Seminar

Hepatocellular carcinoma
Alejandro Forner, Josep M Llovet, Jordi Bruix

Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related Lancet 2012; 379: 1245–55
death. Patients with cirrhosis are at highest risk of developing this malignant disease, and ultrasonography every Published Online
6 months is recommended. Surveillance with ultrasonography allows diagnosis at early stages when the tumour February 20, 2012
DOI:10.1016/S0140-
might be curable by resection, liver transplantation, or ablation, and 5-year survival higher than 50% can be achieved.
6736(11)61347-0
Patients with small solitary tumours and very well preserved liver function are the best candidates for surgical
Barcelona Clinic Liver Cancer
resection. Liver transplantation is most beneficial for individuals who are not good candidates for resection, especially group, Liver Unit, Hospital
those within Milano criteria (solitary tumour ≤5 cm and up to three nodules ≤3 cm). Donor shortage greatly limits its Clínic Barcelona, August Pi
applicability. Percutaneous ablation is the most frequently used treatment but its effectiveness is limited by tumour i Sunyer Biomedical Research
Institute, University of
size and localisation. In asymptomatic patients with multifocal disease without vascular invasion or extrahepatic
Barcelona, Barcelona, Spain
spread not amenable to curative treatments, chemoembolisation can provide survival benefit. Findings of randomised (A Forner MD, J M Llovet MD,
trials of sorafenib have shown survival benefits for individuals with advanced hepatocellular carcinoma, suggesting J Bruix MD); Centro de
that molecular-targeted therapies could be effective in this chemoresistant cancer. Research is active in the area of Investigación Biomédica en
Red de Enfermedades
pathogenesis and treatment of hepatocellular carcinoma.
Hepáticas y Digestivas,
Barcelona, Spain (A Forner,
Introduction than 50% of all cases.4 The relative risk of tumour J M Llovet, J Bruix); Mount Sinai
Hepatocellular carcinoma is the sixth most common development is about 100 in carriers of HBV versus non- Liver Cancer Program, Division
of Liver Diseases, Mount Sinai
neoplasm and the third most frequent cause of cancer carriers, and in HBV carriers with cirrhosis it is even
School of Medicine, New York,
death.1 More than 700 000 cases of this malignant disease higher.4,14 Incidence of hepatocellular carcinoma increases NY, USA (J M Llovet); and
were diagnosed in 2008, with an age-adjusted worldwide with viral load and duration of infection,15 suggesting an Institució Catalana de Recerca
incidence of 16 cases per 100 000 inhabitants.1 Hepato- accumulated risk of long-lasting oncogenic damage. Occult i Estudis Avançats, Barcelona,
Spain (J M Llovet)
cellular carcinoma is the leading cause of death among HBV infection is also associated with increased risk of
Correspondence to:
patients with cirrhosis.2 Here, we update our 2003 Lancet hepatocellular carcinoma because of DNA damage induced
Dr Jordi Bruix, Barcelona Clinic
Seminar3 to include major advances in prevention, by HBV integration.16,17 Hepatocellular carcinoma related Liver Cancer group, Liver Unit,
detection, diagnosis, and treatment that have happened to HBV can be prevented by vaccination. Nationwide IDIBAPS, Hospital Clínic,
since then. vaccination of infants in Taiwan reduced the incidence of Villarrel 170, 08036 Barcelona,
Spain
hepatocellular carcinoma in children aged 6–9 years from
jbruix@clinic.ub.es
Risk factors and prevention 0·52 per 100 000 for those born between 1974 and 1984 to
In most cases, hepatocellular carcinoma develops within 0·13 for those born between 1984 and 1986.18 If infection is
an established background of chronic liver disease chronic, viral replication can be abrogated by antiviral
(70–90% of all patients).4 The worldwide heterogeneous agents, which would prevent progression of liver disease
incidence reflects variations in the main risk factors and, possibly, hepatocellular carcinoma in the long term.19
(table 1).1,5 Most cases of hepatocellular carcinoma (80%) The incidence of hepatocellular carcinoma in individuals
arise in eastern Asia and sub-Saharan Africa, where the with HCV cirrhosis is 3–5% per year.20 Prevention of HCV
dominant risk factor is chronic infection with hepatitis B infection relies on avoidance of viral transmission through
virus (HBV), together with exposure to aflatoxin B1. By contaminated blood. Interruption of evolution from acute
contrast, in North America, Europe, and Japan, infection infection into chronic hepatitis and, ultimately, cirrhosis
with hepatitis C virus (HCV) is the main risk factor, by use of antiviral agents should prevent development of
together with alcohol use.6 Time trends in incidence of hepatocellular carcinoma.21,22 However, if cirrhosis is
hepatocellular carcinoma in developed countries parallel established, risk of hepatocellular carcinoma persists
the timing of HCV spread. In Japan and Europe, where despite antiviral treatment.21 Findings of initial studies
HCV infection spread earlier than in the USA, the suggested that interferon might prevent development of
incidence of hepatocellular carcinoma has almost reached hepatocellular carcinoma in patients with cirrhosis.23,24
a plateau and in some areas it is declining;5,7 however, in However, in randomised controlled trials, long-term
the USA, incidence is still increasing8,9 and the infection
could have a synergistic effect with other risk factors, such
as non-alcoholic fatty liver disease. Diabetes is an Search strategy and selection criteria
independent risk factor for hepatocellular carcinoma,6,10 We searched Medline, Embase, and the Cochrane Library (from January, 2000, to
and mortality rates for liver cancer are five times higher November, 2011) with the terms “hepatocellular carcinoma”, “liver cancer”, and “primary
among men with baseline body-mass index greater than liver carcinoma”. We also searched and reviewed the reference lists of retrieved
40, versus those with a lower body-mass index.11 Tobacco publications for other relevant papers. We only considered papers published in English
raises risk whereas coffee reduces it.12,13 and Spanish. We selected publications largely from the past 5 years, but we did not
The most frequent risk factor for hepatocellular carci- exclude commonly referenced and highly regarded older publications.
noma is chronic HBV infection, which accounts for more

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(mammalian target of rapamycin) pathway is disrupted in

Age-adjusted Risk factors
incidence (x100 000; 40–50% of liver cancers owing to upstream signalling,
[men/women]) inactivation of the tumour suppressor PTEN, or mutations
Hepatitis C virus Hepatitis B virus Alcohol Others of phosphoinositide-3-kinase.32,33 Similarly, insulin-like
growth factor receptor 1 (IGF1R) signalling was active in
Europe ·· 60–70% 10–15% 20% 10%
20% of early hepatocellular carcinomas, and deregulation
Western 7·2/2·1 ·· ·· ·· ··
of the hepatocyte growth factor (HGF) and c-MET pathway
Southern 9·8/3·2 ·· ·· ·· ··
is a common event.29 Wingless (Wnt) signalling is
Northern 3·8/1·6 ·· ·· ·· ··
activated in a third of hepatocellular carcinomas, as a
North America 6·8/2·2 50–60% 20% 20% >10%
result of activating mutations in the transcription factor
Asia and Africa ·· 20% 70% 10% <10%
β catenin, overexpression of Wnt receptors, or inactivation
Eastern Asia 35·5/12·6 ·· ·· ·· ··
of E-cadherin. However, hepatocellular carcinoma is a
Southern Asia 13·9/5·1 ·· ·· ·· ·· highly vascularised cancer and angiogenic activity through
Central Africa 18·9/9·6 ·· ·· ·· ·· signalling of VEGFA, ANGPT2, and fibroblast growth
Data taken from references 1 and 5. factor (FGF) is a key event.28,29,34 Angiogenesis is complex
and has been reviewed elsewhere.28,29,34
Table 1: Age-adjusted incidence and risk factors for hepatocellular carcinoma worldwide, by
geographical area
Molecular classification of hepatocellular
carcinoma
treatment with interferon did not affect the rate of disease Molecular profiling is relevant in cancers such as those
progression and development of hepatocellular carcinoma of breast, lung, colon, and melanoma, and in some
in patients with chronic hepatitis C and advanced instances molecular subclasses and response to treatment
fibrosis.25,26 Alcohol is an important risk factor for are linked—eg, amplification of ERBB2 and response
development of hepatocellular carcinoma and exerts a to trastuzumab. Outcome prediction depends on both
synergistic effect in individuals with chronic infection tumour profiling (defining Wnt subclass, tumour growth
with HBV, HCV, or both.20 Patients who are co-infected factor β [TGF β], and epithelial cell adhesion molecule
with HIV and either HBV or HCV seem to have more [EPCAM] and inflammation class)29,35 and gene expression
rapidly progressive liver disease than patients without of adjacent non-tumoral tissue.36,37 Transfer of this infor-
HIV infection, and when they develop cirrhosis they are mation into treatment decision-making would need
also at increased risk of hepatocellular carcinoma.27 additional validation.

Molecular pathogenesis Surveillance and diagnosis

Hepatocarcinogenesis is a complex multistep process in
which many signalling cascades are altered, leading to a
heterogeneous molecular profile.28,29 The main mutations
include the tumour suppressor gene TP53 (present in
about 25–40% of cancers, depending on tumour stage),
and the gene for β catenin, CTNNB1 (about 25%, pre-
dominantly in HCV-related hepatocellular carcinoma).
Other mutations are less frequent. Chromosomal amplifi-
cations (1q, 6p, 8q, 17q, and 20q) and deletions (4q, 8p, 11q,
13q, 16q, and 17p) are common and affect important
oncogenes and tumour suppressors. High-level amplifi-
cations have been described in 6p21 (VEGFA) and 11q13
(cyclin D1 [CCND1]) in 5–10% of patients.28,29 Epigenetic
alterations are ill-defined in hepatocellular carcinoma, but
silencing of tumour suppressors (ie, RASSF1, SOCS1,
E-cadherin [CDH1]) and reactivation of oncogenes (MYC)
have been shown.28,29 Finally, microRNA (miRNA) seems
to be able to modulate transcription of key oncogenes.30,31
As a result of these alterations, several signalling
cascades related to cell survival and proliferation are
activated and respond to targeted treatments in preclinical
and early clinical studies. With respect to proliferation
cascades, epithelial growth factor receptor (EGFR) and
Ras signalling is activated in more than 50% of
hepatocellular carcinomas,29 whereas the MTOR
Surveillance for hepatocellular carcinoma aims to reduce
disease-related mortality. In uncontrolled studies, survival
seemed to be improved with surveillance but these studies
are affected by biases of lead time (the apparent
improvement in survival that comes from the diagnosis
being made early in the course of a disease) and length
time (the apparent improvement in survival that arises
because surveillance preferentially detects slow-growing
cancers).38 One randomised controlled trial of surveillance
has been done in China (18 816 patients with hepatitis B) to
compare twice-yearly ultrasonography and measurement
of serum α-fetoprotein (AFP) concentration with no sur-
veillance.39 Despite suboptimum adherence to surveillance
(<60%), survival of screened participants was 66% at 1 year,
53% at 3 years, and 46% at 5 years versus 31%, 7%, and 0%,
respectively, in unscreened patients. A validation trial in
developed regions is not feasible: ultrasonography is part
of routine assessment for patients with liver disease and
the perceived benefit from surveillance would impair
recruitment of patients.40 Indeed, early detection and
treatment of hepatocellular carcinoma is the sole option to
achieve long-term disease-free survival.
The decision to begin surveillance depends on the
degree of risk of hepatocellular carcinoma for the
individual and the extent to which he or she would be

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treated if diagnosed with the malignant disease. Since no

experimental data to indicate the degree of risk that Mass on surveillance
ultrasonography in a
should trigger surveillance are available, the decision is <1 cm
patient with cirrhosis
>1 cm

based on cost-effectiveness models with heterogeneous or chronic hepatitis B

design. They all suggest that surveillance is cost effective
and that efficacy is dictated by incidence of hepatocellular
4-phase MDCT/dynamic MR
carcinoma.41,42 Accordingly, surveillance is recommended
both for patients with cirrhosis who would be treated
effectively if diagnosed with hepatocellular carcinoma Arterial hypervascularisation and
and for those with HBV infection but without cirrhosis, venous or delayed-phase washout

with an annual incidence of more than 0·2%.43 Individuals

with highly impaired liver function (Child-Pugh class C)
should be assessed for liver transplantation. If this
procedure cannot be offered surveillance is of no benefit
because diagnosis will not be followed by effective
treatment. Similarly, if liver function deteriorates and
prompts major decompensation not leading to assessment
for transplantation, surveillance should be cancelled.
The preferred imaging method for surveillance is
ultrasonography; it is well tolerated and widely avail-
able, and it has sensitivity of 60–80% and specificity
beyond 90%.44 The most used serological test is AFP.
Unfortunately, even with the most efficient cutoff
(10–20 μg/L), diagnostic sensitivity is around 60%.45–47
Figures for surveillance are even worse and do not
support AFP as a surveillance test. Combined use of AFP
and ultrasonography not only does not increase detection
rates but also raises false-positive suspicions and cost.44,48
Other tumour markers, such as des-γ carboxiprothrombin
or AFP fractions, do not have better accuracy.46,47
On the basis of tumour-doubling times and data from
the one available trial, screening of patients every
6 months is recommended. A 3-month interval increases
detection of small nodules but has no effect on survival,49
and twice-yearly screening has better results than
annual.50 Since tumour growth rate is not dictated by risk,
increased risk should not prompt a shorter interval.
Figure 1 shows the diagnostic algorithm used once a
nodule has been detected.43 Nodules 1 cm or smaller are
diagnosed infrequently as hepatocellular carcinoma and
are almost impossible to diagnose confidently by available
techniques (biopsy could miss the target and the diagnostic
hypervascular profile is not in place at this stage).
Furthermore, for these small lesions, pursuing a diagnosis
of hepatocellular carcinoma would probably lead to more
harm than benefit.51 When the nodule exceeds 1 cm,
diagnosis can be established by biopsy or by imaging in
the setting of liver cirrhosis. The specific imaging pattern
is defined by intense contrast uptake during the arterial
phase followed by contrast washout during venous or
delayed phases in a contrast-enhanced study such as CT or
MRI (magnetic resonance is being validated extensively).52,53
The value of these non-invasive criteria for hepatocellular
carcinoma in cirrhosis has been confirmed prospectively.54–56
In nodules of 1–2 cm, typical imaging features have
specificities and predictive positive values of near 100%
and sensitivity that can reach 71%. Contrast-enhanced
Repeat ultrasonography
every 3 months Positive Negative
Stable over Enlarging Other imaging modality Biopsy
18–24 months (CT or MRI)
Arterial hypervascularisation and
venous or delayed-phase washout
Positive Negative
Return to Proceed
standard according to
surveillance lesion size Treat as hepatocellular carcinoma
Figure 1: Diagnostic algorithm for hepatocellular carcinoma
Modified from reference 43, with permission of John Wiley and Sons. MDCT=multidetector CT.
MR=magnetic resonance.
ultrasonography is not recommended as the sole diagnostic
imaging technique because it cannot distinguish
intrahepatic cholangiocarcinoma from hepatocellular
carcinoma57,58 and MRI or CT is still needed for staging.
Non-invasive diagnostic criteria are valid only for
investigation of screen-detected lesions in the liver in
patients with either cirrhosis or long-lasting chronic HBV
infection who might not have fully developed cirrhosis. In
other clinical scenarios, a diagnostic biopsy should be
requested. However, a negative finding after biopsy does
not rule out hepatocellular carcinoma since the false-
negative rate can reach 30%54 because of sampling error or
absence of specific histological hallmarks for diagnosis of
this cancer. A three-gene signature including glypican 3
(GPC3), LYVE1, and survivin (BIRC5) has been proposed,59
but more tissue is needed with this method than for
conventional immunohistochemical staining for GPC3,
glutamine synthetase, clathrin heavy chain, and heat-shock
protein 70. This immunohistochemical panel provides
100% specificity but still with suboptimum sensitivity.60
Staging and prognosis assessment
Assessment of prognosis is a crucial step in management
of patients with hepatocellular carcinoma. Years ago,
most affected individuals were diagnosed at an advanced

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 Seminar
symptomatic stage, when treatment was not feasible and
short-term prognosis was dismal. Diagnosis has now
advanced, and effective early treatment of patients is
associated with median survival beyond 5 years. Any attempt
to assess prognosis should account for tumour stage, degree
of liver function impairment, and presence of cancer-related
symptoms.61 Several proposals have been raised to stratify
patients according to expected outcome.61 Some approaches
do not take into account the presence of cancer-related
symptoms that are major prognostic predictors.62–65 Others
assess tumour burden roughly62 or investigate liver function
according to the presence or absence of cirrhosis.66 This
approach limits clinical usefulness.
The classification that stratifies patients according to
outcome and simultaneously links it with treatment
indication is the Barcelona Clinic Liver Cancer (BCLC)
strategy (figure 2). The BCLC classification has been
validated in different settings and establishes treatment
recommendations for all stages of hepatocellular carci-
noma.67 Patients with early-stage cancer are treated by
resection, liver transplantation, or ablation, and prognosis
can be refined for all these procedures according to
different variables. The very early stage (BCLC 0) corres-
ponds to patients with well-preserved liver function (Child-
Pugh A) diagnosed with one asymptomatic nodule of less
than 2 cm without vascular invasion or satellites. This
stage corresponds to the carcinoma-in-situ entity that, if
resected or ablated, would have excellent outcome with
almost zero risk of recurrence. Currently, confident
diagnosis is not feasible by imaging techniques or biopsy
Hepatocellular carcinoma
Very early stage (0) Early stage (A)
Single <2 cm Single or 3 nodules <3 cm
Child-Pugh A, PS 0 Child-Pugh A–B, PS 0
Potential candidate for Single Three nodules ≤3 cm
liver transplantation
No Yes Portal pressure, bilirubin
Normal Increased Associated diseases
No
Ablation Resection Liver transplantation
Curative treatments
Figure 2: BCLC staging and treatment strategy
The BCLC system establishes a prognosis in accordance with the five stages that are linked to first-line treatment recommendation. If the recommended option is not feasible because of an
individual patient’s condition, the treatment approach for the next evolutionary disease stage should be considered. Accordingly, patients in BCLC stage A may benefit from transarterial
chemoembolisation, BCLC B patients from sorafenib, and some patients in BCLC stage C with contraindications for sorafenib could enter research trials to assess new agents. BCLC=Barcelona Clinic
Liver Cancer. PS=performance status.
1248
and it is classified as such at explant. End-stage patients are
identified easily by any clinical method. They have a very
poor prognosis and no intervention will be of benefit.
Patients with end-stage liver disease (Child-Pugh C or
advanced Child-Pugh B) should be considered for trans-
plantation, but recognition of hepatocellular carcinoma
could become a contraindication because of excessive
tumour burden. Between these two extreme situations, the
clinical profile is very heterogeneous; liver function
includes Child-Pugh classes A and B, and tumour burden
encompasses liver-only disease without vascular invasion
or extensive disease with metastatic spread. Patients can be
asymptomatic (performance status 0) or already have
cancer-related symptoms such as pain or malaise (per-
formance status 1–2). As a result, the term non-surgical
hepatocellular carcinoma does not indicate any specific
clinical profile or prognosis. The BCLC classification68
divides this heterogeneous group into two categories: the
intermediate stage (BCLC B), defined by absence of any
adverse predictor, and the advanced stage (BCLC C), which
includes patients with symptoms, vascular invasion,
extrahepatic spread, or a combination. The BCLC strategy
has been validated externally in prospective studies69 and
has been endorsed by several scientific associations, but
further refinement is still needed. Liver function is
assessed by the Child-Pugh classification, but class B
includes a wide range of patients. Similarly, presence of
ascites within Child-Pugh class A indicates impaired
prognosis, which should be factored into individual
assessment of patients and treatment proposals.
Intermediate stage (B) Advanced stage (C) Terminal stage (D)
Large multinodular Portal invasion Child-Pugh C
Child-Pugh A–B, PS 0 Extrahepatic spread PS 3–4
Child-Pugh A–B, PS 1–2
Yes
Ablation Chemoembolisation Sorafenib Best supportive care
Palliative treatments
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Biomarkers should enable better stratification. High

Benefit Level of evidence
AFP concentration is associated with a poor prognosis,
but no cutoff that would imply a modification in treatment Surgical treatments

decision has been defined. Other tumour markers do not Surgical resection Increases survival 3ii A
refine prognosis or justify their use for staging or Adjuvant treatments Controversial 1 A–D
treatment selection. The same applies for biomarkers Liver transplantation Increases survival 3ii A
such as VEGF, angiopoietin 2, or the proto-oncogene Adjuvant treatments Treatment response 3 Diii
c-Kit. They can refine prognostic prediction within Locoregional treatments
statistical modelling but cannot yet be incorporated into Percutaneous treatment Increases survival 3ii A
assessment of an individual patient. Radiofrequency Increases survival 1ii A
Other modalities Treatment response 2D
Treatment Combined modalities Treatment response 3ii D
For treatment to be most effective, patients should be Chemoembolisation Increases survival 1ii A
selected carefully and the treatment applied skilfully. In Internal radiotherapy (iodine-131, yttrium-90) Treatment response 3ii Diii
view of the complexity of hepatocellular carcinoma and Systemic treatments
the many potentially useful treatments, patients diag- Sorafenib Increases survival 1i A
nosed with this malignant disease should be referred Hormonal compounds No survival benefit 1i A
to multidisciplinary teams that include hepatologists, Tamoxifen ..
radiologists, surgeons, pathologists, and oncologists. By Antiandrogen ..
contrast with other highly prevalent cancers, the level of Seocalcitiol ..
evidence for most therapeutic options for hepatocellular Systemic chemotherapy No survival benefit 1i A
carcinoma is restricted to cohort investigations with a few Immunotherapy No survival benefit 1ii A
randomised controlled trials, most of which addressed
Modified from reference 70, with permission of Oxford University Press. Evidence-based classification adapted from
treatment of advanced disease (table 2).70 Furthermore, as
the National Cancer Institute. 1=randomised controlled trial or meta-analysis (1i=double-blinded, 1ii=non-blinded).
far as we know, no large robust studies have been done to 2=non-randomised controlled trial. 3=case series (3i=population-based, 3ii=non-population-based, consecutive,
compare treatments regarded as potentially curative for 3iii=non-population-based, non-consecutive). A=survival endpoint. B=cause-specific mortality. C=quality of life.
early-stage disease (surgical resection, transplantation, D=indirect surrogates (Di=disease-free survival, Dii=progression-free survival, Diii=tumour response).

percutaneous ablation), and no studies have compared
these methods with no treatment. Surgical resection,
transplantation, and ablation are treatments that offer a
high rate of complete responses and, thus, potential for
cure.43 The only non-curative treatments that improve
survival are transarterial chemoembolisation and sora-
fenib.71–73 Arterial embolisation without chemotherapy,71
external radiotherapy,74,75 and radioembolisation have
shown antitumour activity,76–78 but survival benefit has not
been proven. Systemic chemotherapy has marginal
activity with frequent toxic effects, without survival
benefit, and agents such as tamoxifen, octreotide, or
antiandrogens are completely ineffective.43,71
Resection
Hepatic resection is the treatment of choice for
hepatocellular carcinoma in individuals without cirrhosis
(5% of patients in the USA and Europe, 40% in Asia).
These patients tolerate major resections with low rates of
life-threatening complications. In individuals with
cirrhosis, careful selection of candidates is vital to avoid
treatment-related complications—eg, liver failure with
increased risk of death.
For years, selection of candidates for resection has been
based on the Child-Pugh classification,79 but this strategy
has inconsistent predictive value. Some Child-Pugh A
patients already have liver functional impairment with
raised bilirubin concentrations, clinically significant portal
hypertension, or even minor fluid retention necessitating
diuretic treatment.80 In Japan, the indocyanine green
Table 2: Evidence-based benefits of treatments
retention rate is used to identify the best candidates for For the National Cancer
resection,81 whereas portal pressure and bilirubin are the Institute see http://www.
cancer.gov
variables used in Europe and the USA.43 Clinically relevant
portal hypertension is defined as a hepatic vein pressure
gradient greater than 10 mm Hg, but it can also be
confirmed by oesophageal varices or splenomegaly
associated with a platelet count lower than 100×10⁹/L. In
patients without relevant portal hypertension and normal
concentrations of bilirubin, survival at 5 years is 70%,
whereas it is 50% for individuals with portal hypertension
and is even lower when both adverse factors are present.82,83
With respect to the best candidates for resection, blood
transfusion will be needed in fewer than 10% of cases, and
treatment-related mortality should be less than 1%.
Therefore, assessment of portal pressure is crucial for
prediction of long-term survival.43
Most groups restrict the indication for resection to
patients with one tumour, because multifocality is
associated with high recurrence and impaired survival.
Although multifocality need not be viewed as a contra-
indication to resection, careful assessment to estimate
survival (and associated risks) that might be offered by
other options, such as transplantation, ablation,84 or
chemoembolisation,85–87 is mandatory. Tumour size is not
a clear-cut limiting factor, but risk of vascular invasion
and dissemination increases with diameter. Malignant
vascular invasion should be viewed as a contraindication

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for resection. By application of these restrictive criteria,
the proportion of patients in whom resection can be
offered is 5–10%.
Tumour recurrence complicates 70% of cases at 5 years,
combining true recurrence, which usually arises within
the first 2 years after resection, and de novo tumours.81
Microvascular invasion, poor histological differentiation,
satellites, and multifocal disease predict early recurrence.81,88
Late recurrence depends mainly on the carcinogenic effect
of underlying chronic liver disease.36 This risk can be
estimated by liver function variables related to inflammatory
activity, evolutionary stage, or both. No effective neoadjuvant
or adjuvant treatment options to reduce risk of recurrence
are available. Systemic chemotherapy and chemoembol-
isation have no effect, whereas immunotherapy, retinoids,
and interferon have shown some potential efficacy, but
evidence is not strong enough for them to be used in
clinical practice.81 Findings of meta-analyses have
reinforced the benefits of interferon but heterogeneity of
the interferon used, the duration of the regimen, the
patients recruited, and trial endpoints prevent valid assess-
ment.89–91 The most effective option to prevent intrahepatic
recurrence is liver transplantation. Although post-resection
recurrence affects more than 70% of patients at 5 years in
those with a risky profile, it affects fewer than 25% of
individuals treated by transplantation. Transplantation can,
therefore, be offered to patients initially treated by resection
but with a high risk of recurrence according to pathological
analysis. This policy not only allows some individuals to be
treated effectively by resection with avoidance of trans-
plantation but also permits best use of the few organs that
are available by offering transplantation to patients whose
cancer would recur after resection.92
Liver transplantation
Hepatocellular carcinoma is the only solid cancer that can
be treated by liver transplantation, which has completely
changed the treatment strategy for this malignant disease.
In theory, transplantation could simultaneously cure the
tumour and underlying cirrhosis, and effectiveness of the
procedure is not affected by the degree of liver function
impairment. Mazzaferro and colleagues93 showed that
selection of patients with one hepatocellular carcinoma of
5 cm or smaller, or up to three nodules of 3 cm or smaller,
without vascular invasion or extrahepatic spread (known
as the Milano criteria) offered 4-year survival of 75%, with
recurrence rates below 15%. These results have been
validated82,94,95 and are accepted as the benchmark for
selection of patients in the USA and Europe.43,96,97
These excellent results were achieved in an era with
prompt availability of organs. The shortage of donors has
imposed a delay before transplantation, and during this
period the tumour can progress and impede trans-
plantation.98 This delay impairs the effectiveness of liver
transplantation when considered according to intention
to treat.82 When waiting time exceeds 6 months, treatments
aimed at delaying tumour progression (eg, ablation,
1250
transarterial chemoembolisation) are done, even though
effectiveness is unproven.99 Policies for transplantation
are implemented that aim to prioritise the sickest
patients,52,100 but the only effective method to avoid waiting
is to increase the number of donations. Live donation is a
valid strategy, with outcomes similar to those of cadaveric
donation, but applicability is reduced because of societal
constraints and, scarcity of appropriate donors.
Despite the shortage of liver donors, several researchers
have proposed expansion of current limits.101–105 Most
suggestions are based on analysis of tumour stage in the
explanted liver and not on imaging findings at the time of
the patient’s assessment. Furthermore, transplantation to
patients who do not meet the Milano criteria is associated
with increased prevalence of variables associated with risk
of recurrence (microscopic vascular invasion or satellites).
If the number of livers available exceeded the number of
candidates for transplantation, a slight expansion would
be feasible because it would not negatively affect patients
with the best transplant profiles.106 The MTOR inhibitor
sirolimus seemed to improve tumour-free survival in
recipients of liver transplants with a pre-transplantation
diagnosis of hepatocellular carcinoma in preliminary
studies, but this hypothesis should be confirmed in a trial
due to finish in 2014.107
Image-guided tumour ablation
Image-guided tumour ablation is now a conventional
treatment option for patients with early-stage hepato-
cellular carcinoma. Ablation induces tumour necrosis by
injection of chemicals (eg, ethanol, acetic acid) or
temperature modification (ablation by radiofrequency,
microwave, or laser, or cryoablation). Although tumour
ablation can be undertaken at laparoscopy or surgery, most
procedures are done percutaneously. The first-line
technique is now radiofrequency ablation.108 Both ethanol
injection and radiofrequency ablation achieve complete
necrosis of almost 100% in hepatocellular carcinomas
smaller than 2 cm, but the effectiveness of ethanol injection
falls in larger tumours, in which radiofrequency ablation
can still be highly effective. Effectiveness diminishes in
larger lesions, and ablation is not recommended for
tumours larger than 5 cm. Better disease control with
radiofrequency ablation than with ethanol injection could
translate into better outcomes.109–111 Side-effects are more
frequent after radiofrequency ablation than after other
approaches and some tumour locations (subcapsular,
vicinity of major blood vessels or biliary tree, near to bowel
or heart) should be avoided.112 Novel techniques such as
microwave or electroporation are being evaluated.108
Survival after ablation in Child-Pugh A patients is
50–75% at 5 years, thus paralleling the outcome after
surgical resection.108–111 This finding has challenged resec-
tion as the first-line treatment in patients with small
solitary hepatocellular carcinomas. Ablation has been
compared with resection in early hepatocellular carcinoma
in several randomised controlled trials, but the results
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have varied.113–115 However, these trials had some limitations
in terms of sample size, and concerns have been raised in
some instances about randomisation, treatment allo-
cation, and trial implementation; further studies under-
taken in the USA and Europe are needed urgently.
A specific scenario for ablation is the very early stage of
hepatocellular carcinoma. Ablation is nearly 100% effective
in hepatocellular carcinomas smaller than 2 cm and
survival is almost identical after resection or ablation.
Thus, if transplantation is not an option, ablation would
become the first-line option and surgery would be justified
only in patients with failure of or contraindication to
ablation. However, if the strategy of transplantation owing
to risk of recurrence as per tumour pathology is in place,
patients who could benefit from transplantation should
still have resection as the first-line approach. Analysis of
resected tumour would distinguish between very early
hepatocellular carcinoma (BCLC 0) with marginal risk of
recurrence (thus, no need to consider transplantation) and
more advanced malignant disease with presence of
microscopic vascular invasion or satellites that indicate
transplantation because of high risk of recurrence. This
change represents a major alteration in BCLC decision-
making, as described in figure 2, because patients
diagnosed at a very early stage would be considered for
resection only if a transplant were available. In the future,
imaging techniques or molecular profiling might
distinguish between these two evolutionary tumour stages
and decide between ablation and transplantation without
need for resection with pathological assessment.
Image-guided transcatheter tumour treatment
Image-guided transcatheter treatments are based on
selective intravascular delivery of drugs into arterial
vessels nourishing the tumour, and are considered in
patients with large cancers or multifocal disease that is
not amenable to curative treatments. Chemotherapeutic
drugs, embolic particles, or radioactive materials can be
injected and induce tumour necrosis.108 The only option
that has shown survival benefit116,117 is transarterial chemo-
embolisation. It combines injection of chemotherapeutic
agents with obstruction of arterial blood supply. More
than 50% of patients have an objective response, as shown
trials that found improved survival because of risk of bias
(according to Cochrane criteria).117,121 Finally, the Cochrane
analysis had very stringent expectations for survival
improvement (10%).
After initial success with transarterial chemoembol-
isation, treated tumours are revascularised and can be
re-treated. However, in the long term, the capacity to keep
the cancer under control is lost. Development of poly-
vinylalcohol spheres that provide a calibrated vessel
obstruction with slow release of chemotherapeutic agents
has allowed the procedure to be standardised while
maintaining effectiveness and reducing drug-related
adverse events.122 In current trials, researchers are
investigating whether the combination of transarterial
chemoembolisation with molecular-targeted agents might
delay tumour progression after treatment and, ultimately,
improve survival. Median survival in old series was almost
2 years but, with better selection criteria and optimum
treatment delivery, median survival exceeds 3 years.85–87
Therefore, the best candidates for transarterial chemo-
embolisation are patients with compensated Child-Pugh A
with asymptomatic multifocal or large hepatocellular
carcinomas not amenable to resection (ie, BCLC stage B).
Portal vein thrombosis, even if segmental, is a predictor
of poor tolerability and impaired outcome.123
Radioembolisation with yttrium-90 (Yt⁹⁰)-labelled
spheres has much potential, and findings show anti-
tumour activity,76–78 but without randomised controlled
trials to compare this option with any other established
treatment, definition of its role in clinical practice is not
feasible. Validation of safety and effectiveness in different
cohort studies could indicate its target population.
Sorafenib
Until lately, no effective treatment was available for patients
diagnosed at advanced stage or who progressed into an
advanced stage after other treatments failed. Knowledge of
molecular events that govern tumour progression and
100 Sorafenib
Placebo
75
Proportion surviving (%)

by extensive tumour necrosis, which translates into

improved survival.71 In a recent meta-analysis, evidence
50 p=0·0001
supporting the benefits of transarterial chemoembolisation
was defined as still limited.118 However, this Cochrane
analysis had several controversial features. It included a 25
randomised controlled trial undertaken in patients with
early hepatocellular carcinoma, in whom transarterial
embolisation (not chemoembolisation) was assessed in 0
0 8 16 24 32 40 48 56 64 72 80
combination with standard treatment for those patients
Weeks
(ablation by ethanol injection or radiofrequency ablation). Number at risk
It also included a trial using absorbable gelatin powder Sorafenib 299 274 241 205 161 108 67 38 12 0 0
Placebo 303 276 224 179 126 78 47 25 7 2 0
with short follow-up that showed poor 1-year survival119 (a
characteristic shared by the most recent investigation)120 Figure 3: Overall survival of patients with advanced hepatocellular carcinoma assigned sorafenib or placebo
without extended follow-up. Furthermore, it excluded two Adapted from reference 72 with permission of the Massachusetts Medical Society.

www.thelancet.com Vol 379 March 31, 2012 1251

 Seminar

602 patients, median overall survival in the sorafenib group

Llovet (2008)72 Cheng (2009)73
was 10·7 months (95% CI 9·4–13·3) versus 7·9 months
Sorafenib 800 mg Placebo Sorafenib 800 mg Placebo (6·8–9·1) in the placebo group (hazard ratio 0·69, 95% CI
per day (n=303) (n=299) per day (n=150) (n=76)
0·55–0·87; p=0·0001; figure 3). Survival benefit was
Response rate .. .. .. .. preceded by a delay in time to progression: 5·5 months for
Complete response 0 0 0 0 sorafenib versus 2·8 months for placebo (0·58, 0·45–0·74;
Partial response 7 2 5 1 p<0·001).72 The two groups did not differ in median time
Stable disease 211 204 81 21 to symptomatic progression (4·1 months vs 4·9 months;
Progressive disease .. .. 46 41 p=0·77). The overall incidence of treatment-related adverse
Time to progression (months) 5·5 2·8 2·8 1·4 events (predominantly grade 1 or 2 in severity) was 80% in
Hazard ratio (95% CI) 0·58 (0·45–0·74) .. 0·57 (0·42–0·79) .. the sorafenib group and 52% in the placebo group.
Median survival (months) 10·7 7·9 6·5 4·2 Most frequent adverse events were gastrointestinal,
Hazard ratio (95% CI) 0·69 (0·55–0·87) .. 0·68 (0·50–0·93) .. constitutional, and dermatological in nature. Treatment
interruption owing to side-effects was recorded in 38% of
Data are number of patients, unless otherwise stated.
treated patients versus 37% in controls. These findings
Table 3: Phase 3 clinical trials of sorafenib in patients with advanced hepatocellular carcinoma have been replicated by a randomised controlled trial in
Asia (table 3),73 and safety data were reproduced in a large
phase 4 study of sorafenib in more than 1500 patients.124
Control Phase Identifier*
These results have established sorafenib as the standard of
Adjuvant treatment after resection or ablation care for advanced hepatocellular carcinoma43,125 and have
Sorafenib Placebo 3 NCT00692770 paved the way for development of combination or
Adjuvant treatment after transarterial chemoembolisation sequential strategies to improve the effectiveness of
Sorafenib Placebo 2 NCT00855218 sorafenib as one agent. Several trials are underway (table 4).
Brivanib Placebo 3 NCT00908752 The key issue in early development phases was how to
First-line treatment in advanced hepatocellular carcinoma assess potential effectiveness and to proceed to phase 3
Sorafenib and erlotinib Sorafenib 3 NCT00901901 trials. In all studies with sorafenib so far, survival is
Sorafenib and doxorubicin Sorafenib 3 NCT01015833 improved in the absence of treatment response, according
Sorafenib and C1008 Sorafenib 2 NCT01033240 to conventional definitions.126 New criteria based on
Sorafenib and mapatumumab Sorafenib 2 NCT01258608 biomarkers or functional imaging will have to be developed
Sorafenib and BIBF-1120 Sorafenib 2 NCT01004003 for assessment of efficacy. Until then, the potential
Sorafenib and oxaliplatin and capecitabine Sorafenib 3 NCT01245582 effectiveness of novel agents will have to rely on time to
Sorafenib and bevacizumab Sorafenib 2 NCT00867321 progression, which also marks the time for recruitment of
Bevacizumab and erlotinib Sorafenib 2 NCT00881751 patients into trials to assess the efficacy of novel agents
Brivanib Sorafenib 3 NCT00858871 beyond sorafenib.70 Some attempts will fail, as has
Dovitinib Sorafenib 2 NCT01232296 happened for sunitinib. This drug had a similar molecular
Linifanib (ABT-869) Sorafenib 3 NCT01009593 profile to sorafenib but the trial was interrupted because of
Second-line treatment in advanced hepatocellular carcinoma
futility and safety concerns.127 Others could be positive and,
Brivanib Placebo 3 NCT00825955
hence, changes in management of advanced hepatocellular
ARQ197 Placebo 2 NCT00988741
carcinoma might be introduced in coming years.
Axitinib Placebo 2 NCT01210495
Ramucirumab Placebo 3 NCT01140347
Future perspectives
Treatment of hepatocellular carcinoma has changed greatly
Everolimus Placebo 3 NCT01035229
within the past decade and has become a major area for
OSI-906 Placebo 2 NCT01101906
research. Patients diagnosed with this malignant disease
*From http://www.clinicaltrials.gov. can benefit from effective options that will improve their
survival, whatever the evolutionary stage at which they
Table 4: Randomised phase 2 and 3 multicentre trials in progress
have been diagnosed. Obviously, improvement in several
areas is still needed. Recurrence after ablation or resection
dissemination has allowed development of targeted is a major drawback, and effective preventive agents are
treatments that aim to abrogate these disrupted pathways. needed. Also, progression after effective chemoembolisation
Several drugs are under development, but the only one is an area in which any positive strategy should result in
with proven survival benefit is sorafenib.72,73 This agent, relevant benefit. Finally, identification of novel targets and
which can be administered orally, is a multikinase inhibitor predictors through molecular cell biology will identify new
that blocks Raf signalling and VEGF, PDGF, and c-Kit. therapeutic strategies for advanced stage hepatocellular
It has antiproliferative and antiangiogenic activity and carcinoma and provide better methods for outcome
delays tumour progression. In our phase 3, multicentre, prediction. For that reason, collection of tissue samples
randomised, double-blind, placebo-controlled trial of should be considered in research studies. Molecular

1252 www.thelancet.com Vol 379 March 31, 2012


biology data might offer the insight to abrogate malignant
transformation within cirrhotic livers. For these advances
to take place, continuing active clinical and experimental
research is essential. Only by combination of all areas of
expertise will these hopes be realised.
Contributors
AF did the literature research. All authors wrote the Seminar and have
reviewed and approved the final version.
Conflicts of interest
AF has received consultancy and lecture fees from Bayer Schering
Pharma. JML has received grant support, consultancy fees, or both from
Bayer Schering Pharma, Bristol-Myers Squibb, Biocompatibles,
Biosphere, Novartis, Imclone, Jennerex, Abbott, and OSI. JB has received
grant support, consultancy fees, or both from Bayer Schering Pharma,
Bristol-Myers Squibb, Biocompatibles, Terumo, Novartis, Schering
Plough, Eisai, Arqule, Angiodynamics, Kowa, GlaxoSmithKline,
Sumitomo, Lilly, and OSI.
Acknowledgments
The Barcelona Clinic Liver Cancer (BCLC) is funded through the Spanish
Biomedical Research Network (CIBER) for the area of Hepatic and
Digestive disorders. This work was supported partly by grants from the
Instituto de Salud Carlos III (PI 08/0146). JML has received grants from
the US National Institutes of Health-NIDDK 1R01DK076986-01, National
Institute of Health (Spain) grant I+D Program (SAF-2007-61898), and the
Samuel Waxman Cancer Research Foundation.
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