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Systemic treatment

From Volume 28 Number 5 October 2014
Hepatocellular carcinoma: current state of the art in diagnosis and treatment

Jordi Bruix and Massimo Colombo
Guest Editors

Best Pract Res Clin Gastroenterol. 2014;28(5):921-35


In the last years the management of patients with liver cancer has been improved. The BCLC staging/treatment strategy identifies the optimal candidates for each treatment option and sorafenib is the only effective systemic treatment. Others (sunitinib, brivanib, linifanib, everolimus, ramucirumab) have failed in terms of safety/survival benefit. Some patients at intermediate/early stage, may be considered for systemic therapy when options of higher priority may have failed or not be feasible. The 800 mg/day is the recommended starting dose. Close follow-up and easy access for the patients so that they can report any adverse event and implement dose adjustments is the key point in the management of them. Development of early dermatologic adverse events has been correlated with better outcome and the pattern of radiologic progression characterizes better the prognosis/outcome of these patients. Treatment beyond progression may be considered if there is no option for a second line research trial.

Keywords: Hepatocellular carcinoma, Systemic treatment, Patients selection, Management, Tumour response, RECIST.


Treatment of hepatocellular carcinoma (HCC) should aim to improve the survival of the patients with a proper balance between risks and benefits. The BCLC staging and treatment strategy[∗1] and [∗2]( Fig. 1 ) serves this aim as it incorporates the effective options that are now fully accepted according to proper data and identifies the optimal candidates for each options. The survival benefit offered by a given option should have been demonstrated through robust investigations. The optimal method is through phase 3 randomised trials that compare any proposed intervention versus the standard of care if this exists, or versus no treatment if such established approach is not available [3] . Interestingly, such high quality evidence is not available for options that aim to provide complete removal of the malignant disease (surgical resection, ablation and liver transplantation) and the evidence is based on cohort analysis with major validation by independent groups [4] . For intermediate BCLC B stage there is adequate evidence through randomized trials and metanalysis to have transarterial chemoembolization as first option[5], [6], and [7]. Until the development of sorafenib no systemic approach had shown to improve survival, and now this agent constitutes the first line intervention for patients with advanced BCLC C stage HCC and for patients with earlier stages that cannot receive the treatment that would correspond to such stage.


Fig. 1 BCLC staging and treatment strategy [modified from Forner et al (Lancet 2012; 379:1245–55)]. The figure represents the first approach to the evaluation of the patients with expected prognosis and initial treatment option to be considered. As shown, the upper part of the scheme defines prognosis according to the relevant clinical and tumour related parameters. Bottom part depicts the decision process to select a treatment option for first consideration. As in all recommendations, final treatment indication should take into account a detailed evaluation of additional characteristics (age, comorbidties) of the patients that imply a personalized decision making. * Note that Child-Pugh classification is not sensitive to accurately identify those patients with advanced liver failure that would deserve liver transplant consideration. Some patients fitting in Child-Pugh B, and even A, may present a poor prognosis because of clinical events not captured by such system, ie: spontaneous bacterial peritonitis, recurrent variceal bleeding, refractory ascites with or without hepatorenal syndrome, recurrent encephalopathy, severe malnutrition. ** Patients with end stage cirrhosis due to heavily impaired liver function (Child-Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. Among them, HCC may become a contraindication if exceeding the enlistment criteria.

The BCLC staging and treatments strategy[∗1] and [∗2]links initial staging for prognosis estimation with the first line option to be considered. It has been reviewed in extense elsewhere[∗1], [∗2], and [8]and in this chapter we will review the current approach for systemic treatment and the still unmet needs in this field.

Systemic treatment

Conventional chemotherapy has never been proven to improve survival. Several agents alone or in combination, administered intravenously or selectively into the hepatic artery have never proven their benefit. In some areas the intrarterial injection of chemotherapy is based in its emulsion in lipiodol. This aims to enhance tumour cells exposure to the drug while reducing systemic adverse events. Unfortunately, the emulsion in lipiodol is not stable and the advantages of such administration are not established. A recent trial suggested that folfox-4 regime was effective as it compared positively with doxorubicin administration [9] . However, the primary endpoint of the study (survival) was not met and hence, there is no scientific strength to support this view. Agents such as antiestrogens [10] , antiandrogens [11] , vitamin D derivatives [12] or interferon [13] have also failed to offer benefit.

This negative situation primed the research of novel agents that would target molecular mechanisms driving proliferation, angiogenesis or apoptosis. The list of agents that have been raised during the recent years is quite extense but only a minority have reached advanced phase 2 leading to phase 3 ( Table 1 ). Among them, the only one that has been successful to improve the survival of the patients is sorafenib[∗14] and [∗15].

Table 1 Phase III, first and second line trials done in advanced hepatocellular carcinoma.

First line
Drug in study Author Year Randomized drugs n DCR (%) p Value TTP (mo) p Value OS (mo) p Value
Sorafenib Llovet et al. 2008 Sorafenib vs. Placebo 299/303 43 vs.32 0.002 5.5 vs. 2.8 <0.001 10.7 vs. 7.9 <0.001
Cheng et al. 2009 150/76 35.3 vs.15.8 0.0019 2.8 vs. 1.4 <0.001 6.5 vs 4.2 0.01
Sorafenib plus Erlotinib Zhu et al. 2012 Sorafenib + erlotinib vs. sorafenib 362/358 43.9 vs.52.5 NS 3.2 vs. 4 NS 9.5 vs 8.5 NS
Linifanib Cainap et al. 2012 Linifanib vs. sorafenib 514/521 NR NR 5.4 vs. 4 0.001 9.1 vs 9.8 NS
Sunitinib Cheng et al. 2013 Sunitinib vs. sorafenib 530/544 50.8 vs.51.5 NS 4.1 vs. 3.8 NS 7.9 vs 10.2 NS
Brivanib Johnson et al. 2013 Brivanib vs. sorafenib 577/578 66 vs. 65 NS 4.2 vs. 4.1 NS 9.5 vs 9.9 NS
FOLFOX-4 Qin et al. 2013 FOLFOX-4 vs. doxorrubicin 184/187 52.2 vs.31.5 <0.001 NR NS 6.4 vs4.9 NS
Second line
Drug Author Year Drug n DCR (%) p Value TTP (mo) p Value OS (mo) p Value
Brivanib Llovet et al. 2013 Brivanib vs. placebo 263/132 61 vs.40 <0.001 4.2 vs. 2.7 0.001 9.4 vs 8.2 NS
Everolimus Zhu et al. 2014 Everolimus vs. placebo 362/184 56.1 vs. 45.1 0.01 2.9 vs.2.6 NS 7.6 vs. 7.3 NS

Child = Child-Pugh score; PS = performance status; BCLC = Barcelona Clinic Liver Cancer.

DCR = disease control rate; TTP = time to progression; OS = overall survival.

NS = not significant; NR = not reported.


This agent is a multikinase inhibitor that inhibits tumour-cell proliferation and tumour angiogenesis and increases the rate of apoptosis in a wide range of tumour models. It acts by inhibiting the serine–threonine kinases Raf-1 and B-Raf and the receptor tyrosine kinase activity of vascular endothelial growth factor receptors (VEGFRs) one, two, and three and platelet-derived growth [16] . In a single arm phase 2 trial [17] it was shown that the drug had an adequate safety profile, but it did not induce a significant rate of treatment responses according to the conventional oncology RECIST criteria [18] . As a consequence the study was classified as negative and the further development of the drug was controversial. In that sense, it was realised that the tumour progression rate and the survival of the treated patients were encouraging if compared with the available data derived from prior prospective investigations[5], [6], [7], [10], [11], and [12]. In addition, in some patients treatment was associated to significant tumour necrosis indicating a certain activity. Because of these data, it was decided to run a phase 3 trial of sorafenib vs best supportive care in a large Western population [14] . At the same time, a similar trial was launched in Asian-Pacific population [15] . Both investigations obtained positive results and of the same magnitude. Overall survival in the Western trial was improved from 7.9 months in the placebo arm to 10.7 months in the sorafenib arm. This represented a HR of 0.69 reflecting a 30% increase in the likelihood to be alive during follow-up. The survival in the Eastern trials was lower due to the recruitment of patients at a more advanced stage. Patients in the placebo arm had a median survival of 4.2 months while this was 6.5 in the control arm. The magnitude of improvement was the same as in the Western trial confirming that the drug was active in all populations. Subgroup analysis showed that the benefits of the drug were no affected by gender, aetiologies of underlying disease, degree of liver function impairment or tumour burden[19] and [20]. The search of biomarkers to identify patients with significantly higher benefit or those not benefitting of treatment did not offer meaningful results [21] . Thus, sorafenib is now the established first line option for HCC patients being considered for systemic therapy[∗4], [∗22], and [23].

The results of the pivotal sorafenib trials confirmed the phase 2 findings of improvement in survival in the absence of significant tumour burden reduction[∗14] and [17]. Sorafenib showed a higher disease control rate and significantly delayed tumour progression and this is translated into survival improvement without significant impairment of the quality of life. Indeed sorafenib was safe and treatment related adverse events were manageable. The most frequent were hand food skin reaction, asthenia, diarrhoea and arterial hypertension[∗14], [∗15], [∗24], and [25]. Interestingly, the incidence of AE is higher in Asian patient [15] , and recent studies have shown that the emergence of drug related adverse events correlates with better outcome[∗24], [26], and [27].

The design of the sorafenib trials introduced several novelties that are relevant [14] . The target population was selected to have a well preserved liver function (Child-Pugh A) so that the competing risk of death due to liver function impairment because of underlying liver cirrhosis was minimised. Thus, the potential to capture the benefits of sorafenib was facilitated. Patient stratification was done following the BCLC parameters and this ensured the needed balance between treatment arms by avoiding the misguiding selection based on ‘unresectable’ HCC. However, the most relevant aspect was the possibility to keep on treating patients even beyond radiology progression. Treatment was to be maintained until symptomatic progression as it was envisioned that some disease progressions at radiology would not reflect treatment failure. They could correspond to the recognition of already existing sites or the appearance of minute additional nodules without prognostic impact. At the same time, the fact that sorafenib was envisioned as a ‘brake’ prompted the concept of ‘not releasing the brake if there is slight motion’. This design was sure relevant as later studies in our unit have shown that progression pattern determines post-progression survival [28] . Obviously, disease progression in general has a negative impact in survival, but some progressions do not have such negative implications. Thereby, new intrahepatic sites and growth of already known tumour sites are not independent predictors of survival [28] . By contrast, new extrahepatic nests or appearance of vascular invasion are highly relevant, together with liver function impairment or increase in cancer related symptoms as measured by PS [28] .

A key aspect in the assessment of disease progression is the definitions to be used. The WHO criteria [29] with size cut-offs to establish size reduction or increase, were developed at a time were such measurements were done by palpation and without any analysis of the correlation with survival [30] . The cut-offs have been kept when tumour burden is measured by radiology with just slight refinements to accommodate bidimensional measurements or volumetric analysis. This may explain why mere tumour growth may not be relevant. The definitions for new tumour sites have also experienced a sequential refinement and in the sorafenib trials it was needed to develop some amendments to the established RECIST criteria[18] and [∗31]. The most important affected the need to classify newly detected ascites or pleural effusion as progression only if proven by pathology. Since lymph nodes in the hepatic hilum may be observed in patients with cirrhosis such finding would be classified as malignant if size were more than 2 cm or with arterial vascularization. New intrahepatic HCC sites should also display a specific pattern to be registered as progression. Thereby, nodules <10 mm should be reported as Inconclusive; nodules ≥1 cm in longest diameter showing arterial hypervascularization should be classified as progression; Nodules larger than 10 mm but not showing arterial vascularization would not reflect progression until growth beyond 20 mm. Portal vein thrombosis would be classified as malignant if it would be expansive with arterial vascularization (in some cases malignancy could be proven by biopsy). All these concepts and definitions are key for the optimal management of sorafenib treatment that is commented below.

Sorafenib in conventional clinical practice

Sorafenib is the standard of care for advanced HCC patients and it is the first treatment option in the BCLC strategy for BCLC-C patients (performance status ≤2, Child-Pugh A–B and/or extrahepatic spread and/or vascular invasion)[∗4], [∗22], and [23]. However, in clinical practice sorafenib is also indicated in patients with early or intermediate HCC stages who are not candidates for curative or locoregional treatments due to ‘treatment stage migration’ and/or ‘untreatable progression’[32] and [33]. The first possibility is represented by patients with intrahepatic HCC with compensated cirrhosis and good performance status (intermediate HCC stage) but in whom it is not technical possible or advisable to perform TACE due to diffuse, multifocal bilobar HCC. The technically untreatable progression category is formed by those patients who despite of at least two initial consecutive TACE sessions do not present objective response or develop new HCC lesions that cannot be treated by TACE because of vascular invasion/extrahepatic spread, or because they present liver function impairment or cancer-related symptoms exceeding the criteria used to indicate TACE at first. Finally, patients who were diagnosed at early stage and received surgery, liver transplantation and/or loco-regional treatments but developed recurrence/disease progression and reached advanced HCC stage (evolutionary progression) are also considered for sorafenib after transition through to several therapeutic options in a sequential manner.

Before the incorporation of sorafenib in clinical practice, TACE was the last effective option of treatment for HCC. Thus, it could have been applied even in suboptimal candidates. While initial morbidity or mortality could be seen as acceptable, the long term survival results were clearly less encouraging that the data in optimal patients as defined in AASLD and EASL practice guidelines[∗4] and [∗22]. The fact that it is technically feasible should not prime the use of TACE without proper criteria and patients may now benefit from sorafenib and achieve similar outcome. Regardless of the lack of evidence and the risk of decompensation due to TACE some groups have treated advanced HCC with TACE. Table 2 exposes the outcome of several series of TACE treated patients including optimal and suboptimal candidates to allow comparison with the data obtained with sorafenib. The reported survival is highly heterogeneous and this sure is due to the lack of widely accepted criteria about when to start TACE and when to interrupt it because of failure to achieve response or development of contraindications. As mentioned before the selection of patients to be started on TACE are exposed in the guidelines and the simplest strategy to interrupt it is to apply two criteria: – absence of response after to follow-up TACE sessions beyond the initial procedures during follow-up, and/or disease progression beyond the initial selection criteria for TACE (this includes appearance of vascular invasion or extrahepatic spread) – development of liver function impairment or cancer-related symptoms beyond the limits used to start TACE. In such instance, patients should be optimally considered for sorafenib.

Table 2 Cohorts of HCC patients treated with transarterial chemoembolization; including optimal and suboptimal candidates.

Author–year Year Number of patients Staging system End point PS 1–2 Child B–C with ascitis Portal vein thrombosis M1 TACE Number of TACE (median-range) Median OS(95%CI)-months
Takayasu et al 2006 8510 TNM OS NR Yes* Yes No Lipiodol + not especifal chemiotherapy NR 34
Sacco et al 2009 71 TNM OS NR Yes Yes Yes Lipiodol + epirubicina 1.4 (±0.61) mean OS probability at 24: 98.18%
Takayasu et al 2010 8507 TNM OS, efficacy and/or superiority of TACE with or without embolization NR Yes* Yes No Lipiodol + doxo or epirubicin or mitomycin C or cisplatin or zinostatin NR 33,12
Lewandowski et al 2010 172 BCLC + TNM OS and TTP Yes Yes Yes Yes Cisplatin + Doxo + lipiodol + mytomycin C 2 (1–5) BCLCA: 40


Malagari et al 2012 173 OKUDA + BCLC five year OS Yes Yes Yes No DEB-DOX mean 5,6 (1–9) mean 43.8 (1.2–64.8)
Georgiades et al 2012 116 NA Response after two TACE and Yes Yes No No Cisplatin + Doxo + lipiodol + mytomycin C NR NR
OS according response
Terzi et al 2012 151 BCLC Outcome after 1st TACE, 2nd TACE, OS Yes Yes Yes No Doxo + lipiodol NR NR
Kudo et al 2013 253 (placebo arm) NR OS NR NR NR NR NR NR 26.1
Jung et al 2013 114 (only 98 analized) BCLC Differences among Who, RECISt, mRECIST, EASl to predict OS and TTP Yes Yes Yes NR Adriamycin + lipiodol NR BCLCA: 47.2


BCLCC 13.7
Sieghart et al 2013 107 (T)

113 (V)
ART score NR Yes No No T = DEB/lipiodol/TAE

V = Doxo + lipiodol
T = 3 (2–12)

V = 3 (2–20)
T = 16.2 (13.4–19)

V = NR
Vandecaveye et al 2014 30 Predictive utility of Diffusion MR NR Yes NR NR DEB-DOX/Doxo + lipiodol 3 (1–4) 17 [range 4–69]
Kim et al 2014 855 OS after remaining, progressing or recurring HCC NR Yes Yes Yes Doxo + lipiodol NR 18.8 (16.6–21)
Moschouris et al 2014 47 mRECIST and CEUs as predictors of response NR Yes Yes NR DEB-DOX + Hepassferes NR 33 (12.27–53.74)
Golfieri et al 2014 88 (cTACE) and 89 (DEB-TACE) Compare two-year OS between two arm No Yes No No Lipiodol + Epirubicin/DEB-DOX NR 29 (Expected survival in both goup)
Hucke et al 2014 109 BCLC + TNM Validation ART score in pts with more than three TACE NR Yes No No DEB-DOX/Doxo + lipiodol/TAE 4 (3–20) 17.1 (11.4–22.7)

Child = Child-Pugh score; PS = performance status; BCLC = Barcelona Clinic Liver Cancer; M1 = extrahepatic spread.

OS = overall survival.

T = training cohort.

V = validation cohort.

*using the Liver Damage classification defined by the Liver Cancer Study Group of Japan.

Pretreatment evaluation of patients

This should consider several aspects including tumour burden, liver function status and presence of comorbidities that may increase the probability of treatment related adverse events [34] . If liver function if severely impaired, administration of sorafenib should be carefully weighted. Variceal bleeding should be controlled and inactive for 30 days. Ascites should be easily controlled by low sodium diet and/or low dose of diuretics. This would fit into Child-Pugh A status or just Child-Pugh B seven points without ascites or encephalopathy. It is important to stress that Child-Pugh status does not accurately predict survival [35] . Some relevant parameters or events are not taken into account and may predict poor short term prognosis: spontaneous bacterial peritonitis, hyponatremia, hepatorenal syndrome or malnutrition [36] . Therefore, expert hepatologist insight is key to avoid interventions in patients in whom prognosis is already poor because of the underlying advanced cirrhosis. MELD score [37] may capture such patients but in some cases neither Child-Pugh [35] , nor MELD [37] will identify such dismal clinical status.

Major consideration should be given to cancer-related symptoms. The PS scale is very useful in that regard. It has a correlation with the Karnofsky index ( Table 3 ) [38] and it is common to avoid treatment of patients beyond PS 1. The analysis of research trials shows that even if PS 2 patients are allowed to enter, they are always a minority and their survival is very short. Hence, treatment benefit may not be significant.

Table 3 Proposed conversion table for KP and ECOG. a

100 0
90 1
70 2
50 3
30 4

a Table adapted from Ma et al [38] .

KPS = Karnofsky performance status.

ECOG = Eastern Cooperative Oncology Group.

Tumour burden is not a limitation but it is important to have a proper staging by imaging. This is key to detect progression and inform patients about the evolutionary status of their condition and their life expectancy. As mentioned before, not all disease progressions detected during follow-up have negative impact in survival and the decision to stop treatment and enter into a second line research trial has to be carefully weighted [28] . It is worth to recall that in the sorafenib pivotal trials treatment was maintained until symptomatic progression[∗14] and [∗15].

Age by itself is not a relevant parameter but prior cardiovascular events should be recorded and the potential risks of an antiangiogenic agent carefully gauged. Patients with arterial hypertension should be treated according to standard recommendations so that arterial pressure is properly controlled. Active vascular disease (coronary or peripheral) should be considered a contraindication. Concomitant medication should be monitored to avoid potential interaction [34] .

The recommended starting dose is 800 mg/day as this was the dose used in SHARP trial that demonstrated the survival improvement [39] . Treatment related adverse events (AE) emerge in almost all patients and this should prime dose adjustments. Some authors suggest modifying the starting dose to a half dose[40] and [41]aiming to reduce the risk of developing AE and planning to increase dosage if the drug is well tolerated. No prospective study has shown the benefits of such strategy and indeed, it may prevent effective drug exposure and treatment efficacy. Thus, the recommendation is to start at full dose and establish close follow-up and easy access for the patients so that they can report any adverse event and implement dose adjustments as needed[∗4] and [∗22]. The median time between sorafenib initiation and first dose modification due to AE in prospective investigations is around 20 days and this stresses the need for close follow-up by the attending team within which a specialized nurse may play a principal role[∗24], [∗28], and [34]. Interestingly, development of dermatologic adverse events is a predictor of better OS [24] ( Fig. 2 ). Transient treatment interruption due to AE does not impact outcome, while definitive interruption is a predictor of worse survival [28] . Accordingly, expert management is key to avoid improper treatment maintenance/interruption.


Fig. 2 Time to progression and overall survival according to the presence of dermatologic adverse events within the first 60 days (DAE60). TTP was significantly different according to the presence of DAE60 (p = 0.016): [8.1 months (CI95%:1.6–14.5) vs. 3.9 months (CI95%:2.08–5.7) (Panel A). We also observed a different OS when dividing the patients according to the presence or not of DAE60, 18.2 months (95% CI; 11.9–24.4) in patients with DAE60 vs. 10.1 months (CI 95%: 10.1–13.0) in patients without them (p = 0.009) (Panel b).

Management of adverse events and cirrhosis complications

The risk of developing cirrhosis complications is in place during the whole treatment and it should be evaluated in every visit. The severity of the specific sorafenib adverse events is done according to the Common Terminology of Adverse Events (CTCAE). For mild adverse events (Grade I) symptomatic treatment is recommended. For moderate (grade II) or severe AE (grade III/IV) it is needed to adjust dosing ( Fig. 3 ). The BCLC divides the AE according to their time of appearance.Very early and early AEare those that appear within the first two months. They are: arterial hypertension, dermatologic skin reaction (hand–foot reaction, folliculitis, rash and erytema), gastrointestinal symptoms (increase in bowel movements without diarrhoea or constipation), asthenia or weight loss.Intermediate AEare those that appear between the second and the sixth months and they are: new dermatologic reaction (dry skin, folliculate or pruritus), cardiac rhythm alteration and others less frequent such as voice changes, pancreatitis or proteinuria. Finally, events that appear beyond six months are classified aslate AE. The most frequent are ischaemia or peripheral vascular disease and they are related to the antiangiogenic mechanism of sorafenib ( Fig. 3 ).


Fig. 3 Management of the adverse events in patients with HCC treated with sorafenib according to the BCLC recommendation. It is based on the time of appearance and severity of the event (sorafenib related adverse event, no-sorafenib related adverse event or cirrhosis complication).

It is important to distinguish if a given clinical event represents a complication of cirrhosis that could appear independently of sorafenib, a consequence of tumour progression, or if it is truly an AE potentially related to the drug. If the event needs interruption of sorafenib, the decision to re-start treatment will depend on this distinction. For example, if a patient presents a liver dysfunction defined by the impairment of the Child-Pugh score, it could be related to an increase of bilirubin, a decrease of the albumin or to the development of ascites or encephalopathy. In most instances, these events may reflect liver function impairment. However, they could sometimes be related to confounding factors, which are not related to liver dysfunction ( Fig. 4 ). An increase of indirect bilirubin may be due to the interaction of sorafenib with bilirubin metabolism. A decrease in prothrombin time may be due to concomitant medication (acecumarol should be carefully adjusted if administered). Encephalopathy may be facilitated by drug related constipation and is easily solved. Thus, critical insight into all aspects is mandatory.


Fig. 4 Factors related to Child Pugh impairment but not related to a true liver dysfunction in HCC patients under sorafenib treatment. BCLC approach.

The performance status deterioration is a big issue in the management of this population because it is one of the specific AE of sorafenib [24] . For this reason, it is important to accurately establish the baseline PS and if it deteriorates evaluate if this is sofarenib related or due to disease progressions. In this case, transient treatment interruption will solve the doubts.

Tumour response evaluation

As mentioned, sorafenib treatment does not reduce tumour burden even if it is efficacious[∗14] and [∗15]. Hence, novel instruments to detect the effects of sorafenib are actively searched. Unfortunately, we do not have yet robust tools for this aim. Tumour marker evolution is suggestive but not reliable [21] . Dynamic imaging techniques have also been proposed but up to now there are no criteria to correlate changes in tumour perfusion by any technique and outcome. Modifications of conventional RECIST criteria such as Choi [42] , RECICL [43] or mRECIST [44] have been raised but all proposal need to be prospectively tested to assess their validity for proper decision making.

In oncology disease progression by radiology is assumed to reflect treatment failure and prime treatment interruptions. As mentioned before, this has not been adequately validated and in conventional practice it is valid to follow the strategy applied in the pivotal trials: maintain treatment until symptomatic progression [14] . If criteria to accurately detect treatment failure and escape from sorafenib are developed, this recommendation may be changed. Monitoring of disease status is recommended every 6–8 weeks in order to inform patients about disease evolution. This may not impact clinical decision but clinical care includes informing patients about evolution of their disease and expected prognosis.

Novel drugs and current research

The success of sorafenib primed a major research activity around molecular targeted drugs that could exceed the benefits of sorafenib either as a single agent or in combination with it. Interest has been placed also in second line options after intolerance to sorafenib or progression under it. Unfortunately, none of the trials conducted have offered positive results ( Table 1 ). Combinations with everolimus aiming to block complementary pathways have shown toxicity and lack of efficacy[45] and [46]. Same negative outcome has been found with the combination with erlotinib, an agent acting in the EGF realm.

Head to head trials versus sorafenib testing sunitinib [47] , brivanib [48] and linifanib [49] in first line have also failed because of toxicity and lack of survival benefit ( Table 1 ). In second line brivanib [50] , everolimus [51] and ramucirumab [52] have also failed ( Table 1 ). This series of failures has raised the need to critically evaluate why encouraging results in preclinical and early clinical testing in phase 1–2 have not been confirmed in phase 3. An easy reason is that drugs were not good enough, but it may also be that trial design has not been optimal. This may affect the target population to be recruited (prior evolutionary events may be relevant to define prognosis). Similarly, it could be argued that patients to be recruited are heterogeneous in terms of molecular mechanisms involved in disease progression. Hence, trial enrichment according to the pathways to be affected by the drug to be tested may be a promising strategy as has happened in other neoplasms. However, for this concept to be successfully applied it is mandatory to have an accurate tool to identify such molecular status. In addition, the mechanism in place should be relevant enough to determine the prognosis of the disease and the drug to be tested should effectively targets it with enough potency. All these steps are not secured by any of the available research proposals and identification of the target population is based in biopsy of the tumour. This has major limitations to be reliable as tumours are heterogeneous across nodules and also along evolution.

In any case, the repeated failures have been a learning experience. Conventional end-points in Oncology have failed to have a surrogacy for survival. The frequently definitions of disease control rate [51] , time to progression[49] and [50]and progression free survival [47] have not consistently been a surrogate of better or worse survival. Hence, this lack of predictive value should be taken into account in the future development of new therapeutic strategies.

Currently, several phase 3 trials testing new agents are in place. Novel agents such as lenvatinib are tested head to head vs sorafenib after the successful results in thyroid cancer [53] . In first line, sorafenib is also challenged by radioembolization in patients with liver only disease in a head to head trial (NCT01482442), but trials are also in place testing the combination of sorafenib with radioembolization (NCT01900002). The second line setting is also very active. The METIV trial (NCT01755767), testing Tivantinib in an enriched population as per c-met positivity is the only one that incorporates molecular profiling into the selection of the target population. This is the result of the data raised in a randomized phase 2 trial in which c-met positive status predicted an improved survival when patients were treated with tivantinib. Phase 3 trial testing cabozantinib (a c-met inhibitor) (NCT01908426) does not select the target population as per molecular status and the same stands for the trial testing regorafenib in patients progressing under sorafenib (NCT01774344).

Finally, some studies may face different strategies. A USA trial evaluated the combination of sorafenib with chemotherapy (NCT01015833), while some pursue the benefits of modified doxorubicin formulation (NCT01655693). A phase 1–2 trial assesses the potential development of a MEK inhibitor (remafenib) [54] in patients with ras mutations. This is a very infrequent abnormality (more usual in colorectal cancer) but as shown in lung cancer testing crizotinib [55] , such small niche may be a successful opportunity for targeted drug development. In addition, interventions based in virus mediated oncolytic immunotherapy [56] that reactivate immune surveillance[57] and [58]or modulation of gene methylation [59] are another area of interested research. Recent advancements in melanoma fuel the interest in this approach and hopefully, intensive research may be in place and ultimately turn into a major success.


This chapter reviews all the literature about systemic treatment in HCC and the impact of it on the clinical practice and research. It discusses the controversial aspects that affect systemic treatment initiation and maintenance, how should response to treatment be evaluated and what are the needs that are faced by current research. Up to now the only systemic treatment used in clinical practice is sorafenib; other agents (sunitinib, brivanib, linifanib, everolimus, ramucirumab) have failed in terms of safety/survival benefit. The conventional end points that were used in clinical trials (progression free survival, time to progression and disease control) need to be refined because all the phase 3 evaluation of these agents has not fulfilled the expectations generated. This has raised doubts about the validity of the tools used in preclinical or early clinical testing. Thus, the time dependent events developed during treatments, such as early dermatologic adverse events in sorafenib treatment, liver function or performance status modifications as well as the pattern of progression are key to better characterize the prognosis of patients and is also useful for the designing clinical trials. The recommended starting dose is 800 mg/day and a close follow-up is key to optimize the management of these patients. Before implementing a sorafenib dose adjustment, is needed to rule out the potential confounding factors related to Child-Pugh impairment but not to liver dysfunction and distinguish between sorafenib and cirrhosis complication. Treatment beyond progression may be considered if there is no option for a second line research trial.

Practice points


  • The BCLC staging system is recommended for defining the prognosis and first option treatment in hepatocellular carcinoma (HCC).
  • Sorafenib is the only effective systemic treatment in HCC. All phase 3 trials in advanced HCC testing new agents (sunitinib, brivanib, linifanib, everolimus, ramucirumab) have been negative.
  • Patients who are candidates for systemic treatment with sorafenib should present a compensated liver disease with good performance status and low cardiovascular risk.
  • The recommended starting dose of sorafenib is 800 mg/d and dose adjustments may be needed according to the development of adverse events. Dermatology adverse events are associated with better survival
  • Treatment may be maintained until symptomatic progression.
  • Pattern of progression is a relevant predictor to estimate overall survival in patients under sorafenib.
Research agenda


  • Sorafenib is the only effective systemic treatment in hepatocellular carcinoma, but the precise mechanism of the balance between efficacy and safety is not known.
  • No biomarkers have been identified to predict response to treatment and better survival, and this is a relevant unmet clinical need.
  • Development of dermatologic adverse events is associated with better survival and the molecular basis for this association needs to be investigated.
  • Pattern of tumour progression at radiology is a relevant predictor of overall survival in patients under sorafenib. This exposes the need to refine the current definitions of progression in order to distinguish relevant progression events from those without prognostic impact.
  • The survival benefits obtained by sorafenib are significant but limited. Hence, novel strategies in first and second line are needed to further improve the outcome of the patients.

Conflict of interest

Jordi Bruix: consulting for Bayer Schering Pharma, Pharmexa, Eisai, Lilly, Biocompatibles, ArQule, BioAlliance, Novartis, ImClone, Schering-Plough, MedImmune, Roche, Abbott, BMS, Jennerex, OSI, Sanofi, GSK, AngioDynamics, Celgene, Terumo, Syrtex and Kowa. Research funding by Bayer Schering Pharma.

Maria Reig: consulting for Bayer.

Financial support

No financial support was received to prepare this manuscript.


This study has been supported by grants from the Instituto de Salud Carlos III (JB; PI11/01830) CIBERehd is funded by Instituto de Salud Carlos III.


  • ∗[1] A. Forner, J.M. Llovet, J. Bruix. Hepatocellular carcinoma. Lancet. 2012 Mar 31;379(9822):1245-1255 Crossref
  • ∗[2] Reig M, Darnell A, Forner A, Rimola J, Ayuso C, Bruix J. Systemic therapy for hepatocellular carcinoma. The issue of treatment stage migration and registration of progression using the BCLC refined RECIST. Semin Liver Dis. 2015.
  • [3] J.M. Croswell, B.S. Kramer. Clinical trial design and evidence-based outcomes in the study of liver diseases. J Hepatol. 2009 Apr;50(4):817-826 Crossref
  • ∗[4] J. Bruix, M. Sherman. Management of hepatocellular carcinoma: an update. Hepatology. 2011 Mar;53(3):1020-1022 Crossref
  • [5] J.M. Llovet, M.I. Real, X. Montana, R. Planas, S. Coll, J. Aponte, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1734-1739 Crossref
  • [6] C.M. Lo, H. Ngan, W.K. Tso, C.L. Liu, C.M. Lam, R.T. Poon, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002 May;35(5):1164-1171 Crossref
  • [7] J.M. Llovet, J. Bruix. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003 Feb;37(2):429-442 Crossref
  • [8] C.R. de Lope, S. Tremosini, A. Forner, M. Reig, J. Bruix. Management of HCC. J Hepatol. 2012;56(Suppl. 1):S75-S87 Crossref
  • [9] S. Qin, Y. Bai, H.Y. Lim, S. Thongprasert, Y. Chao, J. Fan, et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013 Oct 1;31(28):3501-3508 Crossref
  • [10] A. Castells, J. Bruix, C. Bru, C. Ayuso, M. Roca, L. Boix, et al. Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients. Gastroenterology. 1995 Sep;109(3):917-922 Crossref
  • [11] Randomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated with tamoxifen. Hepatology. 2004 Dec;40(6):1361-1369
  • [12] M. Beaugrand, M. Sala, F. Degos. Treatment of advanced hepatocellular carcinoma by seocalcitol (a vit D analogue): an international randomized double-blind placebo-controlled study in 747 patients. J Hepatol. 2005;42(Suppl. 2):17A
  • [13] J.M. Llovet, M. Sala, L. Castells, Y. Suarez, R. Vilana, L. Bianchi, et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology. 2000 Jan;31(1):54-58 Crossref
  • ∗[14] J.M. Llovet, S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J.F. Blanc, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-390 Crossref
  • ∗[15] A.L. Cheng, Y.K. Kang, Z. Chen, C.J. Tsao, S. Qin, J.S. Kim, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009 Jan;10(1):25-34 Crossref
  • [16] S.M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-7109 Crossref
  • [17] G.K. Abou-Alfa, L. Schwartz, S. Ricci, D. Amadori, A. Santoro, A. Figer, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006 Sep 10;24(26):4293-4300 Crossref
  • [18] P. Therasse, S.G. Arbuck, E.A. Eisenhauer, J. Wanders, R.S. Kaplan, L. Rubinstein, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000 Feb 2;92(3):205-216 Crossref
  • [19] J.L. Raoul, J. Bruix, T.F. Greten, M. Sherman, V. Mazzaferro, P. Hilgard, et al. Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. J Hepatol. 2012 May;56(5):1080-1088 Crossref
  • [20] J. Bruix, J.L. Raoul, M. Sherman, V. Mazzaferro, L. Bolondi, A. Craxi, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012 Oct;57(4):821-829 Crossref
  • ∗[21] J.M. Llovet, C.E. Pena, C.D. Lathia, M. Shan, G. Meinhardt, J. Bruix. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012 Apr 15;18(8):2290-2300 Crossref
  • ∗[22] EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012 Apr;56(4):908-943
  • [23] C. Verslype, O. Rosmorduc, P. Rougier. Hepatocellular carcinoma: ESMO-ESDO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012 Oct;23(Suppl. 7):vii41-vii48 Crossref
  • ∗[24] M. Reig, F. Torres, C. Rodriguez-Lope, A. Forner, N. LLarch, J. Rimola, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol. 2014 Apr 2;10.1016/j.jhep.2014.03.030 pii: S0168–8278(14)00211-6[Epub ahead of print]
  • [25] J. Marrero, Riccardo Lencioni, Sheng-Long Ye, Masatoshi Kudo, Jean-Pierre Bronowicki, Chen Xiao-Ping, et al. Final analysis of GIDEON (Global investigation of therapeutic decisions in hepatocellular carcinoma [HCC] and of its treatment with sorafenib [Sor]) in >3000 Sor-treated patients (pts): clinical findings in pts with liver dysfunction. J Clin Oncol. 2013;31(Suppl.) abstr 4126
  • [26] G.G. Di Costanzo, R. Tortora, L. Iodice, A.G. Lanza, F. Lampasi, M.T. Tartaglione, et al. Safety and effectiveness of sorafenib in patients with hepatocellular carcinoma in clinical practice. Dig Liver Dis. 2012 Sep;44(9):788-792 Crossref
  • [27] T. Nakazawa, H. Hidaka, J. Takada, Y. Okuwaki, Y. Tanaka, M. Watanabe, et al. Early increase in alpha-fetoprotein for predicting unfavorable clinical outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib. Eur J Gastroenterol Hepatol. 2013 Jun;25(6):683-689 Crossref
  • ∗[28] M. Reig, J. Rimola, F. Torres, A. Darnell, C. Rodriguez-Lope, A. Forner, et al. Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design. Hepatology. 2013 Dec;58(6):2023-2031 Crossref
  • [29] Organization WH. WHO handbook for reporting results of cancer treatment. (World Health Organization, Geneva Switzerland, 1979) (Offset Publication 48)
  • [30] C.G. Moertel, J.A. Hanley. The effect of measuring error on the results of therapeutic trials in advanced cancer. Cancer. 1976 Jul;38(1):388-394 Crossref
  • ∗[31] E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-247 Crossref
  • [32] J. Bruix, M. Reig, J. Rimola, A. Forner, M. Burrel, R. Vilana, et al. Clinical decision making and research in hepatocellular carcinoma: pivotal role of imaging techniques. Hepatology. 2011 Dec;54(6):2238-2244 Crossref
  • [33] M. Burrel, M. Reig, A. Forner, M. Barrufet, C.R. de Lope, S. Tremosini, et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using drug eluting beads. Implications for clinical practice and trial design. J Hepatol. 2012 Jun;56(6):1330-1335 Crossref
  • [34] M. Reig, A. Matilla, J. Bustamante, L. Castells, M. de La Mata, M. Delgado, et al. Recommendations for the management of sorafenib in patients with hepatocellular carcinoma. Gastroenterol Hepatol. 2010 Dec;33(10):741-752 Crossref
  • [35] R.N. Pugh, I.M. Murray-Lyon, J.L. Dawson, M.C. Pietroni, R. Williams. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973 Aug;60(8):646-649 Crossref
  • [36] P. Martin, A. DiMartini, S. Feng, R. Brown Jr., M. Fallon. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59(3):1144-1165 Crossref
  • [37] M. Malinchoc, P.S. Kamath, F.D. Gordon, C.J. Peine, J. Rank, P.C. ter Borg. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000 Apr;31(4):864-871 Crossref
  • [38] C. Ma, S. Bandukwala, D. Burman, J. Bryson, D. Seccareccia, S. Banerjee, et al. Interconversion of three measures of performance status: an empirical analysis. Eur J Cancer. 2010 Dec;46(18):3175-3183 Crossref
  • [39] European Medicines Agency. Sorafenib (Nexavar): summary of product characteristics. (, 2013) http://wwwemeaeuropaeu/humandocs/PDFs/EPAR/nexavar/H-690-PI-enpdf [online]. URL
  • [40] R.S. Finn. Drug therapy: sorafenib. Hepatology. 2010 May;51(5):1843-1849 Crossref
  • [41] M. Iavarone, G. Cabibbo, F. Piscaglia, C. Zavaglia, A. Grieco, E. Villa, et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology. 2011 Dec;54(6):2055-2063 Crossref
  • [42] H. Choi, C. Charnsangavej, S.C. Faria, H.A. Macapinlac, M.A. Burgess, S.R. Patel, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007 May 1;25(13):1753-1759 Crossref
  • [43] M. Kudo, S. Kubo, K. Takayasu, M. Sakamoto, M. Tanaka, I. Ikai, et al. Response evaluation criteria in cancer of the liver (RECICL) proposed by the liver cancer study group of Japan (2009 revised version). Hepatol Res. 2010 Jul;40(7):686-692 Crossref
  • *[44] R. Lencioni, J.M. Llovet. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010 Feb;30(1):52-60
  • [45] R.S. Finn, R.T. Poon, T. Yau, H.J. Klumpen, L.T. Chen, Y.K. Kang, et al. Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma. J Hepatol. 2013 Dec;59(6):1271-1277 Crossref
  • [46] D. Koeberle, J.-F. Dufour, G. Demeter, P. Samaras, P. Saletti, Q. Li, et al. Sorafenib with or without everolimus in patients with unresectable hepatocellular carcinoma (HCC): a randomized multicenter phase II trial (SAKK 77/08 and SASL 29). J Clin Oncol. 2014;32(5s) Suppl. abstr 4099
  • [47] A.L. Cheng, Y.K. Kang, D.Y. Lin, J.W. Park, M. Kudo, S. Qin, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013 Nov 10;31(32):4067-4075 Crossref
  • [48] P.J. Johnson, S. Qin, J.W. Park, R.T. Poon, J.L. Raoul, P.A. Philip, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013 Oct 1;31(28):3517-3524 Crossref
  • [49] C. Cainap, S. Qin, W.-T. Huang, I.-J. Chung, H. Pan, Y. Cheng, et al. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2013;31 Gastrointestinal Cancers Symposium (January 24-26, 2013).No 4_suppl (February 1 Supplement), 249):(suppl 4; abstr 249
  • [50] J.M. Llovet, T. Decaens, J.L. Raoul, E. Boucher, M. Kudo, C. Chang, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013 Oct 1;31(28):3509-3516 Crossref
  • [51] A.X. Zhu, M. Kudo, E. Assenat, S. Cattan, Y.K. Kang, H.Y. Lim, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib. The EVOLVE-1 randomized clinical trial. JAMA. 2014;312(1):57-67
  • [52] REACH. Lilly announces top-line results of phase III REACH trial of CYRAMZA™ (ramucirumab) in patients with hepatocellular carcinoma. (, 2014) https://investorlillycom/releasedetailcfm?releaseid=854049
  • [53] M. Schlumberger, M. Tahara, L.J. Wirth, B. Robinson, M.S. Brose, R. Elisei, et al. A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT). J Clin Oncol. 2014;32(5s) Suppl. abstr LBA6008
  • [54] Refametinib in RAS Mutant hepatocellular carcinoma (HCC). http://clinicaltrialsgov/ct2/show/NCT01915589?term=ras+mutation%2C+hepatocellular+carcinoma&rank=1 .
  • [55] A.T. Shaw, D.W. Kim, K. Nakagawa, T. Seto, L. Crino, M.J. Ahn, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-2394 Crossref
  • [56] J. Heo, T. Reid, L. Ruo, C.J. Breitbach, S. Rose, M. Bloomston, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013 Mar;19(3):329-336 Crossref
  • [57] L. Zitvogel, A. Tesniere, G. Kroemer. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 2006 Oct;6(10):715-727 Crossref
  • [58] S.A. Rosenberg. Cell transfer immunotherapy for metastatic solid cancer – what clinicians need to know. Nat Rev Clin Oncol. 2011 Oct;8(10):577-585 Crossref
  • [59] W. Yeo, H.C. Chung, S.L. Chan, L.Z. Wang, R. Lim, J. Picus, et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J Clin Oncol. 2012 Sep 20;30(27):3361-3367 Crossref


a Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Spain

b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain

Corresponding author. BCLC group, Liver Unit, Hospital Clínic, C/Villarroel 170, Floor 4 Stair 11, 08036 Barcelona, Spain. Tel.: +34 93 227 9803; fax: +34 93 227 5792.

1 Tel.: +34 93 227 9803; fax: +34 93 227 5792.

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