Locoregional Treatment for Hepatocellular Carcinoma:

From Clinical Exploration to Robust Clinical Data,

Changing Standards of Care
nance imaging have shown their high accuracy to estab-
See Articles on Pages 71 and 82
lish tumor stage, a critical requirement for any treatment
approach. Importantly, imaging techniques and radiolo-

T
he field of hepatocellular carcinoma (HCC) has
gists executing them have not only had a major impact on
experienced major changes during the last few
diagnosis and staging, but also in several image-guided
years. Until very recently, HCC was regarded as a
therapeutic interventions. The capacity to identify the
neoplasm with marginal incidence in Europe and North
tumor site(s) in real time allowed percutaneous tumor
America. In addition, its diagnosis was commonly done at
ablation, either through the injection of agents (ethanol,
an advanced stage, and the sole therapeutic option to be
acetic acid) or through temperature modification (radio-
offered was surgical resection. Not surprisingly, the sur-
frequency, cryotherapy). Although initially seen as a
vival after diagnosis was not encouraging and this primed
primitive method to treat liver cancer, several cohort stud-
a very skeptical view about the benefits of screening for
ies and randomized trials have shown the value of abla-
HCC and developing new treatments. The situation has
tion; currently, radiofrequency ablation and ethanol
sharply changed: HCC is now recognized as one of the
injection are established therapies in conventional clinical
major cancer causes of death, its incidence has increased
practice. The same transition from first proposal to estab-
in several Western countries,1 and it is the leading cause of
lished therapy has occurred with transarterial chemoem-
death in patients with cirrhosis. Furthermore, screening
bolization. Known to be effective in terms of tumor
allows detection at an early stage and there is a large range
burden reduction, only in recent years has it been proven
of therapeutic options to be considered while taking into
to positively affect patient survival.4
consideration tumor burden and liver function. Effective
At first, it might appear that the work done has been
treatment options include conventional resection, liver
easy and simple. Yet, the accomplishments have been the
transplantation, ablation, transarterial chemoemboliza-
result of brilliant pioneering ideas that, after an initial
tion,2 and recently, a large, randomized, placebo-con-
assessment, have been repeatedly evaluated to establish
trolled trial has shown that sorafenib, a nonselective
the value of each option, to refine its application, and to
tyrosine kinase inhibitor with antiangiogenic activity, im-
identify the best candidates who would benefit from
proves survival of patients with advanced HCC.3
them. This step-by-step assessment is well established in
Obviously, all these developments have been the result
pharmacologic options that begin their human path in
of years of efforts by several groups that have combined
phase 1 trials and thereafter, advance to phase 2 and phase
the needed expertise of different areas of knowledge in-
3 trials, to ultimately get approval by the health authori-
volved in the diagnosis and management of patients with
ties.5
HCC. Among them, we must acknowledge the major role
In this issue of HEPATOLOGY, we focus attention on
that imaging techniques have had in this evolution. Ex-
two phase 2 studies that open new avenues in the field of
pert ultrasound examination is of paramount importance
locoregional treatment for HCC.6,7 Both raise novel con-
in conducting screening to detect HCC at an early stage,
cepts and present the experience gathered in cohort inves-
and dynamic computed tomography and magnetic reso-
tigations. The Italian multicenter report coordinated by
Livraghi6 exposes the outcome of a large series of more
Abbreviation: HCC, hepatocellular carcinoma.
than 200 patients with cirrhosis with solitary HCC ⱕ 2
Address reprint requests to: Jordi Bruix, BCLC group, Liver Unit, Hospital cm treated by radiofrequency. In most centers, such small
Clinic, Villarroel 170, Barcelona 08036, Catalonia, Spain. E-mail: tumors would be first considered for resection, but the
jbruix@clinic.ub.es; fax: (34) 93 227 5792.
A. Forner is supported by a grant of the Instituto de Salud Carlos III (grant PI
authors challenge this proposal by showing that the out-
05/645) and a grant of the BBVA foundation. This work has been partially funded come obtained with radiofrequency may be the same as
by a grant of the Instituto de Salud Carlos III (grant PI 05/150). with resection. This possibility has been previously raised
Copyright © 2007 by the American Association for the Study of Liver Diseases.
by small randomized controlled trials comparing surgery
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.22152 versus ablation.8,9 The novelty comes from the recruit-
Potential conflict of interest: Nothing to report. ment of a large number of patients with minute HCC
5
6 FORNER AND BRUIX
potentially fitting the description of very early HCC. This
entity would represent the first evolutionary step in liver
cancer. Kojiro et al. have subdivided HCC ⱕ 2 cm into
the indistinctly (vaguely) nodular and the distinctly nod-
ular type.10 The first type would have not reached an
invasive profile and the likelihood of vascular invasion
and/or satellite tumor nests is very low. Conversely, the
distinctly nodular type would more frequently exhibit the
more advanced pathologic profile that implies a higher
risk of dissemination, and hence, disease recurrence after
therapy. The vaguely nodular HCC is usually poorly vas-
cularized and therefore, it is unlikely to be diagnosed by
noninvasive criteria based on the findings on dynamic
imaging techniques, and hence, confident diagnosis
should be established by biopsy. However, cells of very
early HCC retain good differentiation capability, and this
prompts a high false negative rate. These considerations
are relevant to carefully evaluate the data provided by
Livraghi et al. As expected, the efficacy of radiofrequency
on the tumor is very high because more than 95% of the
cases present complete nodule necrosis that is maintained
during follow-up. However, this major activity against
the first tumor is followed by a high recurrence rate (80%
at 5 years) that, as acknowledged by the authors, is exces-
sive if the selection process would have effectively cap-
tured a majority of patients with very early HCC. Hence,
the series surely includes patients with more advanced
phenotype probably having evolved beyond very early
stage and this allows recurrence due to dissemination
prior to ablation to take place. What mechanism can be
proposed to explain this unexpected finding if it has to be
assumed that pretreatment staging has ruled out addi-
tional nodules? Likely, the key point is the establishment
of HCC diagnosis. As mentioned before, very early HCC
is poorly vascularized, and noninvasive imaging tech-
niques will not permit its diagnosis. Hence, Livraghi et al.
have used biopsy confirmation for the nodules without
increased arterial contrast uptake on dynamic computed
tomography or magnetic resonance imaging. Recognition
of stromal invasion as raised by Kojiro et al.10 would per-
mit HCC diagnosis, but while this feature may be de-
tected in explanted tissue, the diagnostic sensitivity of this
criterion in tissue obtained by fine-needle biopsy is at least
suboptimal. Accordingly, with the current diagnostic
tools, the majority of cases recruited with tumors less than
2 cm in size will infrequently correspond to very early
HCC and dissemination risk will already be acquired.
These comments do not diminish the value of the
data offered by Livraghi et al. They show that the out-
come after ablation of solitary HCC tumors ⱕ 2 cm
can be as good as that obtained with surgical resection
and thus confirm in European patients what has been
HEPATOLOGY, January 2008
already reported in Asia. Is the proposal to be accepted
without hesitation? It could be argued that ablation is
highly effective and if it fails, surgery could become a
salvage approach. However, the information offered by
examination of the resected tumor may be relevant to
predict the risk of recurrence and recommend adjuvant
treatment if in the future there is proof of efficacy with
any option. Currently, the sole effective approach is
liver transplantation. The recurrence rate is signifi-
cantly lower even in the presence of microscopic vas-
cular invasion or satellites. Based on this fact, some
groups recommend transplantation for patients with
resection if the pathology examination detects these
recurrence predictors.11 Accordingly, resection in pa-
tients who otherwise would be candidates for trans-
plant still has a place, while those in whom transplant is
not an option may have ablation as the initial ap-
proach. Careful analysis of new cohort studies will con-
firm the data of Livraghi et al., and hopefully with
incorporation of new imaging techniques and molecu-
lar data we will be able to confidently diagnose very
early HCC that surely is the best target for ablation.
The second study that provides novel information
refers to the efficacy of selective intra-arterial radiother-
apy using 90Y spheres.7 This option is tested in the
other extreme of the evolution of HCC: patients with
advanced disease who cannot benefit from treatment
options with positive impact in survival. Until very
recently, those patients who have reached this evolu-
tionary stage had no effective option, and it was rec-
ommended to include them in research trials to
evaluate new options. Kulik et al. describe the results
obtained with this approach in a large series of HCC
patients that combines the pioneering experience of the
Pittsburgh and Chicago groups. Their data show that
the technique has antitumoral efficacy and that it is
well tolerated without major associated side effects.
Survival of patients is encouraging, but it is not feasible
to establish if this is due to the effects of therapy or to
the selection of patients with a heterogeneous clinical
profile in terms of tumor burden and underlying liver
function. In any case, it is clear that the technology
requires a complex setting to be in place and thus is not
an option that will be easily implemented. The authors
have extensively worked in all aspects related to its
development and in the article, they present all the
information needed to incorporate it. At present, it
would be the time to test it versus no treatment. How-
ever, while crafting all the data to produce all the
needed background to design such a trial, it has been
shown that the target population benefits from treat-
ment with sorafenib. Therefore, it is no longer feasible
HEPATOLOGY, Vol. 47, No. 1, 2008
to test any new approach versus best supportive care.
Combination trials will be proposed to demonstrate
the benefits of this novel option, but new extensive
work will have to be initiated to have the safety and
baseline data to design a proper trial with robust re-
sults.
As said above, clinical research studies offering valu-
able data are not easy to conduct. They require the
willingness of skilled interventional radiologists to ex-
plore new technical opportunities and assess their fea-
sibility. Joining radiology and clinical skills allows the
design of proper clinical evaluation, which in a usual
step-by-step policy will finally lead to randomized clin-
ical trials. These provide the top degree of scientific
evidence that may change the standards of care. Thus,
pioneering studies are instrumental to develop robust
trials. The key for success is to wisely balance them in a
multidisciplinary effort that can only be done by a
generous exchange of knowledge coming from all areas
of attitude and expertise.
ALEJANDRO FORNER
JORDI BRUIX
Barcelona Clinic Liver Cancer group, Liver Unit
Hospital Clı́nic, University of Barcelona
Centro de Investigación Biomédica en Red de
Enfermedades Hepáticas y Digestivas (CIBERehd)
Institut d’Investigacions Biomédiques Agusti Pi i Sunyer
(IDIBAPS)
FORNER AND BRUIX 7
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