1. REVIEWS
Medical therapies for hepatocellular
carcinoma: a critical view of the evidence
Augusto Villanueva, Virginia Hernandez-Gea and Josep M. Llovet
Abstract | The management of hepatocellular carcinoma (HCC) has substantially changed in the past few
decades. Improvements in patient stratification (for example, using the Barcelona Clinic Liver Cancer
staging system) and the introduction of novel therapies (such as sorafenib) have improved patient survival.
Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decisionmaking largely relies on evidence-based criteria, as depicted in the US and European clinical practice
guidelines, which endorse five therapeutic recommendations: resection; transplantation; radiofrequency
ablation; chemoembolization; and sorafenib. However, areas still exist in which uncertainty precludes a strong
recommendation, such as the role of adjuvant therapies after resection, radioembolization with yttrium‑90
or second-line therapies for advanced HCC. Many clinical trials that are currently ongoing aim to answer
these questions. The first reported studies, however, failed to identify novel therapeutic alternatives (that is,
sunitinib, erlotinib or brivanib). Moreover, genomic profiling has enabled patient classification on the basis
of molecular parameters, and has facilitated the development of new effective drugs. However, no oncogene
addiction loops have been identified so far, as has been the case with other cancers such as melanoma, lung
or breast cancer. Efforts that focus on the implementation of personalized medicine approaches in HCC will
probably dominate research in the next decade.
Villanueva, A. et al. Nat. Rev. Gastroenterol. Hepatol. 10, 34–42 (2013); published online 13 November 2012; doi:10.1038/nrgastro.2012.199
Introduction
Hepatocellular
Carcinoma
Translational Research
Laboratory, Barcelona
Clinic Liver Cancer
Group, Institut
d’Investigacions
Biomèdiques August Pi
i Sunyer (IDIBAPS),
Liver Unit, Hospital
Clínic, Villarroel 170,
Barcelona 08036,
Catalonia, Spain
(A. Villanueva,
V. Hernandez-Gea,
J. M. Llovet).
Correspondence to:
J. M. Llovet
jmllovet@clinic.ub.es
Disease burden owing to hepatocellular carcinoma
(HCC) is increasing markedly worldwide.1 In the USA,
epidemiological data published in 2009 show a substantial increase in HCC mortality in the past few decades2—
a trend that underscores the importance of this disease
in upcoming years.3 Nonetheless, major improvements
have been made in HCC management during the past
30 years. Traditionally, HCC was considered a deadly
disease without curative options, with an overall survival of <6 months. 4 Advances in early detection,
imaging techniques and novel therapies have improved
patient selection and enabled evidence-based treatment
approaches.5 Consequently, prognostic algorithms, such
as the Barcelona Clinic Liver Cancer (BCLC) classification, have been introduced in routine clinical care.4 The
BCLC approach classifies patients according to tumour
burden, underlying liver dysfunction and patient symptoms (Figure 1); it additionally links each stage to specific
therapeutic interventions.5 The BCLC system is widely
accepted, being currently endorsed by US and European
associations for the study of liver diseases and oncology.5,6 Better patient selection has resulted in improvements in patient outcomes for almost every approved
Competing interests
J. M. Llovet declares associations with the following companies:
Bayer Pharmaceutical, Biocompatibles, Bristol–Myers–Squibb,
Imclone. See the article online for full details of the
relationships. The other authors declare no competing interests.
34 | JANUARY 2013 | VOLUME 10
therapeutic intervention in HCC, including curative (for
example, resection, transplantation, local ablation) and
palliative (for example, transarterial chemoembolization
[TACE]) approaches. In addition, the molecular-targeted
agent sorafenib has shown antitumour activity in patients
with advanced HCC, improving 3 months overall
survival and delaying tumour progression.7
HCC frequently occurs in a damaged organ; liver cirrhosis owing to viral hepatitis (HBV or HCV infection)
and alcohol abuse are the main risk factors. 8 However,
the rapid development of potent antiviral agents and
the increasing incidence of cirrhosis owing to NASH
and overweight will modify the aetiological landscape
of chronic liver disease in the next decades.9 The unique
coexistence of two diseases—cirrhosis and HCC—in
the same patient complicates the prognostic prediction and therapeutic strategies. This coexistence was
observed in a phase III trial assessing sunitinib versus
sorafenib in patients with advanced HCC, which was
prematurely halted owing to toxicity and futility in the
sunitinib arm.10
This finding emphasizes the fact that patients with
cirrhosis, even at early stages of liver failure, are more
susceptible to toxicities associated with drugs that are
otherwise harmless in individuals without liver disease
(sunitinib is approved for renal cell carcinoma). This
issue, in addition to the fact that conventional chemotherapy was proven ineffective for this malignancy, 11
makes HCC management particularly challenging. This
www.nature.com/nrgastro
© 2013 Macmillan Publishers Limited. All rights reserved

2. REVIEWS
Review will dissect the evidence behind medical interventions in HCC, and discuss some relevant areas of
controversy in disease management.
Milestones in research and management
Evidence-based approaches are progressively governing decision-making in medicine. This development is
particularly relevant in oncology, in which the disease
is frequently lethal and medical interventions can have
major adverse effects. Hence, changes in the standard of
care need to be supported by robust data. In fact, clinical
practice guidelines tend to follow evidence-based criteria to select and grade clinical recommendations, as is
the case for HCC.5 This approach enables the establishment of a hierarchy of recommendations based on levels
of evidence, and identifies those ‘grey areas’ in which
more research is required to provide clear recommendations. When considering HCC management, only five
interventions reach the highest level of evidence, being
worldwide accepted recommendations for the treatment
of HCC:5 resection for patients with solitary tumours
and well-preserved liver function; liver transplantation
for patients with tumours within Milan criteria (single
nodules 5 cm or three nodules 3 cm);12 percutaneous ablation with radiofrequency in early tumours not
suitable for surgical treatment; TACE for patients with
multinodular asymptomatic tumours without vascular
invasion or extrahepatic spread (BCLC B); and sorafenib
for patients at advanced stage (Figure 1). Beyond this
framework, all other interventions require additional
research to prove survival advantages when confronted
with the above-mentioned standards of care. Such is the
case for internal radioembolization with ytrrium-90 or
the role of adjuvant therapies after resection.5 Herein,
we discuss some of the areas of HCC management that
require improvement and summarize the evidence
currently available.
The most relevant advances in HCC management
have resulted from randomized studies, meta-analysis
and cohort studies providing different levels of evidence
and strength of recommendations in guidelines of clinical practice (Figure 2). Some of these pivotal studies
have been widely cited, and represent scientific milestones in liver cancer research (Table 1); even though
clinical decision-making should rely on recommendations based on levels of evidence, showing how frequently these recommendations reflect the importance
of published research when evaluating the total number
of citations is interesting. Table 1 summarizes the most
relevant achievements and milestones in HCC research
during the past 30 years, represented in hierarchical
order according to number of citations and topic. These
milestone studies in HCC address different aspects of
clinical management such as epidemiology (association
between viral hepatitis and HCC development), surgery
(Milan criteria for liver transplantation, intention-totreat analysis for resection), locoregional therapies
(percutaneous ablation in small tumours, randomized
trials and meta-analyses of TACE), chemoprevention
(HBV vaccination or interferon therapy and decreased
Key points
■■ Epidemiological data indicate that the disease burden of hepatocellular
carcinoma (HCC) is increasing worldwide, both in terms of incidence and mortality
■■ The Barcelona Clinic Liver Cancer staging system provides a general framework
for decision-making in patients with HCC, and facilitates stage-based unified
selection criteria for clinical trials
■■ Evidence-based criteria dominate recommendations for HCC management,
enabling stratification of evidence according to scientific standards and
providing a hierarchy of medical recommendations
■■ Five treatments are strongly recommended in HCC on the basis of evidencebased data: resection; liver transplantation; radiofrequency ablation;
chemoembolization; and sorafenib
■■ Sorafenib, a molecular targeted agent, prolongs survival in patients with
advanced HCC and is the sole systemic drug that is proved to be effective in
this disease
■■ No oncogenic addiction loops have so far been identified in HCC; research
initiatives should aim to identify subgroups of patients with targetable dominant
molecular alterations
HCC risk) and systemic therapies (such as sorafenib).
Besides clinically oriented studies, few other studies
represent true breakthroughs in the understanding of
the pathogenesis of HCC, such as TP53 mutations and
HCC in aflatoxin endemic areas, or the oncogenic role
of HBV and core proteins in transgenic mice.13 With
respect to HCC management, to date, the highest cited
paper (Table 1; n = 2,331 citations) is the landmark study
published in 1996 by Mazzaferro et al.12 that introduced
the Milan criteria for selection of optimal HCC candidates for liver transplantation. When analysing the
manuscripts according to number of citations per year,
the sorafenib study ranks first with an average of 325
citations per year. Not surprisingly, both studies provide
the rationale for strong clinical practice recommendations in HCC management.5,6 In fact, substantial overlap
exists between findings from the top cited papers and
the clinical recommendations made in guidelines.5
Breakthroughs in the management of human cancers
have been dominated by the discovery and selective
blockade of so-called oncogenic addiction loops.14,15
The concept of oncogene addiction describes the selective dependence of cancer cell proliferation to certain
molecular aberrations. Tumoural cells become dependent on and/or addicted to a specific molecular alteration
responsible for its own controlled proliferation.16 Many
of these loops have been therapeutically exploited and
some have substantially improved patient survival. 14
Examples include BRAF-mutated metastatic melanoma
and response to vemurafenib,17 or ALK rearrangements
in lung cancer and response to crizotinib.18 Strikingly,
ALK oncogenic addiction in lung tumours was discovered after a fairly short timeframe: 3 years passed
between the identification of ALK rearrangement 19 and
publication of the phase II trial.18 Unfortunately, not a
single oncogenic addiction loop has thus far been identified in HCC.15 However, several efforts aimed at improving patient selection for novel therapies in HCC, such as
deep sequencing and genomic profiling,20 are ongoing
and could elucidate oncogenic addiction loops in the
setting of HCC.
NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY
© 2013 Macmillan Publishers Limited. All rights reserved
VOLUME 10 | JANUARY 2013 | 35

3. REVIEWS
HCC
Stage 0
PST 0, Child–Pugh A
Stage A–C
PST 0–2, Child–Pugh A–B
Very early stage (0)
Single 2 cm
Carcinoma in situ
Early stage (A)
Single or 3 nodules ≤3 cm
PST 0
Single
Stage D
PST 2, Child–Pugh C
Intermediate stage (B)
Multinodular
PST 0
Advanced stage (C)
Portal invasion
N1, M1, PST 1–2
Terminal stage (D)
TACE
Sorafenib
Best supportive care
Target: 20%
OS: 20 months
(SD 14–45)
Target: 40%
OS: 11 months
(SD 6–14)
Target: 10%
OS: 3 months
3 nodules ≤3 cm
Portal pressure
and/or bilirubin
Increased
Normal
Resection
Associated diseases
No
Liver transplantation
(DDLT/LDLT)
Yes
RF/PEI
Curative treatment (30–40%)
Median OS 60 months; 5-year survival: 40–70%
Figure 1 | BCLC staging system and therapeutic strategy according to EASL–EORTC guidelines. Staging classification
comprises five stages that select the best candidates for the best therapies currently available. Patients with asymptomatic
early tumours (stage 0–A) are candidates for radical therapies (resection, transplantation or local ablation). Asymptomatic
patients with multinodular HCC (stage B) are suitable for chemoembolization (TACE), whereas patients with advanced
symptomatic tumours and/or an invasive tumoural pattern (stage C) are candidates to receive sorafenib. End-stage disease
(stage D) includes patients with grim prognosis that should be treated by best supportive care. Abbreviations: BCLC,
Barcelona Clinic Liver Cancer; DDLT, deceased donor liver transplantation; EASL, European Association for the Study of Liver
Disease; EORTC, European Organisation for Research and Treatment of Cancer; GRADE, grading of recommendations
assessment, development and evaluation; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; PEI,
percutaneous ethanol injection; RF, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; OS, overall
survival; PST, performance status. Permission obtained from Elsevier © European Association for the Study of the Liver;
European Organisation for Research and Treatment of Cancer. J. Hepatol. 56, 908–943 (2012).
Evidence-based management of HCC
Chemoprevention
Identification of patients at risk of HCC development
has become a public health priority. Assuming that
close to 1% of the global population has cirrhosis21 and
one-third of patients develop HCC in their lifespan,5
the expected number of lives saved following successful prevention of HCC is substantial. Cirrhosis of any
aetiology is, by itself, a risk factor for the development
of HCC.22 In terms of primary prevention, studies from
Taiwan clearly demonstrated that prevention of HBVrelated liver disease with universal vaccination is highly
effective at diminishing HCC rates. 23 Consequently,
since 1991, the WHO has recommended vaccination
of all newborn babies and high-risk individuals.24 In
the setting of chronic hepatitis B or C, the main risk
factors for the development of HCC are the presence
of advanced hepatic fibrosis or cirrhosis, and high viral
load.25 In fact, current guidelines recommend antiviral
treatment to suppress virus replication and prevent the
progression of fibrosis.26 Few randomized controlled
trials (RCTs) are available that evaluate the role of HBV
treatment for HCC prevention as a primary end point.
The only two RCTs designed to measure the importance
36 | JANUARY 2013 | VOLUME 10
of treatment on HCC development showed that both
interferon27 and lamivudine28 are effective in increasing
HBV clearance, decreasing cirrhosis progression and
subsequently reducing HCC risk. Studies with PEGIFN‑α are limited and restricted to the demonstration of
improvement of surrogate markers (for example, viral
DNA suppression, hepatitis B e antigen sero­ onversion
c
and hepatitis B surface antigen loss),29 although the clinical benefits are expected to be at least similar to those
with conventional IFN‑α. Regarding chronic HCV
infection, achievement of sustained virologic response
has been shown to decrease the risk of HCC in patients
with chronic hepatitis C.30 However, once cirrhosis is
established, the benefit of antiviral treatment for HCV
infection in terms of HCC prevention remains unclear.31
Moreover, maintenance treatment in nonresponders with
IFN‑α was neither beneficial for fibrosis progression nor
for HCC development.32
As previously mentioned, the vast majority of HCC
occurs in cirrhotic livers and increasing evidence suggests
that fibrosis per se confers carcinogenic risk.33 Molecular
data also point towards a major pathogenic role for diseased liver microenvironment (‘field effect’) in HCC
development.34 Hence, reversal of fibrosis regardless
www.nature.com/nrgastro
© 2013 Macmillan Publishers Limited. All rights reserved

4. REVIEWS
Treatment
Stage-oriented HCC management based on the BCLC
algorithm (Figure 1) classifies medical interventions
as potentially curative (for example, surgical resection,
liver transplantation or percutaneous ablation) or palliative (for example, TACE and sorafenib).5 Treatment
allocation is based on levels of evidence as defined by
the National Cancer Institute, which rely on strengths of
study design and end points. Herein, we summarized the
different therapeutic interventions for HCC according to
these evidence-based parameters (Figure 2).
Surgical treatments
Surgical resection and liver transplantation are
first-line options for patients with early stage HCC
(BCLC)0–A), as they confer 5‑year survival rates of
70%.39 Improvements in surgical approaches and refined
selection of candidates for surgery (single nodule without
liver dysfunction of portal hypertension40) have contributed to increased patient survival, minimization of complications and reduced recurrence.41 Overall, recurrence
after resection reaches 70% at 5 years, either because of
true metastases or de novo HCC,42 and no adjuvant therapies able to reduce recurrence are currently approved.
Local ablation has been suggested as a competitive
alternative to resection in patients with a single tumour
2 cm.43 As no RCT has been designed ad hoc to address
this issue, the role of local ablation as a first-line option in
this setting remains controversial. Patients within Milan
criteria (that is, single tumour 5 cm or three nodules
3 cm), without vascular invasion (BCLC A) should be
evaluated for liver transplantation.5 These criteria have
Sorafenib
1
Levels of evidence
of primary aetiology could theoretically prevent HCC
development. However, studies targeting fibrosis as a
chemopreventive strategy are scarce. Only two large,
prospective, placebo-controlled studies have tested antifibrotic agents and showed no effects on fibrosis after
1 year of therapy.35,36 Overall, besides primary prevention efforts aimed at avoiding known environmental
risks for liver disease (including, HBV vaccination and
withdrawal of alcohol intake), or antiviral therapy to suppress viral load in chronic hepatitis, no clear measures
to decrease HCC incidence in patients with cirrhosis
are available. In addition, little is known about the predictors that confer higher risk among individuals with
cirrhosis, which justifies the recommendation of surveillance with abdominal ultrasonography every 6 months
in all patients with cirrhosis.5 Preliminary evidence at
the molecular level in experimental studies has identified different signalling pathways as potential targets for
chemoprevention (for example, EGFR and PDGFR37,38).
However, there are two major drawbacks to developing
effective drugs in the chemoprevention setting: first,
the expected long duration of these trials requires the
inclusion of enrichment strategies to increase feasibility by selecting those patients at very high risk of HCC
development; second, a pressing need exists to identify
accurate and non­ nvasive biomarkers for diagnosis and
i
monitoring of fibrosis progression.
Chemoembolization
Adjuvant therapy after resection RF (5 cm), RF and/or PEI (2 cm)
Resection
LDLT
Internal radiation
OLT-extended
Neoadjuvant therapy in waiting list
2
OLT-Milan
Downstaging
3
External and/or palliative radiotherapy
C
B
A
C
2 (weak)
B
A
1 (strong)
Grade of recommendation
Figure 2 | Therapeutic interventions in HCC according to level of evidence and
grade of recommendation. Level of evidence (based on NCI classification and
grade of recommendation based on GRADE criteria. Abbreviations: GRADE, grading
of recommendations assessment, development and evaluation; HCC,
hepatocellular carcinoma; LDLT, living donor liver transplantation; OLT, orthotopic
liver transplantation; NCI, National Cancer Institute; PEI, percutaneous ethanol
injection; RF, radiofrequency ablation. Permission obtained from Elsevier ©
European Association for the Study of the Liver; European Organisation for
Research and Treatment of Cancer. J. Hepatol. 56, 908–943 (2012).
been independently validated by several groups and
are widely adopted in transplant centres in Europe and
the USA.39 Despite their utility, Milan criteria might
be too restrictive and preliminary evidence indicates
that some patients with tumours exceeding Milan criteria are potentially curable by liver transplantation.44,45
Studies using clinical or pathological variables to expand
Milan criteria have a number of methodological limitations, such as small sample size46 and their retrospective
nature,47 which prevents providing any recommendation
owing to lack of robust data. A retrospective study suggested that microvascular invasion was a limiting factor
to discriminate good and poor outcome among patients
with HCC who underwent liver transplantation within
and beyond Milan criteria (under the so-called up-toseven rule).45 These data emphasize the need to unravel
molecular readouts of tumour biology to enable proper
decision-making.48
Locoregional therapies
Local ablation is the standard of care for patients with
early stage tumours who are not suitable for surgery;
survival rates are 50–70% at 5 years with this approach.5
Radiofrequency is the first option, and percutaneous
ethanol injection is only reserved as a complementary
treatment in cases of difficult tumour location.5 Patients
with multinodular disease, preserved liver function,
without tumour-related symptoms and absence of
vascular invasion or extrahepatic spread (BCLC B,
intermediate stage) are candidates for TACE, with the
goal of delaying tumour progression and extension of
patient survival.5,6 Evidence to support this recommendation comes from a meta-analysis of pooled data.11
Improvements in embolization devices (for example,
drug-eluting beads) provide median survival rates
NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY
© 2013 Macmillan Publishers Limited. All rights reserved
VOLUME 10 | JANUARY 2013 | 37

5. REVIEWS
Table 1 | Milestones in HCC research reported during the past 30 years*
Citations
Reference
Title
Thematic area
Direct influence
on CPG
Citations
per year
Molecular pathogenesis
1,640
Knowles et al. (1980)83
Human HCC cell lines secrete the major plasma proteins and
hepatitis B surface antigen
Basic science
No
49
1,285
Hsu et al. (1991)84
Mutational hotspot in the p53 gene in human HCCs
Basic science
No
56
1,085
Bressac et al. (1991)85
Selective G‑mutation to T‑mutation of p53 gene in HCC from
Southern Africa
Basic science
No
48
788
Kim et al. (1991)86
HBx gene of HBV induces liver cancer in transgenic mice
Basic science
No
34
736
Moriya et al. (1998)87
The core protein of HCV induces HCC in transgenic mice
Basic science
No
46
Epidemiology and natural history
1,867
Beasley et al. (1981)88
HCC and HBV: a prospective study of 22,707 men in Taiwan
Epidemiology
No
57
1,661
El-Serag et al. (1999)89
Rising incidence of HCC in the US
Epidemiology
No
116
1,215
Okuda et al. (1985)
Natural history of HCC and prognosis in relation to treatment:
study of 850 patients
Prognosis
No
42
978
Kiyosawa et al. (1990)91
Interrelationship of blood transfusion, non‑A, non‑B hepatitis and
HCC: analysis by detection of antibody to HCV
Epidemiology
No
42
943
Saito et al. (1990)92
HCV infection is associated with the development of HCC
Epidemiology
No
40
881
Chang et al. (1997)23
Universal HBV vaccination in Taiwan and the incidence of HCC in
children
Chemoprevention
Yes
54
899
Chen et al. (2006)25
Risk of HCC across a biological gradient of serum HBV DNA level
Epidemiology
No
118
720
Tsukuma et al. (1993)93
Risk factors for HCC among patients with chronic liver disease
Epidemiology
No
35
683
Nishiguchi et al. (1995)
Randomized trial of effects of IFN-α on incidence of HCC in
chronic active hepatitis C with cirrhosis
Chemoprevention
No
37
668
Bruix et al. (1989)95
Prevalence of antibodies to HCV in Spanish patients with HCC
and hepatic cirrhosis
Epidemiology
No
28
2,331
Mazzaferro et al. (1996)12
Liver transplantation for the treatment of small HCC in patients
with cirrhosis
Surgery
Yes
129
1,777
Llovet et al. (2008)7
Sorafenib in advanced HCC
Systemic therapy
Yes
325
984
Llovet et al. (2002)
Arterial embolization or chemoembolization vs symptomatic
treatment in patients with unresectable HCC: a randomized
controlled trial
Locoregional
Yes
84
831
Llovet et al. (2003)11
Systematic review of randomized trials for unresectable HCC:
chemoembolization improves survival
Locoregional
Yes
78
791
Livraghi et al. (1999)97
Small HCC: treatment with radiofrequency ablation vs ethanol
injection
Locoregional
Yes
56
791
Lo et al. (2002)98
Randomized controlled trial of transarterial lipiodol
chemoembolization for unresectable HCC
Locoregional
Yes
59
722
Llovet et al. (1999)99
Intention-to-treat analysis of surgical treatment for early HCC:
resection vs transplantation
Surgery
Yes
50
730
Curley et al. (1999)100
Radiofrequency ablation of unresectable primary and metastatic
hepatic malignancies: results in 123 patients
Locoregional
No
49
663
Livraghi et al. (1995)101
HCC and cirrhosis in 146 patients: long-term results of
percutaneous ethanol injection
Locoregional
Yes
36
90
94
Treatment
96
Data accessed on Web of Science®(Thomson Reuters, New York, USA), using the search terms “hepatocellular carcinoma” or “liver cancer” on 20 September 2012. *Sorted by number of
citations. Abbreviations: CPG, clinical practice guidelines; HCC, hepatocellular carcinoma.
beyond 30–40 months, at least in referral centres. 49
Findings from a Cochrane Review have challenged the
role of TACE as the standard of care for patients with
intermediate stage HCC,50 but the inclusion of studies
using inadequate control arms and suboptimal patient
selection might bias this conclusion.51 Regarding other
embolization approaches (such as radioembolization
with microspheres loaded with yttrium‑90), data suggest
38 | JANUARY 2013 | VOLUME 10
it has a favourable safety profile,52 but only well-designed,
properly powered RCTs will determine the therapeutic
niche, if any, of this intervention.
Systemic therapies
Until 2007, and despite substantial efforts, no single
systemic agent had shown survival benefits in patients
with HCC. This finding can be partially explained by
www.nature.com/nrgastro
© 2013 Macmillan Publishers Limited. All rights reserved

6. REVIEWS
the frequent coexistence of HCC and cirrhosis, its high
molecular heterogeneity and a relative resistance to
conventional chemotherapy.53 The SHARP trial demonstrated that sorafenib, a tyrosine kinase inhibitor with
a broad inhibitory profile (for example, BRAF, PDGFR
and VEGFR), was able to substantially increase survival
in patients with advanced HCC (stage C of the BCLC
classification: patients with well-preserved liver function and extrahepatic spread or vascular invasion) from
7.9 months to 10.7 months (HR 0.69).5,6 The effects of
sorafenib in delaying tumour progression and improving
survival were further validated in Asian HBV-infected
patients.54 Adverse events such as diarrhoea or hand–foot
skin reaction associated with sorafenib were manageable.
On the basis of these data, sorafenib (400 mg, twice daily)
is the standard of care for patients at advanced stages of
HCC, and it should be maintained at least until radiological progression with periodic monitoring of adverse
effects (mostly cardiovascular, diarrhoea and skin reactions).15 Thus far, no strong biomarkers are available to
accurately predict a patient’s response to sorafenib.50
Numerous targeted therapies are currently under evaluation in different developmental phases for the systemic
treatment of HCC, both as first and second-line therapies
(thoroughly reviewed elsewhere15). Regarding potential
registration trials, initial results have been negative:
the sunitinib trial was prematurely halted because of
adverse events and futility in the sunitinib arm as a firstline therapy. Brivanib showed an antitumoural effect
that did not markedly improve survival compared with
placebo in second-line therapies,55 and the phase III trial
testing the multikinase inhibitor linifanib has therefore
been halted.56 Furthermore, the combination of sorafenib
and EGFR inhibitors (erlotinib) failed in comparison to
sorafenib alone as a first-line therapy.57 The remaining
ongoing phase III trials are testing monoclonal anti­
bodies against VEGFR2 (ramucirumab) and mTOR
(mammalian target of rapamycin) inhibitor (everolimus).
In addition, 250 early phase clinical trials of HCC therapies are ongoing, testing 56 molecular therapies.15 If more
trial results are negative, alternative approaches will be
needed to improve on the results already achieved with
sorafenib. Potential alternatives are, first, the identification of drugs that can be safely used in combination with
sorafenib. Second, the discovery of oncogene addiction
loops that restrict survival benefits in a subpopulation of
patients with HCC (for example, MET-positive patients),
and third, to develop drugs targeting novel signalling
cascades (for example, WNT–β-catenin and Notch) or
molecular mechanisms (for example, epigenetic aberrations). In any case, it will be necessary to implement
changes to the current paradigm of trial design (Box 1).
Progressively, enrolment criteria should include mol­
ecular information of the mechanisms responsible for
tumour progression in each patient, following previous
examples in other solid tumours.58
Adjuvant therapies as a first unmet need
Tumour recurrence is a major complication after
resection, occurring in 70% of patients at 5 years after
Box 1 | Main issues for phase II/III trial design in patients with HCC102,103
To select the target population
■■ BCLC stage: include patients at specific BCLC stage (A–C)
■■ Child–Pugh classification: include Child–Pugh A
To choose the appropriate end points
■■ Overall survival (main end point in cancer research)
■■ Time to progression*
■■ Objective response rate*
To decide the adequate control arm
■■ TACE for intermediate stage
■■ Sorafenib for advanced stage (first-line therapy)
■■ Placebo plus best supportive care for advanced stages (second-line therapy)
To stratify factors before randomization
■■ ECOG performance status
■■ Tumour burden (extrahepatic spread and/or vascular invasion)
■■ AFP levels 200 ng/ml
*Time to progression and overall response rate should be assessed according to modified
RECIST criteria. Abbreviations: AFP α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; ECOG,
,
Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; OS, overall survival;
RECIST, response evaluation criteria in solid tumours; TACE, transarterial chemoembolization.
surgery. 39 Unlike most malignancies, two clear patterns of recurrence exist in HCC. Early recurrences
(2 years) are related to early dissemination of the
primary tumour (that is, true metastasis) whereas late
recurrences (2 years) are a result of the carcinogenic
cirrhotic milieu present in the remaining liver that promotes the progression of new malignant clones (that is,
de novo tumours).42,59 Feasibly, each type might have a
different molecular background and therefore would
require different therapeutic approaches for its prevention.60 Unfortunately, despite the fact that several RCTs
have been conducted to evaluate adjuvant therapy, no
agent has shown robust efficacy in preventing or delaying
tumour recurrence.5
The role of IFN‑α as adjuvant therapy after resection
has been frequently evaluated in different studies, including RCTs.61,62 One of the largest trials analysed the use of
IFN‑α in 150 patients with HCC, finding a negative trend
for the primary end point (recurrence-free survival), but
a positive trend in terms of prevention of late recurrence
of HCC in the patients tested.63 Additionally, different
meta-analyses have tried to provide a more comprehensive answer for the role of IFN‑α in preventing HCC
recurrence.64–66 Owing to conflicting data and issues
related to study design (such as trial selection for metaanalysis and mixing end points), IFN‑α is currently not
recommended as an adjuvant therapy after resection.5
In HBV-related HCC, a systematic review including 230
patients with HCC treated with ablation or resection
found no evidence to support the use lamivudine with
or without adefovir as adjuvant therapy.67
Besides IFN‑α, other agents such as vitamin analogues
have been evaluated in the adjuvant setting. Vitamin K
was believed to have a beneficial effect in prolonging disease-free survival on the basis of findings from
small studies.68–70 However, when tested in a large RCT
including 500 patients, vitamin K was unable to prevent
either HCC recurrence or death.71 Vitamin A analogues
also have controversial results. Although the acyclic
NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY
© 2013 Macmillan Publishers Limited. All rights reserved
VOLUME 10 | JANUARY 2013 | 39

7. REVIEWS
retinoid prevented the development of secondary HCC
after resection and improved survival in one RCT, 72
this result was not validated in an, as yet unpublished,
large, multicentre RCT.73 Regarding adoptive immunotherapy with IL‑2-activated lymphocytes, despite initial
encouraging results,74 this strategy has not been subsequently validated and it is not recommended in HCC
clinical management.5 Also, no survival benefits have
been established with other immunotherapy regimens
including cytokine-induced killer cells.75 Currently, two
large phase III RCTs are ongoing that are evaluating the
role of sorafenib and rapamycin in preventing tumour
recurrence after resection and/or ablation (STORM
trial)76 and after liver transplantation (SiLVER trial)77 in
patients with HCC.
One of the main limitations of liver transplantation
for HCC is donor shortage, which causes longer waiting
times and increases drop-out rates as a result of tumour
progression whilst waiting for a graft. Therefore, transplant groups are applying locoregional therapies upon
listing to prevent drop out. 78 Evidence behind this
approach comes from uncontrolled studies and cost–
benefit analysis,78 showing that when expected waiting
time exceeds 6 months it is cost-effective to offer the
patient neoadjuvant therapies. This approach has been
incorporated in a consensus document on HCC and
liver transplantation that recommends locoregional
therapies in patients with HCC within Milan criteria or
United Network for Organ Sharing stage T2 (one nodule
2–5 cm or ≤3 nodules each ≤3 cm), with an expected
waiting time longer than 6 months.5,79 Medical therapies,
including sorafenib, have not been able to demonstrate a
beneficial effect in this particular setting.
Towards molecular medicine in HCC
The future paradigm for treating patients with HCC
includes customization of medical interventions on
the basis of molecular alterations that govern tumour
develop­ ent and progression on an individual basis.
m
In this regard, the most straightforward approach is to
identify and validate oncogenic addiction loops, following the path opened in other solid tumours (for example,
mutated BRAF melanoma, ALK rearrangements in lung
cancer, and so on). Deep analysis of the HCC genome
(such as exome and RNA sequencing) could provide new
candidates. Several failures of systemic treatment in firstline therapy (brivanib versus placebo,80 sorafenib plus
erlotinib versus sorafenib,81 sorafenib versus linifanib56
and sorafenib versus sunitinib)82 and second-line therapy
1.
2.
3.
4.
Altekruse, S. F., McGlynn, K. A.
Reichman, M. E. Hepatocellular carcinoma
incidence, mortality, and survival trends in the
United States from 1975 to 2005. J. Clin. Oncol.
27, 1485–1491 (2009).
Jemal, A. et al. Cancer statistics, 2009. CA
Cancer J. Clin. 59, 225–249 (2009).
El-Serag, H. B. Hepatocellular carcinoma.
N. Engl. J. Med. 365, 1118–1127 (2011).
Llovet, J. M., Bru, C. Bruix, J. Prognosis of
hepatocellular carcinoma: the BCLC staging
40 | JANUARY 2013 | VOLUME 10
5.
6.
(brivanib versus placebo)55 alert us to several concerns:
the heterogeneity of the disease; toxicity of multikinase
inhibitors in patients with cirrhosis; complexity of the
disease; and the need for a more stratified approach by
using reliable biomarkers and drugs for specific mol­
ecular aberrations. Targeting oncogenic addiction loops
is expected to add survival benefits to the existing HCC
therapy that currently relies on sorafenib.
Besides trial enrichment, combination therapies can
also improve the current standard of care. The wide
inhibitory profile of sorafenib, in addition to an anti­
angiogenic effect and good safety profile confirms this
drug as the benchmark for systemic management of
HCC. The bottleneck of the combination approach will
be drug toxicity. The trade-off between efficacy and
adverse effects is pivotal in this scenario, as patients with
cirrhosis are clearly more susceptible to adverse effects
of drugs than patients without cirrhosis. When considering changing the standard of care for HCC management,
any intervention should be evaluated in the context of
well-designed, properly powered, high-level RCTs—only
these types of studies can currently change accepted
treatment recommendations in guidelines.
Conclusions
The management of HCC has changed substantially
in the past few decades, and five treatment options are
accepted in clinical guidelines. Decision-making relies
on evidence-based criteria; however, despite the recent
advance in the understanding of HCC patho­ hysiology
p
and development of new therapies, several clinical areas
lack strong recommendations. The approval of sorafenib
changed the understanding of HCC and brought in a
new era in the management of liver cancer, led by the
effort in understanding the molecular regulation and the
identification of new molecular targets. Efforts on the
implementation of personalized medicine will probably
dominate research in the next decade.
Review criteria
A search for original articles focusing on hepatocellular
carcinoma was performed in MEDLINE and PubMed. The
search terms used were “hepatocellular carcinoma”,
“liver cancer”, “treatment”, “management”, “medical
therapies”, “randomized” and “systemic review”, alone
and in combination. All articles identified were Englishlanguage, full-text papers. We also searched the reference
lists of identified articles for further relevant papers.
classification. Semin. Liver Dis. 19, 329–338
(1999).
European Association for the Study of the Liver;
European Organisation for Research and
Treatment of Cancer. EASL–EORTC clinical
practice guidelines: management of
hepatocellular carcinoma. J. Hepatol. 56,
908–943 (2012).
Bruix, J. Sherman, M. Management of
hepatocellular carcinoma: an update.
Hepatology 53, 1020–1022 (2011).
7.
Llovet, J. M. et al. Sorafenib in advanced
hepatocellular carcinoma. N. Engl. J. Med. 359,
378–390 (2008).
8. Forner, A., Llovet, J. M. Bruix, J. Hepatocellular
carcinoma. Lancet 379, 1245–1255 (2012).
9. Ascha, M. S. et al. The incidence and risk factors
of hepatocellular carcinoma in patients with
nonalcoholic steatohepatitis. Hepatology 51,
1972–1978 (2010).
10. Cheng, A. et al. Phase III trial of sunitinib versus
sorafenib in advanced hepatocellular carcinoma
www.nature.com/nrgastro
© 2013 Macmillan Publishers Limited. All rights reserved

8. REVIEWS
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
[abstract 4000]. J. Clin. Oncol. 29 (Suppl.), 4000
(2011).
Llovet, J. M. Bruix, J. Systematic review of
randomized trials for unresectable hepatocellular
carcinoma: chemoembolization improves
survival. Hepatology 37, 429–442 (2003).
Mazzaferro, V. et al. Liver transplantation for the
treatment of small hepatocellular carcinomas in
patients with cirrhosis. N. Engl. J. Med. 334,
693–699 (1996).
Hsu, I. C. et al. Mutational hotspot in the p53
gene in human hepatocellular carcinomas.
Nature 350, 427–428 (1991).
Dancey, J. E., Bedard, P
. L., Onetto, N.
Hudson, T. J. The genetic basis for cancer
treatment decisions. Cell 148, 409–420 (2012).
Villanueva, A. Llovet, J. M. Targeted therapies
for hepatocellular carcinoma. Gastroenterology
140, 1410–1426 (2011).
Weinstein, I. B. Cancer. Addiction to
oncogenes—the Achilles heal of cancer. Science
297, 63–64 (2002).
Chapman, P et al. Improved survival with
. B.
vemurafenib in melanoma with BRAF V600E
mutation. N. Engl. J. Med. 364, 2507–2516
(2011).
Kwak, E. L. et al. Anaplastic lymphoma kinase
inhibition in non‑small‑cell lung cancer. N. Engl. J.
Med. 363, 1693–1703 (2010).
Soda, M. et al. Identification of the transforming
EML4-ALK fusion gene in non‑small‑cell lung
cancer. Nature 448, 561–566 (2007).
Zender, L. et al. Cancer gene discovery in
hepatocellular carcinoma. J. Hepatol. 52,
921–929 (2010).
Schuppan, D. Afdhal, N. H. Liver cirrhosis.
Lancet 371, 838–851 (2008).
Ioannou, G. N. et al. Incidence and predictors of
hepatocellular carcinoma in patients with
cirrhosis. Clin. Gastroenterol. Hepatol. 5,
938–945 (2007).
Chang, M. H. et al. Universal hepatitis B
vaccination in Taiwan and the incidence of
hepatocellular carcinoma in children. Taiwan
Childhood Hepatoma Study Group. N. Engl. J.
Med. 336, 1855–1859 (1997).
[No authors listed] Expanded programme on
immunization. Global Advisory Group—Part II.
Wkly Epidemiol. Rec. 67, 17–19 (1992).
Chen, C. J. et al. Risk of hepatocellular
carcinoma across a biological gradient of serum
hepatitis B virus DNA level. JAMA 295, 65–73
(2006).
Lok, A. S. McMahon, B. J. Chronic hepatitis B:
update 2009. Hepatology 50, 661–662 (2009).
Lin, S. M., Sheen, I. S., Chien, R. N., Chu, C. M.
Liaw, Y. F. Long-term beneficial effect of
interferon therapy in patients with chronic
hepatitis B virus infection. Hepatology 29,
971–975 (1999).
Liaw, Y. F. et al. Lamivudine for patients with
chronic hepatitis B and advanced liver disease.
N. Engl. J. Med. 351, 1521–1531 (2004).
Marcellin, P et al. Peginterferon α-2a alone,
.
lamivudine alone, and the two in combination in
patients with HBeAg-negative chronic
hepatitis B. N. Engl. J. Med. 351, 1206–1217
(2004).
Singal, A. G., Volk, M. L., Jensen, D.,
Di Bisceglie, A. M. Schoenfeld, P
. S.
A sustained viral response is associated with
reduced liver-related morbidity and mortality in
patients with hepatitis C virus. Clin.
Gastroenterol. Hepatol. 8, 280–288 (2010).
Di Bisceglie, A. M. et al. Excess mortality in
patients with advanced chronic hepatitis C
treated with long-term peginterferon. Hepatology
53, 1100–1108 (2011).
32. Bruix, J. et al. Maintenance therapy with
peginterferon α-2b does not prevent
hepatocellular carcinoma in cirrhotic patients
with chronic hepatitis C. Gastroenterology 140,
1990–1999 (2011).
33. Zhang, D. Y. Friedman, S. L. Fibrosis-dependent
mechanisms of hepatocarcinogenesis.
Hepatology 56, 769–775 (2012).
34. Hoshida, Y. et al. Gene expression in fixed
tissues and outcome in hepatocellular
carcinoma. N. Engl. J. Med. 359, 1995–2004
(2008).
35. Pockros, P et al. Final results of a double-blind,
. J.
placebo-controlled trial of the antifibrotic efficacy
of interferon-γ1b in chronic hepatitis C patients
with advanced fibrosis or cirrhosis. Hepatology
45, 569–578 (2007).
36. McHutchison, J. et al. Farglitazar lacks antifibrotic
activity in patients with chronic hepatitis C
infection. Gastroenterology 138, 1365–1373
(2010).
37. Tanabe, K. K. et al. Epidermal growth factor gene
functional polymorphism and the risk of
hepatocellular carcinoma in patients with
cirrhosis. JAMA 299, 53–60 (2008).
38. Mejias, M. et al. Beneficial effects of sorafenib
on splanchnic, intrahepatic, and portocollateral
circulations in portal hypertensive and cirrhotic
rats. Hepatology 49, 1245–1256 (2009).
39. Llovet, J. M., Schwartz, M. Mazzaferro, V.
Resection and liver transplantation for
hepatocellular carcinoma. Semin. Liver Dis. 25,
181–200 (2005).
40. Bruix, J. et al. Surgical resection of hepatocellular
carcinoma in cirrhotic patients: prognostic value
of preoperative portal pressure. Gastroenterology
111, 1018–1022 (1996).
41. Ishizawa, T. et al. Neither multiple tumors nor
portal hypertension are surgical
contraindications for hepatocellular carcinoma.
Gastroenterology 134, 1908–1916 (2008).
42. Imamura, H. et al. Risk factors contributing to
early and late phase intrahepatic recurrence of
hepatocellular carcinoma after hepatectomy.
J. Hepatol. 38, 200–207 (2003).
43. Livraghi, T. et al. Sustained complete response
and complications rates after radiofrequency
ablation of very early hepatocellular carcinoma in
cirrhosis: Is resection still the treatment of
choice? Hepatology 47, 82–89 (2008).
44. Roayaie, S. et al. Long-term results with
multimodal adjuvant therapy and liver
transplantation for the treatment of
hepatocellular carcinomas larger than 5
centimeters. Ann. Surg. 235, 533–539 (2002).
45. Mazzaferro, V. et al. Predicting survival after liver
transplantation in patients with hepatocellular
carcinoma beyond the Milan criteria:
a retrospective, exploratory analysis. Lancet
Oncol. 10, 35–43 (2009).
46. Yao, F. Y. et al. Liver transplantation for
hepatocellular carcinoma: expansion of the
tumor size limits does not adversely impact
survival. Hepatology 33, 1394–1403 (2001).
47. Forner, A. Bruix, J. To expand or not to expand
the criteria for hepatocellular carcinoma
transplantation: is downstaging the answer?
Gastroenterology 137, 375–376 (2009).
48. Llovet, J. M., Paradis, V., Kudo, M. ZucmanRossi, J. Tissue biomarkers as predictors of
outcome and selection of transplant candidates
with hepatocellular carcinoma. Liver Transpl.
17 (Suppl. 2), S67–S71 (2011).
49. Burrel, M. et al. Survival of patients with
hepatocellular carcinoma treated by transarterial
chemoembolisation (TACE) using Drug Eluting
Beads. Implications for clinical practice and trial
design. J. Hepatol. 56, 1330–1335 (2012).
NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY
© 2013 Macmillan Publishers Limited. All rights reserved
50. Oliveri, R. S., Wetterslev, J. Gluud, C.
Transarterial (chemo)embolisation for
unresectable hepatocellular carcinoma.
Cochrane Database Syst. Rev. Issue 1, Art. No.:
CD004787. http://dx.doi.org/10.1002/
14651858.
51. Forner, A., Llovet, J. M. Bruix, J.
Chemoembolization for intermediate HCC:
is there proof of survival benefit? J. Hepatol. 56,
984–986 (2012).
52. Salem, R. et al. Radioembolization results in
longer time‑to‑progression and reduced toxicity
compared with chemoembolization in patients
with hepatocellular carcinoma. Gastroenterology
140, 497–507 e492 (2011).
53. Yeo, W. et al. A randomized phase III study of
doxorubicin versus cisplatin/interferon
alpha-2b/doxorubicin/fluorouracil (PIAF)
combination chemotherapy for unresectable
hepatocellular carcinoma. J. Natl Cancer Inst. 97,
1532–1538 (2005).
54. Cheng, A. L. et al. Efficacy and safety of
sorafenib in patients in the Asia-Pacific region
with advanced hepatocellular carcinoma:
a phase III randomised, double-blind, placebocontrolled trial. Lancet Oncol. 10, 25–34 (2009).
55. Llovet, J. M. et al. Brivanib versus placebo in
patients with advanced hepatocellular
carcinoma who failed or were intolerant to
sorafenib: results from the phase 3 BRISK-PS
study. J. Hepatol. 56, S549 (2012).
56. US National Library of Medicine. Clinicaltrials.gov
[online], http://clinicaltrials.gov/show/
NCT01009593 (2012).
57. Bayer Investor Relations. Phase III trial
evaluating the addition of tarceva®(erlotinib) to
nexavar®(sorafenib) did not provide additional
benefit to patients with liver cancer versus
nexavar alone. Bayer [online], http://www.
investor.bayer.de/user_upload/4112 (2012).
58. Kim, E. S. et al. The BATTLE trial: personalizing
therapy for lung cancer. Cancer Discov. 1, 44–53
(2011).
59. Hoshida, Y. et al. Molecular classification and
novel targets in hepatocellular carcinoma:
recent advancements. Semin. Liver Dis. 30,
35–51 (2010).
60. Villanueva, A. et al. Combining clinical, pathology,
and gene expression data to predict recurrence
of hepatocellular carcinoma. Gastroenterology
140, 1501–1512 e1502 (2011).
61. Breitenstein, S. et al. Systematic review and
meta-analysis of interferon after curative
treatment of hepatocellular carcinoma in
patients with viral hepatitis. Br. J. Surg. 96,
975–981 (2009).
62. Miao, R. Y. et al. Postoperative adjuvant antiviral
therapy for hepatitis B/C virus-related
hepatocellular carcinoma: a meta-analysis.
World J. Gastroenterol 16, 2931–2942 (2010).
63. Mazzaferro, V. et al. Prevention of hepatocellular
carcinoma recurrence with α-interferon after liver
resection in HCV cirrhosis. Hepatology 44,
1543–1554 (2006).
64. Miyake, Y., Takaki, A., Iwasaki, Y. Yamamoto, K.
Meta-analysis: interferon-alpha prevents the
recurrence after curative treatment of hepatitis C
virus-related hepatocellular carcinoma. J. Viral
Hepat. 17, 287–292 (2010).
65. Singal, A. K., Freeman, D. H. Jr Anand, B. S.
Meta-analysis: interferon improves outcomes
following ablation or resection of hepatocellular
carcinoma. Aliment. Pharmacol. Ther. 32,
851–858 (2010).
66. Shen, Y. C. et al. Adjuvant interferon therapy after
curative therapy for hepatocellular carcinoma
(HCC): a meta-regression approach. J. Hepatol.
52, 889–894 (2010).
VOLUME 10 | JANUARY 2013 | 41

9. REVIEWS
67. Zhong, J. H., Li, L. Q. Wu, L. C. Lamivudine with
or without adefovir dipivoxil for postoperative
hepatocellular carcinoma. Cochrane Database
Syst. Rev. Issue 12, Art. No.: CD008713. http://
dx.doi.org/10.1002/14651858.CD008713.
pub2.
68. Hotta, N. et al. Effect of vitamin K2 on the
recurrence in patients with hepatocellular
carcinoma. Hepatogastroenterology 54,
2073–2077 (2007).
69. Mizuta, T. et al. The effect of menatetrenone, a
vitamin K2 analog, on disease recurrence and
survival in patients with hepatocellular
carcinoma after curative treatment: a pilot study.
Cancer 106, 867–872 (2006).
70. Kakizaki, S. et al. Preventive effects of vitamin K
on recurrent disease in patients with
hepatocellular carcinoma arising from hepatitis C
viral infection. J. Gastroenterol. Hepatol. 22,
518–522 (2007).
71. Yoshida, H. et al. Effect of vitamin K2 on the
recurrence of hepatocellular carcinoma.
Hepatology 54, 532–540 (2011).
72. Muto, Y. et al. Prevention of second primary
tumors by an acyclic retinoid, polyprenoic acid, in
patients with hepatocellular carcinoma.
Hepatoma Prevention Study Group. N. Engl. J.
Med. 334, 1561–1567 (1996).
73. Okita, K. et al. Peretinoin reduces recurrence of
hepatocellular carcinoma: Results of a phase II/
III randomized placebo-controlled trial
[abstract 4024]. J. Clin. Oncol. 28 (Suppl.), 15s
(2010).
74. Takayama, T. et al. Early hepatocellular carcinoma
as an entity with a high rate of surgical cure.
Hepatology 28, 1241–1246 (1998).
75. Hui, D., Qiang, L., Jian, W., Ti, Z. Da-Lu, K.
A randomized, controlled trial of postoperative
adjuvant cytokine-induced killer cells
immunotherapy after radical resection of
hepatocellular carcinoma. Dig. Liver Dis. 41,
36–41 (2009).
76. US National Library of Medicine. Clinicaltrials.gov
[online], http://clinicaltrials.gov/show/
NCT00692770 (2012).
77. US National Library of Medicine. Clinicaltrials.gov
[online], http://clinicaltrials.gov/show/
NCT00355862 (2011).
78. Llovet, J. M. et al. Cost effectiveness of adjuvant
therapy for hepatocellular carcinoma during the
waiting list for liver transplantation. Gut 50,
123–128 (2002).
42 | JANUARY 2013 | VOLUME 10
79. Clavien, P et al. Recommendations for liver
. A.
transplantation for hepatocellular carcinoma:
an international consensus conference report.
Lancet Oncol. 13, e11–22 (2012).
80. US National Library of Medicine. Clinicaltrials.gov
[online], http://clinicaltrials.gov/show/
NCT00858871 (2012).
81. US National Library of Medicine. Clinicaltrials.gov
[online], http://clinicaltrials.gov/show/
NCT00901901 (2012).
82. US National Library of Medicine. Clinicaltrials.gov
[online], http://clinicaltrials.gov/show/
NCT00699374 (2012).
83. Knowles, B. B., Howe, C. C. Aden, D. P Human
.
hepatocellular carcinoma cell lines secrete the
major plasma proteins and hepatitis B surface
antigen. Science 209, 497–499 (1980).
84. Hsu, I. C. et al. Mutational hotspot in the p53
gene in human hepatocellular carcinomas.
Nature 350, 427–428 (1991).
85. Bressac, B., Kew, M., Wands, J. Ozturk, M.
Selective G to T mutations of p53 gene in
hepatocellular carcinoma from southern Africa.
Nature 350, 429–431 (1991).
86. Kim, C. M., Koike, K., Saito, I., Miyamura, T.
Jay, G. HBx gene of hepatitis B virus induces
liver cancer in transgenic mice. Nature 351,
317–320 (1991).
87. Moriya, K. et al. The core protein of hepatitis C
virus induces hepatocellular carcinoma in
transgenic mice. Nat. Med. 4, 1065–1067
(1998).
88. Beasley, R. P Hwang, L. Y., Lin, C. C.
.,
Chien, C. S. Hepatocellular carcinoma and
hepatitis B virus. A prospective study of 22,707
men in Taiwan. Lancet 2, 1129–1133 (1981).
89. El-Serag, H. B. Mason, A. C. Rising incidence
of hepatocellular carcinoma in the United
States. N. Engl. J. Med. 340, 745–750 (1999).
90. Okuda, K. et al. Natural history of hepatocellular
carcinoma and prognosis in relation to
treatment. Study of 850 patients. Cancer 56,
918–928 (1985).
91. Kiyosawa, K. et al. Interrelationship of blood
transfusion, non‑A, non‑B hepatitis and
hepatocellular carcinoma: analysis by detection
of antibody to hepatitis C virus. Hepatology 12,
671–675 (1990).
92. Saito, I. et al. Hepatitis C virus infection is
associated with the development of
hepatocellular carcinoma. Proc. Natl Acad. Sci.
USA 87, 6547–6549 (1990).
93. Tsukuma, H. et al. Risk factors for
hepatocellular carcinoma among patients with
chronic liver disease. N. Engl. J. Med. 328,
1797–1801 (1993).
94. Nishiguchi, S. et al. Randomised trial of effects
of interferon-alpha on incidence of
hepatocellular carcinoma in chronic active
hepatitis C with cirrhosis. Lancet 346,
1051–1055 (1995).
95. Bruix, J. et al. Prevalence of antibodies to
hepatitis C virus in Spanish patients with
hepatocellular carcinoma and hepatic
cirrhosis. Lancet 2, 1004–1006 (1989).
96. Llovet, J. M. et al. Arterial emobolisation or
chemoembolisation versus symptomatic
treatment in patients with unresectable
hepatocellular carcinoma: a randomised
controlled trial. Lancet. 359, 1734–1739
(2002).
97. Livraghi, T. et al. Small hepatocellular
carcinoma: treatment with radio-frequency
ablation versus ethanol injection. Radiology
210, 655–661 (1999).
98. Lo, C. M. et al. Randomized controlled trial of
transarterial lipiodol chemoembolization for
unresectable hepatocellular carcinoma.
Hepatology 35, 1164–1171 (2002).
99. Llovet, J. M., Fuster, J. Bruix, J.
Intention‑to‑treat analysis of surgical treatment
for early hepatocellular carcinoma: resection
versus transplantation. Hepatology 30,
1434–1440 (1999).
100. Curley, S. A. et al. Radiofrequency ablation of
unresectable primary and metastatic hepatic
malignancies: results in 123 patients. Ann.
Surg. 230, 1–8 (1999).
101. Livraghi, T. et al. Hepatocellular carcinoma and
cirrhosis in 746 patients: long-term results of
percutaneous ethanol injection. Radiology 197,
101–108 (1995).
102. Llovet, J. M. et al. Design and endpoints of
clinical trials in hepatocellular carcinoma.
J Natl Cancer Inst. 100, 698–711 (2008).
103. Lencioni, R. Llovet, J. M. Modified RECIST
(mRECIST) assessment for hepatocellular
carcinoma. Semin. Liver Dis. 30, 52–60
(2010).
Author contributions
All authors contributed equally to all aspects of this
manuscript.
www.nature.com/nrgastro
© 2013 Macmillan Publishers Limited. All rights reserved