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Annals of Oncology 24 (Supplement 2): ii24–ii29, 2013
Intermediate hepatocellular carcinoma: currenttreatments and future perspectives
J.-F. Dufour1,2*, I. Bargellini3, N. De Maria4, P. De Simone4, I. Goulis5 & R. T. Marinho61Hepatology, Department of Clinical Research, University of Berne, Berne; 2University Clinic for Visceral Surgery and Medicine, Inselspital, University of Berne, Berne,Switzerland; 3Department of Diagnostic and Interventional Radiology, University of Pisa, Pisa; 4Gastroenterology, Department of Internal Medicine, University Hospital of
Modena, Modena, Italy; 54th Department of Internal Medicine, Aristotelian University of Thessaloniki, Greece; 6Liver Unit, Department of Gastroenterology and
Hepatology, Hospital de Santa Maria, Medical School of Lisbon, Lisboa, Portugal
Current guidelines recommend transarterial chemoembolization (TACE) as the standard treatment of Barcelona-Clinic
Liver Cancer (BCLC)-B patients. However, the long-term survival outcomes of patients managed with this technique do
not appear fully satisfactory; in addition, intermediate-stage hepatocellular carcinoma (HCC) includes a heterogeneous
population of patients with varying tumour burdens, liver function and disease aetiology. Therefore, not all patients with
intermediate-stage HCC may derive similar beneﬁt from TACE, and some patients may beneﬁt from other treatmentoptions, which are currently approved or being explored. These include different TACE modalities, such as selective
TACE or drug-eluting beads TACE and radioembolization. The introduction of sorafenib in the therapeutic
armamentarium for HCC has provided a new therapeutic option for the treatment of BCLC-B patients who are
unsuitable to TACE or in whom TACE resulted in unacceptable toxicity. In addition, clinical trials aimed at investigating
the potential role of this molecule in the treatment of patients with intermediate-stage HCC within combination
therapeutic regimens are ongoing. This narrative review will present and discuss the most recent evidence on the
locoregional or medical treatment with sorafenib in patients with intermediate-stage HCC.
Key words: adverse events, chemoembolization, locoregional, SIRT, sorafenib, systemic targeted therapy, TACE
with still well-preserved liver function (Child-Pugh A5 due toalbumin 4.8 g/dl, total bilirubin 0.9 mg/dl, INR 0.99) and only
The recent guidelines issued by the European Association for
two nodules <3 cm and a patient with persistent ascites and
the Study of Liver (EASL) endorse the Barcelona-Clinic Liver
jaundice (Child-Pugh B) with multifocal large tumours will be
Cancer (BCLC) classiﬁcation for the staging of hepatocellular
classiﬁed as affected by intermediate-stage HCC.
carcinoma (HCC) . This classiﬁcation divides HCC
Therefore, not all patients with intermediate-stage HCC will
patients into ﬁve stages (0, A, B, C and D) according to
derive similar beneﬁt from TACE, and some patients may
different prognostic variables and allocates therapies according
beneﬁt from other treatment options, which are currently
approved or being explored (Figure ) These include
About 20% of HCC patients are classiﬁed as affected by
different TACE modalities, such as selective TACE or drug-
BCLC-B, or intermediate-stage HCC, and present a 2-year
eluting beads (DB)-TACE, and radioembolization or
survival of ∼50% . The management of these patients, like
combination approaches [–For instance, the combination
that of other HCC subjects, should be based on themultidisciplinary interaction among different specialists ].
of TACE and radiofrequency ablation gave promising results in
Current guidelines recommend transarterial
chemoembolization (TACE) as the standard treatment of
The introduction of sorafenib in the therapeutic
BCLC-B patients ]. However, despite several recent
armamentarium for HCC has provided a new therapeutic
advances and technical reﬁnements, the long-term survival
option for the treatment of BCLC-B patients who are
outcomes of patients managed with this technique do not
unsuitable to TACE or in whom TACE resulted in
appear fully satisfactory [in addition, intermediate-stage
unacceptable toxicity. In addition, clinical trials aimed at
HCC includes a heterogeneous population of patients with
investigating the potential role of this molecule in the
varying tumour burdens, liver function and disease aetiology
treatment of patients with intermediate-stage HCC within
. As reported by Piscaglia and Bolondi both a patient
combination therapeutic regimens are ongoing.
This review will present and discuss the most recent
evidence on the locoregional or medical treatment withsorafenib in patients with intermediate-stage HCC. Surgical
*Correspondence to: Prof. Jean-Francois Dufour, Hepatology, Department of Clinical
procedures, including resection or transplantation, can be
Research, University of Berne, Murtenstrasse 35, 3010 Bern, Switzerland; Tel: +41-31-632-31-91; Fax: +41-31-632-49-97; E-mail: email@example.com
considered in selected patients, as reviewed in Zhang et al.
The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: firstname.lastname@example.org.
the imaging modalities for locoregional treatments is beyondthe scopes of this review.
TACE is considered as the standard treatment of patients withcompensated liver function (Child B up to 8 points), with largesingle nodule or multifocal HCC (<5 cm) not occluding theportal venous vessels and without extrahepatic spreadSurvival beneﬁts determined by TACE were reportedin two randomized, controlled trials (RCTs): Llovet et al. [
Figure 1. Locoregional (LR) or medical treatment of patients with
showed a signiﬁcant survival advantage in favour of TACE over
intermediate-stage HCC, either approved or under investigation. Asterisk
transarterial embolization [hazard ratio (HR) for death: 0.47;
95% conﬁdence interval (CI), 0.25–0.91; P = 0.025], and Lo
et al. [showed a 50% reduction in the relative risk of deathwith TACE versus symptomatic treatment (95% CI, 0.31–0.81;
Resection may be a valid option in selected patients ]. More
P = 0.005). In addition, the efﬁcacy of TACE has been
in detail, radical resection can be considered in: (i) patients
evaluated in other RCTs, and two of these did not show a
with single HCC and large tumour nodule, swelling outward,
prolonged survival time with respect to controls
clear border or pseudocapsule and <30% hepatic tissue
Despite this, the results of a meta-analysis published in 2003
destroyed or >50% compensatory hepatic hypertrophy and (ii)
indicated that treatment with transarterial embolization/TACE
patients with multiple HCC with ≤3 nodules localized in one
is associated with a signiﬁcantly higher 2-year survival rate
lobe or segment of the liver . Other patients may be eligible
than in the control group (odds ratio, 0.53; 95% CI, 0.32–0.89;
for palliative resection (see Zhang et al. ] for a deeper
P = 0.017) . These ﬁndings are in agreement with those
discussion on indication for palliative resection). Due to the
reported in another meta-analysis of 18 RCTs, which shows
shortage of available organs, it is currently recommended that
that TACE improves the overall survival (OS) at 2 years
only those HCC patients with an estimated high probability of
compared with non-active treatment; however, the magnitude
post-transplant survival beneﬁt may be selected for liver
of this beneﬁt is relatively small .
transplantation. The Milan criteria (1 lesion ≤5 cm or 2–3
TACE-associated adverse events (AEs), although usually
lesions ≤3 cm), proposed in 1996, still represent the basis for
transient and manageable, occur in a signiﬁcant proportion
the selection of the best candidates for liver transplant [–
(35–100%) of patients: they include post-embolization
]. However, the adoption of expanded and/or down-staging
syndrome (comprising fever, abdominal pain and a moderate
criteria for liver transplant has been proposed and is currently
degree of ileus), relevant liver function deterioration, ascites
under clinical investigation ]. For instance, a study by
and gastrointestinal bleeding In addition, TACE does
Mazzaferro—the leading investigator of the team who
have some contra-indications, both absolute and relative
identiﬁed the same Milan criteria —conducted on 1556
patients has suggested that more HCC patients could be
Collectively, these ﬁndings indicated that treatment with
eligible for transplantation if the Milan criteria were replaced
TACE may be associated with some beneﬁts in terms of OS,
by a more precise estimation of survival based on individual
although the level of beneﬁt varies and considerable AEs may
tumour characteristics and up-to-seven criteria ].
occur: therefore, a careful selection of patients appears crucial
These ﬁndings are conﬁrmed by a study on more than 6000
before the initiation of TACE therapy ].
patients included in the US Scientiﬁc Registry of Transplant
In the future, additional trials should be conducted to
Recipients database: this analysis shows that the Milan criteria
investigate some ‘grey areas’ still present in the current
are too restrictive, and patients with larger total tumour
knowledge of TACE, such as the use and type of the
volume can enjoy satisfactory post-transplant survivals .
chemotherapeutic agent, as well as the best type of embolizing
Moreover, a composite patient selection score combining total
medium Of note, recent evidence supports the use of the
tumour volume and alpha fetoprotein can be considered the
EASL criteria or the mRECIST criteria, rather than the
most effective of all tested staging criteria for the prediction of
standard RECIST criteria, in the evaluation of clinical response
the survival of transplanted patients .
after TACE ]. Gilmore et al. reported a signiﬁcantassociation between survival and overall EASL and mRECIST
responses: response was associated with a 44% risk reduction
and mRECIST with a 42% reduction. Conversely, there was nosigniﬁcant association between survival and RECIST 1.1
The most widely used locoregional therapies for the treatment
responses These data are corroborated by those reported
of intermediate-stage HCC are TACE, selective TACE, DB-
by Shim et al. who show that the HRs for time to
progression (TTP) and OS in responders were 0.15 (95% CI:
interventions are image-guided and therefore a careful
0.10–0.21) and 0.18 (95% CI: 0.13–0.26), respectively, when the
imaging, also before and after treatment, represents an essential
mRECIST deﬁnition of an objective response was used and
prerequisite for their success A detailed description of
0.16 (95% CI: 0.11–0.22) and 0.23 (95% CI: 0.16–0.33),
Table 1. Absolute and relative contraindications for TACE (reproducedfrom Raoul et al. with permission)
• Decompensated cirrhosis (Child-Pugh B ≥8) including:
– Jaundice– Clinical encephalopathy– Refractory ascites– Hepatorenal syndrome
• Extensive tumour with massive replacement of both entire lobes
• Severely reduced portal vein ﬂow (e.g. non-tumoural portal vein
• Technical contraindications to hepatic intra-arterial treatment,
• Renal insufﬁciency (creatinine ≥2 mg/dl or creatinine clearance
Figure 2. Complete response, objective response and disease control rate
[cumulative number (%) of patients] at 6 months in the PRECISION V
trial (reproduced from Lammer et al. , with permission).
• Co-morbidities involving compromised organ function:
The randomized, controlled PRECISION V trial has
compared DB-TACE with the standard TACE for the treatment
of 212 cirrhotic patients with HCC ]. At 6 months, the DB-
• Untreated varices at high risk of bleeding
TACE group showed higher rates of complete response,
• Bile-duct occlusion or incompetent papilla due to stent or surgery
objective response and disease control compared with thecTACE group (Figure ) . Although the predeﬁnedhypothesis of superiority was not met in the overall population,
respectively, with the EASL response criteria. In a recent paper,
patients with Child-Pugh B, Eastern Cooperative Oncology
Kim et al. reached the same conclusions, further supporting
Group 1, bilobar disease and recurrent disease presented a
the signiﬁcant association between TACE response and OS
signiﬁcant increase in objective response (P = 0.038). In
addition, DB-TACE was associated with a reduction in serious
Selectivity in positioning the catheter may enhance the
liver toxicity and a lower rate of doxorubicin-related side-effects
efﬁcacy of TACE. Selective TACE indeed comprises the
when compared with the standard TACE.
injection of chemotherapeutic agents into the segmental or
These ﬁndings are overall in line with those reported in
subsegmental branches feeding the tumours [Golﬁeri et al.
another RCT by Malagari et al. ], which compared DB-
 compared the effectiveness of selective/superselective
TACE with doxorubicin (n = 41) and bland embolization
TACE versus standard TACE in determining tumour necrosis,
(n = 43). At 6 months, a complete response, assessed with the
in a prospective database of 67 consecutive patients (122
EASL criteria, was seen in 11 patients (26.8%) in the DB-TACE
nodules, all <5 cm). The mean histological necrosis level was
group versus 6 patients (14%) in the bland embolization group,
64.7%; complete tumour necrosis was obtained in 42.6% of the
whereas a partial response was achieved in 19 patients (46.3%)
nodules. When compared with the standard TACE, selective/
and 18 (41.9%) patients, respectively. An advantage for DB-
superselective TACE was associated with higher mean levels of
TACE has been also reported in terms of rate of recurrences
necrosis (75.1 versus 52.8%; P = 0.002) and a higher rate of
and TTP (42.4 ± 9.5 versus 36.2 ± 9.0 weeks; P = 0.008).
complete necrosis (53.8 versus 29.8%, P = 0.013). A direct
The overall favourable efﬁcacy of DB-TACE is further
relationship was reported between the tumour diameter and
corroborated by a recent international, long-term (5 years of
the mean tumour necrosis level (59.6% for lesions <2 cm,
follow-up) study In total, 173 HCC patients not suitable
68.4% for lesions 2.1–3 cm and 76.2% for lesions >3 cm).
for curative treatments were enrolled; 41% were classiﬁed as
These ﬁndings suggest that selective/superselective TACE may
Child-Pugh B. The OS at 5 years was 22.5%, with higher rates
determine a higher rate of tumour necrosis than the standard
achieved in Child-Pugh class A compared with Child-Pugh
TACE; however, very small nodules (<2 cm) may not respond
class B patients (29.4 versus 12.8%). The mean OS was 43.8
months. Multivariate analysis identiﬁed some signiﬁcant andindependent determinants of 5-year survival: these were thenumber of lesions, lesion vascularity, initially achieved
complete response and objective response.
DB-TACE uses doxorubicin-loaded beads rather than the
In a recent observational study by Burrel et al.  (n = 104;
conventional doxorubicin Lipiodol® (Guerbet, Genoa, Italy)
63 patients were BCLC-B), DB-TACE was associated with the
emulsion It has been suggested that this approach could
median survival of 48.6 months, and only 10 patients reported
result in an overall favourable toxicity proﬁle and antitumor
major complications associated with this intervention. This
activity (response rates ranging from 13.3 to 80.7%)
study conﬁrmed the safety of DB-TACE in patients with HCC
and deﬁned the survival gain that can be obtained, providing
key evidence to decide among controversial indications and
TACE [However, these data might not be directly extendedto clinical practice, since they were collected in a single, highly
Sorafenib is currently the only drug approved for the treatment
specialized centre. In addition, included patients had to meet
of patients with advanced HCC (BCLC-C stage); however, the
very stringent selection criteria ( preserved liver function,
use of this molecule in the treatment of intermediate patients is
absence of symptoms, extrahepatic spread or vascular
approved in patients with BCLC-B HCC who are unsuitable to
TACE or in whom TACE resulted in unacceptable toxicityAccording to available evidence, sorafenib has arole in patients who fail or are not eligible to TACE, as recently
suggested by a Panel of Experts . We propose here a
Radioembolization is an investigational technique which
slightly modiﬁed version of the same algorithm (Figure ).
has given some promising results in preliminary experiences
Bruix et al.  carried out a subanalysis of the landmark
]. It is deﬁned as the infusion of radioactive substances
SHARP study to compare the efﬁcacy and safety of sorafenib
(such as Iodine-131-labelled lipiodol or microspheres
alone in patients with BCLC-B (sorafenib, n = 54; placebo,
containing Yttrium-90) into the hepatic artery ]. Given the
n = 51) versus BCLC-C (sorafenib, n = 245; placebo, n = 252)
hypervascularity of HCC, microspheres will be preferentially
stage of HCC. Overall, the beneﬁt determined by sorafenib,
delivered to the tumour area and selectively emit high-energy,
expressed in terms of OS and TTP, was similar in BCLC-B
low-penetration radiation to the tumour Salem et al. ]
(median OS: 14.5 months, +39% versus placebo; median TTP:
have reported the results of a feasibility study which included
6.9 months, +113% versus placebo, P = 0.0016) and BCLC-C
291 patients with HCC, who received a total of 526 treatments
(median OS: 9.7 months, +43% versus placebo, P = 0.018;
with radioembolization. The response rate according to the
median TTP: 4.9 months, +69% versus placebo, P = 0.00003)
EASL criteria was 57%; the overall TTP was 7.9 months.
subgroups and was consistent with that reported in the overall
Survival times were longer in patients with Child-Pugh A (17.2
population The incidence of grade 3/4 drug-related AEs
months) than in those with Child-Pugh B disease (7.7 months;
was not different in the two subgroups and was similar to that
P = 0.002). Reported toxic effects included fatigue (57%), pain
reported for the overall SHARP study population. The authors
(23%) and nausea/vomiting (20%); 19% exhibited grade 3/4
concluded that these ﬁndings conﬁrm a retained efﬁcacy of
bilirubin toxicity. The 30-day mortality rate was 3%.
sorafenib even in the intermediate-stage HCC .
However, the relevant costs associated with
In an observational setting, a subanalysis of the global phase
radioembolization may limit a wide use of this technique .
IV GIDEON study documented an OS of 12.6 months for
Moreover, the recent EASL Guidelines stressed that, due to the
BCLC-B patients, as assessed in a cohort of 311 Child-Pugh A
lack of RCTs comparing radioembolization with
and B patients . In the smaller Italian SOFIA study, the OS
chemoembolization or sorafenib in patients with intermediate-
of the 74 BCLC-B patients treated with sorafenib was longer
or advanced-stage HCC, further research is needed to establish
than that reported in the 222 BCLC-C patients evaluated (20.6
a competitive efﬁcacy role in these populations [
versus 8.4 months; P < 0.0001) . Taken together, these
Figure 3. Proposed algorithm for the treatment of patients with intermediate-stage HCC. Response is deﬁned according to mRECIST criteria.
preliminary results lend some support to the potential use of
multidisciplinary perspective. Lastly, sorafenib, the only
sorafenib monotherapy in patients with BCLC-B stage of HCC.
systemic treatment currently approved for the treatment of
It is widely accepted that TACE promotes the synthesis of
HCC, has a role in the treatment of patients with BCLC-B
proangiogenic factors via a hypoxia-driven mechanism
stage of HCC who are unsuitable to TACE or in whom TACE
Therefore, there may be a rationale for the combination of
sorafenib with TACE, since sorafenib inhibits the action of
Another intriguing arena is represented by the combination
or the sequential use of locoregional approaches and sorafenib.
Preliminary evidence, collected in a phase I trial, shows that
Moreover, preliminary evidence suggests that sorafenib may be
the combination of sorafenib and TACE is not associated with
used in patients who fail or are not eligible to TACE, in a
major AEs and, therefore, could deserve further investigations
sequential manner. The potential combination of TACE (either
. Moreover, given the overall more favourable efﬁcacy/
standard TACE or DB-TACE) and systemic targeted therapy
safety proﬁle of DB-TACE compared with the standard TACE,
also represents a promising treatment strategy, currently being
the combination of sorafenib with DB-TACE appears
explored in different phase III trials.
promising. Clinical trials investigating this therapeuticapproach (namely the START, SOCRATES and TACTIS) are
ongoing and will likely provide new evidence on the efﬁcacyand safety of a combination of TACE and sorafenib in the
Editorial assistance was provided by Luca Giacomelli, PhD, on
treatment of intermediate-stage HCC patients. The results of
behalf of inScience Communication, Springer Healthcare; this
the global phase II SPACE trial have been recently published in
assistance was funded by Bayer Italy.
an abstract form . In total, 307 patients with BCLC-B stageof HCC were randomized to sorafenib (n = 154) or placebo(n = 153) in combination with TACE with doxorubicin-eluting
beads (DEBDOX). Even if this study met its primary end point
JFD participated in advisory boards for BMS, Bayer, Gilead,
from a statistical point of view (P = 0.072 for TTP), the actual
Novartis, Roche. IG participated in advisory boards for BMS,
improvement of the median TTP was not clinically relevant
Gilead, Novartis, Roche, MSD. Other authors declare no
(from 166 to 169 days). The results of other ongoing studies
conﬂict of interest directly relevant to this study.
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Bicamerale sul ciclo dei rifiuti: L’allegra scampagnata dei signori Commissari Probabilmente gli autorevoli membri della Commissione bicamerale sul ciclo dei rifiuti, nel superare le colonne d’ercole di Eboli, si aspettavano di trovare all’altezza di Sicignano dei picciotti con la coppola e la lupara. Attonito ho assistito alla rappresentazione di tutto ciò che non dovrebbe fare un
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