Current Strategy for Staging and Treatment:

The BCLC Update and Future Prospects

Alejandro Forner, M.D.,1,2 Marı́a E. Reig, M.D.,1,2 Carlos Rodriguez de Lope, M.D.,1
and Jordi Bruix, M.D.1,2

ABSTRACT

Staging and treatment indication are relevant topics in the management of

patients with hepatocellular carcinoma (HCC) and for optimal results, they have to take
into account liver function, tumor stage, and physical status. For any staging system to be
meaningful it has to link staging with treatment indication; this should be based on robust
scientific data. Currently, the sole proposal that serves both aims is the Barcelona Clinic

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Liver Cancer (BCLC) approach. It takes into account the relevant parameters of all
important dimensions and divides patients into very early/early, intermediate, advanced,
and end-stage. Early-stage HCC patients should be considered for potentially curative
options such as resection, ablation, and transplantation. Patients at intermediate stage
benefit from chemoembolization, whereas patients at an advanced stage, or who cannot
benefit from options of higher priority, have sorafenib as the standard treatment. Finally,
patients at end-stage should merely receive palliative care.

KEYWORDS: Hepatocellular carcinoma, staging, prognosis, treatment, survival

C linical management of patients with HCC is a should not be disregarded: the best health care will be
decision-making process that should be approached achieved when the evidence-based data are combined
following evidence-based data. In that way, the care with the expert medical evaluation that is mandatory
offered to patients will be supported by a reliable back- when managing patients with HCC. It has to be stressed
ground and result in the best available outcomes. Upon that HCC usually affects patients with underlying liver
diagnosis of HCC, patients need to be adequately staged disease2 and this results in the need to carefully evaluate
so that a treatment option may be proposed that would both tumor burden and liver function at the time of
best serve that individual patient.1 Obviously, recom- prognostic prediction and treatment recommendation.1
mendations and guidelines serve to frame the situation, In this article, we explore both aims in the
but ultimately, the decision to be made will never be Barcelona Clinic Liver Cancer (BCLC) current strategy.
automatic, but rather the result of a personalized evalua- The BCLC was first presented in 1999 in Seminars in
tion that takes into account the scientific evidence and Liver Disease3 and constitutes an evolving approach as it
the specific profile of the patient. Any available infor- has regularly incorporated changes that have emerged
mation such as guidelines or consensus documents since its original publication.

1
Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hepatocellular Carcinoma; Guest Editors, Jordi Bruix, M.D., and
Hospital Clı́nic, IDIBAPS, University of Barcelona, Barcelona, Josep M. Llovet, M.D.
Spain; 2Centro de Investigación Biomédica en Red de Enfermedades Semin Liver Dis 2010;30:61–74. Copyright # 2010 by Thieme
Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
Address for correspondence and reprint requests: Jordi Bruix, 10001, USA. Tel: +1(212) 584-4662.
M.D., BCLC Group, Liver Unit, Hospital Clı́nic, c/Villarroel, DOI: http://dx.doi.org/10.1055/s-0030-1247133.
170, Escala 11, 4 planta, 08036 Barcelona, Spain (e-mail: jbruix@ ISSN 0272-8087.
clinic.ub.es).
61
62 SEMINARS IN LIVER DISEASE/VOLUME 30, NUMBER 1 2010

PROGNOSTIC PREDICTION Most research trials exclude patients just because of

Outcome estimation is one of the main questions that this easy and validated assessment.
physicians have to face when a patient is diagnosed with Table 1 describes the proposals that have gained
HCC. Years ago, there was not much difficulty as the more visibility and may have been considered for strat-
majority of the patients were diagnosed at an advanced ifications of patients when including in the analysis all
symptomatic stage that usually coincided with liver evolutionary stages. All of them may successfully divide
decompensation.4–9 There was no difficulty in envision- the cohorts according to outcome, but unfortunately
ing a dismal outcome with no hope for effective therapy. their application in clinical practice and research is not
All type of data can be retrieved from those years to show optimal. As previously commented, identification of
that any indication of advanced cancer stage, heavily end-stage patients is no longer a challenge and some
impaired liver function, and presence of intense cancer- classifications may just gain power because of this
related symptoms, easily predicts poor short-term sur- capacity that would equally be achieved by asking for
vival. Hence, HCC patients with impaired performance cancer-related symptoms. Furthermore, because a stag-
status10 or who fit into the Child–Pugh C category are to ing system should optimally attempt to link prognostic
be classified as end-stage.4–9 Obviously, patients with prediction and treatment indication, any system aiming
Child–Pugh C without HCC should be considered for to be clinically successful has to serve both aims. Un-
liver transplantation11 and if HCC is diagnosed, it may fortunately, this is not the case with any of the scoring or
become a transplant contraindication if not at an early category allocation systems, which, to some extent, may
stage. This is relevant because the evaluation of the include in the same category patients who would be
patient should be done because of end-stage liver disease candidates for curative therapy and patients who would

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and not because of HCC. This distinction is critical merely receive palliation.
when staging is linked to treatment and should be taken Years ago, we approached this problem in a
into account when classifying an HCC patient as end- different way. It is clear that patients with early-stage
stage and not a candidate for any therapeutic option. HCC (whatever definition is used) would be treated by
If end-stage patients are easily identified, it is resection, liver transplantation, or ablation. Those pa-
controversial as to how to establish a stage for those tients with advanced-stage HCC would be considered
patients that are diagnosed prior to such a dismal for chemoembolization (its efficacy was still controver-
scenario. The old division between ‘‘surgical’’ and ‘‘non- sial at that time) or for inclusion in any research trial
surgical’’ makes no sense today, as surgery is no longer with novel agents because there was no therapy with
the sole established therapy that can aim for cure. In proven positive impact on survival for patients who
addition, ‘‘nonsurgical’’ would include those already would not benefit from the three well-established po-
classified as end-stage and also patients with early tentially curative options. According to this concept, we
HCC who would be candidates for ablation. Several had two well-defined populations: early and end-stage;
groups have developed different systems or scores to in the middle group we had a mix of patients with very
permit a stratification of HCC patients escaping from heterogeneous profiles according to liver function
the dichotomous surgical approach3,12–22 Most of them (Child–Pugh A and B), tumor burden (confined to the
result from an analysis of the association of any clinical or liver or with vascular invasion or extrahepatic dissem-
pathology parameter with survival, ultimately resulting ination), and presence/absence of symptoms. The fact
in a division according to an equation derived from the that we had run two prospective trials with an untreated
multivariate Cox regression analysis or to a score ob- control group24,25 allowed us to reevaluate the natural
tained by the sum of the values allocated to the signifi- history of this segment of patients and define their
cant parameters. The value of each variable would vary independent predictive factors for prognosis. Findings
according to the statistical predictive power and in that were straightforward and established the presence of
way balance their relevance. In almost all instances, the constitutional syndrome and cancer-related symptoms
systems are the result of assessing liver function and as per ECOG performance status, presence of vascular
tumor burden; however, it is unfortunate that in some invasion, and/or extrahepatic spread as the sole inde-
patients, there is no assessment at all of the presence of pendent predictors.26 Hence, we could define the so-
cancer-related symptoms.14,15,17,19–21 All physicians called intermediate stage defined by the absence of any
dealing with patients are aware that asking for symptoms adverse predictor, and the real advanced stage that
using the usual ‘‘how do you feel’’ is standard clinical included those with symptoms and/or vascular invasion
practice, and the answer given by patients is always taken and/or extrahepatic spread (Fig. 1). Liver function did
into account. Not surprisingly, assessment of ECOG not emerge as significant as in those trials: the number of
performance status10 or Karnofsky index23 is a well- patients with impaired liver function reflected by ad-
established procedure in an oncology practice. Patients vanced Child–Pugh B stage were a minority. Indeed,
with a performance status >2 carry a grim prognosis heavily impaired liver function is usually associated with
with highly doubtful survival impact of any therapy. impaired physical condition and obvious poor prognosis.
 THE BCLC UPDATE AND FUTURE PROSPECTS/FORNER ET AL 63

Table 1 Prognostic Systems to Predict Outcome in Hepatocellular Carcinoma (HCC) Patients

Author (year) n Tumor Stage Liver Function Health Status

Primack et al (1975)4 72 - Ascites, bilirubin, portal Weight loss

hypertension
Chlebowski et al (1984)6 121 Metastases Bilirubin Age
Okuda et al (1985)12 850 Tumor involvement >50% Bilirubin, albumin, ascites —
Attali et al (1987)7 127 - Encephalopathy, alcohol —
bilirubin, AST, BUN
Falkson et al (1988)8 432 - Jaundice Male sex, PS, appetite, age
Calvet et al (1990)13 206 Tumor size, metastases Bilirubin, serum sodium, Constitutional syndrome, age
BUN, GGT, ascites
Stuart et al (1996)14 314 Portal vein invasion, AFP Albumin —
CLIP (1998)15 435 Tumor morphology, AFP, Child–Pugh —
portal vein invasion
Chevret et al (1999)16 761 Portal vein invasion, AFP Bilirubin, alkaline phosphatase Karnofsky
Llovet et al (1999)26 102 Portal vein invasion, - PS
metastases
Villa et al (2000)17 96 Estrogen receptor status Bilirubin —
CUPI (2002)18 926 TNM, AFP Bilirubin, ascites, alkaline Symptoms

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phosphatase
JIS (2003)19 722 TNM by LCSGJ Child–Pugh —
SliDE (2004)20 177 TNM by LCSGJ Liver damage by LCSGJ, PIVKA —
Tokyo score (2005)21 403 Size, number Albumin, bilirubin —
Bonnetain et al (2008)22 489 Portal thrombosis, AFP, Bilirubin, albumin, ascites Hepatomegaly, hepatalgia,
small HCC Spitzer QoL Index
HCC, hepatocellular carcinoma; AFP, a-fetoprotein; TNM, tumor node metastases; GGT, gamma-glutamyl transferase; BUN, blood urea
nitrogen; PS, performance status; LCSGJ, Liver Cancer Study Group of Japan; QoL, quality of life; small HCC, inside Milano Criteria (1 nodule
<5 cm or 2–3 nodules <3 cm).

This set of data permitted the birth of the first BCLC appears when a wide range of impairment is present.
proposal3 that ultimately became the basis for the strat- At this point it is worth stating that the Child–Pugh
ification of a double-blind placebo controlled trial classification was developed to predict the risk of porto-
testing the efficacy of seocalcitol.27 The trial was systemic surgery for the treatment of variceal bleeding.46
negative, but as a collateral outcome helped to validate Hence, its value outside this initial aim is relevant, but
the stratification using the BCLC model. Later on, the lacks enough capacity to accurately stratify patients
SHARP trial testing sorafenib also followed the same according to prognosis. This is why the Mayo Model
methodology and again, the stratification capacity was for End Stage Liver Disease (MELD) was developed.47
externally validated.28 Finally, the Asian–Pacific trial It is highly useful to predict mortality at 3 months in
also testing sorafenib with positive results confirmed patients with cirrhosis and some have tested if it would
the stratification capacity of the BCLC system in East- serve to predict survival in HCC patients.48 Despite
ern countries.29 In addition to these prospective valida- some positive suggestions in that regard, it is acknowl-
tions, several studies have shown the capacity of the edged that it will be merely useful to detect end-stage
model30,31 and this has prompted its wide recognition patients. However, it will not have any efficacy for the
and endorsement.1,32–34 Obviously, no model is a dogma evaluation of patients where proper stratification is
to stay unchanged and the prospective trials conducted needed. This limitation is valid for all proposals that
so far will give the rationale to incorporate more param- take into account only one of the dimensions to be
eters for a refined stratification. Among them, a-feto- considered: liver function, tumor burden, and symptoms.
protein (AFP) is likely to gain some relevance as it Accordingly, neither the Child–Pugh,46 the MELD,47
emerges as an independent predictor in some of these the TNM classification,49 the estimation of tumor vol-
trials35–41 and also in other studies and prognostic ume,50 the assessment of ECOG/Karnofsky,10,23 nor
systems.15,16,18,42,43 In a recent meta-analysis of all any other unidimensional system will be clinically val-
cohorts of untreated HCC patients, the parameters of uable.
the BCLC system are again identified,44 whereas other Having exposed the tools to use for the ‘‘middle
data suggest a potential prognostic power for AFP.45 class’’ patients, it became obvious that patients at
Clearly, liver function is relevant and its value sure an earlier stage would be better served by different
64 SEMINARS IN LIVER DISEASE/VOLUME 30, NUMBER 1 2010

Figure 1 Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy. As explained in the text, patients diagnosed
with hepatocellular carcinoma (HCC) are stratified into five stages: very early, early, intermediate, advanced, and end-stage
according to tumor burden, liver function and physical condition. Staging is linked to treatment indication according to evidence-

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based data. (Modified from Llovet et al.32) CLT, cadaveric liver transplantation; LDLT, living donor liver transplantation.

prognostic models both at baseline and according to the prediction requires different tools. Baseline tumor size,
treatment proposed and potentially received. Patients multinodularity, AFP concentration, treatment failure to
with earlier stage HCC should be free of cancer-related achieve tumor necrosis and growth while waiting, are
symptoms as per ECOG performance status (several markers of risk of uncontrolled HCC progression and
studies link symptomatic disease to advanced stage and exclusion from the waiting list.62–64 As such, have to be
poor outcome and several others show that early tumors considered when informing prognosis, likelihood of
are unlikely associated to symptoms). Indeed, this is the transplantation, and ultimately, development of priority
rationale for early detection plans based on surveillance: policy. Interestingly, none of these parameters is in-
to detect early-stage disease at an asymptomatic stage cluded in the MELD system; this explains the difficulty
amenable to potentially curative therapy.1 Obviously, in getting an effective and qualitative priority policy for
vascular invasion and extrahepatic disease also exclude HCC patients by granting MELD points. After trans-
early-stage HCC. In a study in surgical patients, we plantation, the outcome prediction is far more complex
established that the presence of portal hypertension and and involves tumor profile,62 but also graft quality,
increased bilirubin predicted a worse outcome as com- etiology of underlying liver disease, and several others.
pared with patients without such findings even if limit- Vascular invasion is associated with higher risk of
ing resection to Child–Pugh A patients.51 Accordingly, recurrence, but even if present just microscopically,
these parameters serve to predict survival in these strata recurrence will affect less than 50% of the surviving
of patients and their value has recently been validated in patients.62 Finally, patients considered for ablation will
Japan.52 Resected patients can have further refinement of not have the data from pathology and differentiation
their prognostic prediction by the presence of established degree will never be robust enough. Vascular invasion
pathology markers of high risk of recurrence: micro- will not be captured and the potential correlation be-
vascular invasion and presence of satellites or additional tween poor differentiation and vascular invasion will not
nodules53 (Fig. 2). Poor differentiation degree is less be useful as HCC 3cm (the optimal candidates for
robust for prediction54 and tumor size may also have ablation) do not frequently show poor differentiation.
reduced power in the absence of satellites or vascular Several studies have shown that prognosis prediction
invasion.55–57 These considerations show that surgical can be refined after therapy as achievement of an
patients require a set of data to predict prognosis that initial complete response is associated to improved
differs from that used for patients undergoing liver survival.41,65,66
transplantation or ablation. Outcome prediction in pa-
tients considered for transplantation should take into
account expected waiting time (it may differ according to GENOMIC PROFILING AND PROGNOSIS
blood group and geographic location)58–61 and liver Molecular biology has experienced a major expansion
function has no impact in outcome. Hence, prognostic and our knowledge about the events that promote cancer
 THE BCLC UPDATE AND FUTURE PROSPECTS/FORNER ET AL 65

further specified when commenting on the different

treatment options.

 The first stratum consists of patients with very early-

or early-stage HCC. Very early stage (stage 0) is
formed by those patients with single HCC 2cm in
a well-compensated cirrhotic liver without portal
hypertension. These patients present what may be
named carcinoma in situ and if treated by resection
have an optimal outcome exceeding 90% at 5 years.73
The presence of vascular invasion and/or satellites is
anecdotal if they correspond to the indistinctly nod-
ular type defined by Kojiro et al.74 A proportion of
such small nodules will show the distinctly nodular
type and in them the risk of vascular invasion and
satellites is slightly higher (27% and 10%, respec-
tively). Establishing an unequivocal diagnosis prior
to resection is a current challenge as this stage should
be the target of early detection plans. Both imaging75
and molecular biology tools76 should help to properly

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define the type of tumor and the risk of recurrence.
With this information, prognosis and optimal therapy
Figure 2 Small hepatocellular carcinoma (HCC) treated by
liver transplantation. Pathology examination shows the al-
should be established.
ready known tumor as well as satellite nodules located in the  Early-stage HCC (BCLC A) classification consists of
vicinity. It is conventional to define as satellites those addi- patients with single HCC or with up to three nodules
tional sites located within 1 cm of the main nodule, but in this <3 cm. Liver function is defined by Child–Pugh A
case obvious satellites were encountered beyond this limit, and Child–Pugh B status not reaching the criteria for
but still in the same segment. transplantation because of impaired liver function
reflecting poor short-term survival and deserving
transplantation in the absence of contraindications.
development and progression has grown in recent As noted here earlier, we already exposed the fact that
years.67 The goal here is to identify the abnormalities we consider in this scheme those patients diagnosed
that reflect a higher risk of cancer and the biologic profile with HCC and being evaluated for it; those with
as well. Genomic studies have attempted to provide the impaired liver function and candidates for transplan-
basis for such refinement and link a specific profile with tation constitute another scenario. Tumor size is an
etiology and prognosis.68–70 However, despite the ap- established criteria for transplant selection77 as the
pealing nature of such an approach, the findings have not proposals for expansion according to imaging infor-
allowed for the incorporation of any criteria in clinical mation at the time of decision making are not yet
practice. The approach should be considered a work in validated. Size is also key for ablation success and
progress as reflected by a recent meta-analysis where all nodules beyond 5 cm are seldom fully necrosed, and
the proposed molecular classifications have been merged the same applies in multifocal nodules
and resulted in a system with just three strata.71 Clearly, <3 cm.39,65,78,79 By contrast (and as mentioned
the future is in this direction, but we are not there yet. above), in some instances HCCs may grow beyond
The same applies to the prediction of recurrence 5 cm and still be compact and show no vascular
after resection and the identification of the profile that invasion or satellites. This is especially frequent in
may predict a higher risk of de novo tumors or response hepatitis B virus (HBV) carriers and justifies no clear
to interventions aimed to prevent this unfortunate cutoff for surgical resection. However, the risk of
event.72 vascular invasion goes in parallel with tumor size;62
hence, such large HCCs should never be classified as
optimal candidates.
THE BCLC STAGING IN 2010  Intermediate stage (BCLC B) is formed by those
All these comments should serve to expose the validity of patients with single large HCCs and those with
the BCLC staging system and treatment allocation that multifocal disease who are asymptomatic and do not
is reflected in Fig. 2 and summarized as follows. The present vascular invasion or extrahepatic spread. Liver
connection to treatment indication is briefly outlined for function is again preserved fitting into Child–Pugh A
each stage, but the rationale for each recommendation is and B classification. If compensated, these patients are
66 SEMINARS IN LIVER DISEASE/VOLUME 30, NUMBER 1 2010

optimal candidates for chemoembolization.1,80 Ex- Table 2 Levels of Evidence According to Study Design
pected median survival is around 16 months with Grade Definition
wide variation according to confounding factors such
I Randomized controlled trials
as prior therapies and degree of renal function impair-
II-1 Controlled trials without randomization
ment with requirement for low sodium diet and
II-2 Cohort or case-controlled analytic studies
diuretics.27 Treatment with chemoembolization im-
II-3 Multiple time series, uncontrolled experiments
proves outcome to a median of 20 months,80–82 and is
III Opinion of respected authorities; descriptive
further expanded according to the achievement of an
epidemiologic studies
objective response, which in part is mediated by the
tumor characteristics. However, there are no robust Adapted from Bruix and Sherman.1
criteria to stratify candidates according to HCC
characteristics.
 Advanced stage (BCLC C). This stage applies to The least robust information comes from personal opin-
patients who have evolved beyond the profile depicted ions and isolated clinical observations, but in several
in BCLC B. They may have symptoms and/or present debates such personal experiences and unusual case
vascular invasion or extrahepatic spread. Any degree reports are proposed as the proof of the value of any
of vascular invasion (segmental or lobar or trunk) has type of atypical or uncommon therapeutic approach. The
the same implications in terms of tumor invasiveness same value could be given to the well-known cases of
and prognosis. Liver function is not well established as spontaneous regression,83 but no one should use these
a prognostic predictor, but the presence of ascites and fortunate observations as the basis to recommend no

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diuretic requirement as well as increased bilirubin level therapy when an effective one would be feasible.
that qualify for Child–Pugh B status may imply a It is also worth stressing that the management
worse prognosis. Advanced Child–Pugh B stage and treatment of patients with HCC should be done in
should raise the consideration of transplant; it is expert settings where all the knowledge and skills related
unlikely that they present as just mildly symptomatic to the specialities involved is readily available.33 Only if
as per performance status. this partnership is in place will optimal care be delivered
 End stage (BCLC D) includes those patients with with state of the art outcomes. All effective options
severe impairment of liver function (Child–Pugh C) should be available (it is acknowledged that liver trans-
who are not candidates for liver transplantation and plantation is not an option in some areas and access to it
those patients with heavily impaired physical con- is unfeasible), but resection, ablation, chemoemboliza-
dition as established by an ECOG performance tion, and sorafenib should be currently considered stand-
status >2. ard of care and be integrated into the treatment
algorithm. Cost is a frequent concern, but this is beyond
the focus of this review and will not be discussed.
TREATMENT STRATEGY
It is important to stress that the aim of treatment is to
improve survival of patients while maintaining the most Treatment of BCLC 0 (Very Early HCC)
preserved quality of life. This apparently simple state- If this entity could be properly diagnosed and the
ment is of paramount importance as quite frequently the absence of vascular invasion/satellites guaranteed, it is
debate of treatment indication is established around clear that the optimal choice would be percutaneous
what can be done, rather than around what is worth ablation. An almost 100% success rate is feasible because
being done. In all life-threatening conditions, physicians of tumor location and if the risk of dissemination is
and patients would like to have an option that would almost zero, the treatment would have a high curative
provide a cure or at least, a significant life improvement. rate—just leave behind the cirrhotic liver with its risk of
However, evidence for such a benefit may not be avail- metachronic tumors. Cohort studies indicate that the
able and this should not serve as a basis for any desperate survival of patients treated by ablation is very similar to
attempt to engage in a treatment approach, but rather as that of resected patients in such a very early stage;84
a trigger for designing a research trial to evaluate pro- hence, both options could be considered equally effec-
spectively the benefits of any therapy that could be tive. However, unequivocal diagnosis of very early HCC
considered potentially effective. Through this approach, is still not consolidated in real practice and ablation may
relevant information will be made available and if strong not be feasible in all cases. Expert surgery may also
and positive, it may become ultimately part of the provide optimal results in expert settings. Because of
standard of care. This raises the need to recall that the the preserved liver function and the low risk of recur-
strength of scientific evidence is ranked as shown in rence, these patients would not need to be considered
Table 2. Major data will come from large randomized for transplantation. However, as said above, because
double-blind placebo controlled trials or even unblinded. diagnosis of this very early HCC is now unreliable, the
 THE BCLC UPDATE AND FUTURE PROSPECTS/FORNER ET AL 67

decision process will in most instances still be the same as time point may be more likely due to metachronic HCC
that of early stage. in the oncogenic cirrhotic liver. Whatever the mecha-
nism, there is no option of proven efficacy to prevent
recurrence in patients with HCV or HBV cirrhosis.63
Treatment of BCLC A (Early HCC) Controlling viral replication may prevent deterioration
There are no large randomized controlled trials compar- of liver function in HBV patients101 and to a lesser
ing any of the available options in patients that would be extent in patients with HCV, but this should not be
optimal candidates for all options. Small trials compar- expected to prevent tumor dissemination (the most
ing surgical resection and ablation report a very similar frequent path to recurrence), but rather potentially
survival rate.85–87 According to available data from impact metachronic oncogenesis at long term.102
cohort studies, the survival and recurrence rate in pa- Large size per se should not be taken as a contra-
tients treated for solitary HCC 2 cm is very similar indication to surgery if staging suggests it is still a
between resection and ablation.84 Ablation has a marked solitary HCC that has grown in a compact way. Risk
decrease in efficacy when tumor size exceeds 3 cm and of liver failure becomes an issue, but if such a big mass
when more than 2 nodules are targeted.39,65,78,79,88,89 occupies the whole lobe, it is already not providing
Current data with both options indicate a 5 year survival normal liver function and tolerance is better than that
of 70% at 5 years in patients with well preserved liver of resection of a small HCC that requires large non-
function, but as previously commented, if portal hyper- tumor removal because of location in the central part of
tension is present and/or HCC is multifocal the survival the liver. As said, the risk of microscopic vascular
rate at 5 years decreases to around 50% for surgical invasion increases in parallel with tumor size, but the

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candidates52,58 and in ablated patients that have not same risk is present in smaller tumors with the same
been considered for surgical resection. Contrarily, liver degree of vascular invasion. In that sense, recent retro-
transplantation would offer a 70% survival rate irrespec- spective assessment of a large surgical series at Mount
tive of liver function,58,77,90,91 but in cases where path- Sinai suggests a correlation with magnitude of vascular
ology shows microscopic vascular invasion and/or invasion and risk of recurrence.103 Prospective valida-
satellites, the risk of recurrence is significantly less tion is needed prior to using this criterion to estimate
compared with surgical resection and ablation. A major outcome.
limitation for the successful application of transplanta- As previously mentioned, ablation is highly
tion is the shortage of donors, which implies a waiting effective and even curative in patients with small
time of varying magnitude. During this period, HCC. However, when the nodule size exceeds 3 cm
the tumor may progress and impede the procedure. the likelihood for complete response and the absence of
Despite the lack of any trial showing the benefits of recurrence within or surrounding the treated nodule is
any adjuvant therapy, it is common practice to perform significantly reduced.39,65,78 The decrease of efficacy
adjuvant therapy by ablation or chemoembolization, with nodule size is well known with ethanol injection
whereas chemotherapy has no efficacy.63 These locore- because tumor septa may prevent adequate tissue dif-
gional interventions may be effective at the individual fusion, but all data indicate that the reduction in
level, but will not address the lack of enough dona- effectiveness is also registered with radiofrequency
tions.92 Thus, a major emphasis has to be placed on any (RF), despite its capacity to induce complete necrosis
action aiming to induce donation, either from a brain and ablation of the peritumoral area, where micro-
death donor or from live donations. The shortage scopic satellites may already be present. The higher
of donors justifies a strict selection of candidates to initial control rate may translate a better outcome in
ensure adequate posttransplant survival. The successful patients treated with RF.88,104,105 Hence, RF is cur-
Mazzaferro criteria77 are still the accepted standards for rently the first ablation technique to be considered and
selection, as all the proposals for expansion have not is established as the standard ablation technique to be
been properly validated using homogeneous radiology beaten by any other technology. High-intensity fo-
definitions for staging.93–97 The same applies to the cused ultrasound is still in the evaluation phase. Un-
so-called downstaging that would allow patients with fortunately, it requires more time for therapy to be
excessive tumor burden to be transplanted if they meet effective; in some instances, it may require higher
the Mazzaferro criteria after any sort of therapy.98–100 invasiveness. Breath movements may impede its suc-
Until these data are available with enough strength, it is cessful application: this is a relevant limiting factor for
not feasible to recommend the acceptance of these its application in liver tumors.106
approaches. Some authors have suggested that tumors beyond
Recurrence during follow-up is frequent after 3 cm could benefit from sequential treatment by trans-
resection and ablation as it affects more than 70% at arterial chemoembolization (TACE) and RF, as also
5 years.36 Early recurrence before 2 years is convention- proposed years ago with ethanol injection.107 Despite
ally attributed to dissemination; recurrence beyond this several suggestive phase 2 studies,108,109 no valid
68 SEMINARS IN LIVER DISEASE/VOLUME 30, NUMBER 1 2010

prospective controlled trial has proven yet the benefit of that this option has antitumor activity,114–116 but un-
this combined approach. fortunately, there is no information available comparing
this option versus any other established treatment.
Hence, its real value is not yet established.
Treatment of BCLC B (Intermediate HCC)
This stratum of patients is formed by patients in whom
resection, transplantation, and ablation have been dis- Treatment of BCLC C (Advanced HCC)
missed because of too large tumor size and/or multi- This has been an area of extensive research as until very
focality; however, they still are asymptomatic and recently, there was no effective therapy to be offered to
maintain a preserved liver function. The standard of those patients that were diagnosed at advanced stage or
care in them is chemoembolization according to the transitioned into it after initial therapy. Chemotherapy
results of randomized controlled trials and cumula- has no activity either intravenously or intraarterially,
tive meta-analysis.80–82 Chemoembolization induces a both if tested as a single agent regimen or in combina-
>50% response rate and this translates in slower tumor tion.117 In addition, in all instances the lack of impact on
progression and improved survival. Some groups propose survival is associated with toxicity that results in im-
to perform TACE even in symptomatic patients or even paired quality of life or even impaired survival.118 Be-
if they have segmental vascular invasion and/or extra- cause of this unmet need, a major expectation was placed
hepatic spread. Impact of therapy is significant in in the potential of targeted therapies that would aim to
patients without symptoms and the existence of vascular abrogate the abnormal molecular events that govern
invasion as detected by imaging increases the risk of tumor progression and dissemination. Several studies

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severe adverse events and liver failure. The same applies identified angiogenesis as one of the most promising
to patients with decompensated cirrhosis or fitting into targets for intervention in HCC.119 It is a highly
Child–Pugh B classification.110 Hence, the patients that vascularized cancer and markers of enhanced vasculari-
will benefit the most from this therapy are those without zation such as VEGF concentration have been correlated
any of these adverse characteristics; those with them may with survival.120 Several agents were in the race for
not benefit at all from this locoregional intervention. success and the one that was unequivocally effective in
Unfortunately, after an initial treatment response, improving survival has been sorafenib. This agent is an
the treated tumors gain vascularization again, the disease oral tyrosine kinase inhibitor that blocks the Raf/MEK/
progresses, and despite repeated treatment sessions, the ERK pathway and the receptor for VEGFR 2 and
capacity to keep the cancer under control is lost. This PDGFR-b.121,122 After showing activity in experimen-
emphasizes the need to develop better techniques to tal models and potential delayed tumor progression rate
perform the procedure and enhance the efficacy of in a large phase 2 study,123 it was tested in a phase III,
chemoembolization by increasing the exposure of the multicenter, randomized, double-blind, trial including
tumor to chemotherapy, while reducing its systemic 602 patients. The median overall survival of sorafenib
toxicity. This has been partially achieved by the use of treated patients treated was 10.7 months versus the
drug-eluting beads that can produce a highly calibrated 7.9 months in those treated with placebo (HR 0.69;
obstruction while simultaneously slowly releasing the 95% CI 0.55–0.87; p < 0.001) (Fig. 3). The impact on
drug into the blood flow. Treatment methodology is survival was preceded by a slower tumor progression that
highly standardized and the efficacy is maintained, if not confirmed the data raised in the phase 2 trial. Median
increased, while avoiding the systemic toxicity due to time to progression (TTP) was 5.5 months in sorafenib-
chemotherapy.111–113 The current challenge is to eval- treated patients, whereas it was just 2.8 months in the
uate a combination of TACE using this refined tech- placebo arm (HR 0.58; 95% CI 0.45–0.74; p < 0.001)
nology with molecular-targeted agents (sorafenib) that (Fig. 4). The most frequent severe drug-related adverse
have been shown to reduce tumor proliferation and events were hand–foot skin reaction, diarrhea, and
angiogenesis (see Treatment of BCLC C section). fatigue.28 The same positive findings have been regis-
It is important to note that arterial embolization tered in a randomized placebo controlled trial in East-
without associated chemotherapy can induce a relevant ern countries.29 Thus, sorafenib is confirmed across
rate of objective tumor response.80 However, there is no geographic regions and in different etiology popula-
proof of a positive impact in survival as proven for tions and is now standard of care for advanced
chemoembolization. Selective arterial injection of che- HCC.32,124
motherapy without arterial obstruction does not result in These results represent a major breakthrough and
relevant antitumor effect and has never been shown to have initiated the quest to develop combination or
improve survival. sequential strategies to further enhance the impact
Recently, a major emphasis has been placed achieved with sorafenib as a single agent. Several trials
on the potential efficacy of radioembolization with are now ongoing (see www.clinicaltrial.gov) and affect
Yttrium-90 labeled spheres. Phase 2 studies confirm several pathways and agents such as mTOR inhibitors,
 THE BCLC UPDATE AND FUTURE PROSPECTS/FORNER ET AL 69

Figure 3 Survival of patients with hepatocellular carcinoma (HCC) in the SHARP trial comparing sorafenib versus placebo in a

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double-blind randomized controlled trial. The median overall survival of sorafenib-treated patients was 10.7 months versus the
7.9 months in those treated with placebo, that represents a 0.69 hazard rate of dying during follow-up (95% CI 0.55–0.87;
p < 0.001).

blockade of aurora kinase, epidermal growth factor, conventional RECIST125 will fail to capture any existing
insulin-like growth factor, c-MET, or fibroblast growth positive signal. New criteria based on functional imaging
factor among several others, while at the same time still measuring perfusion and diffusion will be developed in
acting through the sorafenib mechanisms of action. The the near future and become instrumental for efficacy
critical point will be how to balance the willingness to evaluation. Meanwhile, the most reliable parameter
enhance the antitumoral effect while assuring safety, and should be time to progression. Optimally, studies should
how to evaluate the potential efficacy. In most instances, be run in a randomized fashion so that a comparator is
there is no reduction in tumor burden and hence, available to ensure unbiased assessment.32

Figure 4 Time to tumor progression of patients in the SHARP trial. Median time to progression (TTP) was 5.5 months in
sorafenib-treated patients, whereas it was just 2.8 months in the placebo arm (HR 0.58; 95% CI 0.45–0.74; p < 0.001). Because
sorafenib administration was not associated with any tumor burden reduction as per Response Evaluation Criteria in Solid
Tumors (RECIST) criteria, the efficacy of the drug in improving survival is mediated through this impact in tumor growth and
dissemination.
70 SEMINARS IN LIVER DISEASE/VOLUME 30, NUMBER 1 2010

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Reig is funded by a grant of the BBVA foundation.
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