres has
shown more sustained and tumour-selective drug delivery
and permanent embolisation.520 A randomised phase II study
comparing the short-term outcomes of TACE-DEB and conventional TACE indicated some advantages of TACE-DEB in terms
of toxicity and radiologic tumour response, particularly in fragile subgroups, such as Child-Pugh B and performance status >0
patients, and in those with bilobar or recurrent tumours.521

However, the leading safety issue favouring TACE-DEB was
alopecia. Another RCT compared TACE-DEB and conventional
TACE in patients followed-up for at least two years or until
death. There were no differences in OS (one- and two-year survival rates were 86.2% and 56.8% after TACE-DEB and 83.5% and
55.4% after conventional TACE, respectively). There were no differences according to the median number of procedures (two in
each arm), in-hospital stay and local and overall tumour
response (median TTP of nine months in both arms). The incidence and severity of adverse events did not differ between
the arms, except for post-procedural pain, which was more frequent and severe after conventional TACE.522 This result was
confirmed by a meta-analysis based on seven studies (693
patients) that demonstrated that the two procedures had equivalent results.523 Conversely, a retrospective study has shown
that biliary injuries, intrahepatic bilioma, and global hepatic
damage were significantly higher following TACE-DEB than
with conventional TACE, especially in patients with advanced
cirrhosis.524 Accordingly, at present there is insufficient evidence to recommend one TACE technique over another and
the choice is left to the operator.
Patient selection
The indication for TACE should consider tumour burden, underlying liver disease, and performance status. Patients with
declining performance status (Eastern Cooperative Oncology
Group PS ≥2) or severe hepatic decompensation (Child-Pugh C
or Child-Pugh B decompensated cirrhosis) are unlikely to benefit from TACE, which is often detrimental in such patients. Inadequate hepatic function, such as serum bilirubin >2 mg/dl, and a
tumour burden >50% of total liver volume, increase the risk of
hepatic decompensation after TACE.325,512 Macrovascular invasion of the main portal branches or the main portal vein are contraindications for TACE.313 Impaired portal vein blood flow (for
example, a portal vein thrombus, hepatofugal blood flow) is
considered an absolute contraindication for TACE, although it
can be performed safely in patients with segmental or sub-segmental portal vein obstruction if the treatment is selective.525
However, TACE is not recommended in patients with segmental
portal vein tumour invasion. Such indications should be discussed in multidisciplinary team sessions, in light of TARE and
alternative first and second-line systemic treatments. Patients
with biliary-enteric anastomosis or biliary stent are at higher
risk of hepatic abscess, therefore other treatments should be
preferred. As Barcelona Clinic Liver Cancer (BCLC) stage B represents a heterogeneous group of patients, a subclassification was
proposed in order to select patients most likely to benefit from
TACE treatment.316 According to the available information, the
best candidates are those patients with uni- or pauci-nodular
disease without vascular invasion or metastases, who are
asymptomatic and have a Child-Pugh stage of ≤B7. In such
patients, the median survival after TACE in modern series is
40–50 months.293,314,315
Technical factors
Super-selective chemoembolisation is recommended to
increase treatment efficacy and minimise the ischaemic insult
to non-tumoural tissue. Then, identification of tumoural feeders
is crucial to better target the tumour and obtain complete
necrosis. It can be done prior to the procedure on arterial phase
contrast-enhanced CT and is best in the angiographic suite with
3D-angiography obtained with a rotational flat panel detector

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system (cone-beam CT). Additionally, dedicated computeraided software may help identify tumour feeders.526 Contrastenhanced cone-beam CT imaging obtained immediately after
TACE enables assessment of treatment success.

growth factor receptor, as an adjuvant to TACE in patients with
HCC.541 Likewise, Orantinib combined with cTACE did not
improve overall survival in patients with unresectable hepatocellular carcinoma.542

Treatment schedule
To date, no solid data suggest that scheduled TACE at regular
intervals is more or less effective at improving patient survival
than on demand TACE according to tumour response assessment. However, the repetition of TACE procedures according
to an aggressive schedule (i.e. TACE every two months) might
induce liver failure in an unacceptable proportion of patients.527
Given the improvement in imaging techniques in detecting
residual viable tissue, at present a subsequent course of TACE
appears recommended only when residual viable HCC is documented by contrast-enhanced imaging, CT, rather than planned
upfront regardless of the outcome of the first TACE session.
After initial TACE success, the treated tumours gain vascularisation and may be re-treated. The decision on when TACE therapy should be interrupted is complex. In recent years, several
scores have been proposed to guide the decision to retreat.528–531 Regrettably, their applicability is controversial
and such scoring systems probably identify patients who were
poor candidates for TACE at baseline, as defined in these guidelines.532–535 TACE should not be repeated when substantial
necrosis is not achieved after two rounds of treatment or when
follow-up treatment fails to induce marked necrosis at sites that
have progressed after an initial tumour response. Additionally,
TACE should not be repeated upon ‘untreatable progression’
defined as tumour progression associated with a clinical profile
that prevents re-treatment. Definitions of untreatable progressions may include major progression –extensive liver involvement, extrahepatic metastasis or vascular invasion – but also
minor intrahepatic progression associated with impaired liver
function and performance status.326 Finally, doxorubicin like
any other anthracycline may induce cardiotoxicity. It is mostly
a dose-dependent chronic cardiomyopathy. Left ventricular
ejection fraction should be checked by echocardiogram in
patients receiving multiple TACE sessions and the cumulative
dose should not exceed 450 mg/m.2

Transarterial embolisation
Four meta-analyses compared the outcomes of TACE vs.
TAE.517,543–545 All of them showed that the OS was statistically
similar between the two groups. More recently, a randomised
trial of 101 patients did not find differences between TACE
and TAE in terms of tumour response, progression-free survival
and OS,546 but nearly half of the patients recruited were at an
advanced stage, limiting the results’ reliability. These results
are in line with a Cochrane review on TACE advocating for more
adequately powered and bias protected trials.518 Yet, the standard of care for patients with intermediate HCC is TACE in the
vast majority of institutions, while very few will perform TAE
only.

Combination of TACE and RFA
In patients with HCC, the combination of TACE and RFA is associated with significantly higher OS and recurrence-free survival,
than RFA monotherapy, without a significant difference in major
complications. This benefit is more important in HCC larger than
3 cm in diameter,480,536,537 however the combination of the two
techniques on the same occasion is quite demanding in terms of
resources.
Combination of TACE and antiangiogenics
The local hypoxia and ischaemic necrosis achieved by TACE
results in activation of hypoxia-inducible factors (HIFs) and
increased levels of vascular endothelial growth factor (VEGF).
Accordingly, the combination of TACE with anti-angiogenic
agents might constitute an effective strategy to improve outcomes. Sorafenib, which inhibits the vascular endothelial
growth factor receptor receptors, has been extensively evaluated in combination with TACE. This combination therapy has
shown an acceptable safety profile, but conclusive efficacy has
not been demonstrated.538–540 Similarly, negative results were
obtained for brivanib, an inhibitor of VEFGR2 and the fibroblast
212

Other indications of TACE
TACE is also used in patients with early-stage HCC as a bridge to
liver transplantation or when liver transplantation, hepatic
resection, and image-guided ablation are not possible, in keeping with the stage migration strategy.547 Actually, two surveys,
an Italian one and an international one, have shown that TACE is
widely used outside intermediate HCCs.509,548 Both demonstrated that TACE represents a major part of daily clinical practice in patients with HCC worldwide. Although TACE is the firstline treatment option for intermediate-stage HCC, in real life
approximately 40% of TACEs are performed in either early or,
more rarely, advanced stages.293,314,315,546,549
Selective internal radiation therapy
Selective internal radiation therapy (SIRT) also called radioembolization is defined as the infusion of radioactive substances
such as 131-Iodine-labelled Lipiodol550 or microspheres containing yttrium-90 (Y90)511 or similar agents into the hepatic
artery. Given the hypervascularity of HCC, intra-arterialinjected microspheres are preferentially delivered to the
tumour-bearing area and selectively emit high-energy, lowpenetration radiation to the tumour. Currently, the most popular technique uses resin or glass microspheres coated with Y90,
a ß-emitting isotope. This treatment requires a close collaboration between interventional radiologists, nuclear medicine specialists, radiopharmacists, and physicists. Patients undergo
preliminary angiography of the hepatic artery, and protective
coiling of extrahepatic branches if necessary. In the same session, 99Tc macroaggregated albumin is injected into the hepatic
artery using the same catheter position chosen for the scheduled SIRT session. Calculation of the dose to the tumour, dose
to the adjacent liver, hepato-pulmonary shunt fraction, and tracer distribution are evaluated with macroaggregated albumin
single-photon emission CT imaging. Severe lung shunting and
extrahepatic uptake contraindicate the procedure. Patients are
usually readmitted for SIRT one or two weeks later. SIRT is performed in a lobar, sectorial, or segmental approach according to
tumour size and location. In patients with HCC developed on
chronic liver disease, whole-liver treatment in one session is
discouraged. Because of the minimally embolic effect of Y90
microspheres, treatment can be safely used in patients with
portal vein thrombosis.551 Cohort studies reporting long-term
outcomes showed a median survival time of 16.9 months to

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17.2 months for patients at intermediate stages and 10 months
to 12 months for patients at advanced stages with portal vein
invasion.382,552–554 Objective response rates range from 35% to
50%.382,552,554 Around 20% of patients present liver-related toxicity and 3% treatment-related death,552 but adverse events are
neither more common nor more severe in elderly patients, and
survival is no shorter.555
SIRT vs. sorafenib
One of the most common indications of SIRT is treatment of
patients with locally advanced HCC. Two RCTs comparing efficacy and safety in patients treated with SIRT vs. sorafenib have
completed patient enrolment and have been presented.556,557 In
both studies, designed for superiority of SIRT, the primary endpoint was not reached as no statistically significant differences
in OS were observed in intention-to-treat or per-protocol populations. In both studies, tumour response rate was significantly
higher with SIRT, although this finding did not translate into
longer survival. In both trials, the applicability of Y-90 was limited to 72–77% of patients because of treatment contraindications. In the SIRveNIB trial,557 progression-free survival and
time to progression were significantly higher in the SIRT group
than in the sorafenib group in the treated population. In the
SARAH trial,556 the total and median number of treatmentrelated adverse events per patient were twice as frequent with
sorafenib vs. SIRT including Grade ≥3 treatment-related adverse
events. However, the course of the adverse event (rate of remission in the two arms) was not reported. A head-to-head RCT of
SIRT vs. sorafenib is ongoing, and the added value of sorafenib in
patients treated with SIRT is being evaluated in another RCT
(SORAMIC trial). Another phase III clinical trial (STOP-HCC)
evaluating yttrium-90 trans-arterial radioembolization (TheraSphereÒ) prior to sorafenib vs. Sorafenib alone in the treatment
of patients with unresectable HCC is ongoing. At present, the
survival benefit of SIRT compared to sorafenib in advanced
HCC is still not proven, and its use either alone or in combination with systemic therapy should only be adopted after multidisciplinary board discussion.
SIRT vs. TACE
Up to now, all studies comparing SIRT with TACE have been retrospective with a small number of patients. Compared to TACE,
SIRT induces less toxicity (possibly because of better patient
selection in those treated with SIRT than those treated with
TACE), provides significantly longer time to progression and
better tumour control, and maintains higher quality of life,
although it does not provide longer survival.558–560 Regrettably,
its performance is more demanding than TACE and it is less
available.
Other indications
Few studies have evaluated SIRT as a bridge to liver transplant.
In a small series, patients treated with SIRT showed better
tumour control and a higher proportion received liver transplantation than those with TACE, leading to speculation that
SIRT could reduce drop-out from transplant waiting lists.560
SIRT has also been tested in patients with borderline resectable
HCC. Besides its effect on tumour control, SIRT might prepare or
select patients for surgery as it induces substantial hypertrophy
in the liver lobe contralateral to the target.561

Systemic therapies
Recommendations
  Sorafenib is the standard first-line systemic therapy for
HCC. It is indicated for patients with well-preserved liver
function (Child-Pugh A) and with advanced tumours
(BCLC–C) or earlier stage tumours progressing upon or
unsuitable for loco-regional therapies (evidence high;
recommendation strong).
  Lenvatinib has been shown to be non-inferior to sorafenib and is also recommended in first-line therapy for
HCC given its approval. It is indicated for patients with
well-preserved liver function (Child-Pugh A class), good
performance status and with advanced tumours –
BCLC-C without main portal vein invasion – or those
tumours progressing upon or unsuitable for loco-regional therapies (evidence high; recommendation
strong).
  There are no clinical or molecular biomarkers established to predict response to first or second-line systemic treatments (evidence moderate).
  Regorafenib is recommended as second-line treatment
for patients tolerating and progressing on sorafenib
and with well-preserved liver function (Child-Pugh A
class) and good performance status (evidence high; recommendation strong). Recently, Cabozantinib has
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 III data for
conventional approval. At present, the data are not
mature enough to give a clear recommendation
(evidence moderate; recommendation weak).
  Treatments that failed to meet their endpoints in randomised trials are not recommended. Further clinical trials are needed to confirm claims of non-inferiority
(Fig. 10), or any trends of better outcome identified in
subgroup analysis (evidence high). TARE in combination
with systemic therapy is under investigation.
  Patients at BCLC D stage, who are not candidates for liver
transplantation should receive palliative support, including management of pain, nutrition and psychological
support. In general, they should not be considered for
clinical trials (evidence low; recommendation strong).

Molecular pathogenesis and targets for therapies
Molecular targeted therapies have changed the landscape of
cancer management. Molecular subclasses of hepatocellular
carcinoma (HCC) have been proposed as proliferation/non-proliferation, and the key drivers of this cancer have been identified
after sequencing more than 1,500 samples in several studies.562
The most prominent drivers (TERT, CTNNB1 and TP53) are currently not actionable mutations. Potential targets for precise
therapies with monoclonal anti-bodies and tyrosine kinase

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inhibitors (TKIs), such as high-focal amplification FGF19 or
VEGFA, have a prevalence of less than 10%.563,564 Three systemic
drugs have shown survival benefits in the setting of phase III
studies for advanced HCC, sorafenib and lenvatinib in first-line
treatment and regorafenib in second-line.320–323 These drugs
are multi-kinase inhibitors, abrogating several pathways simultaneously. At ASCO GI in January 2018 a fourth drug, cabozantinib (60 mg po qd) showed superiority over placebo in
second- and third-line treatment with an improved overall survival from 8.0 months to 10.2 months.324 Promising signals of
efficacy have been reported in large phase II studies with the
checkpoint inhibitor nivolumab.565 So far, no proof-of-concept
biomarker-enriched study has yet demonstrated efficacy for
precision medicine in HCC.
Treatments for advanced HCC
Hepatocellular carcinoma is recognised as among the most
chemo-resistant tumour types, and until 2007 no systemic drug
was recommended for patients with advanced tumours, an
unparalleled situation in oncology. Sorafenib emerged as the
first effective systemic treatment in HCC after 30 years of
research, and is currently the standard of care for patients with
advanced tumours.320,321 Following the approval of sorafenib,
several substances were tested for either non-inferiority (brivanib, linifanib)566,567 or superiority (sunitinib, erlotinib plus
sorafenib)568,569 but most of them did not reach their primary
endpoint. Furthermore, systemic chemotherapy with doxorubicin570 or FOLFOX571 did not demonstrate survival benefits.
Moreover, two recent phase III superiority trials comparing
internal radiation with Y-90 resin microspheres vs. sorafenib
did not hit the primary endpoint.556,557 Meanwhile, phase III trials investigating brivanib, everolimus, ramucirumab, and tivantinib in second-line therapy failed to show improved outcome
compared to placebo.295,572–574 Toxicity in the setting of
impaired liver function, lack of efficacy of the investigational
substance, and an imbalance in prognostically relevant factors
in the different study arms have all been discussed as reasons
for the large number of unsuccessful phase III trials.575
It took 10 years from the approval of sorafenib for a second
phase III trial to be positive, defining a role for another TKI, regorafenib, for patients progressing on sorafenib.322 Very recently,
lenvatinib, an anti-angiogenic TKI was found to be non-inferior
to sorafenib, offering another upfront therapy for patients with
HCC.323 Furthermore, the positive results of cabozantinib vs.
placebo in second-line (CELESTIAL trial) were presented in January 2018 at ASCO GI.324 High expectations characterise
recently published and ongoing trials investigating checkpoint
inhibitors, the current mainstay of immune oncology, as a
new treatment option for HCC. Until now, only uncontrolled
data exist, however, the objective response rates (15–20%) and
the median survival reported (16 months) for nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, are unseen with other therapies and raise hope for a rapid
broadening of the therapeutic armamentarium in HCC beyond
TKIs.565
First-line therapies
Sorafenib
Sorafenib, an oral multi-TKI, was the first drug to demonstrate a
survival benefit in patients with advanced HCC. Following an
initial phase II study showing a signal of efficacy,576 a large
double-blinded placebo-controlled phase III investigation was
214

conducted, leading to positive survival results.320 In this trial,
the median overall survival (OS) of patients in the sorafenib
group was 10.7 months compared to 7.9 months in the placebo
group (HR, 0.69; 95% CI 0.55–0.87; p = 0.00058), representing a
31% decrease in the relative risk of death. The magnitude of survival benefit was similar to that demonstrated in a parallel
phase III trial conducted in the Asian-Pacific population, in
which hepatitis B was the main cause of HCC.321 Sorafenib is
well tolerated, the most common grade 3 drug-related adverse
events observed are diarrhoea and hand-foot skin reaction,
which occurred in 8–9%, and 8–16% of patients, respectively.
Discontinuation due to adverse events was 15% in the sorafenib
arm and 7% in the placebo. As a result, sorafenib received
approval by regulatory agencies in 2007. Following the approval
of sorafenib, several phase III trials compared sorafenib with
investigational agents, resulting in a median OS of around 10
months (range between 6.5 and 11.8 months [Table 5]). In addition, several post-marketing studies produced real-life data and
reported OS for Barcelona Clinic Liver Cancer (BCLC) B patients
of 15.6–20.1 months and for BCLC-C of 8.4–13.6 months.577–580
The panel of experts recommends using sorafenib as the
standard systemic therapy for HCC. It is indicated for patients
with well-preserved liver function (Child-Pugh A class) and with
advanced tumours, BCLC-C, or tumours progressing on locoregional therapies (concept of treatment stage migration). No
clear recommendation can be made in Child-Pugh B patients,
although cohort studies have reported a similar safety profile
in patients of this class with no decompensation,581,582 however, the reported outcome for Child-Pugh B patients from the
non-interventional GIDEON trial was poor.583 Sorafenib treatment should be maintained at least until radiographic progression, and beyond that point second-line treatment with
regorafenib is recommended.
Sorafenib has been tested in the adjuvant setting after
resection or complete local ablation for early HCC stages and
in combination with chemoembolisation for intermediate
stages.394,538,540 These trials did not support the use of sorafenib
as an adjuvant agent nor in combination with TACE.
Lenvatinib
Lenvatinib is an oral multi-kinase inhibitor that targets vascular
endothelial growth factor receptor (VEGFR1-3); fibroblast
growth factor receptor (FGFR1-4); platelet-derived growth factor receptor a (PDFGRa), RET, and KIT.584 Lenvatinib was investigated in an open-label, phase III, multicentre, non-inferiority
trial involving patients (two-thirds from the Asia-Pacific region)
with advanced HCC (excluding main portal vein invasion and
>50% tumour to total liver volume occupancy), Child-Pugh A,
performance status 0/1, randomised to lenvatinib (body weight
≥60 kg: 12 mg/day; <60 kg: 8 mg/day) vs. sorafenib (Table 5).
The study met its primary endpoint of non-inferiority in OS
(median OS: lenvatinib, 13.6 months vs. sorafenib, 12.3 months;
hazard ratio [HR]: 0.92; 95% CI 0.79–1.06). Lenvatinib also
improved progression-free survival (7.4 months vs. 3.7 months
on sorafenib) and TTP (8.9 months vs. 3.7 months on sorafenib).
In terms of response, the objective response rate defined by
modified Response Evaluation Criteria In Solid Tumours (mRECIST) was significantly better for lenvatinib (24.1% vs. 9.2% sorafenib; p <0.001). Grade ≥3 TEAEs were more common with
lenvatinib vs. sorafenib (57% vs. 49%, respectively). The most
common grade 3/4 treatment-related AEs with lenvatinib and
sorafenib, respectively, were hypertension (23% vs. 14%),

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decreased weight (8% vs. 3%), decreased platelet count (6% vs.
3%), elevated aspartate aminotransferase (5% vs. 8%), decreased
appetite (5% vs. 1%), diarrhoea (4% vs. 4%), and palmar-plantar
erythrodysesthesia (3% vs. 11%). Median time on lenvatinib
and sorafenib was 5.7 months and 3.7 months, respectively.
These results indicate that lenvatinib is an active drug that provides clinically significant benefits to patients with advanced
HCC or those progressing to chemoembolisation.323 The openlabel design makes it difficult to interpret other differences
related to patient reported outcomes. No cost-effectiveness
studies comparing both drugs are available. In summary, the
panel recommend its use in the indicated populations once
the drug is approved by regulatory agencies.
Treatments with no benefit in first-line
Sunitinib is an oral multi-TKI approved for the treatment of renal
cell carcinoma, gastrointestinal stromal tumours and pancreatic
neuroendocrine tumours. A multicentre, open-label sorafenibcontrolled randomised phase III trial was prematurely discontinued for safety issues and futility reasons.568 This drug is presently not recommended for treatment of HCC.
Brivanib alaninate, an oral VEGFR and FGFR TKI, was evaluated
in two phase II studies in first and second-line patients with
advanced stage HCC. The median OS was 10 months in the
first-line treated group and 9.8 months in the second-line treated
group, with manageable adverse events.585 Three phase III trials
testing brivanib in first-line blinded to sorafenib,566 in secondline blinded to placebo572 and in combination with chemoembolisation541 resulted in negative results for primary endpoints.
Linifanib, an oral TKI targeting VEGF and PDGF, and ramucirumab, a monoclonal antibody against VEGFR2586 failed in
phase III studies in first-line and second-line indications, respectively.295,567 Other new anti-angiogenic agents, such as vatalanib, axitinib and cediranib are at very early stages of
investigation. Other molecules such as c-MET inhibitors, MEK
(MAP2K1) inhibitors, transforming growth factor-beta (TGFb)
and Janus kinase 2 (JAK2) inhibitors are being tested in early
clinical investigations.587
Chemotherapy
The problem of using chemotherapy in HCC stems from the coexistence of two diseases. Cirrhosis can perturb the metabolism
of chemotherapeutic drugs and enhance their toxicity. In addition, some chemotherapy-related complications, such as systemic infections, are particularly severe in immunocompromised patients, like cirrhotics. HCC has also been shown
to be chemo-resistant to the most common chemotherapies,
which as single agents have caused modest anti-tumoural
responses.310,588–590 Systemic doxorubicin has been evaluated
in more than 1,000 patients in clinical trials with an objective
response rate of around 10% and negative or inconclusive survival benefits. Furthermore, a recent phase III trial combining
doxorubicin and sorafenib vs. sorafenib alone did not meet its
primary endpoint. The addition of doxorubicin to sorafenib
resulted in higher toxicity but did not improve OS570 (Table 5).
Three other regimens have also shown negative results: PIAF
regimen (Cisplatin/Interferon a2b/Doxorubicin/FluorouracilPIAF regimen), FOLFOX and hepatic intra-arterial chemotherapy
(HIAC) with cisplatin and 5-FU. The phase III trial comparing
PIAF vs. doxorubicin showed median survival of 8.67 months
and 6.83 months, respectively, without differences between
groups. PIAF was associated with a significantly higher rate of
myelotoxicity compared with doxorubicin and treatment-related

mortality of 9%.590 A second randomised controlled trial (RCT)
conducted in Asia compared the efficacy of the FOLFOX regimen
combining 5-fluorouracil, folinic acid and oxaliplatin against
doxorubicin alone. This study included 371 patients with
Child-Pugh A/B advanced non-operable or metastatic HCC
(BCLC-B/C). There was a non-significant trend favouring the
FOLFOX group (median survival 6.4 months vs. 4.9 months;
p = 0.07) associated with a better time to progression
(2.9 months vs. 1.7 months).571 Finally, HIAC with cisplatin
and 5-FU combined with sorafenib did not meet the primary
endpoint of better survival compared to sorafenib alone
(Table 5) Chemotherapy for HCC in non-cirrhotic patients is
an underexplored area.591 Thus, considering the available
evidence, systemic chemotherapy is not recommended for the
treatment of HCC, nor as a control regimen for any trial because
of its well-known toxic effects, although the panel acknowledges that inappropriate patient selection and trial design have
contributed to the failure of appropriate drug development for
chemotherapy. Chemotherapy for HCC in non-cirrhotic patients
needs to be further investigated.591
Hormonal compounds
Hormonal compounds have not shown survival benefits in HCC.
A meta-analysis of seven RCTs comparing tamoxifen vs. conservative management, comprising 898 patients, showed neither
anti-tumoural effects nor survival benefits for tamoxifen.310
Two large RCTs were reported afterwards assessing tamoxifen592,593 with negative results in terms of survival. Thus, this
treatment is discouraged in advanced HCC. Anti-androgen therapy is not recommended.594
Other treatments
A large RCT compared seocalcitol – a vitamin-D like anti-proliferative molecule – with placebo in 746 patients and showed no
differences in OS (9.6 months seocalcitol vs. 9.2 months
placebo).311 Finally, negative results were also reported with a
tubulin inhibitor (T-67) in a large multicentre RCT.595
Second-line therapies
Regorafenib
Regorafenib is an oral multi-kinase inhibitor that blocks the
activity of protein kinases involved in angiogenesis, oncogenesis, and the tumour microenvironment.596 Regorafenib (160
mg po once daily 3 weeks on / 1 week off) showed survival benefits compared to placebo in the phase III RESORCE trial in
patients with HCC who tolerated and progressed on sorafenib322
(Table 5). The trial included patients with good liver function
(Child-Pugh A) who previously tolerated sorafenib (defined as
receiving sorafenib ≥400 mg daily for at least 20 of the last 28
days of treatment). The latter avoided unexpected toxicity as
sorafenib and regorafenib have a comparable safety profile.
The primary endpoint OS was met and regorafenib improved
the median OS from 7.8 months on placebo to 10.6 months
(HR 0.63; 95% CI 0.50–0.79); p <0.0001). Radiographic objective
response was 10.6% (mRECIST; 6.6% RECIST 1.1) and disease
control rate 65.2% (mRECIST; 65.7% RECIST 1.1). Adverse events
were manageable and consistent with the known regorafenib
safety profile, leading AEs were hand-foot-skin-reaction, fatigue
and hypertension. Median times on regorafenib or placebo were
3.6 months and 1.9 months, respectively. The FDA and EMA
have approved regorafenib in patients with HCC who have been
previously treated with sorafenib. The panel recommends regorafenib for this indication.

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Immunotherapy
The recent success of checkpoint inhibitors in different tumours
has stimulated several ongoing clinical trials of different checkpoint inhibitors in HCC. Most advanced is nivolumab, that targets PD-1 and has been tested in a dose escalation and
expansion trial in patients with advanced HCC. Nivolumab’s
interference with the PD-1 receptor restores T-cell–mediated
anti-tumour activity. A large phase II study in patients in
front-line (n = 80) and second-line (n = 182) has recently
reported promising results in terms of OS, objective response
and duration of response. This trial tested 48 patients in dose
escalation and 214 in the dose expansion phase. The objective
response rate was 20% (95% CI 15–26) in patients treated in
the dose expansion phase (nivolumab 3 mg/kg), and median
survival was close to 16 months in second-line patients. PD-L1
expression did not predict response and efficacy was similar
across different aetiologies. The safety profile of nivolumab
was manageable and consistent across patient cohorts and
was similar to that observed in other tumour types. The most
common symptoms are fatigue, pruritus, diarrhoea and elevated
liver enzymes.565 As a consequence of these results, the FDA
granted nivolumab conditional approval in second-line therapy,
with conventional approval pending phase III results comparing
nivolumab with sorafenib in treatment-naive patients.
Cabozantinib
Cabozantinib is a MET, VEGFR2 and RET inhibitor approved for
thyroid and renal cancer that showed clinical activity in a phase
II discontinuation study in patients with advanced HCC in second- or third-line treatment.597 The phase III CELESTIAL trial
comparing cabozantinib (60 mg daily) with placebo in secondline treatment of advanced HCC (Child-Pugh A, ECOG PS 0/1)
has been halted at the second interim analysis for efficacy. An
improved overall survival from 8.0 months on placebo to 10.2
months was reported at ASCO GI in January 2018.324
Treatments that failed in second-line
Everolimus, an inhibitor of the mTOR pathway has been tested
(7.5 mg OD) vs. placebo in a 2:1 ratio in a phase III trial, including 546 patients. The trial did not meet the primary endpoint of
improved survival573 (Table 5).
Brivanib was compared to placebo in a 2:1 ratio in 395
patients intolerant to (13%) or progressing (87%) on sorafenib.
Most were PS 0, Child-Pugh A, 2/3 had extrahepatic metastases
and less than one-third vascular invasion. The trial did not show
differences in survival between brivanib and. placebo (Table 5),
despite an improvement in mTTP and in objective response
rate.572
Ramucirumab, a monoclonal antibody targeting VEGFR-2
was compared to placebo (ratio 1:1) in a randomised doubleblind phase III trial including 565 patients progressing on
sorafenib.295 The study did not meet the primary endpoint
(Table 5). The safety profile was as expected with an anti-angiogenic drug and was considered manageable. A pre-specified
subgroup analysis of patients with high baseline alpha-fetoprotein (> 400 ng/ml), showed a significantly better survival with
ramucirumab than placebo (7.8 months vs. 4.2 months; HR
0.67; 95% CI 0.51–0.90). To explore this concept, another phase
III trial (REACH-2) is currently ongoing for this specific
population. According to a press release on April 4th 2018 the
REACH-2 study, investigating Ramucirumab in second line in
patients with HCC and AFP ≥ 400, met its primary endpoint,
216

demonstrating a statistically significant improvement in overall
survival. This will add Ramucirumab to Regorafenib and
Cabozantinib as second line treatment option in advanced
stage HCC.
Tivantinib, a tubulin inhibitor, was tested in phase III after
showing a signal of efficacy in a subgroup analysis of a randomised phase II study in second-line.598 The phase III trial was
the first biomarker-driven (MET-high tumours by immunostaining) study in HCC. The study was negative (Table 5).
Trials ongoing
Aside from the phase III trial comparing nivolumab vs. sorafenib
in front-line therapy and pembrolizumab vs. placebo in secondline therapy, several controlled studies are currently ongoing.
Phase II data on pembrolizumab (KEYNOTE-224) showed an
objective response rate of 16.3%;599 enrolment for the RCT (KEYNOTE-240) is ongoing.

Palliative and best supportive care
Recommendations
  In HCC on cirrhosis, acetaminophen (paracetamol) up to
3 g/day can be utilised for the management of pain of
mild intensity. Non-steroidal anti-inflammatory drugs
should be avoided whenever possible in patients with
underlying cirrhosis. Opioids can be utilised for the management of pain of intermediate or severe intensity, paying attention to proactively avoid constipation (evidence
low; recommendation weak).
  Bone metastases causing pain or at significant risk of
spontaneous secondary fracture benefit from palliative
radiotherapy (evidence low).
  In patients with advanced cirrhosis, the use of psychoactive drugs and particularly of benzodiazepines to treat
psychological distress is associated with an increased
risk of falls and injuries and altered mental status. Therefore, great caution should be adopted when using them
in patients with HCC and cirrhotic liver dysfunction (evidence low; recommendation strong).
  Psycho-oncological support and adequate nutrition is
recommended according to patients’ condition (evidence low; recommendation strong).

Because of the dismal prognosis of patients with terminal
HCC, as defined by the Barcelona Clinic Liver Cancer (BCLC) system, with life expectancy of about 3–4 months,264 the management of end-stage disease is only symptomatic and no tumour
directed treatment is indicated. These patients should receive
palliative support including management of pain, nutrition
and psychological support.600
Symptom management
Unrelieved symptoms have a negative effect on functional status, mood states, and quality of life.601 Effective symptom management allows patients and their families to focus on
maintaining hope, reaffirming important connections, and
attaining a sense of completion.600 The clinical picture of

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patients with terminal HCC is particularly complex, resulting
from a combination of symptoms deriving both from their endstage cirrhotic liver disease and the effect of large tumour bulk.602
Pain has been reported as the most common symptom
(65%),601,603 originating from various aetiologies including
inflammatory adhesions, liver capsular distension and musculoskeletal causes (immobility, metastasis). Since patients with
HCC often suffer underlying liver cirrhosis, clinicians face peculiar problems in the prescription of analgesics, differing from
most other oncological settings.
For pain of mild intensity, acetaminophen (paracetamol) is
the preferred drug, by oral or intravenous administration up
to a total dose of 3 g/day. In fact, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of gastrointestinal bleeding, decompensation of ascites and
nephrotoxicity, particularly in patients with clinically significant portal hypertension and should be avoided.600,604,605
In case of moderate-to-severe pain, which usually is insufficiently controlled by acetaminophen, opioids are the drugs of
choice. However, opioid metabolism may be deeply affected
by liver cirrhosis and opioid-treated patients are at increased
risk of constipation and consequently of hepatic encephalopathy.606 Therefore, opioid prescription should be promptly associated with a purging programme, not waiting for severe
constipation to occur.600 In particular, pharmacologic treatments including osmotic laxatives may be helpful. To this end,
the use of naltrexone might be of value. naltrexone is a pure opioid receptor antagonist, well absorbed orally, but subject to significant first pass metabolism, with oral bioavailability
estimates ranging from 5 to 40%: this leads to greater activity
at the level of the gastrointestinal tract rather than systemic.607
It therefore appears as a convenient agent to be combined with
opioids to limit constipation, as demonstrated in other populations critically vulnerable to opioid-induced constipation, such
as Parkinson’s disease and elderly patients.608,609 However, adequate studies of naltrexone in patients with severe hepatic or
renal impairment have not been conducted so far, which does
not preclude cautious use.
When pain is generated by well identified (not diffuse) bone
metastasis or when a lytic bone metastasis is considered at high
risk of spontaneous fracture, especially due to the body weight
load (e.g. in long bones of the lower limbs or in the spine), palliative radiotherapy is indicated.610 A median radiation dose of
40 Gy (range, 20–66 Gy), with various fraction sizes (range,
2.0–6.0 Gy) was utilised in 91 patients with HCC and spine
metastasis, providing pain response rates of 81%.611 However,
even a single palliative session of irradiation could be proposed
in patients with the shortest expected prognosis. Such therapies
do not interfere with liver function and might temporarily relief
pain and reduce or delay the risk of spontaneous fractures.
Patients with decompensated cirrhosis commonly suffer
weight loss and muscle wasting. These problems are multifactorial and their pathogenesis includes both poor caloric intake and
alterations to absorption and metabolism of ingested nutrients.
Nutritional status, assessed through psoas muscles mass for
example,612 has been found to be independently associated
with overall survival in patients with advanced HCC613 and its
assessment is important for identifying the risk of deteriorating
quality of life or functional status in patients.614 Nutritional
intervention should be considered in cases of low energy intake
for a longer period of time. Since patients with terminal HCC
may also have fluid retention and ascites and are highly subject

to infections, oral supplementation should be preferred over
intravenous administration.600
The assistance of a dietician experienced in liver disease could
be highly valuable, although therapeutic interventions should
consider the individual situation and needs of the patient.
Finally, the psychological burden should not be neglected or
underestimated. In fact, patients with HCC were described to
show the third highest reported level of psychological distress
or depression among patients diagnosed with 14 other types
of cancer.615 Caring for dying patients can be a challenge for
clinicians and can cause strong emotional reactions. A number
of educational interventions focussing attention on clinicians’
emotional response to their patients teach effective coping
strategies.616,617 Further research is needed to find ways to integrate these strategies into healthcare training and continuing
medical education. However, it is worth repeating that benzodiazepines should be avoided whenever possible or utilised with
extreme caution in patients with underlying advanced cirrhosis,
given the risk of easier precipitation of altered mental status up
to coma than in the non-cirrhotic population. Even when such
effects remain apparently subclinical, a higher rate of falls was
observed after adjustment for the contribution of encephalopathy with a triplicated risk of fall-related injuries.618 The latter
adverse event was also reported for other psychoactive drugs,
possibly because of altered pharmacokinetics.618
Palliative Care Network
Palliative care (PC) has well-defined, supportive care goals
related to optimising quality of life and addressing information
needs regarding the illness and prognosis, alongside symptom
control, psychosocial support, and spiritual care of the patient
and their family.619
Despite an increasing number of people dying of end-stage
hepatic diseases, little is reported on the challenge and practical
implication of end-stage patients, as well as the difficulties
faced by the patients, families and service providers.
The timing of activation of the PC network remains one the
most undefined points. The National Comprehensive Cancer
Network (NCCN) clinical guidelines support the incorporation
of PC into the treatment of cancer at time of diagnosis regardless of stage.620 Hospice care, which is a component of PC, is
appropriate for those whose life expectancy is less than six
months, which implies that the majority of patients progressing
under the last possible line of therapy for advanced HCC should
be evaluated for hospice care.
The ‘‘surprise question” is a simple and innovative tool to
recognise patients who would benefit most from PC measures.
The ‘‘surprise question” asks the primary and/or community care
physician ‘‘Would you be surprised if the patient dies within a
defined (short) time interval (e.g. seven days, thirty days or one
year)?”. A prospective study showed that clinicians could screen
cancer patients for seven- or thirty-day survival using surprise
questions with 90% or more sensitivity, although the positive predictive value was not very accurate. Therefore, if the answer to the
surprise question is no, the provider is triggered to initiate primary palliative measures with the patient.621
In the largest study to date on terminal PC in HCC (performed
in a Taiwanese population), Hwang and colleagues622 compared
729 patients with terminal HCC receiving inpatient hospice care
and 729 matched controls selected from 2,482 patients with
HCC receiving usual care. Opioids were more frequently used
in the hospice care group than in the usual care group (72.7%

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Table 5. Phase III clinical trials testing molecular targeted therapies and devices in advanced HCC.
Trial

Drugs

n

Median OS (months)

Hazard Ratio (95% CI)

p-value

Sorafenib
Placebo

299
303

10.7
7.9

0.69
(0.55–0.87)

<0.001

Sorafenib
Placebo

150
76

6.5
4.2

0.68
(0.5–0.93)

0.01

Sunitinib
Sorafenib

530
544

7.9
10.2

1.3
(1.13–1.5)

0.001

Brivanib
Sorafenib

577
578

9.5
9.9

1.07
(0.94–1.23)

0.31

Linifanib
Sorafenib

514
521

9.1
9.8

1.046
(0.896–1.221)

Sorafenib + Erlotinib
Sorafenib

362
358

9.5
8.5

0.92
(0.781–1.106)

Lenvatinib
Sorafenib

478
476

13.6
12.3

0.92
(0.79–1.06)

Sorafenib+ doxo
Sorafenib

173
173

9.3
10.5

1.06
(0.8–1.4)

n.s.

Sorafenib+ HIAC
Sorafenib

88
102

11.8
11,8

1
(0.7–1.4)

n.s.

SIRT (Y-90)
Sorafenib

Total 459

8
9.9

1.15
(0.94–1.41)

n.s.

SIRT (Y-90)
Sorafenib

182
178

8.8
10

1.12
(0.88–1.42)

n.s.

Brivanib
Placebo

263
132

9.4
8.2

0.89
(0.69–1.15)

0.33

Everolimus
Placebo

362
184

7.6
7.3

1.05
(0.86–1.27)

0.68

Ramucirumab
Placebo

283
282

9.2
7.6

0.86
(0.72–1.05)

0.13

Regorafenib
Placebo

379
194

10.6
7.8

0.63
(0.50–0.79)

<0.001

Tivantinib
Placebo

226
114

8.4
9.1

0.97
(0.75–1.25)

n.s.

Cabozantinib
Placebo

467
237

10.2
8.0

0.76
(0.63–0.92)

0.0049

First-line
SHARPa

Asian-Pacifica

SUN1170b

BRISK-FLb

LIGHTb

SEARCHb
0.2

REFLECT/Study304a
<0.05

ALLIANCEb

SILIUSb

SARAHb

SIRveNIBb

Second-line
BRISK-PSb

EVOLVE-1b

REACHb

RESORCEa

METIV-HCCb

CELESTIALa

Superscript a and superscript b indicate positive and negative trials respectively. HCC, hepatocellular carcinoma; OS, overall survival. HCC, hepatocellular
carcinoma.

vs. 25.5%, p <0.001), whereas the length of hospitalisation
(8 ± 7.7 days vs. 14.1 ± 14.3 days, p <0.001), aggressive procedures (all p <0.005), and medical expenses (all p <0.001) were
significantly less in the hospice care group.
However, PC still has a poor application in daily clinical practice. As shown in a retrospective study performed in an American tertiary care centre,623 PC interventions for patients with
218

advanced HCC were infrequent. Specifically, of 141 patients
identified as having advanced HCC, only 15 (10.6%) had any
PC intervention. Even more worrisomely, 70% of people with
end-stage liver disease die in hospital, compared with 55% of
the general population.624
For patients with end-stage HCC, a comprehensive
assessment should be performed, which considers referral to

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community PC and long-term conditions teams. Future studies that improve the identification of critical patients, and
thus the integration of PC into the management of patients
with HCC will be of great benefit to this frail and unfortunate
population.

Trial design and endpoints
Recommendations
  For phase III clinical trials testing primary treatments
(either loco-regional or systemic therapies) the primary
endpoint should be OS, while for adjuvant therapies
after resection/ablation it should be recurrence-free survival or time to response (recommendation strong).
  When testing neoadjuvant treatments for patients on the
liver transplantation waiting list, OS, cancer-related
deaths and waiting list drop-out rates are recommended
as endpoints (recommendation strong).
  There are no optimal surrogate endpoints able to recapitulate OS in HCC. TTP and PFS are not suggested as primary endpoints (evidence high; recommendation
weak).
  ORR, in particular complete response by mRECIST, correlate with OS in patients treated with thermal ablation
and TACE (evidence high). For phase II trials testing
TACE or thermal ablation, ORR and complete response
may be considered as primary endpoints, respectively
(recommendation weak). Conversely, ORR and disease
control rate have not been robustly shown to correlate
with OS in patients receiving systemic therapies.
  Phase II studies testing systemic therapies should be
randomised and should target OS as a primary endpoint
(recommendation strong). ORR, TTP and recurrencefree survival can be assessed as secondary endpoints.
  Use of RECIST1.1. and mRECIST is suggested for the
assessment of response in HCC treated with systemic
therapy (recommendation weak). Use of changes in
serum biomarker levels for assessment of response (i.e.
AFP levels) is under investigation.
  Selection of the target population for clinical trials
should use BCLC staging system, Child-Pugh class and
ECOG performance status (recommendation strong).
  Stratification for prognostic factors prior to randomisation is critical in randomised studies and is recommended (evidence high; recommendation strong).
  The control arm of randomised phase II and III studies
should be the standard of care established in the current
guidelines. When no standard of care is available (adjuvant trials, third-line setting) a placebo-control arm is
recommended (recommendation strong).
  Upfront liver biopsy and blood sampling is recommended for clinical and diagnostic trials (recommendation strong).

Endpoints
Overall survival
Overall survival (OS) – which captures the time from random
assignment until death - is the most important endpoint in
oncology and HCC research, and is the one not subject to
investigator bias. Regulatory agencies rely on OS as the primary
endpoint for drug approval in oncology,625 and it was
recommended as the primary endpoint for HCC research in
our previous guidelines.1 The panel of experts recommends OS
as the primary endpoint for phase III studies at intermediate
and advanced stages in front-line and consecutive lines of treatment thereafter. In addition, this panel considers that OS can
also be recommended as the primary endpoint in phase II studies in advanced cases, owing to the controversies currently
unsolved regarding surrogate endpoints of OS in HCC, discussed
later. Cancer-specific survival – where only deaths caused by
cancer are considered for survival analysis and non-cancerrelated deaths are censored – is a more complex endpoint to
apply in the conventional trial design setting. Deaths due to
competing risk factors, such as liver failure, require a subjective
decision by the investigator, and thus are more prone to bias.
Surrogate endpoints
Overall survival has some limitations as a sole endpoint in
cancer research: it might require a long follow-up to capture
adequate numbers (i.e. median OS for transarterial chemoembolisation (TACE) is 26–30 months) and can be affected by
sequential therapies. Thus, surrogate endpoints that are more
practical for trial execution are needed. However, they are subject to interpretation by investigators and data on surrogates of
OS are lacking in most instances.
Time to progression
Our former guidelines proposed time to progression (TTP),
defined as the time between random assignment and radiological progression, as a less vulnerable surrogate endpoint of OS
compared with progression-free survival (PFS). TTP has been
assessed as a secondary endpoint in HCC in several randomised
controlled trials.295,320–322,566–569,572,573 Data correlating TTP
and OS has been controversial and not fully supportive of our
initial estimates. The sole meta-analysis, including nine RCTs,
specifically assessing TTP as a surrogate endpoint of OS at
advanced stages of HCC showed a medium strength correlation
between treatment effects on TTP and OS (r = 0.73).626 Discordant signals keep emerging in very recent randomised phase II
trials at intermediate and advanced stages.560 All these data
support revisiting TTP as a reliable endpoint in HCC research.
Whether TTP is failing because of the fact that it is capturing
heterogeneous features (macrovascular invasion and extrahepatic spread vs. liver progression) needs to be further
explored.580,627 The panel of experts recommends capturing
the type of progression in the setting of an RCT, in order to
enable reassessment of TTP in pre-planned analyses.
Progression-free survival
Progression-free survival is a composite endpoint that includes
two types of variables: death and evidence of radiological progression. It may capture (i) rapid progression before radiological
confirmation, (ii) toxicity of therapy or (III) deterioration of liver
function due to toxicity. Our former guidelines discourage this

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composite endpoint because of the competitive risk effect of
dying from the natural history of cirrhosis despite a relevant
anti-tumoural benefit.1 The likelihood of death as a result of
liver decompensation (gastrointestinal bleeding, encephalopathy or infections) is 5% at one year.255 Thus, a restrictive selection of patients with well-preserved liver function is
recommended to minimise the impact of death unrelated to
tumour progression if PFS is applied.
Time to recurrence and recurrence-free survival
In the former guidelines, time to recurrence was recommended
as the primary endpoint for phase II and III studies assessing
adjuvant therapies after resection or local ablation. Nonetheless,
most phase III studies in the adjuvant setting, conducted under
regulatory agreement, incorporated a composite endpoint of
recurrence-free survival, where around 90% of events were
recurrences.394,628 Regulatory agencies endorse this composite
endpoint because it can also indirectly capture treatmentrelated toxicities.
Response rate and response assessment tools
Tumour response in oncology trials is typically measured
according to Response Evaluation Criteria In Solid Tumours
(RECIST). The RECIST document acknowledges that amendments to the general guideline could be needed for the evaluation of other anticancer therapies, as well as for the assessment
of tumours presenting unique complexities. The modified
RECIST (mRECIST) for HCC252 was adopted by the European
Association for the Study of the Liver guidelines on the management of HCC.1
In the future the advent of immunotherapy might require
modifications (iRECIST) of the basic structure of the RECIST
model. As shown in the setting of melanoma patients treated
with immunotherapies, standard RECIST may not provide a reliable assessment of the antitumour effect. E.g., response to
immunotherapy may take longer compared to other agents,
and can manifest after imaging features that meet the current
criteria for progression.
Objective response in loco-regional therapies
Several clinical investigations have shown that objective
response (OR) measured by mRECIST predicts survival in
patients receiving loco-regional therapies.629 Overall median
OR with TACE and with radioembolization with Y-90 have been
reported to range from 40–80% with either therapy, depending
mainly on whether treatment was applied to patients with
early-stage or intermediate-stage disease.630–633 A recent
meta-analysis identified seven clinical trials assessing survival
outcomes after loco-regional treatments according to mRECIST
response.634 Each individual study showed better survival for
responders (complete response or partial response) compared
to non-responders (stable disease or progressive disease). Overall, the meta-analysis included 1,357 patients. The hazard ratio
for OS (responders vs. non-responders) was 0.39 (95% CI 0.26–
0.61; p <0.0001). Thus, for phase II trials the panel endorses
complete response (for ablation) and OR rate (ORR) (for TACE),
as assessed by mRECIST, as primary endpoints.
Objective response in systemic therapies
Objective response by mRECIST has been shown to correlate
with OS in two clinical trials, and thus additional data is needed
to endorse this approach.635,636 In these studies, OS was signif220

icantly better for responders, a fact that remained an independent prognostic factor. However, OR by RECIST has lower
sensitivity for capturing response, as shown in several phase II
and III investigations. Overall, both measurements are still suboptimal for identification of the maximum number of patients
who benefit from treatment. Also, the advent of immunotherapy (and ‘‘pseudo-progression” patterns) must be properly captured by the above criteria. Investigation of this concept in HCC
clinical trials is a top priority. The panel of experts recommends
assessing tumour response according to mRECIST and conventional RECIST and correlating this with pathological studies
and outcome prediction.
Trial design
Trial design should follow the recommendations posed in the
previous guidelines.1 Selection of patients should be based on
Barcelona Clinic Liver Cancer staging, Child-Pugh class and Eastern Cooperative Oncology Group status, in order to minimise
the competitive risk of death associated with liver failure. The
control arm for clinical trials should be the standard of care stated in the current guidelines. Randomised studies testing
molecular targeted therapies should optimally include biomarker analysis (tissue and/or serum samples) to enable the identification of molecular markers of response and for
pharmacokinetic purposes, as reported in other cancers. Thus,
the panel recommends obtaining tissue biopsy and blood sampling from all patients included in clinical trials in HCC.

Future directions
Hepatocellular carcinoma (HCC) is the result of underlying and
well-defined liver disease in most patients. Thus, it is preventable. The rising incidence of HCC in most European countries suggests an insufficient awareness of liver disease in
general, calling for public health policies aiming to prevent,
detect and treat liver disease – not only for HCC prevention. It
is particularly frustrating to see most patients with HCC diagnosed at a stage no longer amenable to curative treatment,
demonstrating again a neglect of liver disease and appropriate
cancer surveillance.
To make surveillance cost-effective tools need to be developed to stratify patients at high, intermediate and low risk for
hepatocellular carcinoma and to adjust surveillance strategies
accordingly. Surveillance or secondary prevention needs to be
complemented by primary prevention and the development
and the utilization of chemo-preventive strategies is strongly
encouraged.
Hepatocellular carcinomas are characterised by considerable
phenotypic and molecular heterogeneity. During the last two
decades, we have developed an increasing understanding of
the most abundant molecular alterations in HCC which, however, has not translated into improved prognostic assessment
or therapeutic decision making. This is at least in part the result
of a lack of mandatory biopsies in the diagnosis of HCC in individual patients. Material is largely derived from subgroups of
patients, e.g. after resection and thus the collective analyses
are not fully comprehensive. Most trials have not linked molecular signatures with therapeutic response, explaining both the
failure of some drugs in large phase III trials and the discrepancy
with other tumours, such as breast or lung cancer, where molecular tumour boards are a clinical reality. All efforts should be
undertaken to link molecular subclasses in clinical trials with

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OF HEPATOLOGY
therapeutic response and outcome, thus paving the way for
novel therapeutic strategies. It can be predicted that the advent
of next-generation sequencing technologies will play an
increasingly important role in clinical oncology. Molecular characterisation of genetic alterations within the tumour cell population, as well as the cellular composition of tumours and the
corresponding tumour microenvironment, will enable the
development of prognostic (predicting prognosis) and
predictive (predicting therapeutic response) biomarkers that
can be utilised in routine clinical practice.
Such markers (from tumour tissue, blood, urine etc.) are
needed for early diagnosis and surveillance of patients at risk,
to stratify patients for appropriate adjuvant and palliative treatments (including non-targeted therapies), to define mechanisms of escape and resistance and to allow early response
prediction.
Thus, the panel suggests focussing on the following three
goals:
1. Public health policies to prevent, detect, and treat chronic
liver disease
2. Appropriate cancer surveillance to detect HCC in a stage
amenable to curative treatment
3. Link molecular subclasses in clinical trials to therapeutic
response and outcome
In order to achieve these goals a variety of activities are
required, including but not limited to those listed (Table 6).

Disclosures
These guidelines reflect the state of knowledge, current at the
time of publication, on effective and appropriate care, as well
as clinical consensus judgments when knowledge is lacking.
The inevitable changes in the state of scientific information
and technology mandate that periodic review, updating, and
revisions will be needed. These guidelines do not apply to all
patients, and each must be adapted and tailored to each individual patient. Proper use, adaptation modifications or decisions to

disregard these or other guidelines, in whole or in part, are
entirely the responsibility of the clinician who uses the guidelines. The content of this publication does not necessarily reflect
the views or policies of the Department of Health and Human
Services, nor does mention of trade names, commercial products, organizations or imply endorsement by any European or
U.S. Government.

Conflict of interest
Peter R. Galle reports grant/research support from Bayer, Eli
Lilly, BMS, MSD, SillaJen, Merck, Blueprint Medicines, Arqule,
Gilead, AbbVie, WAKO; consultant/advisory roles with Bayer,
Eli Lilly, BMS; sponsored lectures for Bayer, Lilly, WAKO. Fabio
Piscaglia reports grant/research support from ESAOTE; consultant/advisory roles for Bayer, Eisai; sponsored lectures for Bayer,
Bracco, Meda Pharma. Jean-Luc Raoul reports consultant/advisory roles for Bayer SP, BTG, MSD; sponsored lectures for Bayer
SP. Josep Llovet reports grant/research support from Bayer, Blueprint Medicines, Boehringer-Ingelheim, BMS; consultant/advisory roles for Bayer, BMS, Boehringer-Ingelheim, Eli Lilly,
Celsion, Biocompatibles, Novartis, GlaxoSmithKline, Blueprint
Medicines, Eisai, Tiziana Therapeutic, Guerbert; sponsored lectures for AEEH, APASL, AACR, AASLD, EASL, ILCA, Bayer. Peter
Schirmacher reports grant/research support for Novartis; consultant/advisory roles for Novartis, MSD, BMS. Valérie Vilgrain
reports grant/research support from Sirtex; consultant/advisory
roles for Guerbet; sponsored lectures for Supersonic, Bracco,
Guerbet; Sirtex. Vincenzo Mazzaferro reports being on the advisory board of a BTG Inc. sponsored trial that failed recruitment;
sponsored lectures for Bayer Italy; involvement in phase III RCTs
for BMS and Arqule.
Please refer to the accompanying ICMJE disclosure forms for
further details.

Acknowledgement
The logistical and editorial support from the EASL office is
greatly appreciated.
We would like to thank the reviewers of this Clinical Practice
Guideline for their time and critical reviewing: EASL Governing
Board, Tim Meyer, Gregory Gores, Jean-François Dufour.

References
Table 6. Unmet needs in HCC research. HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HCV, hepatitis C virus; OS, overall survival; TKI,
tyrosine kinase inhibitor.
  Major health policy interventions to secure a) universal vaccination
against HBV, b) universal treatment of HCV if indicated and c) prevention
of heavy alcohol intake and obesity
  Need for universal implementation of surveillance programs
  Need for new tools of 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 3rd line therapies in advanced stage
  Need to define optimal sequencing of systemic therapy
  Need for surrogate markers recapitulating OS
  Translate molecular knowledge into precision medicine, linking response
rates in trials to molecular subgroups
  Need to assess the role of prognostic and predictive markers in surgical
and interventional therapies within prospective investigations
  Need to understand the impact of minimal invasive surgery on HCC
recurrence and post-progression survival
  Need to define and evaluate reliable quality of life assement tools in HCC
  Need to stratify patients at risk for hepatocellular carcinoma and the utilisation of chemopreventive strategies

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