Liver International ISSN 1478-3223

REVIEW ARTICLE

Treatment of hepatocellular carcinoma: beyond international guidelines

Massimo Colombo and Angelo Sangiovanni
Head Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Universit
a degli Studi di Milano,
Via F. Sforza 35, Milan, 20122, Italy

Keywords
BCLCA staging chemoembolization
hepatic resection liver transplantation
local ablation sorafenib
Abbreviations
BCLC, score barcelona clinic liver cancer
score; HCC, hepatocellular carcinoma; HCV,
hepatitis C virus; RFA, radiofrequency
abalation; SOC, standard of care; TACE,
transarterial chemoembolization.
Correspondence
Massimo Colombo, MD
Head Division of Gastroenterology and
Hepatology, Fondazione IRCCS Ca Granda
Ospedale Maggiore Policlinico, Universit

a
degli Studi di Milano, Milano
Via F. Sforza 35, 20122 Milan, Italy
Tel: 39-0255035432
Fax: 39-0250320410
E-mail: massimo.colombo@unimi.it
DOI:10.1111/liv.12713

Abstract
The management of hepatocellular carcinoma (HCC) is decided according to
evidence-based recommendations generated by international societies:
according to these recommendations, the tumour stage, as determined by the
Barcelona clinical liver cancer (BCLC) score, divides patients into five prognostic categories, each with a distinct treatment indication. Radical therapies
such as hepatic resection, orthotopic liver transplantation and percutaneous
local ablation are strongly indicated in patients with very early and early stage
tumours (BCLC O and A), a choice which mainly depends on a combination
of tumour volume, status of underlying liver disease, the presence of comorbidities and the patients age. Although radical therapies provide a survival
rate of between 50% and 75% at year five in well selected patients, tumour
recurrence is frequent following resection and ablation compared to transplantation (70% vs. 10% respectively), which has the additional advantage of
preventing morbidity and mortality from portal hypertension. Generally,
while radical therapies are contraindicated in patients with a large tumour
burden, such as those with intermediate stage BCLC B, survival in the subset
of these patients with well compensated cirrhosis may improve from 16 to
20 months, on average, following repeated treatments with transarterial
chemoembolization (TACE). Survival may also improve in patients who are
in poor condition or who do not respond to TACE and in those with an
advanced HCC (BCLC C) following oral therapy with the multikinase inhibitor sorafenib. However, because most recommendations are based on uncontrolled studies and expert opinions rather than well designed, high powered
randomized controlled trials, treatment criteria need to be adapted to special
groups because real life cohorts do not match the selection criteria suggested
by the guidelines. Indeed, up to one-third of patients with early stage
tumours who are unfit for radical therapy because of advanced age, the presence of significant comorbidities or a strategic location of the nodule, are
forced to receive palliative care. BCLC A patients with moderate portal
hypertension and certain BCLC B patients could still be eligible for hepatic
resection if a chance for 50% survival at 5 years is still perceived as being
cost-effective by both the patient and caregivers.

Key points

The treatment of HCC is guided by appropriate

staging of tumour disease. Because of the heterogeneous epidemiology and clinical presentation of
HCC worldwide, there is no single universally
accepted staging score for guidance.
In the West, the Barcelona Clinic Liver Cancer
(BCLC) score is extensively used, because it is the
most accurate approach for identifying the best can-

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didates for radical (BCLC O & A) and palliative

treatment (BCLC B&C).
In real clinical practice, however, many patients
may not fit the therapeutic algorithms recommended
by international societies, mainly because of the anatomical location of the tumour, advanced age or
severe comorbidities.
As a result, patients may be treated outside the
guidelines, for example, those with an early stage
tumour who receive chemoembolization (TACE)

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Colombo and Sangiovanni

after being deferred from resection/ablation or after

a partial response to initial treatment with radiofrequency.
Although multimodal treatments are a highly
effective option to improve treatment outcome in
selected patient populations, adherence to international guidelines is still the mainstay for optimizing
treatment of HCC patients.

Hepatocellular carcinoma (HCC) is a progressive

tumour whose prognosis depends on tumour stage at
diagnosis and the possibility of providing radical treatment (1). In the past few decades, treatment of HCC has
progressed from a single option of surgical resection in
selected patients with small tumours to an array of
choices including orthotopic liver transplantation (LT),
locoregional ablation and transarterial chemoembolization (TACE) in patients who do not meet the criteria
for resection (1). More recently, the multikinase inhibitor sorafenib has been validated to treat patients with
advanced HCC, for whom no therapy was previously
available (2). Thanks to the development of clinically
based staging systems such as the Barcelona clinical liver
cancer (BCLC) classification, which stratifies patients
according to tumour stage and accompanying liver dis-

ease, the life expectancy of HCC patients can be reliably

predicted and appropriate treatment can be identified
according to stage (1, 3) (Table 1, Fig. 1). Not surprisingly, the BCLC classification has become the backbone
of guidelines published by international societies to
standardize clinical practice and study designs to validate new treatments (1, 4). Treatment of HCC based on
the BCLC score has resulted in increased survival by
preventing treatment failures related to faulty staging of
patients and empirical decisions. Interestingly, although
a significant number of patients with HCC do not
match the therapeutic criteria corresponding to their
BCLC stage because of conditions from advanced age to
the anatomic localization of the hepatic tumour, these
patients may be effectively treated outside current
guidelines.

The standard of care

Very early and early HCC (BCLC 0 and A)

Widespread screening programs for HCC and the use of

abdominal ultrasound examinations in clinical practice
have significantly increased the number of patients with
chronic liver disease and a clinically silent, small HCC
nodule (1). The current definition of early HCC is a

Table 1. The Barcelona clinic liver cancer staging classification for hepatocellular carcinoma
BCLC stage

Performance status

Tumour volume, number and invasiveness

Child-Pugh

Expected survival

A early
B intermediate
C advanced
D end-stage

0
0
12
34

Single < 5 cm or three nodules <3 cm each

Large/multinodular
Vascular invasion and/or extrahepatic spread
Any of the above

A and B
A and B
A and B
C

5075% at year
16 months
6 months
<3 months

Fig. 1. Barcelona clinic liver cancer treatment strategy. Staging is linked to treatment indication according to evidence-based data [adapted
from (1)]. HCC, hepatocellular carcinoma

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Colombo and Sangiovanni

tumour <2 cm in size confined to the liver in a patient

with well compensated cirrhosis (2). However, this definition includes a heterogeneous set of tumours, such as
very early HCC, i.e. a vaguely nodular tumour that is
usually not diagnosed on dynamic imaging techniques
such as contrast enhanced CT scan or gadolinium MRI,
and early HCC, i.e. a distinctly nodular tumour that is
detectable on contrast imaging because of arterial neovascularization. In clinical practice, however, the definition of early HCC is broader, including patients with a
single nodule, <5 cm or up to three nodules each 3 cm
or less (Milan criteria) (3). Because the BCLC system
also includes the clinical parameters of liver function,
early stage HCC is further stratified into four classes
according to the number and size of the tumours and
other predictors of survival after surgical resection such
as the portocaval gradient (hepatic venous pressure gradient, HVPG) and serum bilirubin levels (Fig. 2). The
latter parameters are highly important in the selection
of patients for resection, because a combination of
>1 mg serum bilirubin and >10 mmHg HVPG is a significantly predictive risk factor of early mortality from
postoperative decompensation (4). On the other hand,
later mortality following resection and local ablation is
influenced by the size and number of tumour nodules
which are predictive of vascular tumour dissemination
and the inherent risk of tumour recurrence (5, 6).
Patients with nodules 2 cm, which represent 80% of all
tumours detected in patients with cirrhosis followed by
ultrasound surveillance, have a low risk of extranodal
spread (7), and are theoretically ideal candidates for
such radical therapies as local ablation, resection and
liver transplantation (LT). The final therapeutic decision, however, is based on patient characteristics such as
age, liver status, the presence of comorbidities, the
potential of improving underlying liver disease and the
length of the transplantation waiting list. Indeed,
carefully selected patients with a tumour 2 cm and
compensated cirrhosis benefit equally from all radical
therapies in terms of survival (>70% at 5 years), but the
costs and risks of intervention-related mortality differ.
The latter is very low for percutaneous ablation, while it
is 13% for resection and 10% for LT (8). Antiviral
agents reduce the risk of postoperative decompensation
and late onset recurrence from second primary tumours
in patients with hepatitis B or C related tumours
undergoing resection or local ablation of HCC (9, 10).
In patients transplanted for end-stage hepatitis C
virus (HCV), access to new all oral direct antiviral
agents against HCV will prevent and successfully treat
recurrent HCV, which is a major cause of graft failure
and early death in these patients (11).
Percutaneous local radiofrequency ablation (RFA) is
more effective than ethanol injections (PEI) in 2 and
3 cm tumours because of improved prevention of
tumour recurrence on the periphery of the nodule (12,
13). While the efficacy of both ablative techniques is
suboptimal for the treatment of tumours >3 cm because
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HCC treatment beyond guidelines

of an increased risk of tumour recurrence (14), resection

and percutaneous ablation can be proposed to patients
with up to three nodules of 3 cm, but with less encouraging survival rates than in patients with a single 2 cm
nodule, once again because of the increased risk of postoperative recurrence (15) (Fig. 3).
The Milan criteria, i.e. the presence of a single nodule
of <5 cm or of up to three nodules each of 3 cm, are
universally recognized as the guide to listing patients for
orthotopic LT, for an overall predicted survival of 75%
at 5 years (16). In patients with >2 cm tumours who are
in the waiting list, tumour radiofrequency ablation
(RFA) or TACE is currently recommended as a bridge
to LT to prevent tumour progression and removal from
the list or an increased risk of recurrence. However this
assumption is not evidence-based and it is debated in
terms of cost-effectiveness. Although per protocol survival rates in transplanted patients are better than in
similar stage patients treated by resection, the benefits
to survival are less clear when calculated by intention to
treat, because tumour progression in patients on the

Fig. 2. The survival of patients with an early cancer treated by

resection is influenced by portal hypertension and bilirubin: best
candidates have a solitary HCC 5 cm and ChildPugh A score with
low portal hypertension and normal bilirubin. HCC, hepatocellular
carcinoma.

Fig. 3. Retrospective study of 282 consecutive patients with an

HCC within Milan criteria treated in Barcelona during a 15-year period: the initial tumour volume predicts survival after percutaneous
ablation. HCC, hepatocellular carcinoma

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waiting list increases the risk of delisting and of tumour

recurrence after transplantation (17). Although LT is felt
to be the best therapeutic option in patients with early
HCC because it prevents the late-onset complications
of cirrhosis, this option is limited by the limited number
of organ donations worldwide. Living donor LT has
gained popularity to compensate for donor shortage,
but it is associated with high complication rates (>30%)
in recipients and a small, but non-negligible, risk
of donor death (0.5%) (18). In most countries, including Italy, the limited number of donor livers does
not favour strategies to extend the oncological criteria
beyond the Milan criteria for LT in patients with
HCC, since extending criteria is associated with an
increased risk of tumour recurrence and shortened
survival (19).
In real life, the treatment of HCC is multimodal in
patients with more than one nodule who do not reach
the end-point of a radical cure with one type of treatment alone. TACE has been used in combination with
RFA or PEI with promising results, although the
reported benefits to survival in comparison with either
treatment alone has not been validated (20). Because the
results of liver transplantation are better than hepatic
resection for tumour recurrence, LT has been used as
rescue therapy in patients who are found to have microscopic vascular invasion during tumour resection (21).

Colombo and Sangiovanni

Intermediate HCC (BCLC B)

In patients with a tumour burden exceeding the Milan

criteria and in the absence of macroscopic vascular invasion by tumour cells and symptoms of neoplastic disease, the standard of care (SOC) includes TACE. This is
based on a meta-analysis of seven studies (22) showing
that repeated treatment with TACE was associated with
improved survival of an average of 20 months in
patients with intermediate HCC (Fig. 4). However
TACE is limited to patients with compensated cirrhosis
(ChildPugh A or B), including those with small esophageal varices to minimize the risk of hepatic decompensation following procedure-induced liver ischaemia. A
recent expert consensus has identified absolute and relative contraindications for TACE including comorbidities, hepatic encephalopathy, high performance status,
reduced or absent portal vein flow biliary obstruction
and large/massive tumours (23). TACE is also contraindicated in patients with branch or portal vein thrombosis, since occlusion of arterial blood flow may cause liver
failure. While superselective TACE may be safely performed in selected patients with segmental portal vein
thrombosis, a clinical benefit has not been demonstrated
in this population (24). One important point is that
tumour response after conventional or drug-eluting
bead-TACE (DEB-TACE) should be evaluated by EASL

Fig. 4. Meta-analysis of studies of chemioembolization for intermediate hepatocellular carcinoma.

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or modified RECIST criteria combining assessment of

tumour shrinkage and loss of viable cells (25, 26).
There is disagreement about the evidence showing
increased survival following TACE in the above mentioned meta-analysis because the benefits in survival
were based on two randomized studies that enrolled
patients with fairly advanced HCC. In fact, in those two
studies the 3-year predicted spontaneous survival of 8
and 20 months was definitively lower than the 50% predicted survival of untreated patients with an intermediate HCC originally described by Llovet et al. (27).
Another weakness of the meta-analysis was the lack of
standardization of studies with TACE in relation to
embolization procedures while recent developments
with TACE including new, more effective embolizing
agents (28) allow a more standardized approach. TACE
with doxorubicin-loaded (DC) beads is a new paradigm,
since it can cause complete necrosis of <5 cm HCC
nodules, suggesting that TACE may be a radical treatment modality in selected patients (29). In fact, the concept of DEB-TACE is to target tumour nodules with
embolizing particles loaded with chemotherapeutic
agents combining a potent ischaemic effect with controlled release of the cytotoxic drugs (doxorubicin) into
the tumour domain. While DEB-TACE is generally as
well tolerated as conventional TACE, major complications such as liver abscess and liver failure occur in
<10% of patients. Unfortunately incremental survival of
DEB-TACE vs. conventional TACE was not demonstrated even though response rates were slightly higher
(52% vs. 44%) and time to progression slightly longer
(7.1 vs. 6.4 months) for DEB-TACE using DC beads
compared to conventional TACE (30). However,
uncontrolled studies in a large number of patients
report survival rates of up to 38% at year 5 in patients
with early and intermediate tumours (31).
The efficacy of adjuvant pharmacological therapies
has not been confirmed in patients treated by RFA or in
studies with targeted therapies (32). Unfortunately the
multinational SPACE study, investigating the effectiveness of TACE with DC beads in patients with intermediate HCC, who are randomized to receive adjuvant
therapy with the molecular-targeted agent sorafenib vs.
placebo, failed.
In the last decade, radioembolization (TARE) has
become an alternative treatment in patients with intermediate tumours. TARE is based on the injection of
microspheres loaded with Yttrium-90, a pure beta emitter with short tissue penetration, and is it is also indicated in patients with portal thrombosis. The real
limitation of TARE is the presence of arteriovenous
shunts in the lungs which increases the risk of pulmonary embolization and advanced liver disease. The most
challenging adverse event of TARE is liver toxicity
including decompensation or encephalopathy, and radioembolization induced liver disease, which may
appear up to 8 weeks after TARE, at a rate <10%. The
median time to response with tumour shrinkage is
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HCC treatment beyond guidelines

about 6 months and is accompanied by significantly

prolonged overall survival (33). Median survival in
intermediate stage patients treated by TARE was 16
18 months. TARE has been used for bridge therapy in
patients on the waiting list for LT and as down-staging
therapy to bridge local ablation, resection or LT.
Advanced HCC (BCLC C)

In these patients, the presence of tumours is complicated by radiological evidence of portal vein thrombosis
or extrahepatic tumour invasion as well as symptoms of
neoplasia (performance status 1 or 2). The multikinase
inhibitor sorafenib is the SOC for these patients (34, 35)
(Table 2) and is restricted to BCLC C patients with
compensated liver disease (ChildPugh A) who have
either a clinical or a radiological response during the
first 2 months of therapy. As a result, the recently
updated RECIST radiological criteria have been replaced
by the EASL criteria, which include early sorafenib
induced modifications in arterial vascularization of the
tumour and better identification of patients who
respond to sorafenib (2, 36). All of the trials with new
agents inhibiting either the same pathways as sorafenib
or different pathways such as mTOR and growth factors
involved in liver cell carcinogenesis and angiogenesis,
have failed.
End-stage hepatocellular carcinoma (Barcelona clinical
liver cancer stage D)

These patients have tumours of any size with symptoms

of neoplasia and deranged liver function (ChildPugh
C), with an average predicted survival of 3 months,
only. There is no specific treatment available in these
cases, except the best palliative care.
HCC treatment beyond the guidelines

While the shortage of donated livers remains an obstacle

to expanding the current criteria for LT (19,3740), the
SOC Milan criteria for listing are felt to be too restrictive

Table 2. Comparison of randomized-controlled trials of sorafenib

in Western (SHARP) and Asian patients with advanced hepatocellular carcinoma
Study characteristics

SHARP study

Asia study

Median age
BCLC-B stage
Previous treatments
HBV aetiology of cirrhosis
TTP

65 years
18%
67%
19%
5.5 months
(2.8 months)
10.7 months
(7.9 months)
30%

51 years
4%
NA
71%
2.8 months
(1.4 months)
6.5 months
(4.2 months)
24%

Median survival
(control)
Grade 3/4 toxicity

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HCC treatment beyond guidelines

by many since they prevent patients from receiving lifesaving treatment such as LT. Approaches to expand criteria for listing for LT are mostly based on tumour stage
scores obtained from the explanted liver and not on pretransplant imaging findings, which are not accurate
enough to identify predictors of tumour recurrence such
as microscopic vascular invasion and tumour satellites
that are present in patients exceeding Milan criteria
(14).
Surgeons at the University of California, San Francisco (UCSF) developed criteria based on explant histology, and were the first to propose expanded criteria for
listing that were then prospectively validated by radiological imaging in clinical practice (37,41). Listing for
transplantation based on UCSF criteria, which include 1
nodule 6.5 cm, or 23 nodules 4.5 cm to reach a total
tumour diameter 8 cm, resulted in a comparable 5year recurrence-free probability (90% and 94%) in
patients within and outside Milan criteria, while the risk
of pretreatment tumour understaging was similar for
patients within the Milan (20%) and UCSF (29%) criteria (41). Another expanded set of criteria were developed in Pamplona including 1 nodule 6 cm, or 23
nodules each 5 cm. This approach resulted in recurrence free survival rates of 70% in a small group of 47
patients. However, this study was limited by the lack of
separate analysis of the outcomes in patients exceeding
the Milan criteria (42). A more complex approach by
Roayaie et al. (43) was the use of a multimodal neoadjuvant treatment protocol with systemic chemotherapy
with doxorubicin and chemoembolisation that was
applied to 80 patients with 1 or more nodules of
57 cm. Survival was significantly better in patients with
tumours between 5 and 7 cm than >7 cm tumours
(55% vs. 34%, P = 0.024), but it was poorer than
that reported for historical controls listed according to
the Milan criteria (9). Knetenen et al. compared 19
patients with HCC meeting the Milan criteria with 21
patients meeting the expanded criteria (1 nodule
<7.5 cm or any number <5 cm), with a sirolimus-based
protocol of immune-suppression resulting in a 4-year
recurrence free survival rate of 81.1% and 76.8% respectively (44).
A significant difference in survival among groups was
demonstrated by Mazzaferro et al. (17) in a retrospective multicenter study of explanted livers that included
1156 BCLC A patients who underwent OLT for HCC in
36 centres, worldwide. In that study in which patients
outside the Milan criteria were analyzed in two subgroups Up-to-seven (7 cm being the sum of the size of
largest tumour and number of tumours) and Exceeding
up-to seven, the 5-year overall survival was 73.3% in
patients who fulfilled the Milan criteria compared to
53.6% in those who were transplanted outside the criteria. Interestingly, the survival of 283 patients in the Upto-seven group lacking microvascular invasion was as
high as 71.2%, suggesting that more patients with HCC
could be candidates for LT if the current dual approach

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(Milan in/Milan out) for candidacy was replaced with a

more precise estimation of survival in relation to
tumour characteristics and the up-to-seven criteria.
However, the assessment of tumour burden for this
expanded criterion was based on pathology at explant
not on pretreatment radiology, limiting its clinical
application for listing. Using pretreatment radiology,
Guiteau et al. compared the survival of 363 patients
within the Milan criteria and 82 who met the expanded
criteria of 1 lesion <6 cm, 3 lesions and none >5 cm
for a total diameter of 9 cm, and showed better recurrence free survival rates in the expanded group than in
the Milan group (87 vs. 71%) (45). However, it should
be mentioned that UCSF are the only criteria for
expanded access to LT to have been independently
validated by either explant pathology or radiology
(37,4649).
While tumour ablation and palliative therapy are the
SOC in patients with multiple, large and macrovascular
invasive HCC, respectively, survival benefits have been
reported following hepatic resection in a large group of
patients, including those with intermediate and
advanced cancer disease (5052). In a multinational,
retrospective study including 9 tertiary referral centres
for hepatic surgery, the 1-, 3-, and 5-year overall survival rates were 87%, 66%, and 55% for 360 BCLC B
patients with cirrhosis and 71%, 42%, and 31% for 169
BCLC C patients who underwent hepatic resection,
with corresponding 1-, 3-, and 5-year disease-free survival rates of 66%, 42%, and 26% for BCLC B and
42%, 28%, and 17% for BCLC C (53). Because surgery
is currently extensively used even in patients with large,
multinodular, and macrovascular invasive HCC, these
encouraging short- and long-term results were interpreted by the authors as a reason to update the EASL/
AASLD therapeutic guidelines. Another study in Taiwan supports these results showing significantly better
survival in 268 patients with intermediate HCC who
underwent surgery compared to 455 patients who were
conventionally treated by TACE, with 5-year survival
rates of 43% vs. 15% P < 0.001.(54). While these findings seem to confirm the favourable outcomes of the
previously cited multinational study, it should be noted
that in the latter study in Taiwan enrollment of
patients with advanced cirrhosis was significantly
skewed towards the TACE group. In a single centre
study in Italy, hepatic resection of 247 patients with
cirrhosis and intermediate HCC resulted in satisfactory
3- and 5-year survival rates of 49% and 34%, respectively, which was considered to be comparable to
TACE (55). The major caveat in hepatic resection in
patients with cirrhosis, i.e. how to avoid liver failure
caused by the loss of viable liver cells, has mainly been
addressed in relation to the predictive power of portal
hypertension. While patients with a > 10 mm Hg
HVPG have an increased risk of postoperative decompensation, there is growing evidence that surgery can
also be successfully performed in many patients with
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Colombo and Sangiovanni

severe portal hypertension and multiple hepatic lesions

as long as they are carefully selected in relation to the
severity of contraindications (52,56). The Italian society
for the study of the liver (AISF) has suggested that
patients with portal hypertension, hyperbilirubinemia,
or multinodular tumours should be evaluated by an
expert multidisciplinary team to weigh the options of
surgical treatment against the risk of postoperative
decompensation (57). In a recent randomized controlled trial comparing hepatectomy vs. TACE for
resectable multiple HCCs exceeding the Milan criteria,
1-, 2- and 3- year overall survival was 76%, 63% and
51%, respectively, for the resected patients, compared
with 52%, 35% and 18% for the TACE group
(P < 0.001) (58).
BCLA A patients not suitable for hepatic resection
can be considered for RFA. In the grey zone of tumours
>3 cm that have an increased risk of satellite nodules,
techniques to enlarge the ablation field or combination
therapy with other modalities such as TACE, should be
considered. Survival benefits provided by combination
therapy with RFA plus TACE, compared to RFA alone
in HCCs between 3 and 5 cm, was demonstrated in a
RCT in Japan (59) and a consensus-based clinical
practice manual of the Japanese Society of Hepatology
recommends RFA combined with TACE for HCC
>3 cm. (60). The recent availability of the microwave
technique ensures larger areas of tumour necrosis
thereby modifying these recommendations; however,
this approach needs to be validated.
Chemoembolization of HCC is a viable treatment
option to overcome the risks of morbidity during the
treatment of patients with severe portal hypertension. At
present, TACE is used to treat patients with early HCC
in whom surgical or ablative therapies are not applicable
for technical reasons and/or the presence of comorbidities. The results of DEB-TACE using doxorubicinloaded beads rather than the conventional doxorubicin
Lipiodol (Guerbet, Genoa, Italy) emulsion, have
shown an overall favourable toxicity profile and potent
antitumour activity. However, while initial studies
reported response rates ranging from 13.3% to 80.7%
(61), a phase III RCT (PRECISION V) failed to show
that DB-TACE was better than conventional TACE (30).
DEB-TACE has been confirmed as a user friendly, effective technique in a recent international study (62) where
173 patients who were not suitable for curative treatment (41% Child-Pugh B) achieved a 5-year overall survival of 22.5%, with better responses in Child-Pugh A
than in Child-Pugh B patients (29.4 vs. 12.8%).
The infusion of radioactive substances such as
Iodine-131-labelled Lipiodol or microspheres containing Yttrium-90 into the hepatic artery (TARE) is an
alternative approach to treat both unresectable intermediate and advanced stage tumours. In a feasibility trial,
Salem et al. (63) reported a response rate of 57% based
on EASL criteria and an overall time to tumour progression of 7.9 months with an acceptable rate of side
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HCC treatment beyond guidelines

effects, including fatigue (57%), pain (23%) and nausea/vomiting (20%) and a 30-day mortality rate of 3%.
In a phase II trial, 52 patients with intermediate to
advanced HCC treated for a median follow-up of
36 months, showed a median time to progression of
11 months with no significant difference between
patients with portal vein thrombosis and those without
(7 vs. 13 months), while the median overall survival was
15 months (95% confidence interval, 1218 months).
Given the heterogeneity of HCC and the lack of
high level evidence-based data favouring one treatment
over the other, the decision-making process in hepatooncology remains flawed. While the international scientific societies EASL-EORTC and AASLD have built
their treatment algorithms on the stage of BCLC,
defined by tumour burden, liver impairment and performance status, it should be acknowledged that by
default these guidelines disregard clinical variables in
the field which could influence the decision-making
process. In two studies performed in Italy, up to 40%
of patients with HCC were in fact treated outside recommended guidelines (64,65) because of tumour characteristics/location or comorbidities making it difficult
to classify patients according to international recommendations. Until a personalized algorithm based on
genetic predictors of tumour aggressiveness can be
developed, the decision-making process for HCC is
well suited to the regret theory model, which postulates
that treatment choices may be influenced by the decision-makers anticipation that certain outcomes will be
associated with high regret, which he/she would like to
avoid or minimize (55), leaving some renowned HCC
referral centres to question the accuracy of BCLC/
AASLD treatment allocations. In fact, international
guidelines for HCC are not consistently applied in our
centre either, or in other academic hospitals in Italy, a
sign that the caregivers expertise and desire to treat
often goes beyond guidelines. In our centre, where
2005 AALSD recommendations have been the SOC for
the treatment of HCC, 29% of 227 patients consecutively treated in the last 5 years, did not receive a SOC
treatment, including 21% of the best prognosis BCLC
A patients, who ultimately did not receive radical treatment (66). While adjuvant treatment is awaited to
improve the outcome of patients who undergo radical
therapies, a multinational, placebo-controlled randomized trial including more than 1000 patients with early
HCC treated with limited hepatic resection or local
radio frequency ablation (STORM trial: http://clinicaltrials.gov.com, NCT00692770) failed to demonstrate
any adjuvant property of sorafenib in preventing early
recurrence of HCC (33.4 vs. 33.8 months) and reducing mortality at 5 years (25% in both groups) (67). In
particular, 30% of the patients had to discontinue sorafenib in the first 3 months of treatment due to
adverse effects. Previous studies with interferon, traditional chemotherapy and neo-adjuvant immunotherapy, missed the target as well.

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Conclusions

In the last decades, management of HCC has significantly improved thanks to numerous breakthroughs in
standardized therapeutic algorithms. A better understanding of the natural history of the disease was instrumental in the development of evidence-based staging
systems which improve patient selection and treatment.
At present, while treatment of HCC patients is based on
individual evaluation of a patient to guide the decisionmaking process, half of the patients referred to a tertiary
centre will have an early tumour fulfilling the criteria for
radical therapy with resection, local ablation or transplantation. At the same time, one-third of the patients
will have an intermediate HCC, which can benefit from
treatment with TACE in the presence of compensated
cirrhosis (ChildPugh status A or B) and the absence of
portal vein complications such as thrombosis or large
esophageal varices. In the remaining patients with
advanced HCC, sorafenib is a SOC option as long as cirrhosis is well compensated (ChildPugh A) and a radiological or a clinical response can be achieved in the first
2 months of treatment. Because of the extended survival
in patients when tumours are detected early, surveillance of patients with chronic liver disease to obtain an
early diagnosis is the only practical approach to improve
both access to and the outcome of HCC treatment.
Nevertheless, there is also a substantial hope of obtaining clinical benefits in the many patients with more
advanced tumour disease if a multidisciplinary
approach is taken combining different treatment modalities. However, adopting therapeutic algorithms beyond
the recommendations inevitably results in lower survival
benefits compared to a guideline driven treatment of
HCC.

5.

6.

7.

8.
9.

10.

11.

12.

13.

14.
15.

Acknowledgements

Conflict of interest: Massimo Colombo: Grant and

research support: BMS, Gilead Science. Advisory committees: Merck, Roche, Novartis, Bayer, BMS, Gilead
Science, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, GSK, GenSpera, AbbVie, AlfaWasserman, Jennerex Speaking and teaching: Tibotec, Roche, Novartis,
Bayer, BMS, Gilead Science, Vertex, Merck, Janssen,
Sanofi. Angelo Sangiovanni: Bayer.

16.

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