Seminar

Hepatocellular carcinoma
Alejandro Forner, Josep M Llovet, Jordi Bruix

Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. Patients with cirrhosis are at highest risk of developing this malignant disease, and ultrasonography every 6 months is recommended. Surveillance with ultrasonography allows diagnosis at early stages when the tumour might be curable by resection, liver transplantation, or ablation, and 5-year survival higher than 50% can be achieved. Patients with small solitary tumours and very well preserved liver function are the best candidates for surgical resection. Liver transplantation is most benecial for individuals who are not good candidates for resection, especially those within Milano criteria (solitary tumour 5 cm and up to three nodules 3 cm). Donor shortage greatly limits its applicability. Percutaneous ablation is the most frequently used treatment but its eectiveness is limited by tumour size and localisation. In asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread not amenable to curative treatments, chemoembolisation can provide survival benet. Findings of randomised trials of sorafenib have shown survival benets for individuals with advanced hepatocellular carcinoma, suggesting that molecular-targeted therapies could be eective in this chemoresistant cancer. Research is active in the area of pathogenesis and treatment of hepatocellular carcinoma.

Lancet 2012; 379: 124555 Published Online February 20, 2012 DOI:10.1016/S01406736(11)61347-0 Barcelona Clinic Liver Cancer group, Liver Unit, Hospital Clnic Barcelona, August Pi i Sunyer Biomedical Research Institute, University of Barcelona, Barcelona, Spain (A Forner MD, J M Llovet MD, J Bruix MD); Centro de Investigacin Biomdica en Red de Enfermedades Hepticas y Digestivas, Barcelona, Spain (A Forner, J M Llovet, J Bruix); Mount Sinai Liver Cancer Program, Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA (J M Llovet); and Instituci Catalana de Recerca i Estudis Avanats, Barcelona, Spain (J M Llovet) Correspondence to: Dr Jordi Bruix, Barcelona Clinic Liver Cancer group, Liver Unit, IDIBAPS, Hospital Clnic, Villarrel 170, 08036 Barcelona, Spain [email protected]

Introduction
Hepatocellular carcinoma is the sixth most common neoplasm and the third most frequent cause of cancer death.1 More than 700 000 cases of this malignant disease were diagnosed in 2008, with an age-adjusted worldwide incidence of 16 cases per 100 000 inhabitants.1 Hepatocellular carcinoma is the leading cause of death among patients with cirrhosis.2 Here, we update our 2003 Lancet Seminar3 to include major advances in prevention, detection, diagnosis, and treatment that have happened since then.

Risk factors and prevention

In most cases, hepatocellular carcinoma develops within an established background of chronic liver disease (7090% of all patients).4 The worldwide heterogeneous incidence reects variations in the main risk factors (table 1).1,5 Most cases of hepatocellular carcinoma (80%) arise in eastern Asia and sub-Saharan Africa, where the dominant risk factor is chronic infection with hepatitis B virus (HBV), together with exposure to aatoxin B1. By contrast, in North America, Europe, and Japan, infection with hepatitis C virus (HCV) is the main risk factor, together with alcohol use.6 Time trends in incidence of hepatocellular carcinoma in developed countries parallel the timing of HCV spread. In Japan and Europe, where HCV infection spread earlier than in the USA, the incidence of hepatocellular carcinoma has almost reached a plateau and in some areas it is declining;5,7 however, in the USA, incidence is still increasing8,9 and the infection could have a synergistic eect with other risk factors, such as non-alcoholic fatty liver disease. Diabetes is an independent risk factor for hepatocellular carcinoma,6,10 and mortality rates for liver cancer are ve times higher among men with baseline body-mass index greater than 40, versus those with a lower body-mass index.11 Tobacco raises risk whereas coee reduces it.12,13 The most frequent risk factor for hepatocellular carcinoma is chronic HBV infection, which accounts for more
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than 50% of all cases.4 The relative risk of tumour development is about 100 in carriers of HBV versus noncarriers, and in HBV carriers with cirrhosis it is even higher.4,14 Incidence of hepatocellular carcinoma increases with viral load and duration of infection,15 suggesting an accumulated risk of long-lasting oncogenic damage. Occult HBV infection is also associated with increased risk of hepatocellular carcinoma because of DNA damage induced by HBV integration.16,17 Hepatocellular carcinoma related to HBV can be prevented by vaccination. Nationwide vaccination of infants in Taiwan reduced the incidence of hepatocellular carcinoma in children aged 69 years from 052 per 100 000 for those born between 1974 and 1984 to 013 for those born between 1984 and 1986.18 If infection is chronic, viral replication can be abrogated by antiviral agents, which would prevent progression of liver disease and, possibly, hepatocellular carcinoma in the long term.19 The incidence of hepatocellular carcinoma in individuals with HCV cirrhosis is 35% per year.20 Prevention of HCV infection relies on avoidance of viral transmission through contaminated blood. Interruption of evolution from acute infection into chronic hepatitis and, ultimately, cirrhosis by use of antiviral agents should prevent development of hepatocellular carcinoma.21,22 However, if cirrhosis is established, risk of hepatocellular carcinoma persists despite antiviral treatment.21 Findings of initial studies suggested that interferon might prevent development of hepatocellular carcinoma in patients with cirrhosis.23,24 However, in randomised controlled trials, long-term

Search strategy and selection criteria We searched Medline, Embase, and the Cochrane Library (from January, 2000, to November, 2011) with the terms hepatocellular carcinoma, liver cancer, and primary liver carcinoma. We also searched and reviewed the reference lists of retrieved publications for other relevant papers. We only considered papers published in English and Spanish. We selected publications largely from the past 5 years, but we did not exclude commonly referenced and highly regarded older publications.

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Age-adjusted incidence (x100 000; [men/women])

Risk factors

Hepatitis C virus Europe Western Southern Northern North America Asia and Africa Eastern Asia Southern Asia Central Africa 72/21 98/32 38/16 68/22 355/126 139/51 189/96 6070% 5060% 20%

Hepatitis B virus 1015% 20% 70%

Alcohol 20% 20% 10%

Others 10% >10% <10%

Data taken from references 1 and 5.

(mammalian target of rapamycin) pathway is disrupted in 4050% of liver cancers owing to upstream signalling, inactivation of the tumour suppressor PTEN, or mutations of phosphoinositide-3-kinase.32,33 Similarly, insulin-like growth factor receptor 1 (IGF1R) signalling was active in 20% of early hepatocellular carcinomas, and deregulation of the hepatocyte growth factor (HGF) and c-MET pathway is a common event.29 Wingless (Wnt) signalling is activated in a third of hepatocellular carcinomas, as a result of activating mutations in the transcription factor catenin, overexpression of Wnt receptors, or inactivation of E-cadherin. However, hepatocellular carcinoma is a highly vascularised cancer and angiogenic activity through signalling of VEGFA, ANGPT2, and broblast growth factor (FGF) is a key event.28,29,34 Angiogenesis is complex and has been reviewed elsewhere.28,29,34

Table 1: Age-adjusted incidence and risk factors for hepatocellular carcinoma worldwide, by geographical area

Molecular classication of hepatocellular carcinoma

Molecular proling is relevant in cancers such as those of breast, lung, colon, and melanoma, and in some instances molecular subclasses and response to treatment are linkedeg, amplication of ERBB2 and response to trastuzumab. Outcome prediction depends on both tumour proling (dening Wnt subclass, tumour growth factor [TGF ], and epithelial cell adhesion molecule [EPCAM] and inammation class)29,35 and gene expression of adjacent non-tumoral tissue.36,37 Transfer of this information into treatment decision-making would need additional validation.

treatment with interferon did not aect the rate of disease progression and development of hepatocellular carcinoma in patients with chronic hepatitis C and advanced brosis.25,26 Alcohol is an important risk factor for development of hepatocellular carcinoma and exerts a synergistic eect in individuals with chronic infection with HBV, HCV, or both.20 Patients who are co-infected with HIV and either HBV or HCV seem to have more rapidly progressive liver disease than patients without HIV infection, and when they develop cirrhosis they are also at increased risk of hepatocellular carcinoma.27

Molecular pathogenesis
Hepatocarcinogenesis is a complex multistep process in which many signalling cascades are altered, leading to a heterogeneous molecular prole.28,29 The main mutations include the tumour suppressor gene TP53 (present in about 2540% of cancers, depending on tumour stage), and the gene for catenin, CTNNB1 (about 25%, predominantly in HCV-related hepatocellular carcinoma). Other mutations are less frequent. Chromosomal amplications (1q, 6p, 8q, 17q, and 20q) and deletions (4q, 8p, 11q, 13q, 16q, and 17p) are common and aect important oncogenes and tumour suppressors. High-level amplications have been described in 6p21 (VEGFA) and 11q13 (cyclin D1 [CCND1]) in 510% of patients.28,29 Epigenetic alterations are ill-dened in hepatocellular carcinoma, but silencing of tumour suppressors (ie, RASSF1, SOCS1, E-cadherin [CDH1]) and reactivation of oncogenes (MYC) have been shown.28,29 Finally, microRNA (miRNA) seems to be able to modulate transcription of key oncogenes.30,31 As a result of these alterations, several signalling cascades related to cell survival and proliferation are activated and respond to targeted treatments in preclinical and early clinical studies. With respect to proliferation cascades, epithelial growth factor receptor (EGFR) and Ras signalling is activated in more than 50% of hepatocellular carcinomas,29 whereas the MTOR
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Surveillance and diagnosis

Surveillance for hepatocellular carcinoma aims to reduce disease-related mortality. In uncontrolled studies, survival seemed to be improved with surveillance but these studies are aected by biases of lead time (the apparent improvement in survival that comes from the diagnosis being made early in the course of a disease) and length time (the apparent improvement in survival that arises because surveillance preferentially detects slow-growing cancers).38 One randomised controlled trial of surveillance has been done in China (18 816 patients with hepatitis B) to compare twice-yearly ultrasonography and measurement of serum -fetoprotein (AFP) concentration with no surveillance.39 Despite suboptimum adherence to surveillance (<60%), survival of screened participants was 66% at 1 year, 53% at 3 years, and 46% at 5 years versus 31%, 7%, and 0%, respectively, in unscreened patients. A validation trial in developed regions is not feasible: ultrasonography is part of routine assessment for patients with liver disease and the perceived benet from surveillance would impair recruitment of patients.40 Indeed, early detection and treatment of hepatocellular carcinoma is the sole option to achieve long-term disease-free survival. The decision to begin surveillance depends on the degree of risk of hepatocellular carcinoma for the individual and the extent to which he or she would be
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treated if diagnosed with the malignant disease. Since no experimental data to indicate the degree of risk that should trigger surveillance are available, the decision is based on cost-eectiveness models with heterogeneous design. They all suggest that surveillance is cost eective and that ecacy is dictated by incidence of hepatocellular carcinoma.41,42 Accordingly, surveillance is recommended both for patients with cirrhosis who would be treated eectively if diagnosed with hepatocellular carcinoma and for those with HBV infection but without cirrhosis, with an annual incidence of more than 02%.43 Individuals with highly impaired liver function (Child-Pugh class C) should be assessed for liver transplantation. If this procedure cannot be oered surveillance is of no benet because diagnosis will not be followed by eective treatment. Similarly, if liver function deteriorates and prompts major decompensation not leading to assessment for transplantation, surveillance should be cancelled. The preferred imaging method for surveillance is ultrasonography; it is well tolerated and widely available, and it has sensitivity of 6080% and specicity beyond 90%.44 The most used serological test is AFP. Unfortunately, even with the most ecient cuto (1020 g/L), diagnostic sensitivity is around 60%.4547 Figures for surveillance are even worse and do not support AFP as a surveillance test. Combined use of AFP and ultrasonography not only does not increase detection rates but also raises false-positive suspicions and cost.44,48 Other tumour markers, such as des- carboxiprothrombin or AFP fractions, do not have better accuracy.46,47 On the basis of tumour-doubling times and data from the one available trial, screening of patients every 6 months is recommended. A 3-month interval increases detection of small nodules but has no eect on survival,49 and twice-yearly screening has better results than annual.50 Since tumour growth rate is not dictated by risk, increased risk should not prompt a shorter interval. Figure 1 shows the diagnostic algorithm used once a nodule has been detected.43 Nodules 1 cm or smaller are diagnosed infrequently as hepatocellular carcinoma and are almost impossible to diagnose condently by available techniques (biopsy could miss the target and the diagnostic hypervascular prole is not in place at this stage). Furthermore, for these small lesions, pursuing a diagnosis of hepatocellular carcinoma would probably lead to more harm than benet.51 When the nodule exceeds 1 cm, diagnosis can be established by biopsy or by imaging in the setting of liver cirrhosis. The specic imaging pattern is dened by intense contrast uptake during the arterial phase followed by contrast washout during venous or delayed phases in a contrast-enhanced study such as CT or MRI (magnetic resonance is being validated extensively).52,53 The value of these non-invasive criteria for hepatocellular carcinoma in cirrhosis has been conrmed prospectively.5456 In nodules of 12 cm, typical imaging features have specicities and predictive positive values of near 100% and sensitivity that can reach 71%. Contrast-enhanced
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<1 cm

Mass on surveillance ultrasonography in a patient with cirrhosis or chronic hepatitis B

>1 cm

4-phase MDCT/dynamic MR

Arterial hypervascularisation and venous or delayed-phase washout

Repeat ultrasonography every 3 months

Positive

Negative

Stable over 1824 months

Enlarging

Other imaging modality (CT or MRI)

Biopsy

Arterial hypervascularisation and venous or delayed-phase washout

Positive Return to standard surveillance Proceed according to lesion size

Negative

Treat as hepatocellular carcinoma

Figure 1: Diagnostic algorithm for hepatocellular carcinoma Modied from reference 43, with permission of John Wiley and Sons. MDCT=multidetector CT. MR=magnetic resonance.

ultrasonography is not recommended as the sole diagnostic imaging technique because it cannot distinguish intrahepatic cholangiocarcinoma from hepatocellular carcinoma57,58 and MRI or CT is still needed for staging. Non-invasive diagnostic criteria are valid only for investigation of screen-detected lesions in the liver in patients with either cirrhosis or long-lasting chronic HBV infection who might not have fully developed cirrhosis. In other clinical scenarios, a diagnostic biopsy should be requested. However, a negative nding after biopsy does not rule out hepatocellular carcinoma since the falsenegative rate can reach 30%54 because of sampling error or absence of specic histological hallmarks for diagnosis of this cancer. A three-gene signature including glypican 3 (GPC3), LYVE1, and survivin (BIRC5) has been proposed,59 but more tissue is needed with this method than for conventional immunohistochemical staining for GPC3, glutamine synthetase, clathrin heavy chain, and heat-shock protein 70. This immunohistochemical panel provides 100% specicity but still with suboptimum sensitivity.60

Staging and prognosis assessment

Assessment of prognosis is a crucial step in management of patients with hepatocellular carcinoma. Years ago, most aected individuals were diagnosed at an advanced
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symptomatic stage, when treatment was not feasible and short-term prognosis was dismal. Diagnosis has now advanced, and eective early treatment of patients is associated with median survival beyond 5 years. Any attempt to assess prognosis should account for tumour stage, degree of liver function impairment, and presence of cancer-related symptoms.61 Several proposals have been raised to stratify patients according to expected outcome.61 Some approaches do not take into account the presence of cancer-related symptoms that are major prognostic predictors.6265 Others assess tumour burden roughly62 or investigate liver function according to the presence or absence of cirrhosis.66 This approach limits clinical usefulness. The classication that straties patients according to outcome and simultaneously links it with treatment indication is the Barcelona Clinic Liver Cancer (BCLC) strategy (gure 2). The BCLC classication has been validated in dierent settings and establishes treatment recommendations for all stages of hepatocellular carcinoma.67 Patients with early-stage cancer are treated by resection, liver transplantation, or ablation, and prognosis can be rened for all these procedures according to dierent variables. The very early stage (BCLC 0) corresponds to patients with well-preserved liver function (ChildPugh A) diagnosed with one asymptomatic nodule of less than 2 cm without vascular invasion or satellites. This stage corresponds to the carcinoma-in-situ entity that, if resected or ablated, would have excellent outcome with almost zero risk of recurrence. Currently, condent diagnosis is not feasible by imaging techniques or biopsy
Hepatocellular carcinoma

and it is classied as such at explant. End-stage patients are identied easily by any clinical method. They have a very poor prognosis and no intervention will be of benet. Patients with end-stage liver disease (Child-Pugh C or advanced Child-Pugh B) should be considered for transplantation, but recognition of hepatocellular carcinoma could become a contraindication because of excessive tumour burden. Between these two extreme situations, the clinical prole is very heterogeneous; liver function includes Child-Pugh classes A and B, and tumour burden encompasses liver-only disease without vascular invasion or extensive disease with metastatic spread. Patients can be asymptomatic (performance status 0) or already have cancer-related symptoms such as pain or malaise (performance status 12). As a result, the term non-surgical hepatocellular carcinoma does not indicate any specic clinical prole or prognosis. The BCLC classication68 divides this heterogeneous group into two categories: the intermediate stage (BCLC B), dened by absence of any adverse predictor, and the advanced stage (BCLC C), which includes patients with symptoms, vascular invasion, extrahepatic spread, or a combination. The BCLC strategy has been validated externally in prospective studies69 and has been endorsed by several scientic associations, but further renement is still needed. Liver function is assessed by the Child-Pugh classication, but class B includes a wide range of patients. Similarly, presence of ascites within Child-Pugh class A indicates impaired prognosis, which should be factored into individual assessment of patients and treatment proposals.

Very early stage (0) Single <2 cm Child-Pugh A, PS 0

Early stage (A) Single or 3 nodules <3 cm Child-Pugh AB, PS 0

Intermediate stage (B) Large multinodular Child-Pugh AB, PS 0

Advanced stage (C) Portal invasion Extrahepatic spread Child-Pugh AB, PS 12

Terminal stage (D) Child-Pugh C PS 34

Potential candidate for liver transplantation

Single

Three nodules 3 cm

No

Yes

Portal pressure, bilirubin

Normal

Increased

Associated diseases

No Ablation Resection Liver transplantation

Yes Ablation Chemoembolisation Sorafenib Best supportive care

Curative treatments

Palliative treatments

Figure 2: BCLC staging and treatment strategy The BCLC system establishes a prognosis in accordance with the ve stages that are linked to rst-line treatment recommendation. If the recommended option is not feasible because of an individual patients condition, the treatment approach for the next evolutionary disease stage should be considered. Accordingly, patients in BCLC stage A may benet from transarterial chemoembolisation, BCLC B patients from sorafenib, and some patients in BCLC stage C with contraindications for sorafenib could enter research trials to assess new agents. BCLC=Barcelona Clinic Liver Cancer. PS=performance status.

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Biomarkers should enable better stratication. High AFP concentration is associated with a poor prognosis, but no cuto that would imply a modication in treatment decision has been dened. Other tumour markers do not rene prognosis or justify their use for staging or treatment selection. The same applies for biomarkers such as VEGF, angiopoietin 2, or the proto-oncogene c-Kit. They can rene prognostic prediction within statistical modelling but cannot yet be incorporated into assessment of an individual patient.

Benet Surgical treatments Surgical resection Adjuvant treatments Liver transplantation Adjuvant treatments Locoregional treatments Percutaneous treatment Radiofrequency Other modalities Combined modalities Chemoembolisation Internal radiotherapy (iodine-131, yttrium-90) Systemic treatments Sorafenib Hormonal compounds Tamoxifen Antiandrogen Seocalcitiol Systemic chemotherapy Immunotherapy No survival benet No survival benet Increases survival No survival benet Increases survival Increases survival Treatment response Treatment response Increases survival Treatment response Increases survival Controversial Increases survival Treatment response

Level of evidence

3ii A 1 AD 3ii A 3 Diii 3ii A 1ii A 2D 3ii D 1ii A 3ii Diii 1i A 1i A .. .. .. 1i A 1ii A

Treatment
For treatment to be most eective, patients should be selected carefully and the treatment applied skilfully. In view of the complexity of hepatocellular carcinoma and the many potentially useful treatments, patients diagnosed with this malignant disease should be referred to multidisciplinary teams that include hepatologists, radiologists, surgeons, pathologists, and oncologists. By contrast with other highly prevalent cancers, the level of evidence for most therapeutic options for hepatocellular carcinoma is restricted to cohort investigations with a few randomised controlled trials, most of which addressed treatment of advanced disease (table 2).70 Furthermore, as far as we know, no large robust studies have been done to compare treatments regarded as potentially curative for early-stage disease (surgical resection, transplantation, percutaneous ablation), and no studies have compared these methods with no treatment. Surgical resection, transplantation, and ablation are treatments that oer a high rate of complete responses and, thus, potential for cure.43 The only non-curative treatments that improve survival are transarterial chemoembolisation and sorafenib.7173 Arterial embolisation without chemotherapy,71 external radiotherapy,74,75 and radioembolisation have shown antitumour activity,7678 but survival benet has not been proven. Systemic chemotherapy has marginal activity with frequent toxic eects, without survival benet, and agents such as tamoxifen, octreotide, or antiandrogens are completely ineective.43,71

Modied from reference 70, with permission of Oxford University Press. Evidence-based classication adapted from the National Cancer Institute. 1=randomised controlled trial or meta-analysis (1i=double-blinded, 1ii=non-blinded). 2=non-randomised controlled trial. 3=case series (3i=population-based, 3ii=non-population-based, consecutive, 3iii=non-population-based, non-consecutive). A=survival endpoint. B=cause-specic mortality. C=quality of life. D=indirect surrogates (Di=disease-free survival, Dii=progression-free survival, Diii=tumour response).

Table 2: Evidence-based benets of treatments

Resection
Hepatic resection is the treatment of choice for hepatocellular carcinoma in individuals without cirrhosis (5% of patients in the USA and Europe, 40% in Asia). These patients tolerate major resections with low rates of life-threatening complications. In individuals with cirrhosis, careful selection of candidates is vital to avoid treatment-related complicationseg, liver failure with increased risk of death. For years, selection of candidates for resection has been based on the Child-Pugh classication,79 but this strategy has inconsistent predictive value. Some Child-Pugh A patients already have liver functional impairment with raised bilirubin concentrations, clinically signicant portal hypertension, or even minor uid retention necessitating diuretic treatment.80 In Japan, the indocyanine green
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retention rate is used to identify the best candidates for resection,81 whereas portal pressure and bilirubin are the variables used in Europe and the USA.43 Clinically relevant portal hypertension is dened as a hepatic vein pressure gradient greater than 10 mm Hg, but it can also be conrmed by oesophageal varices or splenomegaly associated with a platelet count lower than 10010/L. In patients without relevant portal hypertension and normal concentrations of bilirubin, survival at 5 years is 70%, whereas it is 50% for individuals with portal hypertension and is even lower when both adverse factors are present.82,83 With respect to the best candidates for resection, blood transfusion will be needed in fewer than 10% of cases, and treatment-related mortality should be less than 1%. Therefore, assessment of portal pressure is crucial for prediction of long-term survival.43 Most groups restrict the indication for resection to patients with one tumour, because multifocality is associated with high recurrence and impaired survival. Although multifocality need not be viewed as a contraindication to resection, careful assessment to estimate survival (and associated risks) that might be oered by other options, such as transplantation, ablation,84 or chemoembolisation,8587 is mandatory. Tumour size is not a clear-cut limiting factor, but risk of vascular invasion and dissemination increases with diameter. Malignant vascular invasion should be viewed as a contraindication

For the National Cancer Institute see http://www. cancer.gov

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for resection. By application of these restrictive criteria, the proportion of patients in whom resection can be oered is 510%. Tumour recurrence complicates 70% of cases at 5 years, combining true recurrence, which usually arises within the rst 2 years after resection, and de novo tumours.81 Microvascular invasion, poor histological dierentiation, satellites, and multifocal disease predict early recurrence.81,88 Late recurrence depends mainly on the carcinogenic eect of underlying chronic liver disease.36 This risk can be estimated by liver function variables related to inammatory activity, evolutionary stage, or both. No eective neoadjuvant or adjuvant treatment options to reduce risk of recurrence are available. Systemic chemotherapy and chemoembolisation have no eect, whereas immunotherapy, retinoids, and interferon have shown some potential ecacy, but evidence is not strong enough for them to be used in clinical practice.81 Findings of meta-analyses have reinforced the benets of interferon but heterogeneity of the interferon used, the duration of the regimen, the patients recruited, and trial endpoints prevent valid assessment.8991 The most eective option to prevent intrahepatic recurrence is liver transplantation. Although post-resection recurrence aects more than 70% of patients at 5 years in those with a risky prole, it aects fewer than 25% of individuals treated by transplantation. Transplantation can, therefore, be oered to patients initially treated by resection but with a high risk of recurrence according to pathological analysis. This policy not only allows some individuals to be treated eectively by resection with avoidance of transplantation but also permits best use of the few organs that are available by oering transplantation to patients whose cancer would recur after resection.92

transarterial chemoembolisation) are done, even though eectiveness is unproven.99 Policies for transplantation are implemented that aim to prioritise the sickest patients,52,100 but the only eective method to avoid waiting is to increase the number of donations. Live donation is a valid strategy, with outcomes similar to those of cadaveric donation, but applicability is reduced because of societal constraints and, scarcity of appropriate donors. Despite the shortage of liver donors, several researchers have proposed expansion of current limits.101105 Most suggestions are based on analysis of tumour stage in the explanted liver and not on imaging ndings at the time of the patients assessment. Furthermore, transplantation to patients who do not meet the Milano criteria is associated with increased prevalence of variables associated with risk of recurrence (microscopic vascular invasion or satellites). If the number of livers available exceeded the number of candidates for transplantation, a slight expansion would be feasible because it would not negatively aect patients with the best transplant proles.106 The MTOR inhibitor sirolimus seemed to improve tumour-free survival in recipients of liver transplants with a pre-transplantation diagnosis of hepatocellular carcinoma in preliminary studies, but this hypothesis should be conrmed in a trial due to nish in 2014.107

Image-guided tumour ablation

Image-guided tumour ablation is now a conventional treatment option for patients with early-stage hepatocellular carcinoma. Ablation induces tumour necrosis by injection of chemicals (eg, ethanol, acetic acid) or temperature modication (ablation by radiofrequency, microwave, or laser, or cryoablation). Although tumour ablation can be undertaken at laparoscopy or surgery, most procedures are done percutaneously. The rst-line technique is now radiofrequency ablation.108 Both ethanol injection and radiofrequency ablation achieve complete necrosis of almost 100% in hepatocellular carcinomas smaller than 2 cm, but the eectiveness of ethanol injection falls in larger tumours, in which radiofrequency ablation can still be highly eective. Eectiveness diminishes in larger lesions, and ablation is not recommended for tumours larger than 5 cm. Better disease control with radiofrequency ablation than with ethanol injection could translate into better outcomes.109111 Side-eects are more frequent after radiofrequency ablation than after other approaches and some tumour locations (subcapsular, vicinity of major blood vessels or biliary tree, near to bowel or heart) should be avoided.112 Novel techniques such as microwave or electroporation are being evaluated.108 Survival after ablation in Child-Pugh A patients is 5075% at 5 years, thus paralleling the outcome after surgical resection.108111 This nding has challenged resection as the rst-line treatment in patients with small solitary hepatocellular carcinomas. Ablation has been compared with resection in early hepatocellular carcinoma in several randomised controlled trials, but the results
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Liver transplantation
Hepatocellular carcinoma is the only solid cancer that can be treated by liver transplantation, which has completely changed the treatment strategy for this malignant disease. In theory, transplantation could simultaneously cure the tumour and underlying cirrhosis, and eectiveness of the procedure is not aected by the degree of liver function impairment. Mazzaferro and colleagues93 showed that selection of patients with one hepatocellular carcinoma of 5 cm or smaller, or up to three nodules of 3 cm or smaller, without vascular invasion or extrahepatic spread (known as the Milano criteria) oered 4-year survival of 75%, with recurrence rates below 15%. These results have been validated82,94,95 and are accepted as the benchmark for selection of patients in the USA and Europe.43,96,97 These excellent results were achieved in an era with prompt availability of organs. The shortage of donors has imposed a delay before transplantation, and during this period the tumour can progress and impede transplantation.98 This delay impairs the eectiveness of liver transplantation when considered according to intention to treat.82 When waiting time exceeds 6 months, treatments aimed at delaying tumour progression (eg, ablation,
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have varied.113115 However, these trials had some limitations in terms of sample size, and concerns have been raised in some instances about randomisation, treatment allocation, and trial implementation; further studies undertaken in the USA and Europe are needed urgently. A specic scenario for ablation is the very early stage of hepatocellular carcinoma. Ablation is nearly 100% eective in hepatocellular carcinomas smaller than 2 cm and survival is almost identical after resection or ablation. Thus, if transplantation is not an option, ablation would become the rst-line option and surgery would be justied only in patients with failure of or contraindication to ablation. However, if the strategy of transplantation owing to risk of recurrence as per tumour pathology is in place, patients who could benet from transplantation should still have resection as the rst-line approach. Analysis of resected tumour would distinguish between very early hepatocellular carcinoma (BCLC 0) with marginal risk of recurrence (thus, no need to consider transplantation) and more advanced malignant disease with presence of microscopic vascular invasion or satellites that indicate transplantation because of high risk of recurrence. This change represents a major alteration in BCLC decisionmaking, as described in gure 2, because patients diagnosed at a very early stage would be considered for resection only if a transplant were available. In the future, imaging techniques or molecular proling might distinguish between these two evolutionary tumour stages and decide between ablation and transplantation without need for resection with pathological assessment.

Image-guided transcatheter tumour treatment

Image-guided transcatheter treatments are based on selective intravascular delivery of drugs into arterial vessels nourishing the tumour, and are considered in patients with large cancers or multifocal disease that is not amenable to curative treatments. Chemotherapeutic drugs, embolic particles, or radioactive materials can be injected and induce tumour necrosis.108 The only option that has shown survival benet116,117 is transarterial chemoembolisation. It combines injection of chemotherapeutic agents with obstruction of arterial blood supply. More than 50% of patients have an objective response, as shown by extensive tumour necrosis, which translates into improved survival.71 In a recent meta-analysis, evidence supporting the benets of transarterial chemoembolisation was dened as still limited.118 However, this Cochrane analysis had several controversial features. It included a randomised controlled trial undertaken in patients with early hepatocellular carcinoma, in whom transarterial embolisation (not chemoembolisation) was assessed in combination with standard treatment for those patients (ablation by ethanol injection or radiofrequency ablation). It also included a trial using absorbable gelatin powder with short follow-up that showed poor 1-year survival119 (a characteristic shared by the most recent investigation)120 without extended follow-up. Furthermore, it excluded two
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trials that found improved survival because of risk of bias (according to Cochrane criteria).117,121 Finally, the Cochrane analysis had very stringent expectations for survival improvement (10%). After initial success with transarterial chemoembolisation, treated tumours are revascularised and can be re-treated. However, in the long term, the capacity to keep the cancer under control is lost. Development of polyvinylalcohol spheres that provide a calibrated vessel obstruction with slow release of chemotherapeutic agents has allowed the procedure to be standardised while maintaining eectiveness and reducing drug-related adverse events.122 In current trials, researchers are investigating whether the combination of transarterial chemoembolisation with molecular-targeted agents might delay tumour progression after treatment and, ultimately, improve survival. Median survival in old series was almost 2 years but, with better selection criteria and optimum treatment delivery, median survival exceeds 3 years.8587 Therefore, the best candidates for transarterial chemoembolisation are patients with compensated Child-Pugh A with asymptomatic multifocal or large hepatocellular carcinomas not amenable to resection (ie, BCLC stage B). Portal vein thrombosis, even if segmental, is a predictor of poor tolerability and impaired outcome.123 Radioembolisation with yttrium-90 (Yt)-labelled spheres has much potential, and ndings show antitumour activity,7678 but without randomised controlled trials to compare this option with any other established treatment, denition of its role in clinical practice is not feasible. Validation of safety and eectiveness in dierent cohort studies could indicate its target population.

Sorafenib
Until lately, no eective treatment was available for patients diagnosed at advanced stage or who progressed into an advanced stage after other treatments failed. Knowledge of molecular events that govern tumour progression and
100 Sorafenib Placebo

Proportion surviving (%)

75

50

p=00001

25

16

24

32

40 Weeks

48

56

64

72

80

Number at risk Sorafenib 299 Placebo 303

274 276

241 224

205 179

161 126

108 78

67 47

38 25

12 7

0 2

0 0

Figure 3: Overall survival of patients with advanced hepatocellular carcinoma assigned sorafenib or placebo Adapted from reference 72 with permission of the Massachusetts Medical Society.

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Llovet (2008)72 Sorafenib 800 mg per day (n=303) Response rate Complete response Partial response Stable disease Progressive disease Time to progression (months) Hazard ratio (95% CI) Median survival (months) Hazard ratio (95% CI) .. 0 7 211 .. 55 058 (045074) 107 069 (055087) Placebo (n=299) .. 0 2 204 .. 28 .. 79 ..

Cheng (2009)73 Sorafenib 800 mg per day (n=150) .. 0 5 81 46 28 057 (042079) 65 068 (050093) Placebo (n=76) .. 0 1 21 41 14 .. 42 ..

Data are number of patients, unless otherwise stated.

Table 3: Phase 3 clinical trials of sorafenib in patients with advanced hepatocellular carcinoma

Control Adjuvant treatment after resection or ablation Sorafenib Adjuvant treatment after transarterial chemoembolisation Sorafenib Brivanib First-line treatment in advanced hepatocellular carcinoma Sorafenib and erlotinib Sorafenib and doxorubicin Sorafenib and C1008 Sorafenib and mapatumumab Sorafenib and BIBF-1120 Sorafenib and oxaliplatin and capecitabine Sorafenib and bevacizumab Bevacizumab and erlotinib Brivanib Dovitinib Linifanib (ABT-869) Brivanib ARQ197 Axitinib Ramucirumab Everolimus OSI-906
*From http://www.clinicaltrials.gov.

Phase

Identier*

Placebo Placebo Placebo Sorafenib Sorafenib Sorafenib Sorafenib Sorafenib Sorafenib Sorafenib Sorafenib Sorafenib Sorafenib Sorafenib Placebo Placebo Placebo Placebo Placebo Placebo

3 2 3 3 3 2 2 2 3 2 2 3 2 3 3 2 2 3 3 2

NCT00692770 NCT00855218 NCT00908752 NCT00901901 NCT01015833 NCT01033240 NCT01258608 NCT01004003 NCT01245582 NCT00867321 NCT00881751 NCT00858871 NCT01232296 NCT01009593 NCT00825955 NCT00988741 NCT01210495 NCT01140347 NCT01035229 NCT01101906

Second-line treatment in advanced hepatocellular carcinoma

602 patients, median overall survival in the sorafenib group was 107 months (95% CI 94133) versus 79 months (6891) in the placebo group (hazard ratio 069, 95% CI 055087; p=00001; gure 3). Survival benet was preceded by a delay in time to progression: 55 months for sorafenib versus 28 months for placebo (058, 045074; p<0001).72 The two groups did not dier in median time to symptomatic progression (41 months vs 49 months; p=077). The overall incidence of treatment-related adverse events (predominantly grade 1 or 2 in severity) was 80% in the sorafenib group and 52% in the placebo group. Most frequent adverse events were gastrointestinal, constitutional, and dermatological in nature. Treatment interruption owing to side-eects was recorded in 38% of treated patients versus 37% in controls. These ndings have been replicated by a randomised controlled trial in Asia (table 3),73 and safety data were reproduced in a large phase 4 study of sorafenib in more than 1500 patients.124 These results have established sorafenib as the standard of care for advanced hepatocellular carcinoma43,125 and have paved the way for development of combination or sequential strategies to improve the eectiveness of sorafenib as one agent. Several trials are underway (table 4). The key issue in early development phases was how to assess potential eectiveness and to proceed to phase 3 trials. In all studies with sorafenib so far, survival is improved in the absence of treatment response, according to conventional denitions.126 New criteria based on biomarkers or functional imaging will have to be developed for assessment of ecacy. Until then, the potential eectiveness of novel agents will have to rely on time to progression, which also marks the time for recruitment of patients into trials to assess the ecacy of novel agents beyond sorafenib.70 Some attempts will fail, as has happened for sunitinib. This drug had a similar molecular prole to sorafenib but the trial was interrupted because of futility and safety concerns.127 Others could be positive and, hence, changes in management of advanced hepatocellular carcinoma might be introduced in coming years.

Future perspectives
Treatment of hepatocellular carcinoma has changed greatly within the past decade and has become a major area for research. Patients diagnosed with this malignant disease can benet from eective options that will improve their survival, whatever the evolutionary stage at which they have been diagnosed. Obviously, improvement in several areas is still needed. Recurrence after ablation or resection is a major drawback, and eective preventive agents are needed. Also, progression after eective chemoembolisation is an area in which any positive strategy should result in relevant benet. Finally, identication of novel targets and predictors through molecular cell biology will identify new therapeutic strategies for advanced stage hepatocellular carcinoma and provide better methods for outcome prediction. For that reason, collection of tissue samples should be considered in research studies. Molecular
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Table 4: Randomised phase 2 and 3 multicentre trials in progress

dissemination has allowed development of targeted treatments that aim to abrogate these disrupted pathways. Several drugs are under development, but the only one with proven survival benet is sorafenib.72,73 This agent, which can be administered orally, is a multikinase inhibitor that blocks Raf signalling and VEGF, PDGF, and c-Kit. It has antiproliferative and antiangiogenic activity and delays tumour progression. In our phase 3, multicentre, randomised, double-blind, placebo-controlled trial of
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biology data might oer the insight to abrogate malignant transformation within cirrhotic livers. For these advances to take place, continuing active clinical and experimental research is essential. Only by combination of all areas of expertise will these hopes be realised.
Contributors AF did the literature research. All authors wrote the Seminar and have reviewed and approved the nal version. Conicts of interest AF has received consultancy and lecture fees from Bayer Schering Pharma. JML has received grant support, consultancy fees, or both from Bayer Schering Pharma, Bristol-Myers Squibb, Biocompatibles, Biosphere, Novartis, Imclone, Jennerex, Abbott, and OSI. JB has received grant support, consultancy fees, or both from Bayer Schering Pharma, Bristol-Myers Squibb, Biocompatibles, Terumo, Novartis, Schering Plough, Eisai, Arqule, Angiodynamics, Kowa, GlaxoSmithKline, Sumitomo, Lilly, and OSI. Acknowledgments The Barcelona Clinic Liver Cancer (BCLC) is funded through the Spanish Biomedical Research Network (CIBER) for the area of Hepatic and Digestive disorders. This work was supported partly by grants from the Instituto de Salud Carlos III (PI 08/0146). JML has received grants from the US National Institutes of Health-NIDDK 1R01DK076986-01, National Institute of Health (Spain) grant I+D Program (SAF-2007-61898), and the Samuel Waxman Cancer Research Foundation. References 1 Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893917. 2 Alazawi W, Cunningham M, Dearden J, Foster GR. Systematic review: outcome of compensated cirrhosis due to chronic hepatitis C infection. Aliment Pharmacol Ther 2010; 32: 34455. 3 Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362: 190717. 4 Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis 2010; 30: 316. 5 Bosetti C, Levi F, Boetta P, Lucchini F, Negri E, La Vecchia C. Trends in mortality from hepatocellular carcinoma in Europe, 19802004. Hepatology 2008; 48: 13745. 6 El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365: 111827. 7 Qiu D, Katanoda K, Marugame T, Sobue T. A Joinpoint regression analysis of long-term trends in cancer mortality in Japan (19582004). Int J Cancer 2009; 124: 44348. 8 Tanaka Y, Kurbanov F, Mano S, et al. Molecular tracing of the global hepatitis C virus epidemic predicts regional patterns of hepatocellular carcinoma mortality. Gastroenterology 2006; 130: 70314. 9 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010; 138: 51321. 10 El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126: 46068. 11 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med 2003; 348: 162538. 12 Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol 2005; 42: 21824. 13 Bravi F, Bosetti C, Tavani A, La Vecchia C. Coee drinking and hepatocellular carcinoma: an update. Hepatology 2009; 50: 131718. 14 Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22707 men in Taiwan. Lancet 1981; 318: 112933. 15 Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295: 6573.

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