Journal of Hepatology
Volume 48, Supplement 1 , Pages S20-S37, 2008

Novel advancements in the management of hepatocellular carcinoma in 2008☆

  • Josep M. Llovet

      Affiliations

    • HCC Translational Research Laboratory, Barcelona Clínic Liver Cancer (BCLC) Group, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clìnic, Villarroel 170, 08036 Barcelona, Catalonia, Spain
    • Mount Sinai Liver Cancer Program, Division of Liver Disease, Mount Sinai School of Medicine, NY, USA
    • Corresponding Author InformationCorresponding author. Tel.: +34 93 227 9156; fax: +34 93 227 5792.
    • ,
  • Jordi Bruix

      Affiliations

    • HCC Translational Research Laboratory, Barcelona Clínic Liver Cancer (BCLC) Group, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clìnic, Villarroel 170, 08036 Barcelona, Catalonia, Spain

published online 13 February 2008.

Article Outline

New advancements have emerged in the field of hepatocellular carcinoma (HCC) in recent years. There has been a switch in the type of presentation of HCC in developed countries, with a clear increase of tumors <2cm in diameter as a result of the wide implementation of surveillance programs. Non-invasive radiological techniques have been developed and validated for the diagnosis of small and tiny HCCs. Simultaneously, diagnostic criteria based on molecular profiling of early tumors have been proposed. The current clinical classification of HCC divides patients into 5 stages with a specific treatment-oriented schedule. There is no established molecular classification of HCC, although preliminary proposals have already been published. Advancements in the treatment arena have come from well designed trials. Radiofrequency ablation is currently consolidated as providing better local control of the disease compared with percutaneous ethanol injection. New devices are available to improve the anti-tumoral efficacy of conventional chemoembolization. Sorafenib, a multikinase inhibitor, has shown survival benefits in patients at advanced stages of the disease. This advancement represents a breakthrough in the management of this complex disease, and proves that molecular targeted therapies can be effective in this otherwise chemo-resistant tumor. Consequently, sorafenib will become the standard of care in advanced cases, and the control arm for future trials. Now, the research effort faces other areas of unmet need, such as the adjuvant setting of resection/local ablation and combination therapies.

Abbreviations: HCC, hepatocellular carcinoma, RCT, randomised controlled trial, RF, radiofrequency ablation, TACE, transarterial chemoembolization, HCV, hepatitis C virus, HBV, hepatitis B virus, EASL, European Association for the Study of the Liver, AASLD, American Association for the Study of Liver Diseases

Keywords: Hepatocellular carcinoma, Early diagnosis, Molecular diagnosis, Randomised controlled trials, Systematic review, Evidence-based medicine, Clinical trials, Survival, Molecular targeted therapies, Sorafenib

 

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1. Introduction 

Hepatocellular carcinoma (HCC) is a major health problem, being the sixth most common cancer worldwide with 626,000 new cases in 2002 [1]. The incidence of HCC is increasing in Europe and the United States [2], and is currently the leading cause of death amongst cirrhotic patients [3]. Chronic hepatitis B viral (HBV) infection is the predominant risk factor in Asia and Africa, and chronic hepatitis C viral (HCV) infection in Western countries and Japan. Hepatocellular carcinoma develops in a cirrhotic liver in 80% of cases, and this pre-neoplastic condition is the strongest predisposing factor [4]. Chronic HBV carriers have a 100-fold relative risk for developing HCC, with an annual incidence rate of 2–6% in cirrhotic patients [6]. Aflatoxin B1 intake further enhances the risk. In Western countries and Japan, hepatitis C virus (HCV) infection is the main risk factor, together with other causes of cirrhosis. Around 20–30% of the estimated 170 million HCV-infected individuals worldwide will develop cirrhosis. Once cirrhosis is established, the annual incidence of HCC is of 3–5%, and one third of them will develop a HCC over their lifetime [4].

During recent years, major advancements in the knowledge of this complex disease have been reported. We review herein these new data on surveillance and early diagnosis, the clinical and molecular classification of the disease, and the novel advancements in the management of this neoplasm. Specifically, we will analyze the advent of sorafenib as the first systemic therapy that has shown survival benefits, and pinpoint the most urgent unmet needs and how to design trials to capture benefits from efficacious drugs.

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2. Early diagnosis of HCC: novel markers 

Surveillance with ultrasound every 6 months for detection of early HCC is recommended in cirrhotic patients and other specific risk groups [5], [6]. The only randomised study reported so far comparing surveillance vs. non-surveillance has shown benefits in terms of higher applicability of curative therapies in Chinese patients infected with HBV regardless of the presence of cirrhosis [7]. European cohort studies and cost-effectiveness analysis further reinforce the benefits of this policy [3], [8]. A recent randomised trial aimed at comparing two periodicities of surveillance (3 months vs. 6 months) in 1200 cirrhotic patients concluded that ultrasound-based screening performed every 3 months does not improve the diagnosis and treatment of small HCC [9]. AFP levels are no longer assessed in surveillance programs due to the low capacity of identifying new cases not previously detected by imaging techniques. AFP has been shown to be only marginally effective in special populations or health care environments [10].

The success of surveillance programs and the availability of highly effective therapies for small HCC have changed the clinical scenario faced by the scientific community (Fig. 1). Nowadays, early HCC diagnosis is feasible in 30–60% of cases in developed countries and this enables the application of curative treatments [4]. In fact, while tumors less than 2cm in diameter represented <5% of the cases in the early nineties in Europe, now they represent up to 30% of cases in Japan. This trend is expected to continue in parallel with the wider implementation of surveillance policies in developed countries. However, detection of these minute nodules of ∼2cm poses a diagnostic challenge as they are difficult to characterize by radiological or pathological examination [11], [12], [13]. The distinction between dysplastic nodules and early tumors is an unresolved problem, even among expert hepatopathologists [13]. Immunostaining with CD34 and alpha fetoprotein (AFP) has significant diagnostic limitations [14]. Serum biomarkers such as AFP, des-γ-carboxyprothrombin (DGCP) and AFP-L3 fraction are not accurate for the early diagnosis of HCC [5].

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  • Fig. 1. 

    Representation of the switch in the presentation of HCC in developed countries, as a result of implementation of surveillance among cirrhotic patients. Estimates of applicability of potentially curative therapies have been divided in three periods: until 1990: 5–10% of cases; 1990–2010: 30–40% of cases; 2010–2020: 40–60% of cases.

Proper definition of nodules as pre-neoplastic lesions or early HCC has critical implications according to the guidelines of HCC management in Europe and the US [5], [6]. Dysplastic lesions should be followed by regular imaging studies, since one third of them will develop a malignant phenotype [4]. Conversely, early tumors are treated with potentially curative procedures – albeit expensive – such as resection, transplantation and percutaneous ablation [4]. Thus, there is an urgent need to identify better tools to characterize these lesions. Otherwise, the cost-effectiveness of the recall policies applied within surveillance programs will be significantly undermined.

Therefore, accurate diagnosis of small liver nodules is of paramount importance. Non-invasive radiological criteria have been developed by using state-of-the-art radiological techniques, and endorsed by the European Association for the Study of the Liver (EASL) [6] and the American Association for the study of Liver Disease (AASLD) [5]. In principle, a unique dynamic radiological behavior (contrast up-take in the arterial phase and rapid wash out in the venous/late phase) represents the backbone of radiological diagnosis of early HCC in cirrhotic patients. One imaging technique in nodules >2cm, and coincidental findings by two imaging techniques in nodules between 1 and 2cm are considered diagnostic. A recent prospective study including 89 consecutive cases of nodules between 0.5 and 2cm detected within surveillance programs has shown that the above mentioned criteria are accurate for the diagnosis of HCC, with a specificity of 100% [15]. This investigation prospectively validates the AASLD guidelines, but unfortunately their sensitivity is modest: only 30% of the HCC cases are confirmed by non-invasive criteria and this highlights the need for complementary tools.

Pathological diagnosis of small/tiny nodules is challenging even in expert hands [16]. Tissue markers might provide a more across the board standardized diagnosis of these tumors. Genome-wide DNA microarray or quantitative real time reverse-transcriptase polymerase chain reaction (RT-PCR) studies have attempted to identify markers of early HCC, such as heat shock protein 70 (HSP70), Glypican-3 (GPC3) [17], telomerase reverse-transcriptase (TERT), serine/threonine kinase 15 (STK6) and phospholipase A2 (PLAG12B), reviewed elsewhere [18]. A molecular index including a 13-gene set has also been proposed (including TERT, TOP2A and PDGFRA) [19]. A microarray-generated signature of 120 genes was reported to discriminate between dysplastic nodules and HCC in HBV patients [20]. Proteomic studies in tissue have not identified informative HCC markers so far [21]. More recently a 3-gene set (Glypican-3, LYVE1, and survivin) has been proposed as molecular diagnosis of early HCC with accuracy rates of 85–95% in training and validation sets in more than 70 samples [22] (Fig. 2). Immunostaining for Glypican-3 was also identified as highly predictive of HCC in 75 samples [22] (Fig. 3). Thus, a more accurate diagnosis of small early HCC is currently available, and novel markers identified by microarray analysis still require validation [23].

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  • Fig. 2. 

    Accuracy of the molecular diagnosis of HCC, by using a 3-gene set with Glypican-3, LYVE1 and survivin. Gene expression profiles of the three genes included in the best gene signatures in all the stages of the hepatocarcinogenic process. Results are expressed as fold-change. Boxes reflect median gene expression (25–75 percentile). Legend: controls (C, n=10), cirrhosis (Ci, n=10), dysplastic nodules (D, n=17), early HCC ([E, n=20), advanced HCC [n=20].

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  • Fig. 3. 

    Immunostaining for GPC3, counterstained with hematoxylin: (A) low grade dysplastic nodule, negative for GPC3 (200×); (B) positive GPC3 staining in a 0.8cm HCC and negative staining in the cirrhotic nodule (100×); (C) higher magnification showing diffuse cytoplasmic staining for GPC3 in tumor cells (400×); (D) advanced HCC reacted strongly for GPC3 (100×).

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3. Clinical and molecular classification of HCC 

Cancer classification is aimed to establish prognosis and select the adequate treatment for the best candidates. In addition, it aids researchers to exchange information and design clinical trials with comparable criteria. Clinical classifications have been proposed for most cancers. However, very few involve molecular data. Such is the case of breast cancer, where Her2/nu status discriminates subgroups of patients with different outcomes and treatment responses [24]. Similarly, EGFR mutational status in non-small cell lung cancer identifies a subgroup of responders to tyrosine kinase inhibitors [25]. Clinical classification of HCC is currently available, but no molecular data have been incorporated so far. Specific knowledge of the molecular classification of HCC is preliminary, and further studies are required. Molecular data can be useful to further discriminate the best candidates for resection or liver transplantation, and to guide personalized medicine.

3.1. Barcelona-Clinic Liver Cancer (BCLC) classification 

The Barcelona-Clinic Liver Cancer (BCLC) classification has emerged as the standard classification for clinical management of HCC [4], [26]. This classification has been externally validated [27] and is endorsed by AASLD and EASL [5], [6]. This system links tumor stage with treatment strategy. Table 1 summarizes the current evidence in terms of survival advantages or other benefits obtained from clinical investigations following the National Cancer Institute classification [28]. In addition, it integrates this evidence into the BCLC system, as has recently occurred with sorafenib, a multikinase inhibitor that showed survival advantages in patients with advanced tumors [29]. Unlike breast cancer and lymphoma, no clear biological/genetic markers associated with clinical outcomes have yet been defined in HCC, and thus all the variables used are clinical.

Table 1. Evidence-based benefits of treatments according to the strength of study design and of endpoints and targeted BCLC class, 2007⁎
Treatments assessedBenefitLevel of evidenceBCLC stage
Surgical treatments
Surgical resectionIncreases survival3iiA0-A
Adjuvant therapiesControversial1A–D
Liver transplantationIncreases survival3iiAA
Neo-adjuvant treatmentsTreatment response3Diii
Locoregional treatments
Percutaneous treatmentsIncrease survival3iiA0-A
RadiofrequencyBetter local control1iiD
Embolization/chemoembolizationIncrease survival1iiAB
LipiodolizationTreatment response3iiDiii
Internal radiation (I131, Y90)Treatment response3iiDiii
Systemic treatments
SorafenibIncreases survival1iAC⁎⁎
Hormonal compoundsNo survival benefit1iA
Tamoxifen
Anti-androgens
Systemic chemotherapyNo survival benefit1iiA
ImmunotherapyNo survival benefit1iiA

Study design: randomised controlled trial, meta-analysis=1 (double-blinded: 1i, non-blinded: 1ii). Non-randomised controlled trials=2. Case series=3 (population-based 3i, non-population based, consecutive 3ii, non-population based, non-consecutive: 3iii).

Endpoint: survival (A), cause-specific mortality (B), quality of life (C). Indirect surrogates (D). Disease free survival (Di), progression-free survival (Dii), tumor response (Diii).

⁎⁎80% of patients included in the RCT were BCLC C, and 20% BCLC B [29].

⁎Classification of evidence adapted from NCI: www.cancer.gov [28].

3.1.1. Early stages 

Survival of patients with early HCC reaches 50–70% at 5 years after resection, liver transplantation or percutaneous treatments in selected candidates [4]. These outcomes are the result of applying the so-called treatment-dependent variables in the selection of candidates, referring to restrictive criteria regarding tumor status and liver function. Tumor status is defined by size of the main nodule and multicentricity (single ⩽2cm, single 2–5cm, 3 nodules ⩽3cm), each of these categories showing significantly different outcomes. In patients with tumors less than 2cm, recent pathological and clinical data have led to the concept of very early HCC [13], which correlates with the pathological carcinoma in situ stage. This is a very well-differentiated HCC that contains bile ducts and portal veins, has ill-defined nodular appearance and, by definition, has not invaded any structure. In Japan, these patients show excellent outcome in terms of survival (resection, 5-yr survival: 89%; percutaneous treatment, 5-yr survival of 71%) and recurrence (8% at 3-yr) [4]. Recurrence rate is higher in patients with overt HCC and unfortunately, despite some positive results in isolated randomised controlled trials (RCTs), no adjuvant therapies after complete resection/local ablation are currently accepted as standard of care in HCC [30]. These are grey areas of research that represent an unmet need, and are discussed exhaustively below.

Variables related to liver function are relevant in patients not suitable for transplantation. Thus, absence of clinically relevant portal hypertension and normal bilirubin are key predictors of survival in patients with single tumors undergoing resection [30], [31]. Similarly, Child–Pugh class A is the strongest prognostic variable in patients undergoing percutaneous treatments, along with tumor size and response to treatment [32]. Since liver transplantation may potentially cure both the tumor and the underlying liver disease, variables mostly related with HCC have been clearly established as prognostic factors (single tumors ⩽5cm or 3 nodules ⩽3cm), defining the so-called Milan criteria [33].

3.1.2. Intermediate-advanced HCC 

Prognosis of HCC was assumed to be poor for unresectable cases, the median survival figures being of less than 1 year. Analysis of heterogeneous outcomes within 25 RCT (2 yr survival 8–50%) [34] lead to the identification of at least three subgroups of patients with unresectable HCC: the intermediate, advanced and end-stage classes, according to the BCLC classification [4]. Untreated patients at an intermediate stage (multinodular asymptomatic tumors without an invasive pattern) present a median of 16 months. Chemoembolization expands the median survival of these patients to 19–20 months according to RCTs and meta-analysis of pooled data reported, and is considered their standard of care [34]. Untreated patients at advanced stages (with symptomatic tumors or ECOG 1–2, or vascular invasion/extrahepatic spread) present a median survival of 6 months. Among this group, outcomes may vary according to Child–Pugh class.

In 2006, there was no FDA-approved first line treatment for patients with advanced HCC. This scenario has changed as a result of the data reported showing survival benefits from patients receiving sorafenib – a multi tyrosine kinase inhibitor – in advanced cases [29]. The results of this RCT represent a breakthrough in the management of HCC, as it is discussed in the molecular targeted therapies section.

3.1.3. End-stage HCC 

Patients with end-stage disease are characterized by presenting Okuda stage III, or Performance Status of 3–4, that reflects a severe tumor-related disability. Their median survival is of 3–4 months. Similarly, Child–Pugh C patients with tumors beyond the transplantation threshold also account for a very poor prognosis [26].

3.2. Other clinical classifications of HCC 

The limitations of unidimensional systems, such as the Okuda staging and the Child–Pugh classification, have already been overcome. Several new proposals reported recently largely subclassify patients at advanced stages, with a minor number of effectively treated patients, such as the CUPI [35] and the CLIP score [36]. They use descriptions of tumor stage that are not in accordance with the predictive value of tumor size and multicentricity. For instance, the CLIP score classifies the tumor burden as above/below 50% of liver involvement, thus making it impossible by definition to identify patients at early stages. In addition, it lacks assessment of cancer-related symptoms, a critical point in the evaluation of the prognosis of cancer patients.

The new TNM in accordance with the AJCC has only internal validation, and is based on series of patients undergoing resection [37]. Pathological information is needed in all cases, thus representing a limitation for wide clinical use. Finally, the Japan Integrated Staging (JIS) [38] is a new score system that includes two previous classifications: the TNM endorsed by the Union Internationale Contre le Cancer (UICC) mostly applied in Japan, and the Japanese version of the Child–Pugh classification. A recent validation of the JIS score in more than 4500 patients has shown to be better than the CLIP score [38].

3.3. Molecular classification of HCC: predicting outcomes with gene expression signatures 

There is no molecular classification of HCC [39]. Global gene expression profiling may be the most appropriate technology to unravel the pathogenesis of HCC and explore its heterogeneous origin. In fact, application of gene expression profiling of HCC has identified subgroups of patients according to aetiological factors, different stages of the disease, recurrence and survival (reviewed in [40]). Other molecular classifications based on activation of specific signal transduction pathways have been recently reported [41]. These investigations represent promising progress in the use of gene expression profiling in elucidating the molecular pathogenesis of HCC and in improving the prognostic prediction for HCC patients. Preliminary studies suggest that tumors can be classified according to molecular biology. Signatures coming from the tumor and from the microenvironment have shown capacity to discriminate subgroups of cancers with different survival outcomes, but these data require external validation. The incorporation of the knowledge of molecular biology in the clinical practice might aid in the selection of patients for resection and liver transplantation.

Prediction of survival by gene signatures is limited due to the fact that the patients die not only from tumor progression but also from liver failure. Thus, accurate selection of the cohort and/or use of cancer-related death as an endpoint to minimize this bias should be a priority. A gene signature able to discriminate two populations of good and poor survival was reported in HBV patients [42]. Application of a knowledge-based annotation of the 406 genes revealed molecular pathways responsible for the biological differences observed in the two subclasses of HCC. Measurement of cell proliferation, apoptosis, ubiquitination and histone modification provided the best quantitative separation of the two survival subclasses. More recently, the same group reported one additional HCC subgroup of patients with grim prognosis presenting an hepatoblatoma-like signature assumed to be of progenitor cell origin [43]. Another study analyzed the expression profiles of 67 primary and metastatic HCC samples from 40 patients. Using a supervised machine-learning algorithm, the authors generated a 153-gene molecular signature that permitted classification of metastatic HCC patients and identified genes that were relevant to patient survival [44].

Even with optimal selection of candidates for resection/local ablation, tumor recurrence complicates 50% of cases at 3 years, comprising previously undetected metastases and de novo tumors [30]. Pathological variables including vascular invasion, poor histological differentiation and satellites, predict metastases [30]. Biological markers that predict an aggressive behavior are not well defined. Two studies have employed gene expression profiling to address the issue of HCC recurrence following resection. A Japanese study described a 12-gene signature identified through high-density oligonucleotide microarrays (∼6000 genes), that reported an accuracy in the training and validation set above 90% (overall sample size 60 patients) [45]. Another study analyzed gene expression using a PCR-based array platform of 3072 genes in 100 HCC patients. The authors identified a 20-gene signature that was an independent predictor for recurrence [46].

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4. New advancements and needs in clinical research 

In oncology, the benefits of treatments should be assessed through randomised controlled trials and meta-analysis. Other sources of evidence, such as non-randomised clinical trials or observational studies are considered less robust. Few medical interventions have been thoroughly tested in HCC, in contrast with other cancers with a high prevalence worldwide, such as lung, breast, colo-rectal and stomach cancer [34], [47]. Unfortunately, the fact that HCC is a tumor with a low incidence in developed countries has meant that the amount of information coming from controlled studies is scarce. There are no mega-RCTs (with >1000 patients) or meta-analysis of individual data in the HCC field, which are considered the “best source of evidence”. Thousands of RCTs evaluating therapeutic interventions have been published in each of the major cancers, compared to only about 90 RCTs in HCC. As a result, the strength of evidence for any intervention in HCC is far behind the most prevalent cancers worldwide. There is an urgent need to conduct randomised investigations in liver cancer, which at this point can be considered as an “orphan” neoplasm in terms of clinical research.

The main prognostic factors are related to tumor status (defined by number and size of nodules, presence of vascular invasion, extrahepatic spread), liver function (defined by Child–Pugh’s class, bilirubin, albumin, portal hypertension) and general health status (defined by ECOG classification and presence of symptoms) [4]. Aetiology has not been identified as an independent prognostic factor.

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5. Resection 

Surgery is the mainstay of HCC treatment (Table 1). Resection and transplantation achieve the best outcomes in well-selected candidates (5-yr survival of 60–70%), and compete as the first option in patients with early tumors on an intention-to-treat perspective [4], [30], [31]. Hepatic resection is the treatment of choice for HCC in non-cirrhotic patients (5% of cases in the West, 40% in Asia) [48], [49]. Major resections can be performed with low rates of life-threatening complications. In fact, all types of tumors confined to the liver can be removed as long as enough functional reserve remains to ensure a good outcome. A few large series have reported 5-yr survival rates of 30–50%, and are reviewed elsewhere [34].

Resection of HCC in cirrhotic patients requires an expert selection of the candidates – meaning adequate knowledge of the stage of the disease, the risk factors for postoperative morbidity and mortality, recurrence and survival, and adequate skills in the conduction of the surgical procedure. Advancement in the knowledge of both factors has increased the efficacy of treatment. Nowadays the selection of candidates for resection has been refined, and the surgical technique – ultrasonic dissector, Pringle maneuvre, etc. – and the immediate postoperative management have been optimized. In addition, the implementation of anatomic resections according to Couinaud has ensured a surgical approach based on sound oncologic principles [50].

As a result of these advancements, the modern standards for resection for HCC in cirrhotic patients include perioperative mortality below 3%, blood transfusion requirements of less than 10%, and 5-yr survival rates of at least 50% [30]. In fact, perioperative mortality has decreased from 15% in the eighties to 3–5% in the majority of referral units. Some centers have reported a zero perioperative mortality [51], as is our case in Barcelona in one hundred patients with hepatic venous pressure gradient ⩽10mmHg and single tumors [30]. Blood loss may be controlled both by selecting patients with preserved liver functional reserve and by applying intermittent inflow occlusion during the hepatic parenchimal transection. These strategies have led to a decrease in blood transfusion from 80–90% to less than 10% in two decades [51].

Selection of the ideal candidates involves an adequate assessment of the liver functional reserve and tumor extension. The main predictors of survival and recurrence after resection are summarized in Table 2 [11], [31], [52], [53], [54], [55], [56], [57], [58]. The refinement of assessment of liver function has moved from the gross determination of Child–Pugh class to a more sophisticated measurement of indocyanine green retention rate at 15min (ICG15) in Japan [59], or hepatic venous pressure gradient (HVPG) ⩾10mmHg as a direct measurement of relevant portal hypertension in the West [60]. Selection of patients with HVPG <10mmHg, ICG15 ⩽20% or absence of surrogates of portal hypertension (esophageal varices, or splenomegaly with platelet count <100,000/mm3) leads to a resectability rate of less than 10%. Some groups apply pre-operative portal vein embolization (PVE) of the branches supplying the portion of the liver to be resected in order to increase the residual liver volume if a major resection is envisioned [51]. The effectiveness of this approach has not yet been properly tested in large controlled studies.

Table 2. Resection for HCC
AuthorsnVariables
Survival
Llovet [31]77
Portal hypertension (yes/no)

Bilirubin (<1/>1mg/dL)
Zhao [52]1000
Cirrhosis (yes/no)

γ-GT

Number of tumors (solitary vs. multiple)

Portal vascular invasion (yes/no)
Vauthey [53]557
Macroscopic and microscopic vascular invasion (yes/no)

Number of tumors (single vs. multiple)

Tumor size (<5cm, >5cm)

Fibrosis (Ishak score 0–4 vs. 5–6)
Poon [54]518
Major vascular invasion

Microvascular invasion

Tumor size >5cm

Multiple tumors/bilobar disease

Cirrhosis

AST >50U/L

Invasion of adjancent organs
Ikai [11]12,118
Tumor size (⩽2cm, 2–5cm, 5–10cm, >10cm)

Number of tumors (solitary vs. multiple)

AFP levels (<20, 20–200, 200–1000, >1000ng/mL)

Degree of liver damage (A, B, C)

Vascular invasion (yes/no)

Surgical curability (yes/no)
Recurrence
Belghiti [55]47
Tumor size

AFP levels
Kumada [56]57
AFP levels

Multinodular HCC

Tumor size
Llovet [31]77
Differentiation degree

Multinodular

Satellites
Imamura [57]
Early recurrence (<2 yr)123
Vascular invasion

AFP levels

Non-anatomical resection

Late recurrence (>2 yr)61
Multinodular

Hepatitis activity

HCC gross classification
Ercolani [58]224
Number of nodules

AST levels

Series analyzing independent predictors of survival and recurrence by multivariate analysis.

Vascular invasion is a known predictor of recurrence and survival, directly associated with histological differentiation, degree and size of the main nodule. Characteristically, microscopic vascular invasion involves 20% of tumors of 2cm in diameter, 30–60% of cases in nodules 2–5cm and up to 60–90% in nodules above 5cm in size. Of note is that cancer invasion occurs before the 2cm cut-off level. Kojiro [13] analyzed 106 resected HCC ⩽2cm and distinguished the so-called indistinct type (mean size: 12mm) without local invasiveness, from the distinct nodular type (mean size: 16mm) that showed local invasiveness. In the latter type, satellites surrounding the nodule were found in 10% of cases, and microscopic portal invasion in up to 25%. Ultrasonography detected both types, but only the latter appeared hypervascular on CT-scan, confirming the finding that early tumors have portal blood supply without tumor staining at angiography, while advanced HCC shows tumor staining. Very early HCC equals to stage 0 of BCLC class [4] and H0 by Japanese authors [11]. This was proposed that the earliest clinical entity (very early HCC) would include Child–Pugh’s A patients with carcinoma in situ disease. These patients achieve 5-yr survival of 90% after resection with extremely low recurrence rates (8% at 3-yr) [61].

Tumor extension should be assessed prior to resection by last generation CT scan or MRI. However, even last generation imaging techniques underestimate pathological tumor staging in up to 30% of cases [62]. Intraoperative ultrasonography (IOUS) enables the detection of nodules between 0.5 and 1cm, and is considered the standard of care to discard additional nodules and to guide anatomical resections [63]. Three variables emerge as prognostic factors: size, number of tumors and presence of vascular invasion. The Japanese Nationwide Survey has shown that a cut-off below 2cm is an independent predictor of survival in a series of thousands of patients [11]. Five-year survival rates for patients with HCC ⩽2cm was of 66%, compared with 52% for tumors 2–5cm and 37% for tumors >5cm. In the same study, 5-yr survival after resection of single tumors was 57%, and for 26% for three or more nodules [11].

5.1. Adjuvant treatments to prevent recurrence 

Tumor recurrence complicates 70% of cases at 5 years, reflecting either intrahepatic metastases (true recurrences) or the development of de novo tumors [31], [52], [53], [54], [55], [56], [57], [58]. These entities can be differentiated by means of comparative genomic hybridization, integration pattern of hepatitis B virus, DNA fingerprinting using loss of heterozygosity assays, or DNA microarray studies [64], [65], [66]. From these investigations it can be determined that 60–70% of recurrences correspond to intrahepatic metastases undetected at the time of resection, whereas 30–40% are de novo HCCs. Unfortunately, these entities cannot be distinguished in routine clinical practice. True recurrences characteristically appear within 2 years after resection and their main predictors are vascular invasion, poor histological differentiation degree and satellites (Table 2) [31], [52], [53], [54], [55], [56], [57], [58]. De novo tumors characteristically occur late, defined as more than 2 years after resection [56].

Strategies to prevent and treat recurrence should ultimately vary according to the type of relapse, and have been reviewed elsewhere [30]. From the preventive point of view, undetected intrahepatic metastases might be treated by chemoembolization/lipiodolization, internal radiation, chemotherapy or adoptive immunotherapy, or molecular targeted therapies whereas de novo tumors may be prevented by agents, such as retinoids or interferon [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79] (Fig. 4 and Table 3).

Table 3. Main RCT reported assessing adjuvant treatments for resection/local ablationa in HCC
AuthorsTreatment arms (n)Result (3-yr recurrence rate)Conclusion/study needed
Treatment of residual disease
Adoptive immunotherapyConfirmatory RCT
Takayama [67]Adoptive immunotherapy (76) vs. control (74)33% vs. 48% (p=0.008)

Internal radiationConfirmatory RCT
Lau [68]Intra-arterial lipiodol I131 (21) vs. control (22)DFS: 75% vs. 38% (p=0.03)Small study
Chemoembolization/lipiodolizationNo benefit Optimize strategy
Wu [69]Preop chemoembolization (24) vs. control (28)67% vs. 61%, p=ns
Yamasaki [70]Preop chemoembolization (50) vs. control (47)54% vs. 66%, p=ns
Kohno [71]Postop chemoembolization (48) vs. control (40)63% vs. 68%, p=ns
Lai [72]Postop chemoemboliaztion (30) vs. control (36)82% vs. 52%, p=ns

ChemotherapyNo benefit
Yamamoto [73]5-FU (35) vs. control (32)52% vs. 75%, p=ns
Ono [74]Epirubicin+carmofur (57) vs. control (51) None

Molecular targeted therpies
Sorafenib vs. placebo after resection/local ablationStarting in 2008
PI-88 vs. placebo after resectionStarting in 2008

Chemoprevention for de novo HCC
Atypical retinoidsConfirmatory RCT
Muto [75]Polyprenoic acid (44) vs. placebo (45)2nd HCC: 27% vs. 49% (p=0.04)

InterferonLarge RCT needed
Kubo [76]aInterferon alpha (15) vs. control (15)30% vs. 60% (p=0.03)
Shiratori [77]aInterferon alpha (49) vs. control (25)5-yr survival (68% vs. 48%)
Lin [78]aInterferon alpha (21) vs. control (10)–
Mazzaferro [79]Interferon alpha (75) vs. control (74)No differencesConfirmation of benefit for HCV only cases

aLocal ablation.

A review of RCT assessing adjuvant therapies for resection/local ablation and HCC is summarized in Table 3. Almost all published RCTs have been conducted in Asia. Adjuvant chemoembolization and/or chemotherapy do not add benefit in terms of prevention of relapse [69], [70], [71], [72]. Internal radiation with 131-I-labelled lipiodol had a positive effect in a single RCT that was prematurely stopped after recruiting 43 patients [68]. The effect observed, however, merits further research, as other uncontrolled studies have reported promising results [80]. Adoptive immunotherapy by activated lymphocytes with interleukin-2 and antibody to CD3 reduced first recurrence in a trial with 150 patients [67] (3-yr recurrence: 33% vs. 48% in the control group). A similar effect was described with retinoids preventing de novo tumors [75]. None of these strategies are currently used in clinical practice, and the results need to be confirmed by other investigators. Interferon has shown positive results in some RCTs, including patients after resection/percutaneous ablation [76], [77], [78]. More recently the first Western RCT assessing Interferon-alpha in 150 patients, has shown overall negative results. However, the subgroup analysis of HCV-only patients showed a preventive effect of these treatments for de novo late recurrences, providing the rationale to assess this strategy in future investigations [79].

Clinical trials assessing adjuvant therapies after resection are urgently required as availability of an effective intervention is an unmet need. The primary endpoint of the studies should be time to recurrence. The preventive strategies to target both types of recurrences are completely different, and the combination of treatments seems the most rational approach. Due to the lack of proven-effective treatments it is justified to randomise patients to an untreated control arm. Stratification prior to randomisation should be done according to tumor size, number of nodules/satellites, and vascular invasion. Due to the nature of these investigations, multi-institutional studies are required. The positive results reported with sorafenib for advanced HCC warrant an international study in the adjuvant setting with this multikinase inhibitor.

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6. Liver transplantation 

Liver transplantation is the first treatment choice for patients with small multinodular tumors (3 nodules <3cm) or those with advanced liver dysfunction [4], [31] (Table 1, 3iiA). Theoretically, transplantation may simultaneously cure the tumor and the underlying cirrhosis. The broad selection criteria applied two decades ago led to poor results in terms of recurrence (32–54%) and survival (5-yr survival <40%), but allowed the identification of the best candidates for liver transplantation. These are patients with single HCC ⩽5cm or up to 3 nodules <3cm who in major units achieve 70% survival at 5 years with a recurrence rate below 15% [30], [31], [33]. The major drawback of this treatment is the scarcity of donors. The increase of waiting time has led 20% of the candidates to drop out before receiving the procedure, thus jeopardizing the outcome if analyzed according to intention-to-treat. Adjuvant therapies whilst on the waiting list are used in most centers to prevent tumor progression. Robust data from RCTs are lacking and thus, the potential benefits advocated for percutaneous ablation, chemoembolization or chemotherapy are derived from observational studies and cost-effective analyses (3iiDiii).

6.1. Neo-adjuvant treatments in the waiting list 

The main studies assessing neo-adjuvant therapies in the waiting list of liver transplantation are summarized in Table 4. All the information come from case series, case-control studies and cohort studies, showing that RFA achieves the highest rates of complete necrosis (12–55%) [81], [82], [83] compared with TACE (22–29%) [84], [85], [86], [87], [88]. Complete necrosis is best achieved with percutaneous ablation in tumors smaller than 30mm in diameter. The impact of these treatments on drop-out rate, recurrence and survival are only estimated form non-randomised studies.

Table 4. Studies reporting the outcomes of HCC patients treated in the waiting list of liver transplantation
Treatment Authors, Journal (n)DesignMilan criteria (%)Pathological complete necrosis (%)Waiting list (days)RecurrenceSurvival
Percutaneous ablation
Mazzaferro, Ann Surg [81] (n=50)Cohort80552902 (4%)3 yr:83%
Lu, Hepatology [82] (n=52)Cohort80653810%3 yr:76%
Pompili, Liver Transpl [83] (n=40)Case series95419.5 mo3 (8%)3 yr:85%
Trans-arterial chemoembolization
Majno, Ann Surg [84] (n=111)Case series
TreatedNA28–28%5 yr:55%
Control 16%5 yr:62%
Graziadei, Liver Transpl [85] (n=63)Cohort study7029178–2542%4 yr:93% (Milan)
Maddala, Liver Transpl [86] (n=54)Case series871521111%3 yr:79%
Decaens, Liver Transpl [87]Case control
Treated (n=100)70164.2 mo13%5 yr:59%
Control (n=100) 4.3 mo23%5 yr:59%
Porret, Liver Transpl [88]Case control
Treated (n=31)100236.6 mo23%3 yr:84%
Control (n=33) 10.5 mo12%3 yr:95%

From initial studies reporting drop-out rates it was established an actuarial probability of 15–30% at 1 year [31], [89]. Among the case series and cohort studies reported, some investigations suggest a favorable impact of treatment in decreasing the drop-out rate. This is the case of Mazzaferro’s study where no drop outs were reported in their series of 50 patients within Milan criteria (mean size: 27.5mm; 41 single lesions) treated with a single session of RFA [50]. The heterogeneity of the data is reflected by the fact that some studies reported no drop outs in patients within Milan treated by TACE and short waiting times (178 days) [85], while others reported a cumulative probability of drop-out of 15% at 6 months and 25% at 12 months with the same treatment but longer waiting times (211 days) [86]. Only few heterogeneous uncontrolled studies suggested a slightly decrease in the drop-out rate in the cohort of patients within Milan criteria mainly treated with RFA. For larger tumors, the effect of treatments is even more uncertain.

Since treatments on the waiting list have been applied in an uncontrolled fashion, their effects on survival after LT are difficult to assess. Since the seminal study by Majno et al. [84], two case-control studies including index treated cases and matched controls from France (n=200 patients) [87] and the US (n=64 patients) [88], the survival rates were similar between the groups. Recurrence rates are more related with tumor stage than to neo-adjuvant therapies. It is well known that recurrence rates are low when applying the Milan criteria [30], [31], [33], whereas the rate is higher when exceeded, as has been reported by several authors (>30–50% recurrence rate) [30].

Analysis of the expansion of criteria beyond Milan and downstaging to Milan has been extensively reviewed. In summary, the main concept is that to establish a new policy of expansion it is mandatory to expose robust data for the specific segment included in the expansion. Novel criteria might have major impact in all transplant programs and the data to support any change should be impeccable. To our knowledge, for instance, the expansion to UCSF criteria – which involves around 5% of all enlisted – [89] is still based on a small number of patients (n=24) [90] and has already been challenged from the radiological [91] and pathological point of view (Mazzaferro et al., Metroticket project with 901 HCC exceeding Milan criteria undergoing transplantation, unpublished). The major concerns of this proposal are the lack of specific data on overall survival and drop-out rate on the waiting list for the patients outside the current criteria but fulfilling the expanded criteria. Regarding downstaging, no single RCT or large case-control study is available. Proper data from large well-designed cohort of patients treated consistently and properly followed up are also lacking. The prospective series reported so far include fewer than 50 patients, and this feature alone prevents them from being accredited as being the standard of care in clinical practice. Therefore, nowadays downstaging should be assessed in the setting of clinical research.

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7. Local ablation 

Percutaneous ablation achieves complete responses in more than 80% of tumors smaller than 3cm in diameter, but in 50% of tumors of 3–5cm in size [32] (1iiD). The best results obtained in series of HCC patients treated by percutaneous ethanol injection (PEI) or radiofrequency ablation (RF) provide 5-yr survival rates of 40–70% [91], [92]. The best outcomes have been reported in Child–Pugh A patients with small single tumors, commonly less than 2cm in diameter [32]. Independent predictors of survival are initial complete response, Child–Pugh score, number or size of nodules, and baseline alpha-fetoprotein levels. Thus, Child–Pugh A patients with non-surgical small tumors – that are expected to achieve complete responses – are the ideal candidates to PEI and RF. Treatment of patients with larger tumors (3–5cm), multiple tumors (3 nodules <3cm) and advanced liver failure (Child–Pugh B) is reasonable on an individual basis. Although these treatments provide good results, they are unable to achieve response rates and outcomes comparable to surgical treatments, even when applied as the first option [11] (3iiA).

During the last years, six new RCTs including 822 patients have been reported (reviewed in 47). Four of them compare PEI or percutaneous acetic acid injection (PAI) vs. RF [94], [95], [96], [97]. Survival advantages favouring RF vs. PEI were identified in the Japanese study including 232 patients (4-yr survival 74% vs. 57%, p=0.02) [95]. Conversely, no differences in survival were reported in the European RCT [97] (2-yr survival rates of 98% for RF vs. 88% for PEI, ns). Two additional RCTs from the same group reported survival advantages in the subgroup analysis of tumors larger than 2cm favouring RF compared with either PEI or PAI [94], [96]. Therefore, the characteristics and data provided so far do not provide enough evidence to support survival benefits coming from RF, and further research is needed (1iiA). Contrarily, all studies suggested that the actuarial probability of local recurrence was significantly lower in the RF arm compared with either PEI arm or PAI arm in all four studies [2 yr local recurrence rate: 2–18% vs. 11–45%], either assessed as primary or secondary endpoint [94], [95], [96], [97] (1iiD). It has been speculated that ethanol diffusion is blocked either by the intratumoral fibrotic septa and/or the tumor capsule. This undermines the curative capacity of this technique, particularly in tumors larger than 2cm. The energy generated by RF ablation, in contrast, induces coagulative necrosis of the tumor producing a safety ring of non-tumoral tissue, which might eliminate small-undetected satellites. Consistent with previous studies, RF requires fewer treatment sessions to achieve comparable antitumoral effects. Complete response rates were of 96–100% for RF vs. 86–89% for PEI. The main drawback of RF is its higher rates of adverse events compared to PEI.

Direct comparison between resection and local ablation is ongoing in several parts of the world. To our knowledge only one study including 76 patients with 1–2 tumors of less than 3cm has been reported [98], but methodological issues of this investigation warrant future research.

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8. Chemoembolization and other locoregional treatments 

Arterial embolization is the most widely used primary treatment for unresectable HCC [4], [11], [93]. In early stages, it is not indicated as first-line option, as an outcome review from Japan reported worse results than surgery or percutaneous ablation [11], [93]. Obstruction of hepatic artery induces extensive necrosis in large vascularized HCC. Embolizing agents – usually gelatin or microspheres – may be administered together with selective intra-arterial chemotherapy mixed with lipiodol (chemoembolization). Doxorubicin, mitomycin and cisplatin are the commonly used antitumoral drugs. Arterial chemoembolization achieves partial responses in 15–55% of patients [4], [34], [99], [100], [101], [102], and significantly delays tumor progression and vascular invasion (reviewed in 101) (1iiDii).

A systematic review of RCTs published between 1978 and 2002 identified seven RCTs including a total of 516 patients comparing embolization vs. conservative management, five of which assessing chemoembolization with doxorubicin or cisplatin [34]. Survival benefits were obtained in two studies [99], [100], one of which identified treatment response as an independent predictor of survival [99]. Meta-analysis showed a beneficial survival effect of embolization/chemoembolization in comparison to the control group [34] (1iiA). Overall, the median survival for intermediate HCC cases is expected to be of 16 months, whereas after chemoembolization the median survival is about 20 months. There is no good evidence for the best chemotherapeutical agent and the optimal re-treatment strategy. The two positive RCTs applied 3–4 treatments per year, using doxorubicin and cisplatinum, respectively [99], [100] (1iiA). The benefits of chemoembolization should not be offset by treatment-induced liver failure. The best candidates are patients with preserved liver function and asymptomatic multinodular tumors without vascular invasion or extrahepatic spread [99], [101], while patients with liver decompensation or hepatic failure (Child–Pugh’s B–C), should be excluded since the ischemic insult can lead to severe adverse events [102]. The heterogeneity in the selection of the “ideal candidates” may result in opposite results, and thus should be taken into account when designing and analyzing RCTs.

Strategies to improve antitumoral activity and clinical benefits with chemoembolization have been launched. In a phase II study we showed that drug-eluting beads containing doxorubicin provide objective response rates of 70%, applying the EASL-WHO criteria. High concentrations of doxorubicin were administered (150mg) with neglectable systemic toxicity, since this device allows a slow release of the drug over a 1 week period [103]. These results provide the rationale to move to phase III studies assessing survival outcomes.

None of the other locoregional therapies has been thoroughly tested to demonstrate an advantage in terms of survival. Some strategies provide objective response rates above 20%, as is the case of internal radiation with 131-I-labelled lipiodol or Y-90, or arterial lipiodolization [34], [104], [105]. Internal radiation has emerged as an appealing alternative for intermediate and advanced HCC cases. A seminal RCT comparing chemoembolization vs. internal radiation with I-131, has not been followed by additional trials [104]. Recently, a cohort study comprising 209 patients treated with Y-90 in a single center showed good response rates and a median survival for advanced HCC cases of 12 months [105]. Further phase III trials are required to understand the benefits of this therapy alone or in comparison to the standard of care, sorafenib.

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9. Systemic treatments 

Hormonal compounds and conventional external beam radiation have not shown survival benefits in HCC. A meta-analysis of seven RCTs comparing tamoxifen vs. conservative management, comprising 898 patients, showed neither antitumoral effect nor survival benefit of tamoxifen (1iA) [33]. Two large RCTs were reported afterwards assessing tamoxifen [106], [107] with negative results in terms of survival. Thus, this treatment is discouraged in advanced HCC.

Systemic chemotherapy has been tested in nine RCT [33]. The most active agents in vitro and in vivo are doxorubicin and cisplatin. Systemic doxorubicin has been evaluated in more than 1000 patients within clinical trials and provides partial responses in around 10% of cases, without any evidence of survival advantages (1iiA) [33], [47]. The group of Hong Kong reported a large RCT comparing combination chemotherapy [cisplatin/interferon α2b/doxorrubicin/fluorouracil (PIAF)] [108] with single-agent chemotherapy (doxorubicin). Objective response rates were of 20.9% for the PIAF regime and 10.5% for doxorubicin. The median survival of the PIAF and doxorrubicin groups was 8.67 months and 6.83 months, respectively, without differences between groups. PIAF was associated with a significantly high rate of myelotoxicity compared with doxorubicin. Treatment-related mortality was 9% in the PIAF regimen arm as a result of HBV reactivation and liver failure. Thus, systemic chemotherapy is discouraged for the treatment of HCC, and as control regime for any trial due to the well-known toxic effects.

The encouraging results of initial trials with interferon and octreotide have not been reproduced by others. Three relevant phase III studies have been finished with negative results in the treatment of advanced HCC. The largest RCT ever conducted in HCC compared seocalcitol – a vitamin-D-like antiproliferative molecule – vs. placebo in 746 patients showing no differences in overall survival (9.6 months seocalcitol vs. 9.2 months placebo) [109]. Nolatrexed, an inhibitor of thymidylate synthase, was compared with systemic doxorubicin in 446 patients with negative results (median survival 5 months vs. 7.5 months, respectively) [110]. Finally, negative results were also reported with a tubulin inhibitor (T-67, from Tularik) in a large multicenter RCT [111].

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10. Molecular therapies in HCC: the case of sorafenib 

The increasing knowledge in the molecular pathogenesis of HCC as well as the introduction of molecular targeted therapies in oncology have created an encouraging trend in the management of this malignancy (see reviews on [39], [112]). Table 5 depicts the molecular therapies currently tested within phase II and III clinical trials in HCC. Most of the treatments aim to abrogate signaling pathways related to proliferation and cell survival. Alternatively, other treatments rely on the blockade of growth factors and signals related to dissemination of the disease (e.g. angiogenesis, telomerase activation) etc.

Table 5. Molecular targeted therapies assessed in clinical trials in HCC
TreatmentType molecule (target)Clinical phasePublication
SorafenibSmall molecule (TKI)III-positiveLlovet, ASCO [29]
RAF, VEGF, PDGFR
ErlotinibSmall molecule (TKI)II-closedPhilip, JCO [118]
EGFR inhibitor (TKI)
CetuximabMonoclonal antibody (Mab)II-ongoing–
EGFR inhibitor
LapatinibSmall molecule (TKI)II-ongoing–
EGFR, Her2/nu
SunitinibSmall moleculeII-closedFavre, ASCO [123]
PDGFR, VEGFR, KIT (KI)Zhu, ASCO [124]
Erlotinib+bevacizumabsmall molecular+Mab Thomas, ASCO [119]
EGFR (TKI), VEGF (Mab)
BevacizumabMonoclonal antibodiesII-closed
VEGF (Ab)
BortezomibProteasome inhibitorII-negative
Acyclic retinoidsDifferentiationIII-design
NolatrexedThymidylate synthaseIII-negativeGish, JCO [111]
T138067Tubulin inhibitorIII-negative

Most of the agents currently under investigation block membranous tyrosine kinase receptors (TKRs). The ligands for these receptors include EGF, PDGF, VEGF, and HGF, among others. These ligands activate the RAS/MAPK signaling pathway and induce transcription of genes of the AP1 family, such as c-fos and c-jun, which are key elements in the induction of cell proliferation. As described in other malignancies, somatic mutations of the receptors, especially of EGFR, may also activate constitutively this pathway [25]. Moreover, inactivation of tumor suppressor genes like RASSFR1 and NORE1 is almost universal in advanced stages of HCC [39]. Alternatively, these growth factors may induce activation of the PI3K/Akt/mTOR signaling pathway or HGF/c-met pathway [39].

10.1. Phase III studies: sorafenib 

Sorafenib (nexavar®) is an oral multikinase inhibitor with activity against several tyrosine kinase (VEGFR2, PDGFR, c-Kit receptors), and serine/threonine kinases (b-Raf, p38) [113]. Thus, this drug targets two of the main pathways involved in hepatocarcinogenesis by blocking angiogenesis (VEFGR2 and PDGFR) and cell proliferation through activation of Ras/MAPKK signaling (bRAF). Sorafenib increases progression free survival in renal cancer and has recently been approved for use in the management of this cancer [113]. Pre-clinical studies showed antitumoral activity in xenograft models of HCC [114]. Subsequently, a phase II clinical trial involving 137 patients with advanced HCC exposed that sorafenib induced stable disease for 4 months in 35% of the patients with an overall median survival of 9.7 months. Partial response rate was less than 10%. Interestingly, patients with activation of RAS/MAPK pathway as per the presence of p-Erk immunostaining had a time to progression of 178 days vs. 46 days in those without activation of the pathway [115].

The randomised phase III double-blind placebo-controlled clinical trial conducted in patients with advanced HCC treated with sorafenib has shown improvement in survival of 3 months in patients with advanced HCC, which was not only statistically significant, but also clinically meaningful [29]. This multicenter trial evaluated sorafenib 400mg twice daily (299 patients) vs. placebo (303 patients) in patients with advanced hepatocellular carcinoma who had not received prior systemic treatment. The main primary endpoint was survival. The study was stopped at the second planned interim analysis after 321 deaths had occurred because of survival advantages favoring the treatment arm. The median overall survival was 10.7 months with sorafenib and 7.9 months with placebo (hazard ratio for death, 0.69; 95% confidence interval, 0.55–0.87; p<0.001). Median time to progression was 5.5 months with sorafenib vs. 2.8 months with placebo (hazard ratio 0.58; 95% confidence interval 0.45–0.74; p<0.001). Seven patients (2.3%) in the sorafenib group and two patients (0.7%) in the placebo group achieved a partial response. Diarrhea, weight loss, hand–foot skin reactions, and hypophosphatemia were more frequent with sorafenib. The results of this RCT represent a breakthrough in the management of this complex disease [29]: Sorafenib is the first systemic therapy to prolong survival in HCC and, consequently, is the new reference standard treatment of patients with advanced HCC (Table 1).

Recently, the drug has been approved both by the FDA and EMEA for the treatment of HCC. These results open a new avenue in clinical trial research in HCC. Sorafenib will certainly be assessed in the adjuvant setting after potentially curative treatments, such as resection or local ablation, in combination with chemoembolization for intermediate HCC and combined with other molecular targeted therapies in advanced cases. In the latter scenario, sorafenib should also constitute the control arm of these trials.

10.2. Phase II studies 

Effective blockade of the Ras/MAPK signaling pathway can be achieved by the use of monoclonal antibodies against EGFR (cetuximab, Erbitux®) or ErbB2/Her2/neu (trastuzumab, Herceptin®). Cetuximab is FDA-approved for the treatment of colo-rectal cancer and trastuzumab for overexpressing-Her2 metastatic breast cancer. Alternatively, pathway activation can also be successfully inhibited with small molecules against the catalytic domain of EGFR such as erlotinib (Tarceva®) or gefitinib (Iressa®). Lapatinib (Tykerb®) simultaneously blocks EGFR and Her2. Erlotinib is active in advanced stages of non-small cell lung cancer.

In HCC, erlotinib has shown activity both in pre-clinical and clinical studies. In vitro studies with HCC cell lines using erlotinib alone or in combination with chemotherapy showed a significant inhibition of cell proliferation and an increase in apoptosis. Moreover, there was an additive effect when erlotinib was combined with chemotherapy. Thereafter, the same group reported antiproliferative effects as well as some pro-apoptotic activity of cetuximab in HCC cell lines [116]. Another report used a model of experimental cirrhosis in rats to demonstrate the effect of another tyrosine kinase inhibitor (gefitinib) in decreasing the number of HCC nodules as compared to control rats [117]. A short phase II study testing erlotinib in 38 patients with intermediate and advanced HCC showed a median survival of 13 months, but there is uncertainty on whether this represents a true drug-related effect [118] or reflects patient’s selection. A recent trial with erlotinib plus bevacizumab (monoclonal antibody against VEGF) showed encouraging, but unclear results [119]. Although Her2/neu overexpression and EGFR mutations are uncommon events in HCC there is some promising preliminary data with dual receptor blockade (EGFR and Her2) in experimental models of HCC and the combination is under evaluation in phase II clinical trials (lapatinib).

Approximately half of patients with HCC have activation of the Akt/mTOR signaling pathway as assessed by immunohistochemical analysis of phosphorylated S6. This activation may be the result of increase signaling due to overexpression of ligands (e.g. EGF, IGF1, IGF2) or may be due to mutations in oncogenes (PI3KCA) or tumor suppressor genes (PTEN). Akt activation promotes cell survival through different molecules, mTOR being one of the most relevant [120]. Rapamycin is a well-known inhibitor of mTOR activity and has shown antineoplastic activity in vitro in HCC [121]. Since rapamycin is approved as immunosuppressant in liver transplant, there is some rational to use it as first line anti-rejection therapy in the setting of liver transplantation for HCC. However, this hypothesis has not been tested extensively and there is a need for well-designed trials to address this question. Pre-clinical studies and early clinical studies with rapamycin analogues (e.g. everolimus, temsirolimus) are currently in progress.

HCC is a notoriously hypervascular malignancy, a feature that can be observed even at early stages of the disease, when tumor size is less than 2cm. In fact, it is based on this characteristic that modern imaging techniques such as magnetic resonance imaging can be so sensitive, allowing accurate diagnosis of small HCC lesions (1–2cm) in 30% of patients [15]. Overexpression of pro-angiogenic factors like VEGF, PDGF and angiopoietin 2 has been demonstrated in HCC; indeed, some reports suggest a prognostic value of plasma levels of VEGF. This provides the rationale for the use of antiangiogenic therapies in HCC, by means of monoclonal antibodies (bevacizumab) or of small molecules (sunitinib, sorafenib). Bevacizumab (Avastin®) is a humanized monoclonal antibody approved for the treatment of liver metastasis of colorectal and breast cancer. A phase II trial with this compound in HCC revealed modest antitumoral activity (10% objective response) with almost 60% of patients with stable disease for more than 4 months. However, 5 out of 33 patients included in the treatment arm in this trial had significant adverse effects; among them, there were two treatment-related deaths due to gastrointestinal bleeding [122]. There are other VEGFR inhibitors currently under evaluation: sunitinib (Sutent®) and BMS-582664, both in phase II. Sunitinib is a multikinase inhibitor recently approved by FDA for renal cancer. Two phase II studies in HCC patients have been reported. The European/Asian study described median survival of 10.5 month for patients treated at 50mg/day but with associated liver-related toxicities and death (10% of cases) [123], whereas the 37.5mg US study was less toxic [124].

Because the Wnt canonical pathway is activated in at least 30% of HCC, it would appear as an appealing target for blockade; however, there are not yet any drugs available that effectively block its activation without significant side effects. Molecular targets within the pathway are multiple, including Wnt ligands, Frizzled receptors and TLF/beta-catenin complex. Pre-clinical studies show some activity of ICG-001, a small molecule that interferes with the interaction of β-catenin and TLF [125]. Drugs that inhibit proteasome activation, such as bortezomib (Velcade®), which is approved for multiple myeloma, have been unsuccessfully tested within phase II trials. Finally, telomerase, thought to be essential in cancer cell immortality, may also be considered a potential target in HCC; there are some ongoing studies in phase II applying TERT immunization.

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11. New endpoints in the design of clinical trials in HCC 

The mechanism of action of biological agents against molecular targets has raised the question of which should be the primary and secondary endpoints in controlled phase II and phase III trials. Obviously, the primary endpoint for phase III studies is survival, and for adjuvant studies time to recurrence. Objective response is a weak surrogate of activity in phase II trials, since in most cases, the predominant effect of these compounds is basically cytostatic. In fact, bevacizumab has shown a survival benefit in patients with liver metastases, as has erlotinib in advanced lung cancer and sorafenib in renal cancer, even when objective responses were lower than 10%. Therefore, it is mandatory in phase II trials to select primary endpoints able to capture the effects associated with stabilization of the disease for clinically relevant periods. These endpoints need to have a time-to-event format.

Progression-free survival (PFS) is the best surrogate endpoint in most solid malignancies, but it is a vulnerable endpoint in HCC since it combines two types of events: progression and death due to any aetiology. Hence, a recent consensus conference endorsed by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver (Atlanta 2006) recommended the inclusion of time-to-progression (TTP; time period between the inclusion in the study and the radiological progression of the disease) as the primary endpoint in phase II trials.

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References 

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics 2002. CA Cancer J Clin. 2005;55:74–108
  2. El Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–750
  3. Sangiovanni A, Del Ninno E, Fasani P, De Fazio C, Ronchi G, Romeo R, et al. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology. 2004;126:1005–1014
  4. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907–1917
  5. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–1236
  6. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management on hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. J Hepatol. 2001;35:421–430
  7. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:417–422
  8. Bolondi L, Sofia S, Siringo S, Gaiani S, Casali A, Zironi G, et al. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut. 2001;48:251–259
  9. Trinchet J, Beaugrand M from GRETCH. A randomized trial comparing 3-month vs. 6-month screening for HCC by ultrasonography in cirrhosis. Book of Abstract-International Liver Cancer Association (ILCA), 2007.
  10. McMahon BJ, Bulkow L, Harpster A, Snowball M, Lanier A, Sacco F, et al. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. Hepatology. 2000;32:842–846
  11. Ikai I, Arii S, Kojiro M, Ichida T, Makuuchi M, Matsuyama Y, et al. Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey. Cancer. 2004;101:796–802
  12. Bolondi L, Gaiani S, Celli N, Golfieri R, Grigioni WF, Leoni S, et al. Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma. Hepatology. 2005;42:27–34
  13. Kojiro M. Focus on dysplastic nodules and early hepatocellular carcinoma: an Eastern point of view. Liver Transpl. 2004;10:S3–S8
  14. Park YN, Yang CP, Fernandez GJ, Cubukcu O, Thung SN, Theise ND. Neoangiogenesis and sinusoidal “capillarization” in dysplastic nodules of the liver. Am J Surg Pathol. 1998;22:656–662
  15. Forner A, Vilana R, Ayuso C, Bianchi L, Sole M, Ayuso JR, et al. Diagnosis of hepatic nodules <20mm in cirrhosis. Prospective validation of the AASLD guidelines for Hepatocellular Carcinoma (HCC). Hepatology. 2008;47:97–104
  16. Kojiro M, Roskams T. Early hepatocellular carcinoma and dysplastic nodules. Semin Liver Dis. 2005;25:133–142
  17. Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 2003;125:89–97
  18. Marrero JA, Lok AS. Newer markers for hepatocellular carcinoma. Gastroenterology. 2004;127:S113–S119
  19. Paradis V, Bieche I, Dargere D, Laurendeau I, Laurent C, Bioulac Sage P, et al. Molecular profiling of hepatocellular carcinomas (HCC) using a large-scale real-time RT-PCR approach: determination of a molecular diagnostic index. Am J Pathol. 2003;163:733–741
  20. Nam SW, Park JY, Ramasamy A, Shevade S, Islam A, Long PM, et al. Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling. Hepatology. 2005;42:809–818
  21. Paradis V, Degos F, Dargere D, Pham N, Belghiti J, Degott C, et al. Identification of a new marker of hepatocellular carcinoma by serum protein profiling of patients with chronic liver diseases. Hepatology. 2005;41:40–47
  22. Llovet JM, Chen Y, Wurmbach W, Roayaie S, Fiel I, Schwartz M, et al. A molecular signature to discriminate dysplastic nodules and early hepatocellular carcinoma in HCV-cirrhosis. Gastroenterology. 2006;131:1758–1767
  23. Wurmbach E, Chen Y, Khitrov G, Roayaie S, Fiel I, Schwartz M, et al. Genome-wide profiles of dysplasia and HCC in HCV-cirrhotic patients. Hepatology. 2007;45:938–947
  24. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant hemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–1672
  25. Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–792
  26. Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–338
  27. Marrero JA, Fontana RJ, Barrat A, Askari F, Conjeevaram HS, Su GL, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology. 2005;41:707–716
  28. National Cancer Institute website US National Institute of Health. Available from: http://www.cancer.gov.
  29. Llovet J, Ricci S, Mazzaferro V, Hilgard P, Raoul J, Zeuzem S, et al. Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC): results of a phase III randomized placebo-controlled trial. J Clin Oncol. 2007;25:LBA1
  30. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25:181–200
  31. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30:1434–1440
  32. Sala M, Llovet JM, Vilana R, Bianchi L, Solé M, Ayuso C, et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology. 2004;40:1352–1360
  33. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–699
  34. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37:429–442
  35. Leung TW, Tang AM, Zee B, Lau WY, Lai PB, Leung KL, et al. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients. Cancer. 2002;94:1760–1769
  36. CLIP. Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology 2000;31:840–845.
  37. Liver (including intrahepatic bile ducts). In: Green F, Page D, Fleming I, et al., editors. AJCC Cancer Staging Handbook, 6th ed. New York: Springer; 2002, p. 131–144.
  38. Kudo M, Chung H, Haji S, Osaki Y, Oka H, Seki T, et al. Validation of a new prognostic staging system for hepatocellular carcinoma: the JIS score compared with the CLIP score. Hepatology. 2004;40:1396–1405
  39. Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 2007;27:55–76
  40. Lemmer E, Friedman S, Llovet JM. Molecular diagnosis of chronic liver disease and hepatocellular carcinoma: the potential of gene expression profiling. Semin Liver Dis. 2006;26:373–384
  41. Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45:42–52
  42. Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–676
  43. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med. 2006;12:410–416
  44. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9:416–423
  45. Iizuka N, Oka M, Yamada-Okabe H, Nishida M, Maeda Y, Mori N, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet. 2003;361:923–929
  46. Kurokawa Y, Matoba R, Takemasa I, Nagano H, Dono K, Nakamori S, et al. Molecular-based prediction of early recurrence in hepatocellular carcinoma. J Hepatol. 2004;41:284–291
  47. Lopez P, Villanueva A, Llovet JM. Up-dated systematic review of randomized controlled trials in hepatocellular carcinoma. 2002–2005. Aliment Pharmacol Ther. 2006;23:1535–1547
  48. Belghiti J, Hiramatsu K, Benoist S. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg. 2000;191:38–46
  49. Bismuth H, Majno P. Hepatobiliary surgery. J Hepatol. 2000;32:208–224
  50. Marin-Hargreaves G, Azoulay D, Bismuth H. Hepatocellular carcinoma: surgical indications and results. Crit Rev Oncol Hematol. 2003;47:13–27
  51. Makuuchi M, Sano K. The surgical approach to HCC: our progress and results in Japan. Liver Transpl. 2004;10:S46–S52
  52. Zhou XD, Tang ZY, Yang BH, Lin ZY, Ma ZC, Ye SL, et al. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer. 2001;91:1479–1486
  53. Vauthey J, Lauwers G, Esnaola N, Do KA, Belghiti J, Mirza N, et al. Simplified staging for hepatocellular carcinoma. J Clin Oncol. 2002;20:1527–1536
  54. Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg. 2002;235:373–382
  55. Belghiti J, Panis Y, Farges O, Benhamou JP, Fekete F. Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg. 1991;214:114–117
  56. Kumada T, Nakano S, Takeda I, Sugiyama K, Osada T, Kiriyama S, et al. Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma. Hepatology. 1997;25:87–92
  57. Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200–207
  58. Ercolani G, Grazi GL, Ravaioli M, Del Gaudio M, Gardini A, Cescon M, et al. Liver resection for hepatocellular carcinoma on cirrhosis. Ann Surg. 2003;237:536–543
  59. Murakami T, Mochizuki K, Nakamura H. Imaging evaluation of the cirrhotic liver. Semin Liver Dis. 2001;21:213–224
  60. Bruix J, Castells A, Bosch J, Feu F, Fuster J, Garcia-Pagan JC, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology. 1996;111:1018–1022
  61. Takayama T, Makuuchi S, Hirohashi S, Sakamoto M, Yamamoto J, Shimada K, et al. Early hepatocellular carcinoma as an entity with high rate of surgical cure. Hepatology. 1998;28:1241–1246
  62. Burrel M, Llovet JM, Ayuso C, Iglesias C, Sala M, Miquel R, et al. MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: an explant correlation. Hepatology. 2003;38:1034–1042
  63. Torzilli G, Olivari N, Moroni E, Del Fabbro D, Gambetti A, Leoni P, et al. Contrast-enhanced intraoperative ultrasonography in surgery for hepatocellular carcinoma in cirrhosis. Liver Transpl. 2004;10:S34–S38
  64. Chen Y, Yeh SH, Chen JT, Wu CC, Hsu MT, Tsai SF, et al. Chromosomal changes and clonality relationship between primary and recurrent hepatocellular carcinoma. Gastroenterology. 2000;119:431–440
  65. Finkelstein SD, Marsh W, Demetris AJ, Swalsky PA, Sasatomi E, Bonham A, et al. Microdissection-based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma. Hepatology. 2003;37:871–879
  66. Ng I, Guan X, Poon R, Fan ST, Lee JM. Determination of the molecular relationship between multiple tumor nodules in hepatocellular carcinoma differentiates multicentric origin from intrahepatic metastasis. J Pathol. 2003;199:345–353
  67. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000;356:802–807
  68. Lau WY, Leung TW, Ho SK, Chan M, Machin D, Lau J, et al. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet. 1999;353:797–801
  69. Wu CC, Ho YZ, Ho WL, Wu TC, Liu TJ, P’eng FK. Preoperative transcatheter arterial chemoembolization for respectable large hepatocellular carcinoma: a reappraisal. Br J Surg. 1995;82:122–126
  70. Yamasaki S, Hasegawa H, Kinoshita H, Furukawa M, Imaoka S, Takasaki K, et al. A prospective randomized trial of preventive effect of pre-operative transcatheter arterial embolization against recurrence of hepatocellular carcinoma. Jpn J Cancer Res. 1996;87:206–211
  71. Kohno H, Nagasue H, Hayashi T, Yamanoi A, Uchida M, Ono T, et al. Postoperative adjuvant chemotherapy after radical hepatic resection for hepatocellular carcinoma (HCC). Hepatogastroenterology. 1996;43:1405–1409
  72. Lai EC, Lo CM, Fan ST, Liu CL, Wong J. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma. Arch Surg. 1998;133:183–188
  73. Yamamoto M, Arii S, Sughara K, Tobe T. Adjuvant oral chemotherapy after curative resection of hepatocellular carcinoma. Br J Surg. 1996;83:336–340
  74. Ono T, Nagasue N, Kohno H, Hayashi T, Uchida M, Yukaya H, et al. Adjuvant chemotherapy with epirubicin and carmfur after radical resection of hepatocellular carcinoma: a prospective randomized study. Semin Oncol. 1997;24:S6–S18
  75. Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. N Engl J Med. 1996;334:1561–1567
  76. Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Yamazaki O, et al. Effects of long-term postoperative interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. Ann Intern Med. 2001;134:963–967
  77. Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med. 2003;138:299–306
  78. Lin SM, Lin CJ, Hsu CW. Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors. Cancer. 2003;100:376–382
  79. Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Capussotti L, et al. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology. 2006;44:1543–1554
  80. Boucher E, Corbinais S, Rolland Y. Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma. Hepatology. 2003;38:1237–1241
  81. Mazzaferro V, Battiston C, Perrone S, Pulvirenti A, Regalia E, Romito R, et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg. 2004;240:900–909
  82. Lu DS, Yu NC, Raman SS, Lassman C, Tong MJ, Britten C, et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation. Hepatology. 2005;41:1130–1137
  83. Pompili M, Mirante VG, Rondinara G, Fassati LR, Piscaglia F, Agnes S, et al. Percutaneous ablation procedures in cirrhotic patients with hepatocellular carcinoma submitted to liver transplantation: assessment of efficacy at explant analysis and of safety for tumor recurrence. Liver Transpl. 2005;11:1117–1126
  84. Majno PE, Adam R, Bismuth H, Castaing D, Ariche A, Krissat J, et al. Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Ann Surg. 1997;226:688–701
  85. Graziadei IW, Sandmueller H, Waldenberger P, Koenigsrainer A, Nachbaur K, Jaschke W, et al. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transpl. 2003;9:557–563
  86. Maddala YK, Stadheim L, Andrews JC, Burgart LJ, Rosen CB, Kremers WK, et al. Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization. Liver Transpl. 2004;10:449–455
  87. Decaens T, Roudot-Thoraval F, Bresson-Hadni S, Meyer C, Gugenheim J, Durand F, et al. Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma. Liver Transpl. 2005;11:767–775
  88. Porrett PM, Peterman H, Rosen M, Sonnad S, Soulen M, Markmann JF, et al. Lack of benefit of pre-transplant locoregional hepatic therapy for hepatocellular cancer in the current MELD era. Liver Transpl. 2006;12:665–673
  89. Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: expansion of tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394–1403
  90. Yao FY, Kinkhabwala M, LaBerge JM, Bass NM, Brown R, Kerlan R, et al. The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma. Am J Transplant. 2005;5:795–804
  91. Lencioni R, Cioni D, Crocetti L, Franchini C, Pina CD, Lera J, et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology. 2005;234:961–967
  92. Omata M, Tateishi R, Yoshida H, Shiina S. Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: ethanol injection therapy and radiofrequency ablation. Gastroenterology. 2004;127:S159–S166
  93. Arii S, Yamaoka Y, Futagawa S, Inoue K, Kobayashi K, Kojiro M, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. Hepatology. 2000;32:1224–1229
  94. Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Randomized controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3cm or less. Gut. 2005;54:1151–1156
  95. Shiina S, Teratani T, Obi S, Sato S, Tateishi R, Fujishima T, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology. 2005;129:122–130
  96. Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or =4cm. Gastroenterology. 2004;127:1714–1723
  97. Lencioni RA, Allgaier HP, Cioni D, Olschewski M, Deibert P, Crocetti L, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology. 2003;228:235–240
  98. Huang GT, Lee PH, Tsang YM, Lai MY, Yang PM, Hu RH, et al. Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study. Ann Surg. 2005;242:36–42
  99. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359:1734–1739
  100. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35:1164–1171
  101. Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology. 2004;127:S179–S188
  102. Group d’Etude et de Traitment du Carcinome Hépatocellulaire. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med 1995;332:1256–1261.
  103. Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007;46:474–481
  104. Raoul JL, Guyader D, Bretagne JF, Heautot JF, Duvauferrier R, Bourguet P, et al. Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology. 1997;26:1156–1161
  105. Kulik LM, Carr BI, Mulcahy MF, Lewandowski RJ, Atassi B, Ryu RK, et al. Safety and efficacy of (90)Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology. 2008;47:71–81
  106. Barbare JC, Bouche O, Bonnetain F, Raoul JL, Rougier P, Abergel A, et al. Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma. J Clin Oncol. 2005;23:4338–4346
  107. Chow PK, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, et al. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial. Hepatology. 2002;36:1221–1226
  108. Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005;97:1532–1538
  109. Beaugrand M, Sala M, Degos F, Sherman M, Bolondi L, Evans T, et al. Treatment of advanced hepatocellular carcinoma by seocalcitol (a vit D analogue): an international randomized double-blind placebo-controlled study in 747 patients. J Hepatol. 2003;42:17A
  110. Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, et al. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 2007;25:3069–3075
  111. Posey J, Johnson P, Mok T, Hirmand M, Dahlberg S, Kwei L, et al. Results of a phase 2/3 open-label, randomized trial of T138067 versus doxorubicin in chemotherapy-naive, unresectable hepatocellular carcinoma. J Clin Oncol. 2005;23:16S
  112. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674–687
  113. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5:835–844
  114. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, 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;64:7099–7109
  115. Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:4293–4300
  116. Huether A, Hopfner M, Sutter AP, Schuppan D, Scherubl H. Erlotinib induces cell cycle arrest and apoptosis in hepatocellular cancer cells and enhances chemosensitivity towards cytostatics. J Hepatol. 2005;43:661–669
  117. Schiffer E, Housset C, Cacheux W, Wendum D, Desbois-Mouthon C, Rey C, et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology. 2005;41:307–314
  118. Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase II study of erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol. 2005;23:6657–6663
  119. Thomas MB, Chadha R, Iwasaki M, Glover K, Abbruzzese JL. The combination of bevacizumab (B) and erlotinib (E) shows significant biological activity in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2007;25:214s
  120. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501
  121. Zhang JF, Liu JJ, Lu MQ, Cai CJ, Yang Y, Li H, et al. Rapamycin inhibits cell growth by induction of apoptosis on hepatocellular carcinoma cells in vitro. Transpl Immunol. 2007;17:162–168
  122. Zhu AX, Blaszkowsky LS, Ryan DP, Clark JW, Muzikansky A, Horgan K, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:1898–1903
  123. Faivre S, Raymond E, Douillard JY, Boucher E, Lim HY, Kim JS, et al. Assessment of safety and drug-induced tumor necrosis with sunitinib in patients with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2007;25:149s
  124. Zhu AX, Sahani DV, di Tomaso E, Duda D, Sindhwani V, Yoon SS, et al. A phase II study of sunitinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2007;25:213s
  125. Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription. Proc Natl Acad Sci USA. 2004;101:12682–12687

☆ The authors receive consulting and lecture fees from Bayer Healthcare Pharmaceuticals; consulting fees from MDS Nordion, Bristol-Myers Squibb and Biocompatibles and Research grants from Exelixis. The authors have been supported by the following government grants: Dr. J.M. Llovet, National Institute of Health-NIDDK Grant 1R01DK076986-01, National Institute of Health, Spain (I+D Program, Grant No. SAF-2007-61898), and as Professor of Research at Institut Català de Recerca Avancada (ICREA); and from Samuel Wasman Cancer Research Foundation Dr. J. Bruix: National Institute of Health, Spain (FIS Program, Grant No. PI 05/150). We acknowledge the support of CIBERehd (Centro Investigaciones BioMedicas en Red, Instituto Carlos III).

PII: S0168-8278(08)00078-0

doi:10.1016/j.jhep.2008.01.022

Journal of Hepatology
Volume 48, Supplement 1 , Pages S20-S37, 2008

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