Hepatocellular Carcinoma: ESMO Clinical Practice Guidelines For Diagnosis, Treatment and Follow-Up

Annals of Oncology 29 (Supplement 4): iv238–iv255, 2018
doi:10.1093/annonc/mdy308
CLINICAL PRACTICE GUIDELINES
Hepatocellular carcinoma: ESMO Clinical Practice
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Guidelines for diagnosis, treatment and follow-up†
A. Vogel1, A. Cervantes2, I. Chau3, B. Daniele4, J. Llovet5,6,7, T. Meyer8,9, J.-C. Nault10, U. Neumann11,

J. Ricke12, B. Sangro13, P. Schirmacher14, C. Verslype15, C. J. Zech16, D. Arnold17 & E. Martinelli18,
on behalf of the ESMO Guidelines Committee*
1
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany; 2Department of Medical Oncology, Biomedical
Research Institute INCLIVA, University of Valencia, Valencia, Spain; 3Department of Medicine, Royal Marsden Hospital, Surrey, UK; 4Direttore Dipartimento di
Oncologia e U.O.C. Oncologia Medica A.O., Benevento, Italy; 5Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, Mount Sinai Liver Cancer
Program, New York, USA; 6Barcelona-Clı́nic Liver Cancer Group (BCLC), Unitat d’Hepatologia, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Hospital Clı́nic, Universitat de Barcelona, Barcelona; 7Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; 8Oncology, Royal Free Hospital,
London; 9UCL Cancer Institute, University College London, London, UK; 10Service d’hépatologie, Hôpital Jean Verdier, Bondy, France; 11Klinik für Allgemein- und
Viszeralchirurgie, Medizinische Fakultät der RWTH Aachen; 12Klinik und Poliklinik für Radiologie, Ludwig-Maximilians-Universität München, Munich, Germany; 13Liver
Unit, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain; 14Institute of Pathology, University Hospital, Heidelberg, Germany; 15Campus
Gasthuisberg, UZ Leuven, Leuven, Belgium; 16Klinik für Radiologie und Nuklearmedizin Universität Basel, Basel, Switzerland; 17Department Oncology, Section
Hematology and Palliative Care AK Altona, Asklepios Tumorzentrum Hamburg, Hamburg, Germany; 18Faculty of Medicine, Università della Campania L. Vanvitelli
Naples, Caserta, Italy
*Correspondence to: ESMO Guidelines Committee, ESMO Head Office, Via Ginevra 4, 6900 Lugano, Switzerland. E-mail: clinicalguidelines@esmo.org
†
Approved by the ESMO Guidelines Committee: August 2018.
Incidence and epidemiology non-alcoholic fatty liver disease (NAFLD) and non-alcoholic
steatohepatitis (NASH), which can lead to fibrosis and cirrhosis
The incidence of hepatocellular carcinoma (HCC) has been rising and, eventually, HCC [9]. HCC related to NAFLD/NASH is
worldwide over the last 20 years and is expected to increase until probably underestimated [10] and is expected to rise in the
2030 in some countries including the United States, while in other future, possibly overtaking the other aetiologies in some areas of
countries, such as Japan, the incidence has started to decline [1–3]. the world [11]. A significant proportion of patients with NAFLD/
In 2012, liver cancer represented the fifth most common cancer in NASH-associated HCC do not have histological evidence of
men (554 000 new cases) and the ninth in women (228 000 new cirrhosis [12].
cases) and the second most common cause of cancer-related death The control of other risk factors for chronic liver disease and
(746 000 estimated deaths), worldwide [3]. The incidence varies cancer is more difficult to implement, such as cutting down on
from 3/100 000 in Western countries, to 78.1/100 000 in Mongolia, the consumption of alcohol and programmes aiming at a health-
with the highest incidence in Africa and Asia, mapping the geo- ier lifestyle in the light of the obesity pandemic [13, 14]. In Africa,
graphical distribution of viral hepatitis B (HBV) and hepatitis C
reduction of exposure to aflatoxin B1, especially in HBV-infected
(HCV), the most important causes of chronic liver disease and
individuals, may lower the risk of HCC. HCC may evolve from
HCC [4]. In Europe, in 2012 the estimated incidence rate was 10.0
subclasses of adenomas; in < 10% of cases HCC occurs in an
in men and 3.3 in women per 100 000, respectively, while the esti-
otherwise normal liver.
mated mortality rate was 9.1 and 3.3 per 100 000 in men and
women, respectively [3]. The incidence of HCC shows a strong
male preponderance and increases progressively with advancing
age in all populations. The association of chronic liver disease and
Surveillance
HCC represents the basis for preventive strategies, including uni- Surveillance of HCC involves the repeated application of screen-
versal vaccination at birth against HBV [I, A] [5] and early antiviral ing tools in patients at risk for HCC and aims for the reduction in
treatment of viral HBC and HCV [III, A] [6–8]. mortality of this patient population. The success of surveillance is
The prevalence of obesity and type 2 diabetes has greatly influenced by the incidence of HCC in the target population, the
increased in the past decades, leading to a rising incidence of availability and acceptance of efficient diagnostic tests and the
C The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
V
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Annals of Oncology Clinical Practice Guidelines
Table 1. Diagnostic work-up
History and clinical examination

Risk factors for chronic liver disease: i.v. drug abuse, alcohol intake, metabolic syndrome (obesity, diabetes, arterial hypertension)
Symptoms and signs of chronic liver disease (jaundice, ascites, encephalopathy, bleeding, splenomegaly)
PS (distinguish cancer-related symptoms of recent onset with long-standing symptoms associated with cirrhosis) and nutritional state
Laboratory analysis
Aetiology of liver disease: HBV (at least HBsAg and anti-HBc), HCV (at least anti-HCV), iron status, autoimmune disease
Liver function: prothrombin, albumin, bilirubin
Complete blood cell count including platelets

Tumour marker: serum AFP
Assessment of portal hypertension
Upper endoscopy: varices and/or hypertensive gastropathy
Optional: transjugular measurement of hepatic-venous pressure gradient
Imaging studies
Liver dynamic (multiple phase) MRI or CT studies for diagnosis and evaluation of tumour extent inside the liver (number and size of nodules,
vascular invasion, extrahepatic spread)
CEUS can also be used for the non-invasive diagnosis of HCC if CT scan or MRI are not possible, but is not considered appropriate for tumour staging
CT of the chest, abdomen and pelvis to rule out extrahepatic spread
Tumour biopsy
Useful for nodules with non-diagnostic at imaging
Required to diagnose HCC in non-cirrhotic liver
Should be carried out according to national or institutional policy in all clinical trials and may support centre-based innovative treatment approaches
Ideally, should evaluate tumour and non-tumour tissue when used for scientific purposes
AFP, alpha foetoprotein; CEUS, contrast-enhanced ultrasound; CT, computed tomography; HBc, hepatitis B core antibody; HBsAg, hepatitis B surface
antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; i.v., intravenous; MRI, magnetic resonance imaging; PS, performance
status.
availability of effective treatment. Cost-effectiveness studies sug- Chinese patients with chronic HBV infection compared surveil-
gest surveillance of HCC is warranted in all cirrhotic patients irre- lance (US and serum AFP measurements every 6 months) versus
spective of its aetiology [15], as long as liver function and no surveillance [20]. Despite low compliance with the surveil-
comorbidities allow curative or palliative treatments [III, A]. lance program (55%), HCC-related mortality was reduced by
Surveillance of non-cirrhotic, hepatitis-infected patients should 37% in the surveillance arm. Considering the most appropriate
also be considered in chronic HBV carriers or HCV-infected surveillance interval, a randomised study comparing a 3- versus
patients with bridging fibrosis (F3, numerous septa without cir- 6-month schedule failed to detect any differences [21].
rhosis) [III, A], which are at higher risk than the general popula- Surveillance of patients at risk for HCC should be carried out
tion. Specifically in Asian patients, serum HBV-DNA above by abdominal US every 6 months with or without AFP [II, A].
10 000 copies/mL was associated with a higher annual risk (above
0.2%/year) compared with patients with a lower viral load [16].
Patients with HCV infection and advanced fibrosis remain at Diagnosis and pathology/molecular biology
increased risk for HCC even after achieving sustained virological
The diagnosis of HCC is based on histological analysis and/or
response following antiviral treatment [III, A] [8] and, thus,
contrast-enhanced imaging findings [III, A]. The diagnostic
should remain in a surveillance programme.
work-up of a patient with an HCC-suspicious nodule is given in
Japanese cohort studies have shown that surveillance by ab-
Table 1.
dominal ultrasound (US) resulted in an average size of the
detected tumours of 1.6 6 0.6 cm, with < 2% of the cases exceed-
ing 3 cm [17]. In the Western world and in less experienced
Diagnosis by imaging
centres, the sensitivity of finding early-stage HCC by US is con- In patients with liver cirrhosis and specific imaging criteria, a for-
siderably less effective [18]. There are no data to support the use mal pathological proof is not mandatory for diagnosis and the
of contrast-enhanced computed tomography (CECT) or con- clinician can rely on the contrast-enhanced imaging criteria for
trast-enhanced magnetic resonance imaging (CEMRI) for sur- lesion characterisation [22–24]. These criteria require a multi-
veillance. Adding the determination of serum alpha foetoprotein phasic CECT or CEMRI. The diagnosis can be established if the
(AFP) to US can lead to a 6% gain in the early HCC detection typical vascular hallmarks of HCC (hypervascularity in the arter-
rate, but at the price of false-positive results and of a worse cost- ial phase with washout in the portal venous or delayed phase) are
effectiveness ratio [19]. A randomised controlled trial (RCT) of identified in a nodule of > 1 cm diameter using one of these two
Volume 29 | Supplement 4 | October 2018 doi:10.1093/annonc/mdy308 | iv239

Clinical Practice Guidelines Annals of Oncology
Table 2. CT/MRI LI-RADS diagnostic table
Untreated observation without pathological proof in patient at high risk for HCC
Definitely benign: LR-1
Probably benign: LR-2
Not categorisable, due to image degradation or omission: LR-NC
Definite tumour in vein (TIV): LR-TIV
Probably or definitely malignant but not HCC specific (e.g. if targetoid): LR-M
Otherwise, use CT/MRI diagnostic table below

Intermediate probability of malignancy: LR-3

Probably HCC: LR-4
Definitely HCC: LR-5
Arterial phase hyperenhancement (APHE) No APHE APHE (not rim)

Observation size (mm) < 20 20 < 10 10-19 20
Count major features: None LR-3 LR-3 LR-3 LR-3 LR-4
‘Washout’ (not peripheral) One LR-3 LR-4 LR-4 LR-4/LR-5b LR-5
Enhancing ‘capsule’ Two LR-4 LR-4 LR-4 LR-5 LR-5
a
Threshold growth
a
Threshold growth definition:
50% increase in size in 6 months, OR
Previously unseen on CT or MRI, now 10 mm, in 24 months.
b
Observations in this cell are categorised based on one additional major feature: LR-4 if enhancing ‘capsule’; LR-5 if non-peripheral ‘washout’ OR
threshold growth.
CT, computed tomography; HCC, hepatocellular carcinoma; LI-RADS, Liver Imaging Reporting and Data System; LR, liver resection; MRI, magnetic
resonance imaging.
modalities [III, A]. Compared with multiple detector CT Angiography and fluorodeoxyglucose-positron emission tom-
(MDCT), multiphasic MRI offers a moderate increase in sensitiv- ography (FDG-PET) scan are not recommended for HCC diag-
ity for diagnosing HCC based on the typical vascular hallmarks nosis. When tumour biopsy fails to demonstrate a correlate for a
[III, B] [24–27]. Serum AFP has no role in the diagnostic algo- focal lesion, a second tumour biopsy, a different contrast-
rithm [III, A]. enhanced imaging modality or (if amenable) direct resection of
Based on techniques such as diffusion-weighted imaging and the lesion may be considered according to tumour size [IV, B]. If
the use of hepatobiliary contrast agents, MRI may identify and the patient is a candidate for resection that can be carried out
stratify nodules as high-risk nodules (either HCC not displaying with an acceptable morbidity and mortality risk, then either bi-
the typical imaging hallmarks features or high-grade dysplastic opsy or direct resection may be an option.
nodules) [IV, B] [28–31]. However, the impact of identification
of additional nodules by diffusion-weighted imaging and hepato- Diagnosis by pathology
biliary contrast agents on the therapeutic algorithm remains un- Pathological diagnosis of HCC is based on a biopsy or a surgical
clear and switching to palliative treatments after identification of specimen of the tumour. Concomitant analysis of the non-
potential premalignant nodules by these new techniques should tumour liver may be useful in order to define its status and poten-
be avoided. New imaging criteria for HCC diagnosis called CT/ tial causative diseases. Assessment of resection and explant speci-
R
MRI LI-RADSV v2018 (Liver Imaging Reporting and Data men follows the valid TNM (tumour, node, metastasis)
System) include arterial phase enhancement, tumour size, wash- classification including resection margin evaluation. Usually tu-
out, enhancing capsule and threshold growth and have been pro- mour grade is provided, but currently no uniform grading
posed to improve the diagnosis of HCC, especially for small scheme is used worldwide and data on the independent prognos-
nodules (Table 2) [32, 33]. tic value are inconclusive.
For contrast-enhanced US (CEUS), an overlap between the Histopathological diagnosis of tumour biopsies relies on
vascular profile of HCC and cholangiocarcinoma (CC) has been standard [e.g. haemotoxylin and eosin (H&E)] and special
described. However, recent data suggest CEUS as a suitable tech- stains (e.g. reticulin), and—if required—immunohistochemistry
nique to diagnose HCC non-invasively in the setting of liver cir- (IHC). It should address different challenges: morphologically,
rhosis [IV, B] [34–36]. The typical hallmarks for HCC at CEUS highly differentiated HCC must be distinguished from benign/
differ slightly to those of CT/MRI; at CEUS, hallmarks are arterial premalignant lesions (dysplastic nodules, hepatocellular aden-
hyper-enhancement followed by late (> 60 s) washout of a mild oma, focal nodular hyperplasia). In particular, poorly differenti-
degree. ated HCC should be distinguished from intrahepatic CC,
iv240 | Vogel et al. Volume 29 | Supplement 4 | October 2018

combined HCC/CC and some types of metastases (e.g. lung can- benefit of carrying out FDG-PET scan as a staging modality, des-
cer, head and neck squamous cell carcinoma, breast cancer, neu- pite some evidence that there is a correlation of higher FDG up-
roendocrine tumours). For this reason, histological analyses may take with poor differentiation, tumour size, serum AFP levels and
be supplemented by IHC for lineage-specific markers. It is im- microvascular invasion [IV, D] [45, 46].
portant to distinguish combined HCC/CC from HCC due to the Liver function is classically assessed by the Child-Pugh scoring
different therapeutic modalities; however, the mixed differenti- system (serum bilirubin, serum albumin, ascites, prothrombin
ation features might not be visible in the biopsy. In addition, sig- time and hepatic encephalopathy) [III, A]. Within the Child-
nificant expression of cytokeratin 19 (CK19) has been evaluated Pugh A group, measurement of the albumin-bilirubin (ALBI)
and considered as a sign of poor prognosis in HCC [IV, B]. score (a model incorporating serum albumin and bilirubin levels
In highly differentiated HCC, definitive signs of malignancy alone) is able to split that group into good prognosis (ALBI 1)

(interstitial or vascular invasion) are frequently absent from bi- and poor prognosis (ALBI 2), with median survivals of 26 versus
opsy. Further consented histological (trabecular alterations— 14 months, respectively [IV, B] [47]. A platelet count >
more than two cell broad trabeculae, pseudoglands, reticulin loss, 150 109 cells/L and a non-invasive liver stiffness measurement
capsule formation) and cytological criteria (increased nuclear/ < 20 kPa excludes clinically significant portal hypertension
cytoplasmic ratio, i.e. ‘nuclear crowding’, increased cytoplasmic (Baveno VI criteria) [48]. Otherwise, the finding of oesophageal
basophilia) support HCC diagnosis [III, B] [37]. IHC should be varices and/or splenomegaly with blood platelet counts of
carried out in unclear cases: capillarisation of sinusoids could be 100 109 cells/L suggests clinically important portal hyperten-
assessed using CD34 IHC [IV, B] [37]. Further immunohisto- sion, which can also be measured invasively by the transjugular
chemical markers have been shown to improve the diagnosis of route (hepatic-venous pressure gradient > 10 mmHg) [III, A].
highly differentiated HCC, including glutamine synthetase, glypi- Several staging systems—incorporating some or all of the
can 3, general stress protein (CTC), enhancer of zeste homologue above-mentioned items—have been developed, including TNM,
2 (EZH2) and heat shock protein 70 (HSP70) [IV, B]. A combin- Okuda, Cancer of the Liver Italian Program (CLIP), Japanese
ation of the three markers glutamine synthetase, glypican 3 and Integrated Staging (JIS) Score and the Barcelona Clinic Liver
HSP70 has been consented as a diagnostic panel (2/3 marker Cancer (BCLC) system. Every system has advantages and draw-
positivity has 70% sensitivity and 100% specificity for HCC) and backs. The recently released 8th edition of the TNM system
the use of further markers seems to increase the sensitivity [IV, B] (Table 3) contains changes to the T classifications compared with
[38]. Moreover, histological subtypes of HCC have been defined the previous staging system [49]. The staging system includes
(e.g. fibrolamellar, chromophobe, macrotrabecular massive) microvascular invasion that can only be assessed on pathology
which specifically correlate with clinical and molecular features and is therefore less useful in clinical practice before treatment
[39, 40], which may have future clinical impact. decision making. Moreover, a recent validation study pointed
It is now well accepted that the potential risks of tumour bi- to potential problems of heterogeneity in the T2 category and
opsy, bleeding and needle track seeding, are infrequent, manage- the lack of vascular invasion as a prognostic factor in the T3
able and do not affect the course of the disease or overall survival group [50]. TNM classification provides a means of standardising
(OS) and, therefore, should not be seen as a reason to abstain histopathological reports in patients treated by resection or
from diagnostic liver biopsy. In a comprehensive meta-analysis, transplantation.
the risk of tumour seeding after liver biopsy was reported to be The BCLC staging system was developed on the basis of the
2.7%, with a median time interval between biopsy and seeding of results of RCTs and cohort studies and links tumour stage, liver
17 months [41], but even lower rates are expected in experienced function, cancer-related symptoms and PS to an evidence-based
centres. It was reported that needle track seeding can be treated treatment algorithm (Table 4). The system identifies those patients
well (e.g. by excision or radiation) and did not affect outcome of with early HCC who may benefit from ablative treatment (stage 0
oncological treatment [42] and OS [41]. In a meta-analysis of the and A), those at intermediate (stage B) or advanced stage (stage C)
bleeding risk, mild bleeding complications ranged around 3%– who may benefit from intra-arterial or systemic treatments and
4%, while severe bleeding complications, requiring transfusions,
those with a very poor life expectancy (stage D). Survival without
were reported in 0.5% of the cases [43].
therapy is > 5 years for stage 0 and A, > 2.5 years for stage B, >
1 year for stage C and 3 months for stage D [51]. Treatment as-
signment of the different stages is discussed below. The aetiology of
Staging and risk assessment co-existent liver disease has not been identified as an independent
Staging of HCC is important to determine outcome and planning prognostic factor. Nevertheless, finding a treatable underlying co-
of optimal therapy and includes assessment of tumour extent, existent liver disease may be very relevant, e.g. antiviral treatment
AFP level, liver function, portal pressure and clinical performance in case of HBV, corticosteroid treatment in autoimmune hepatitis
status (PS) (Table 1) [III, A]. Relevant techniques to evaluate tu- or stopping alcohol intake may result in a marked improvement in
mour extent (number and size of nodules, vascular invasion, liver function and improving prognosis.
extrahepatic spread) include CEMRI or helical CT. CT of the Liver decompensation (including jaundice, variceal haemor-
chest, abdomen and pelvis is recommended to rule out extrahe- rhage, ascites or encephalopathy) should be considered a
patic spread. There is no justification for routine preoperative contraindication for any locoregional therapy that may induce
bone scintigraphy to detect asymptomatic skeletal metastases in subclinical liver damage such as resection, percutaneous ablation
patients with resectable HCC [44] and there are no data in the or transarterial therapies. The benefit of systemic therapies has
context of advanced HCC. There is no demonstrated clinical not been established in patients with liver decompensation.

Table 3. UICC 8th edition staging system for hepatocellular carcinoma [49]
T—primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1a Solitary tumour 2 cm or less in greatest dimension with or without vascular invasion
T1b Solitary tumour more than 2 cm in greatest dimension without vascular invasion
T2 Solitary tumour with vascular invasion more than 2 cm dimension or multiple tumours, none more than 5 cm in greatest dimension
T3 Multiple tumours any more than 5 cm in greatest dimension
T4 Tumour(s) involving a major branch of the portal or hepatic vein with direct invasion of adjacent organs (including the diaphragm),

other than the gallbladder or with perforation of visceral peritoneum
N—regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M—distant metastasis
M0 No distant metastasis
M1 Distant metastasis
Stage—liver
Stage IA T1a N0 M0
Stage IB T1b N0 M0
Stage II T2 N0 M0
Stage IIIA T3 N0 M0
Stage IIIB T4 N0 M0
Stage IVA Any T N1 M0
Stage IVB Any T Any N M1
UICC, Union for International Cancer Control.
Management of early and intermediate HCC B]. Child-Pugh C patients are not suitable for surgical therapy. A
recent meta-analysis demonstrates that the presence of portal
Liver resection (LR), orthotopic liver transplantation (OLT) and
hypertension or Child-Pugh B status might not be an absolute
local destruction methods [radiofrequency ablation (RFA) or
contraindication and provide acceptable results for these cohorts
microwave ablation (MWA)] comprise potentially curative treat-
[52, 53]. Therefore, carefully selected patients with Child-Pugh B
ment modalities for patients with HCC (see Figure 1). Selecting
and/or portal hypertension may be candidates for minor surgical
the appropriate treatment for the individual patient remains dif-
resection [III, A].
ficult and there are no randomised phase III trials comparing the
Compared with open LR, laparoscopic LR results in reduced
efficacy of these three approaches; all evidence is based on cure
intraoperative blood loss, faster postoperative recovery and does
rates in patient series.
not impair oncological outcome [54]. LR in cirrhosis should
The predominant arterial vascularisation of HCC resulted in
preferably be carried out as laparoscopic resection [IV, A].
the application of intra-arterial administration of chemotherapy
Currently, there is no high-level evidence to recommend surgical
(e.g. doxorubicin, cisplatin), embolising material (e.g. coils, gel-
resection in cirrhotic HCC patients with advanced tumour bur-
atin sponge particles) or radioactive particles. These therapies are
den and macrovascular invasion.
generally regarded as palliative treatment options but may pro-
After LR, tumour recurrence can be observed in 50%–70% of
vide complete tumour destruction in well-selected candidates.
cases within 5 years following surgery, which constitutes either
intrahepatic metastases (often within 2 years following surgery)
Liver resection or a new HCC in the remaining cirrhotic liver (occurring more
Single tumours in patients with well-preserved liver function is often beyond 2 years). Even though the vast majority of HCC
the mainstay indication for resection, provided a R0 resection recurrences occur within the liver as a result of subclinical micro-
(excision whose margins are clear of tumour cells) can be carried metastases and vascular invasion from the primary tumour, the
out without causing postoperative liver failure due to insufficient extent of surgical resection [anatomical resection (AR) versus
reserve in the liver remnant. LR requires a detailed preoperative non-anatomical wedge resection (NAR)] is still a subject of on-
work-up with the assessment of liver function and future liver going debate. Theoretically, the systematic removal of the hepatic
remnant volume. The combination of both variables determines segment through an AR is considered to be more effective in
the perioperative risk of liver failure and the associated complica- terms of tumour clearance and eradication of micro-metastases
tions. Child-Pugh A patients without significant portal hyperten- [55]. This, however, is rarely possible in cirrhotic HCC patients
sion are considered good candidates for minor/major LRs [III, for whom tissue-sparing NAR is the procedure of choice to

Table 4. BCLC staging and treatment options according to level of evidence and approval status
BCLC stage Treatment Indication constraints based on Alternative treatment Alternative

(standard of care) tumour burden and liver function Not yet EMA-approved treatment
0 – A Single tumour any size or Resection [III, A] Adequate size and function of SBRT [III, C]
up to 3 nodules 3 cm remnant liver
Preserved liver function Transplantation [III, A] Size 5 cm, number 3 HDR brachytherapy
ECOG PS 0 Thermal ablation [III, A] Size 3 cm, not adjacent to vessels [III, C]
or bile duct SIRT [III, C]
TACE [I, A] Contraindications against resection

and thermal ablation. Bridging
to transplantation
B Multinodular TACE [I, A] Size 5–10 cm, tumour nodules Transplantation [III, A]
Preserved liver function accessible to supra-selective Resection [III, A]
ECOG PS 0 catheterisation Systemic therapy
(after TACE failure/
refractoriness) [I, A]
SIRT (after TACE failure/
refractoriness) [III, C]
C Portal invasion Sorafenib (first-line) [I, A] Child-Pugh A Lenvatinib (first-line) [I, A] Nivolumab (second-
line) [I, B]
Extrahepatic spread Regorafenib Child-Pugh A, tolerability to Cabozantinib (second-line) [I, A] Pembrolizumab
Preserved liver function (second-line) [I, A] sorafenib Ramucirumab (AFPhigh; (second-line) [I, B]
ECOG PS 1–2 second-line) [I, A] SIRT (liver confined,
good liver function,
no systemic therapy
feasible) [III, C]
D End-stage liver function BSC
ECOG PS 3–4
AFPhigh, elevated alpha foetoprotein; BCLC, Barcelona Clinic Liver Cancer; BSC, best supportive care; ECOG, Eastern Cooperative Oncology Group; EMA,
European Medicines Agency; HDR, high dose rate; PS, performance status; SBRT, stereotactic body radiotherapy; SIRT, selective internal radiotherapy; TACE,
transarterial chemoembolisation.
reduce the risk of post-operative liver failure [56]. While some The low availability of liver allografts, however, is a major limi-
groups report superiority of AR, overall conflicting results are tation for OLT, and liver transplant candidates are often con-
reported, and no clear recommendation may be given due to a fronted with long waiting times, which may be associated with
lack of currently available high-level clinical evidence [57, 58]. tumour progression beyond the Milan criteria. When a waiting
time (> 3 months) is anticipated, patients may be offered resec-
Orthotopic liver transplantation tion, local ablation or transarterial chemoembolisation (TACE)
Liver transplantation offers the possibility to cure both the tu- in order to minimise the risk of tumour progression and to offer
mour and the underlying liver disease [59]. The Milan criteria a ‘bridge’ to transplant [III, B].
(one lesion < 5 cm; alternatively, up to three lesions, each < 3 cm;
no extrahepatic manifestations; no evidence of macrovascular in- Adjuvant therapies
vasion) are currently the benchmark for the selection of patients Adjuvant therapy is not recommended for HCC patients after
with HCC for OLT. OLT is recommended for patients that fit the OLT, LR or local ablation [I, E]. Mammalian target of rapamycin
Milan criteria, for which < 10% recurrence and 70% 5-year sur- (mTOR) inhibitors are used as immunosuppressant to prevent
vival are expected [II, A] [60]. Among several more liberal pro- graft rejection in liver transplantation (sirolimus) but have failed
posals [up-to-seven criteria, extended Toronto criteria, to improve recurrence-free survival in a recently published phase
University of California San Francisco (UCSF) criteria], only the III study [65]. Similarly, sorafenib did not improve median
UCSF criteria (one tumour 6.5 cm, three nodules at most with recurrence-free survival of HCC patients after LR or local abla-
the largest 4.5 cm and total tumour diameter 8 cm) were
tion [66].
prospectively validated and showed similar outcome and, as
such, may also be considered for OLT in patients with HCC be-
yond Milan criteria [III, B] [60, 61]. The use of marginal grafts or
Thermal tumour ablation
living donor liver transplantation could facilitate the treatment of Thermal ablation by RFA or MWA may be recommended as
these patients [62–64]. first-line treatment in very early-stage disease (BCLC 0) [II, A]. In

BCLC 0-A BCLC B BCLC C BCLC C
iv244 | Vogel et al.

Resectiona LTX Sorafeniba
Ablationa TACEa Nivolumabb BSC
LTX Resection Lenvatiniba
[III, A] [I, A] [I, B] [III, A]
[III, A] [III, A] [I, A]
TACE failure/
refractoriness
SBRT TACE
Brachytherapy [I, B]
SIRT
[III, C]
Systemic
therapy Regorafeniba
[I, A] Cabozantinibb
Ramucirumabb
[I, A]
Nivolumabb
Pembrolizumabb
Clinical Practice Guidelines
[III, B]
SIRT
[III, C]
Figure 1. HCC treatment options depending on BCLC stage.

a
See Table 4 for indication constraints based on tumour burden and liver function.
b
Not EMA-approved as of August 2018.
BCLC, Barcelona Clinic Liver Cancer; BSC, best supportive care; EMA, European Medicines Agency; HCC, hepatocellular carcinoma; LTX, liver transplantation; SBRT, stereotactic body
radiotherapy; SIRT, selective internal radiotherapy; TACE, transarterial chemoembolisation.
Annals of Oncology
Volume 29 | Supplement 4 | October 2018

very early-stage disease (tumours < 2 cm diameter), RFA has transarterial therapy. Important relative contraindications in-
demonstrated similar outcomes to LR and thus may be recom- clude bile duct occlusion or incompetent papilla, reduced PS,
mended as first-line treatment, specifically in light of its lesser impaired liver function (Child-Pugh B), high-risk oesophageal
invasiveness and morbidity compared with surgery [64]. In varices, portal vein thrombosis of any kind for TACE or involving
patients with early-stage HCC (up to three lesions 3 cm), RFA the main trunk for selective internal radiotherapy (SIRT) [81].
has been adopted as an alternative first-line option irrespective of
liver function after demonstrating survival benefit similar to sur- Transarterial chemoembolisation
gery in RCTs and meta-analyses [64, 67–70]. To date, MWA has
Overall, the efficacy of TACE has been explored in seven rando-
not been adequately tested in comparison to RFA and the poten-
mised trials compared with best supportive care (BSC) [82]. Only
tial advantage for tumours between 3 and 5 cm or the reduced
two studies reported a survival benefit for the treatment arm [83,

impact of the cooling effect of adjacent large vessels remains un-
84]. The benefit of TACE in prolonging OS was demonstrated in
known. Both methods have limitations in exophytic tumours as
selected asymptomatic patients with maintained liver function
well as those close to the gallbladder, liver hilum or with neigh-
that belong to the BCLC A stage to early intermediate BCLC B
bouring intestine, which may be overcome by administering lap-
stage, who had a small tumour burden but were not amenable to
aroscopic surgery [71]. Chemical tumour ablation (e.g. by surgery or local ablation [I, A]. Median OS (mOS) of 30–
ethanol injection) plays no role, since thermal ablation has pro- 45 months can be expected in this population [85–87]. Shorter
ven better disease control and outcomes [72]. In very small median survival of < 20 months has been reported in real life
lesions, superiority of thermal ablation is minimal [73]. cohorts when patients with no proven benefit are treated includ-
ing those in Child-Pugh B stage, with portal vein invasion, large
High conformal, high dose rate radioablation tumour burden or deteriorating liver function under TACE [88–
(stereotactic body radiotherapy; high dose rate 91]. Several scores have been developed to identify patients that
brachytherapy) benefit from TACE from retrospective cohort studies. Currently,
High conformal high dose rate (HDR) radioablation and stereo- only the hepatoma arterial-embolisation prognostic (HAP) score
tactic body radiotherapy (SBRT) may be considered as alterna- has been validated in a prospective trial and in multiple large
tives for the ablation of tumours with a high risk of local failure international datasets [92, 93]. The HAP score is able to define
after thermal ablation due to location [III, C]. High conformal ir- four distinct prognostic groups with respect to OS and could be
radiation techniques with hypofractionated (SBRT) or single used as a stratification factor for TACE trials in future [88].
fraction dose regimens (HDR brachytherapy) have evolved as Outside clinical trials, the use of therapeutic algorithms based on
alternatives to thermal ablation in recent years. In contrast to prognostic scores of unknown predictive values is currently not
classic fractionated irradiation schemes, high conformal HDR ir- recommended for the selection of candidates to initial and
radiation techniques such as SBRT or CT-guided HDR brachy- repeated TACE [III, A].
therapy have proven efficacy with tumour control rates > 90% Conventional lipiodol-based TACE is the standard of practice,
after 12 months in 5 cm (SBRT) or 12 cm tumour diameter although using doxorubicin-eluting bead (DEB)-TACE is an op-
(HDR brachytherapy) in single-centre studies [74–77]. However, tion to minimise systemic side effects of chemotherapy [I, C].
a recent comparative trial has demonstrated better survival when Compared with conventional TACE, in RCTs DEB-TACE is asso-
applying RFA than SBRT in small tumours 3 cm [78]. In con- ciated with significantly fewer side effects related to the leakage of
trast to thermal ablation, high conformal HDR radioablation is doxorubicin into the systemic circulation [94] and provides a
not limited by adjacency to large vessels, exophytic growth or more standardised way to perform TACE. No prospective trial
central location. Both SBRT and HDR brachytherapy have dem- has so far demonstrated the superiority of conventional TACE,
onstrated excellent safety profiles [79, 80]. External beam radio- bland embolisation or DEB-TACE. One randomised phase II trial
therapy (EBRT) can be used to control pain in patients with bone compared cisplatin-based conventional TACE with bland embol-
metastases [III, B]. Any ablation recommendation should be pro- isation using polyvinyl alcohol particles alone, and two trials have
posed by the local multidisciplinary meeting (MDM) based on compared DEB-TACE with bland embolisation using unloaded
liver function, tumour size, tumour location and the medical ex- beads [95–97]. None of these trials showed an apparent clinical
pertise provided by the given treatment centre. benefit in terms of OS for the addition of chemotherapy; non-
inferiority was also formally not proven.
The optimal duration and frequency of TACE treatment is not
Transarterial therapies
yet defined. TACE should not be repeated if a substantial necrosis
The almost exclusive arterial vascularisation of HCC resulted in is not achieved after the second session, or when a subsequent ses-
the application of intra-arterial infusion of chemotherapy alone sion fails to induce remission at sites that have initially responded
(doxorubicin, cisplatin, mytomicin C or combinations), mixed to TACE. Additionally, the indication of TACE should be critical-
with the contrast agent lipiodol (ethiodised oil) that is selectively ly re-evaluated in patients with reduced PS and impaired liver
retained by HCC nodules, embolising material (e.g. coils, gelatin function following TACE treatment.
sponge pieces or polyvinyl alcohol-calibrated particles) or tiny The combination of TACE with systemic agents such as
radioactive particles containing yttrium-90 (90Y). sorafenib—either sequential or concomitant—is not
Absolute contraindications for transarterial therapies are de- recommended in clinical practice [I, E]. Five randomised trials
compensated cirrhosis, extensive tumour burden, reduced portal with 2468 patients have not shown a clinical meaningful benefit
vein flow, renal failure or any technical contraindication to of systemic therapy (sorafenib, brivanib or orantinib) in

combination with or following TACE compared with TACE To date, four trials have been reported for which the experi-
alone in terms of median objective response rate (mORR), mental arms were: PIAF (cisplatin/interferon/doxorubicin/fluo-
median progression-free survival (mPFS) or mOS [92, 98–101]. rouracil), the tubulin binding agent T138067, nolatrexed and
FOLFOX (leucovorin/fluorouracil/oxaliplatin) [110–112]. None
Selective internal radiotherapy improved survival compared with doxorubicin, although re-
sponse rates were higher with FOLFOX (8.2% versus 2.7%,
SIRT is based on the injection of microspheres loaded with the
P ¼ 0.0233) and a small benefit in median survival was also seen
pure beta emitter 90Y into the hepatic arterial circulation and has
on long-term follow up (6.4 versus 5.0 months, P ¼ 0.0425). One
no or minimal ischaemic effect. SIRT with 90Y glass or resin
trial has compared sorafenib with the combination of sorafenib
microbeads produces tumour responses and high disease control
and doxorubicin but did not demonstrate improved survival
rates with a safe profile in phase II studies and registries [102].

with combination therapy [113]. In summary, the clinical benefit
SIRT is not recommended as first-line therapy for HCC
of chemotherapy in the management of HCC has not been
patients in intermediate and advanced stage [I, E]. Two recent
established.
phase III trials randomised patients free from extrahepatic metas-
tasis and with preserved liver function to sorafenib or SIRT using
Targeted first-line therapies. Sorafenib is the standard of care for
resin microspheres. The SARAH trial in France (n ¼ 459 patients)
patients with advanced HCC and those with intermediate-stage
and the SIRveNIB trial in Asia-Pacific (360 patients) failed to
(BCLC B) disease not eligible for, or progressing despite, locore-
meet the primary endpoint of improved OS compared with sora-
gional therapies. It is recommended in patients with well-
fenib; survival for the sorafenib arm ranged from 10.2 to
preserved liver function and Eastern Cooperative Oncology
9.9 months compared with 8.8 to 8 months for 90Y [hazard ratio
Group (ECOG) PS 0–2 [I, A].
(HR) 1.12–1.15] [103, 104]. The applicability of 90Y was limited
Lenvatinib showed non-inferiority efficacy compared with sor-
to 72%–77% of patients due to treatment contraindications.
afenib and can be considered in patients with advanced HCC
Also, the per-protocol subgroup analyses did not yield any sur-
without main portal vein invasion and with ECOG PS 0–1 as a
vival advantages. The SORAMIC phase II trial additionally ana-
front-line systemic treatment, pending European Medicines
lysed whether the addition of SIRT to sorafenib improves OS in
Agency (EMA) approval [I, A].
patients with advanced HCC. However, this study failed to meet
the primary endpoint, and the addition of SIRT to sorafenib did
Sorafenib: Sorafenib, a multikinase inhibitor blocking 40 kin-
not show an OS that was superior to sorafenib alone. Whether
ases including vascular endothelial growth factor receptor 2
subgroups such as non-cirrhotic patients or non-alcoholic aeti-
(VEGFR2) and BRAF, was established as the standard systemic
ology of the cirrhosis with high positive HR for SIRT addition to
therapy for HCC according to all international guidelines follow-
sorafenib hold promise must be further validated [105].
ing the results reported a decade ago. It is indicated for patients
In the phase III studies, SIRT was associated with higher re-
with well-preserved liver function (Child-Pugh A class) and with
sponse rates, delayed tumour progression in the liver and fewer
advanced tumours (BCLC C) or those tumours at intermediate
adverse events (AEs) compared with sorafenib. The observed
stage (BCLC B) progressing upon locoregional therapies. In the
delay in tumour progression was also observed in retrospective
SHARP phase III trial, sorafenib improved survival compared
cohort studies with survival rates comparable to those reported
with placebo (HR 0.69; P ¼ 0.001; 7.9–10.7 months) [114]. The
for TACE and sorafenib [106–108]. Thus, in exceptional circum-
target population of this trial was mostly patients with advanced
stances, for patients with liver-confined disease and preserved
HCC (80%, including 35% with macrovascular invasion and
liver function in whom neither TACE nor systemic therapy is
50% with extrahepatic spread). The results of the SHARP trial
possible, SIRT may be considered. Additionally, SIRT may be
were subsequently confirmed in the Asia-Pacific phase III trial
considered instead of TACE for the treatment of small tumours
[115] and in 10 subsequent trials with an mOS in the range of 10–
in patients waiting for liver transplantation, in an attempt to
12 months. Objective responses are uncommon; 2% by Response
avoid drop-out from the list due to tumour progression [106].
Evaluation Criteria in Solid Tumours (RECIST) and 10% by
modified RECIST (mRECIST) [116]. A recent meta-analysis of
individual data of two RCTs testing sorafenib has shown that, al-
Management of advanced disease though of benefit to all patients across the board, it provides bet-
During the past 40 years, numerous RCTs testing treatments for ter outcomes in patients with HCV-related HCC and those with
advanced HCC have been published [109]. Sorafenib showed a liver-only disease [117]. No predictive biomarkers of responsive-
survival benefit and it was established as the sole systemic treat- ness to sorafenib have been identified.
ment for patients with advanced HCC or those progressing from The recommended daily dose of sorafenib is 800 mg. Median
locoregional therapies. More recently, five additional drugs have treatment duration is estimated to be 5–6 months, but early pre-
shown positive clinical results in first- and second-line settings vention of toxicities can enhance tolerability. Treatment is associ-
(see Figure 1). ated with manageable AEs, such as diarrhoea, hand–foot skin
reactions, fatigue and hypertension. Around 15% of patients are
Systemic therapies for advanced HCC intolerant to sorafenib, and thus treatment needs to be withdrawn,
while another 35% of patients require dose reduction. Treatment-
Chemotherapy. Chemotherapy has not been shown to improve related liver failure or life-threatening complications are marginal.
survival in randomised trials and is not recommended as a stand- Considering the restrictive indication of sorafenib in terms of liver
ard of care [II, C]. failure (mostly Child-Pugh A class), it has been estimated that only

half of patients at advanced stages can be suitable for this treat- These patients along with those at BCLC D stage should receive
ment. Clinically symptomatic vascular disease—either coronary or best supportive/palliative care, including management of pain,
peripheral—is considered a formal contraindication. nutrition and psychological support.
Lenvatinib: Several phase III trials have been conducted to Cabozantinib: Cabozantinib is a MET, VEGFR2, AXL and RET
challenge sorafenib in front line (testing sunitinib, brivanib, erlo- inhibitor approved for thyroid and renal cancer. The CELESTIAL
tinib, linifanib or doxorubicin), but lenvatinib has only recently trial, a randomised, global phase III trial, examined cabozantinib
shown non-inferior clinical efficacy [118]. Lenvatinib is an oral versus placebo in patients with advanced HCC who had been pre-
multikinase inhibitor that targets VEGFR1–3 and fibroblast viously treated with sorafenib [120]. In contrast to regorafenib,
growth factor receptor (FGFR)1–4, among others. Lenvatinib this trial allowed the inclusion of patients that were intolerant to

demonstrated non-inferiority results compared with sorafenib in sorafenib and who had progressive disease on one or two systemic
an open-label, phase III, multicentre, non-inferiority trial involv- therapies. In this trial, 30% of patients presented with macrovascu-
ing patients with advanced HCC (excluding main portal vein in- lar invasion, 78% with extrahepatic spread and 42% with AFP
vasion, clear bile duct invasion and > 50% of tumour to total > 400 ng/dL. Treatment was started at 60 mg/day, and median
liver volume occupancy). The dose was adjusted to body weight. time on treatment was 3.8 months. OS results favoured cabozanti-
The study met its primary endpoint of non-inferiority in OS nib compared with placebo (HR 0.76, 95% CI 0.63–0.92;
[HR 0.92; 95% confidence interval (CI) 0.79–1.06; mOS lenva- P ¼ 0.0049; mOS 10.2 versus 8.0 months). Response rate was 4%
tinib, 13.6 months versus sorafenib, 12.3 months]. Secondary with cabozantinib based upon RECIST v1.1. The most common
endpoints such as PFS, time to progression and ORR (24% versus grade 3/4 AEs with cabozantinib versus placebo were palmar–
9.2% for sorafenib, mRECIST ORR) were significantly better plantar erythrodysesthaesia (17% versus 0%), hypertension (16%
for lenvatinib. Lenvatinib-related most common any-grade AEs versus 2%), increased aspartate aminotransferase (AST) (12%
compared with sorafenib were as follows: hypertension (42% ver- versus 7%), fatigue (10% versus 4%) and diarrhoea (10% versus
sus 30%), diarrhoea (39% versus 45%) and hand–foot skin reac- 2%) and led to 62% dose reductions and 16% treatment
tion (27% versus 52%). Median time on lenvatinib was discontinuation.
5.7 months. Time to worsening in quality of life was similar in
both treatment arms (HR 1.01). These results position lenvatinib Ramucirumab: RAM is a human immunoglobulin G1 (IgG1)
as an option in first-line treatment for advanced HCC, once the monoclonal antibody (mAb) that inhibits ligand activation of
drug is approved by regulatory agencies. No cost-effectiveness VEGFR2. In the phase III REACH trial mOS in the overall popula-
studies comparing both drugs are available. tion was not statistically significant, but a meaningful improvement
was observed in a patient subgroup with baseline AFP 400 ng/
Targeted second-line therapies. Regorafenib is the standard of mL. Based on these data, the REACH-2 phase III trial analysed the
care for patients with advanced HCC who have tolerated sorafe- efficacy of RAM in patients with elevated baseline AFP following
nib but progressed. It is recommended in patients with well- therapy with sorafenib. RAM treatment significantly improved
preserved liver function and ECOG PS 0–1 [I, A]. mOS from 7.3 to 8.5 months (HR 0.710; 95% CI 0.531, 0.949;
Cabozantinib can be considered for patients who had progres- P ¼ 0.0199) and mPFS from 1.6 to 2.8 months (HR 0.452; 95% CI
sive disease on one or two systemic therapies with well-preserved 0.339, 0.603; P < 0.0001) compared with placebo [121]. ORR was
liver function and ECOG PS 0–1, pending EMA approval [I, A]. 4.6% with RAM versus 1.1% with placebo (P ¼ 0.1156) and ORR
Ramucirumab (RAM) can be considered for patients in was 59.9% RAM versus 38.9% with placebo (P ¼ 0.0006). The
second-line treatment with baseline AFP 400 ng/mL, well- safety profile observed in the REACH-2 study was consistent with
preserved liver function and ECOG PS 0–1, pending EMA ap- what has been previously observed, and the only grade 3 AEs
proval [I, A]. occurring at a rate of 5% in the RAM arm were hypertension
(12.2% versus 5.3%) and hyponatremia (5.6% versus 0%).
Regorafenib: Recently, a phase III study comparing regorafenib
(a multikinase inhibitor targeting similar kinases as sorafenib)
Immunotherapies
with placebo in patients progressing despite sorafenib has reported
a benefit in survival (HR 0.62; P < 0.0001, mOS 7.8–10.6 months) Immunotherapy with nivolumab and pembrolizumab can be
[119]. Treatment improved survival in all subgroups of patients. considered in patients who are intolerant to, or have progressed
In this trial, 88% of patients were BCLC C and 12% BCLC B, with under, approved tyrosine kinase inhibitors, pending EMA ap-
all of them tolerant to but progressing on sorafenib. Around 30% proval [III, B]. For a definitive recommendation, it is necessary to
of patients presented with macrovascular invasion: 70% with wait for the results of randomised trials.
extrahepatic spread and 45% with AFP > 400 ng/dL. The response To date, the most promising immunotherapeutic approach has
rate was 10%, based upon mRECIST. Treatment was started at been the use of immune checkpoint inhibitors. Initial results from
160 mg/day (3 weeks on/1 week off). Median time on treatment a small single-arm phase II trial of tremelimumab [a fully human-
was 3.5 months. AEs led to 51% dose reductions and 10% treat- ised IgG2 anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) anti-
ment discontinuation. Approval of regorafenib as a standard of body] demonstrated a response rate of 17% and time to
care opens the field for third-line therapies. It should be kept in progression of 6.5 months [122]. More recently, a large single-arm
mind, however, that most patients at BCLC B-C stages not candi- phase I/II trial of the fully human IgG4 programmed cell death
dates to standard-of-care therapies (TACE, sorafenib, regorafenib) protein 1 (PD-1) inhibitor nivolumab (CheckMate 040), has been
are generally unsuitable candidates to enter into clinical trials. reported [123]. A total of 262 patients were treated of which 48

Table 5. Response assessment by RECIST v1.1 and mRECIST for HCC
RECIST mRECIST
CR Disappearance of all target lesions Disappearance of any intratumoural arterial enhancement in all target
lesions
PR At least a 30% decrease in the sum of diameters of target At least a 30% decrease in the sum of diameters of viable (enhancement
lesions, taking as reference the baseline sum of the diameters in the arterial phase) target lesions, taking as reference the baseline
of target lesions sum of the diameters of target lesions
SD Any cases that do not qualify for either partial response or PD Any cases that do not qualify for either partial response or PD
PD An increase of at least 20% in the sum of the diameters of target An increase of at least 20% in the sum of the diameters of viable (enhanc-

lesions (lymph nodes of 1.5 cm diameter), taking as reference ing) target lesions (lymph nodes of 2 cm diameter), taking as reference
the smallest sum of the diameters of target lesions recorded the smallest sum of the diameters of viable (enhancing) target lesions
since treatment started recorded since treatment started
Development of new ascites Development of new ascites with positive cytology
CR, complete response/remission; HCC, hepatocellular carcinoma; mRECIST, modified Response Criteria in Solid Tumours; PD, progressive disease; PR, par-
tial response; RECIST, Response Criteria in Solid Tumours; SD, stable disease.
were in dose escalation and 214 in dose expansion. The dose of However, we recommend obtaining tissue in all research studies
3 mg/kg every 2 weeks was shown to be tolerable during dose escal- for exploring biomarkers of response.
ation and was used in dose expansion (in which patients were There has been increasing interest in stratified trials driven by
required to be Child-Pugh A and ECOG PS 1). In dose expan- predictive biomarkers, and a number of earlier phase trials are
sion, there were no treatment-related deaths and grade 3/4 AST exploring this strategy in HCC. Investigations into the molecular
and alanine aminotransferase (ALT) increase occurred in 4% and pathology of HCC have identified recurrent mutations of which
2%, respectively. The most common AEs of any grade were fatigue the most common are in the TERT promotor, CTNNB1, TP53
(23%), pruritus (21%) and rash (15%). The ORR was 20% and epigenetic regulators including ARID1A and ARID2 [125].
(RECIST v1.1) and the PFS and 9-month OS were 4.0 months and While these pathways provide a challenge for drug development,
74%, respectively. Expression of programmed death-ligand 1 (PD- less common molecular aberrations are tractable and show
L1) on tumour cell membranes was not found to be predictive. promise. For example, overexpression of FGF19 is found in
Overall, 145 patients in the expansion cohort had received prior 20% of HCCs, and several compounds directed against its re-
sorafenib and, after extended follow-up, the mOS was 15.6 months ceptor FGFR4 are in development, including BLU-554 and
(13.2–18.9). This compares favourably with all of the previously FGF401. Despite the disappointing results of the tivantinib
reported phase III second-line trials in HCC, for which mOS has phase III trial [126], there are ongoing studies enriching for
been between 7.6 and 10.6 months in the experimental arm. On MET pathway activation or MET overexpression with INC280
this basis, the United States Food and Drug Administration (FDA) and MSC2156119J. Activation of the transforming growth factor
granted accelerated approval for the use of nivolumab in patients beta 1 (TGFb1) pathway is associated with a more aggressive sub-
previously treated with sorafenib, on the condition that further tri- class of HCC and is being targeted with galunisertib in combina-
als were required to verify the clinical benefit of nivolumab in tions with sorafenib and nivolumab, although these trials are not
patients with HCC. The first-line phase III trial comparing sorafe- currently enriched for pathway activation. Numerous other tar-
nib with nivolumab, CheckMate 459, is expected to report in 2018 gets are being evaluated including androgen receptor, signal
and, if positive, will position nivolumab as a first-line treatment transducer and activator of transcription 3 (STAT3) inhibitor,
option. histone deacetylase inhibitor (HDACi) and cyclin-dependent
Meanwhile, a phase II trial of the anti-PD-1 antibody pembro- kinase 4/6 (CDK 4/6), but, while personalised therapy holds
lizumab as second-line treatment (KEYNOTE-224) has recently promise for the future, there is insufficient evidence for molecu-
been reported. The 16.3% response rate (RECIST v1.1) and 78% lar stratification at the present time.
6-month OS observed among the 104 patients included is in line
with the results seen with nivolumab. Median time to progression
was 4.9 months (95% CI: 3.9–8.0), mPFS was 4.9 months (95% Follow-up, long-term implications and
CI 3.4–7.2) and mOS was 12.9 months (95% CI 9.7–15.5) [124].
survivorship
Many HCC treatments act by induction of tumour necrosis or
Ongoing research in personalised therapy reduction in vascularity, which is not necessarily accompanied
by tumour shrinkage. Viable tumour should be assessed using
for HCC dynamic CT or MRI studies and should be defined as uptake of
Molecular profiling is not recommended as standard of practice contrast agent in the arterial phase [III, A]. mRECIST are recom-
since it currently has no direct implication for decision making. mended for assessment of response/progression to locoregional

Table 6. Summary of recommendations
Incidence, epidemiology and surveillance

• The association of chronic liver disease and HCC represents the basis for preventive strategies, including universal vaccination at birth against HBV [I, A]
and early antiviral treatment of viral HBV and HCV [III, A]
• Cost-effectiveness studies suggest surveillance of HCC is warranted in all cirrhotic patients irrespective of its aetiology, as long as liver function and
comorbidities allow curative or palliative treatments [III, A]
• Surveillance of non-cirrhotic, hepatitis-infected patients is also advocated, especially in HBV carriers with serum viral load > 10 000 copies/mL or
HCV-infected patients with bridging fibrosis (F3) [III, A]
• Surveillance of patients at risk for HCC should be carried out by abdominal US every 6 months with or without AFP [I, A]

Diagnosis and pathology/molecular biology
• The diagnosis of HCC is based on histological analysis and/or contrast-enhanced imaging findings [III, A]
• The diagnosis can be established if the typical vascular hallmarks of HCC (hypervascularity in the arterial phase with washout in the portal venous or
delayed phase) are identified in a nodule of > 1 cm diameter using one of these two modalities in a cirrhotic patient [III, A]
• Based on techniques such as diffusion-weighted imaging and the use of hepatobiliary contrast agents, MRI may allow identification and stratification of
nodules as high-risk nodules (either HCC not displaying the typical imaging hallmarks features or high-grade dysplastic nodules) [IV, B]
• For CEUS, an overlap between the vascular profile of HCC and CC has been described. However, recent data suggest CEUS as a suitable technique to
diagnose HCC non-invasively in the setting of liver cirrhosis [IV, B]
• When tumour biopsy fails to demonstrate a correlate for a focal lesion, a second tumour biopsy, a different contrast enhanced imaging modality or
(if amenable) direct resection of the lesion may be considered according to tumour size [IV, B]
• Histopathological diagnosis of tumour biopsies relies on standard (H&E) and special stains (e.g. reticulin), and—if required—IHC
• It is important to distinguish combined HCC/CC from HCC due to the different therapeutic modalities; however, the mixed differentiation features
might not be visible in the biopsy. In addition, significant expression of CK19 has been evaluated and is considered as a sign of poor prognosis in HCC
[IV, B]
• In highly differentiated HCC, definitive signs of malignancy (interstitial or vascular invasion) are frequently absent from biopsy. Further consented
histological (trabecular alterations—more than two cell broad trabeculae, pseudoglands, reticulin loss, capsule formation) and cytological criteria
(increased nuclear/cytoplasmic ratio, i.e. ‘nuclear crowding’, increased cytoplasmic basophilia) support HCC diagnosis [III, B]
• IHC should be carried out in unclear cases: capillarisation of sinusoids could be assessed using CD34 IHC [IV, B]
• Further immunohistochemical markers have been shown to improve the diagnosis of highly differentiated HCC, including glutamine synthetase, glypican
3, CTC, EZH2 and HSP70 [IV, B]
• A combination of the three markers glutamine synthetase, glypican 3 and HSP70 has been consented as a diagnostic panel (2/3 marker positivity has 70%
sensitivity and 100% specificity for HCC) and the use of further markers seems to increase the sensitivity [IV, B]
Staging and risk assessment
• Staging of HCC is important to determine outcome and planning of optimal therapy and includes assessment of tumour extent, AFP level, liver
function, portal pressure and clinical PS [III, A]
• BCLC is the commonly accepted staging system for prognostic prediction and treatment allocation
• There is no demonstrated clinical benefit of carrying out an FDG-PET scan as a staging modality, despite some evidence that there is a correlation of
higher FDG uptake with poor differentiation, tumour size, serum AFP levels and microvascular invasion [IV, D]
• Liver function is classically assessed by the Child-Pugh scoring system (serum bilirubin, serum albumin, ascites, prothrombin time and hepatic
encephalopathy) [III, A]
• Within the Child-Pugh A group, measurement of the ALBI score is able to split that group into best prognosis (ALBI 1) and lesser prognosis (ALBI 2), with
median survivals of 26 versus 14 months, respectively [IV, B]
• The finding of oesophageal varices and/or splenomegaly with blood platelet counts of 100 109 cells/L suggests clinically important portal hypertension,
which can also be measured invasively by the transjugular route (hepatic-venous pressure gradient > 10 mmHg) [III, A]
Management of early and intermediate HCC
• Child-Pugh A patients without immanent portal hypertension are considered good candidates for minor/major LRs [III, B]
• Carefully selected patients with Child-Pugh B and/or portal hypertension may be candidates for minor surgical resection [III, A]
• LR in cirrhosis should preferably be carried out as laparoscopic resection [IV, A]
• The Milan criteria (one lesion < 5 cm; alternatively, up to three lesions, each < 3 cm; no extrahepatic manifestations; no evidence of macrovascular
invasion) are currently the benchmark for the selection of patients with HCC for OLT. OLT is recommended for patients that fit the Milan criteria, for
which < 10% recurrence and 70% 5-year survival are expected [II, A]
• Among several more liberal proposals (up-to-seven, Toronto criteria, UCSF), only the UCSF criteria (one tumour 6.5 cm, three nodules at most with the
largest 4.5 cm, and total tumour diameter 8 cm) were prospectively validated and showed similar outcome and, as such, may also be considered for
OLT in patients with HCC beyond Milan criteria [III, B]
• In the case of a long-anticipated waiting time (> 3 months), patients may be offered resection, local ablation or TACE in order to minimise the risk of
tumour progression and to offer a ‘bridge’ to transplant [III, B]
• Adjuvant therapy is not recommended for HCC patients after OLT, LR or local ablation [I, E]
• Thermal ablation by means of RFA or MWA may be recommended as first-line treatment in very early-stage disease (BCLC 0) [II, A]

• High conformal HDR radioablation and SBRT may be considered as alternatives for the ablation of tumours with a high risk of local failure after thermal
ablation due to location [III, C]
• Outside clinical trials, the use of therapeutic algorithms based on prognostic scores of unknown predictive values is currently not recommended for the
selection of candidates to initial and repeated TACE [III, A]
• Conventional lipiodol-based TACE is the standard of care for patients with intermediate HCC, although using DEB-TACE is an option to minimise systemic
side effects of chemotherapy [I, C]
• The combination of TACE with systemic agents such as sorafenib—either sequential or concomitant—is not recommended in clinical practice [I, E]
• SIRT is not recommended as first-line therapy for patients in intermediate or advanced stage [I, E]
Management of advanced disease
• Chemotherapy has not been shown to improve survival in randomised trials and is not recommended as a standard of care [II, C]

• Sorafenib is the standard of care for patients with advanced HCC and those with intermediate-stage (BCLC B) disease not eligible for, or progressing des-
pite, locoregional therapies. It is recommended in patients with well-preserved liver function and ECOG PS 0–2 [I, A]
• Lenvatinib showed non-inferiority efficacy compared with sorafenib, and can be considered as first-line therapy in patients with advanced HCC without
main portal vein invasion, clear bile duct invasion and 50% of tumour to total liver volume occupancy, pending EMA approval [I, A]
• Regorafenib is the standard of care for patients with advanced HCC who have tolerated sorafenib but progressed. It is recommended in patients with
well-preserved liver function and ECOG PS 0–1 [I, A]
• Cabozantinib can be considered for patients who had progressive disease on one or two systemic therapies with well-preserved liver function and ECOG
PS 0–1, pending EMA approval [I, A]
• Ramucirumab can be considered for patients in second-line patients with baseline AFP 400 ng/mL, well-preserved liver function and ECOG PS 0–1,
pending EMA approval [I, A]
• Immunotherapy with nivolumab and pembrolizumab can be considered in patients who are intolerant to, or have progressed under, approved tyrosine
kinase inhibitors, pending EMA approval [III, B]. For a definitive recommendation, it is necessary to wait for the results of randomised trials
Follow-up, long-term implications and survivorship
• Viable tumour should be assessed using dynamic CT or MRI studies and be defined as uptake of contrast agent in the arterial phase [III, A]
• mRECIST need further prospective validation but may be recommended in daily clinical practice to consider not only tumour diameters but also lesion via-
bility in therapy decision making [III, B]
• mRECIST are recommended for assessment of response/progression to locoregional therapies [III, B]
• There is limited evidence that OS can be predicted more accurately by mRECIST than RECIST v1.1 [IV, B]
• Follow-up of patients who underwent radical treatments (resection or RFA) should consist of the clinical evaluation of liver decompensation and the early
detection of recurrence by dynamic CT or MRI studies every 3 months during the first 2 years and surveillance every 6 months thereafter [III, A]
• Patients with more advanced stages of HCC who are treated with TACE or systemic agents are evaluated clinically for signs of liver decompensation and
for tumour progression by dynamic CT or MRI every 3 months to guide therapy decisions [III, A]
AFP, alpha foetoprotein; ALBI, albumin-bilirubin; BCLC, Barcelona Clinic Liver Cancer; CC, cholangiocarcinoma; CEUS, contrast-enhanced ultrasound; CK19,
cytokeratin 19; CT, computed tomography; DEB, doxorubicin-eluting bead; ECOG, Eastern Cooperative Oncology Group; EMA, European Medicines Agency;
EZH2, enhancer of zeste homologue 2; FDG, fluorodeoxyglucose; H&E, haemotoxylin and eosin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV,
hepatitis C virus; HDR, high dose rate; HSP70, heat shock protein 70; IHC, immunohistochemistry; LR, liver resection; mRECIST, modified Response Criteria in
Solid Tumours; MRI, magnetic resonance imaging; MWA, microwave ablation; OLT, orthotropic liver transplantation; OS, overall survival; PET, positron emis-
sion tomography; PS; performance status; RECIST, Response Criteria in Solid Tumours; RFA, radiofrequency ablation; SBRT, stereotactic body radiotherapy;
SIRT, selective internal radiotherapy; TACE, trans-arterial chemoembolisation; UCSF, University of California San Francisco; US, ultrasound.
therapies [III, B]. RECIST were primarily designed for the evalu- [131]; however, a higher objective response by mRECIST does
ation of cytotoxic agents. Modifications of RECIST (mRECIST) not correlate with an improved OS in subsequent phase III trials
are available and are based on the measurement of the diameter [118]. In addition, the prospective comparison between
of the viable tumour component of target lesions (Table 5) mRECIST and RECIST in two trials with nintedanib and one
[116]. mRECIST also include guidelines regarding evaluation of trial with regorafenib revealed a very similar outcome, with no
vascular invasion, lymph nodes, effusions and new lesions. In clear advantage of mRECIST [119, 132]. Overall, mRECIST
2011, the first study reported a link between mRECIST, EASL need further prospective validation but may be used in daily
(European Association for the Study of Liver) criteria and OS in clinical practice to consider not only tumour diameters but also
patients treated with TACE in contrast to RECIST v1.1, which lesion viability in therapy decision making [III, B]. There is lim-
was subsequently confirmed and validated [127–130]. In con- ited evidence that OS can be predicted more accurately by
trast to locoregional therapies, the value of mRECIST in the mRECIST than RECIST v1.1 [IV, B].
evaluation of systemic therapy in HCC is not yet established. Response assessment following radioembolisation is
mRECIST were prospectively evaluated in the BRISK trial and challenging and should be carried out by multiple phase MRI
responders had a better OS compared with non-responders or CT at 3–4 months intervals. Imaging carried out early after

Table 7. Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America-United States Public Health Service
Grading Systema)
Levels of evidence
I Evidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of
well-conducted randomised trials without heterogeneity
II Small randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials
with demonstrated heterogeneity
III Prospective cohort studies
IV Retrospective cohort studies or case–control studies

V Studies without control group, case reports, expert opinions
Grades of recommendation
A Strong evidence for efficacy with a substantial clinical benefit, strongly recommended
B Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended
C Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (AEs, costs, . . .), optional
D Moderate evidence against efficacy or for adverse outcome, generally not recommended
E Strong evidence against efficacy or for adverse outcome, never recommended
a
By permission of the Infectious Diseases Society of America [139].
radioembolisation may show arterial enhancement (both rim Guidelines/ESMO-Guidelines-Methodology. The relevant litera-
and intratumoural) related to post-treatment inflammatory ture has been selected by the expert authors. A summary of
changes and may be erroneously labelled as infiltrative recommendations is shown in Table 6. Levels of evidence and
tumour. These findings usually resolve after 6 months [133]. grades of recommendation have been applied using the system
Prospective radiological–pathological studies have shown that shown in Table 7. Statements without grading were considered
EASL criteria and mRECIST—and not World Health justified standard clinical practice by the experts and the ESMO
Organization (WHO) criteria or RECIST—may capture Faculty. This manuscript has been subjected to an anonymous
responses at 3 months after radioembolisation [134]. peer review process.
In the context of immunotherapy, response evaluation may also
be very challenging as pseudoprogression (transient increase in tu-
mour size and AFP, followed by response) has been described also Disclosure
in HCC [135]. Recent trials with immunotherapies reported re-
AV has received honoraria for talks and advisory boards from
sponse rates of up to 25% by RECIST v1.1, and mRECIST have not
Bayer, Roche, Lilly, Bristol-Myers Squibb, Merck Sharp &
been validated in this setting. Serum tumour markers (such as AFP
Dohme, AstraZeneca, Eisai, Novartis and Ipsen; AC has provided
levels) may be helpful particularly in the case of not easily measur-
consulting and advisory services for Merck Serono, Amgen,
able disease but should not be used as the only determinant for
Servier, Roche, Lilly, Novartis, Takeda and Astellas and has
treatment decisions [IV, B]. Pseudoprogression is incredibly rare
received research support from Roche, Merck Serono, Servier,
but, in the future, immune RECIST (iRECIST) should be discussed
Beigene and Astellas; IC has reported being a member of the ad-
in this context [136].
visory boards of Eli-Lilly, Bristol-Myers Squibb, MSD, Bayer,
In summary, follow-up of patients who underwent radical
Roche, Merck-Serono, Five Prime Therapeutics and Astra-
treatments (resection or RFA) should consist of the clinical evalu-
Zeneca and has received research funding from Eli-Lilly, Janssen-
ation of liver decompensation and the early detection of recur-
Cilag, Sanofi Oncology, Merck-Serono and honorarium from
rence by dynamic CT or MRI studies every 3 months during the
Eli-Lilly; BD has received honoraria or consultation fees from
first year and surveillance every 6 months thereafter [III, A] [66,
Bayer, Bristol-Myers Squibb, MSD, Merck KGaA, Ipsen, Eisai
137, 138]. Patients with recurrence following radical therapies
and Lilly; JL has received consultancy fees from Bayer, Bristol-
may still be candidates for curative therapies. Patients with more
Myers Squibb, Incyte, Lilly, Eisai, Celsion, Glycotest, Ipsen,
advanced stages of HCC who are treated with TACE or systemic
Merck and Exelixis and research support from Incyte, Bayer,
agents (e.g. sorafenib) are evaluated clinically for signs of liver de-
Bristol-Myers Squibb and Eisai; TM has received consulting fees
compensation and for tumour progression by dynamic CT or
from Bristol-Myers Squibb, Bayer, Eisai, Ipsen, Merck, BTG and
MRI every 3 months to guide therapy decisions [III, A].
Beigene; UN has given presentations for Merck, Amgen, Roche,
Grünenthal and Bayer on topics other than HCC; JR has received
consulting fees and research grants from Bayer Healthcare and
Methodology Sirtex Medical; BS has received consulting and/or lecture fees
These Clinical Practice Guidelines were developed in accordance from Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb,
with the ESMO standard operating procedures for Clinical BTG, Onxeo, Sirtex and Terumo; PS has reported being a mem-
Practice Guidelines development http://www.esmo.org/ ber of advisory board and has received grants from Novartis and

Bristol-Myers Squibb; CV has received consultancy fees and re- 19. Zhang B, Yang B. Combined alpha fetoprotein testing and ultrasonog-
search funding from Bayer, Sirtex, Novartis and Ipsen; CJZ has raphy as a screening test for primary liver cancer. J Med Screen 1999; 6:
received honoraria for lectures and advisory boards by Bayer 108–110.
20. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening
Healthcare; DA has received honoraria for consultancy from
for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004; 130: 417–422.
Roche, Merck Serono, Bayer Healthcare, Servier, BTG, Terumo, 21. Trinchet JC, Chaffaut C, Bourcier V et al. Ultrasonographic surveil-
Sanofi Oncology and Eli Lilly; EM has received honoraria for lec- lance of hepatocellular carcinoma in cirrhosis: a randomized trial
ture and advisory boards for Roche, Amgen, Servier and Sanofi; comparing 3- and 6-month periodicities. Hepatology 2011; 54:
JCN has reported no conflicts of interest. 1987–1997.
22. Matsui O, Kobayashi S, Sanada J et al. Hepatocelluar nodules in liver
cirrhosis: hemodynamic evaluation (angiography-assisted CT) with
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Hepatocellular Carcinoma: ESMO Clinical Practice Guidelines For Diagnosis, Treatment and Follow-Up

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Annals of Oncology 29 (Supplement 4): iv238–iv255, 2018

CLINICAL PRACTICE GUIDELINES

Hepatocellular carcinoma: ESMO Clinical Practice

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A. Vogel1, A. Cervantes2, I. Chau3, B. Daniele4, J. Llovet5,6,7, T. Meyer8,9, J.-C. Nault10, U. Neumann11,

History and clinical examination

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Otherwise, use CT/MRI diagnostic table below

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Arterial phase hyperenhancement (APHE) No APHE APHE (not rim)

iv240 | Vogel et al. Volume 29 | Supplement 4 | October 2018

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UICC, Union for International Cancer Control.

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BCLC stage Treatment Indication constraints based on Alternative treatment Alternative

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Figure 1. HCC treatment options depending on BCLC stage.

Volume 29 | Supplement 4 | October 2018

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Incidence, epidemiology and surveillance

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