Diagnosis and treatment of hepatocellular carcinoma. Update consensus document from the AEEH, SEOM, SERAM, SERVEI and SETH

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"identificador" => "aff0020" ] ] ] 14 => array:3 [ "nombre" => "Josep" "apellidos" => "Tabernero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "m" "identificador" => "aff0065" ] ] ] 15 => array:4 [ "nombre" => "Jordi" "apellidos" => "Bruix" "email" => array:1 [ 0 => "jbruix@clinic.ub.es" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:13 [ 0 => array:3 [ "entidad" => "Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Oncología Médica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Sociedad Española de Oncología Médica, Madrid, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Unidad de Trasplante Hepático, Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Departamento de Radiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, United States" "etiqueta" => "i" "identificador" => "aff0045" ] 9 => array:3 [ "entidad" => "Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, Spain" "etiqueta" => "j" "identificador" => "aff0050" ] 10 => array:3 [ "entidad" => "Unidad de Hepatología, Departamento de Medicina Interna, Clínica Universidad de Navarra, Pamplona, Spain" "etiqueta" => "k" "identificador" => "aff0055" ] 11 => array:3 [ "entidad" => "Servicio de Cirugi¿a Hepatobliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, Spain" "etiqueta" => "l" "identificador" => "aff0060" ] 12 => array:3 [ "entidad" => "Servicio de Oncología Médica, Hospital Universitario Vall d’Hebrón, Barcelona, Universidad Autónoma de Barcelona, Barcelona, Spain" "etiqueta" => "m" "identificador" => "aff0065" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Diagnóstico y tratamiento del carcinoma hepatocelular. Actualización del documento de consenso de la AEEH, SEOM, SERAM, SERVEI y SETH" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Bruix and Sherman.<a class="elsevierStyleCrossRef" href="#bib1005">2</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1494 "Ancho" => 2322 "Tamanyo" => 183447 ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithm for the study of a liver nodule detected on abdominal ultrasound." ] ] ] "textoCompleto" => "IntroductionHepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver. Predominantly occurs in patients with chronic liver disease who have developed liver cirrhosis and several studies have found that, at present, HCC is one of the most frequent causes of death in this population. Simultaneous to the recognition of the clinical relevance of this neoplasm, we have seen the development of new techniques for early diagnosis of HCC and effective treatment at all stages. In order to review the current situation of HCC regarding its epidemiology, diagnosis and treatment situation, the Spanish Association for the Study of the Liver (AEEH) organized a monothematic conference on HCC (Santander, May 2008) and simultaneously proposed the development of a consensus document was prepared by an expert panel. In order to achieve maximum acceptance and validity, the Spanish Society of Liver Transplantation (SETH), the Spanish Society of Medical Radiology (SERAM), the Spanish Society of Vascular and Interventional Radiology (SERVEI) and the Spanish Society of Medical Oncology (SEOM) were invited to participate in the preparation of this document. Thus, this proposal is integrated into all fields of knowledge involved in the diagnosis and treatment of this neoplasm. In this sense, one of the main conclusions of the expert panel was the need for the diagnosis and treatment of these patients to be carried out in multidisciplinary groups based in reference centres involving all specialties involved: hepatology/gastroenterology, radiology (including interventional radiology), surgery, anatomical pathology and medical oncology. This need encompasses all developmental stages and should be considered a key requirement in the advancement of HCC diagnosis and treatment. The occurring of this neoplasm within a diseased liver involves high complexity, while the entire process of diagnosis, staging and follow-up requires a close relationship between the various specialists and the application of the latest technology. This document was published in 2009<a class="elsevierStyleCrossRef" href="#bib1000">1</a> and subsequently accepted as Clinical Practice Guideline of the National Health System (<a id="intr0025" class="elsevierStyleInterRef" href="http://portal.guiasalud.es/web/guest/catalogo-gpclud">http://portal.guiasalud.es/web/guest/catalogo-gpclud</a>).In recent years there have been important developments in the diagnosis, staging and treatment of HCC. Therefore, the AEEH has driven the need to update clinical practice guidelines, again inviting all institutions involved in the diagnosis and treatment of this disease to participate in the drafting and adoption of the document. The clinical practice guidelines published in 2009, the guidelines of the American Association for the Study of Liver Diseases (AASLD)<a class="elsevierStyleCrossRef" href="#bib1005">2</a> and the guidelines of the European Association for the Study of the Liver/European Organization for Research and Treatment of Cancer (EASL/EORTC)<a class="elsevierStyleCrossRef" href="#bib1010">3</a> have been taken as reference documents, incorporating the most important advances made in recent years. The literature search criteria are described in <a class="elsevierStyleCrossRef" href="#sec0090">Annex 1</a>. Scientific evidence in the treatment of HCC has been evaluated in accordance with the recommendations of the National Cancer Institute(NCI) (<a id="intr0030" class="elsevierStyleInterRef" href="http://www.cancer.gov/">www.cancer.gov</a>) and the strength of the recommendation is based on the GRADE system (<a class="elsevierStyleCrossRefs" href="#tbl0050">Tables 1 and 2</a>). Ultimately, these guidelines aim to show what is the current diagnostic and therapeutic procedure according to the latest scientific evidence, and provide a basis from which to implement research projects to improve existing tools. There has been no external funding for the preparation of this document.<elsevierMultimedia ident="tbl0050"></elsevierMultimedia><elsevierMultimedia ident="tbl0055"></elsevierMultimedia>Epidemiology and preventionHCC is an important medical problem. Currently the sixth most common malignancy worldwide and the third leading cause of cancer deaths.<a class="elsevierStyleCrossRef" href="#bib1015">4</a> Its global distribution is very heterogeneous and is closely related to the variable prevalence of the different risk factors associated with the development of this disease. The highest incidence affects Southeast Asia and sub-Saharan Africa. Most cases occurring in those areas are related to the hepatitis B virus (HBV), associated or not with aflatoxin, and the incidence exceeds 15 cases/100,000 inhabitants/year.<a class="elsevierStyleCrossRef" href="#bib1015">4</a> Southern Europe, including Spain, has an intermediate incidence of 5–10 cases/100,000 inhabitants/year, and finally northern Europe and America have the lowest incidence, approximately 5 cases/100,000 inhabitants/year.<a class="elsevierStyleCrossRefs" href="#bib1020">5,6</a> Hepatitis C virus (HCV) infection<a class="elsevierStyleCrossRef" href="#bib1030">7</a> and alcoholism<a class="elsevierStyleCrossRef" href="#bib1035">8</a> play a predominant role in both areas. However, in recent years, some epidemiological changes have been observed in various areas.<a class="elsevierStyleCrossRefs" href="#bib1040">9,10</a> Thus, in countries where chronic HBV infection is the leading cause of HCC, such as Taiwan, the incidence has decreased due to the implementation of universal vaccination against HBV.<a class="elsevierStyleCrossRefs" href="#bib1050">11,12</a> By contrast, the incidence of HCC has increased in countries such as the UK,<a class="elsevierStyleCrossRef" href="#bib1060">13</a> Canada<a class="elsevierStyleCrossRef" href="#bib1065">14</a> and the US,<a class="elsevierStyleCrossRef" href="#bib1070">15</a> probably reflecting the spread of chronic HCV infection. Finally, those countries where the HCV epidemic appeared early, such as Japan, the incidence has reached its plateau.<a class="elsevierStyleCrossRef" href="#bib1075">16</a> In Spain, HCV is at present the main risk factor associated with the development of HCC, and although the data are heterogeneous, since in many cases liver metastases are recorded as primary liver tumours, there is evidence that the incidence of HCC has increased in recent years.<a class="elsevierStyleCrossRefs" href="#bib1080">17,18</a>The risk of HCC varies in all geographic areas according to the degree of liver involvement, being less than 1% annually in patients with chronic hepatitis without significant fibrosis, increasing to 3–7% annually when the patient develops cirrhosis.<a class="elsevierStyleCrossRef" href="#bib1030">7</a> The major risk is acquired when liver cirrhosis is established and it is obvious that the intensity of liver inflammation (related to viral load or genotype) is responsible for the chronic process of necrosis/regeneration which results in cirrhosis, and therefore this is the parameter to be used to establish a clinically significant risk acquisition. In this sense, once liver cirrhosis is established, the risk of developing HCC remains despite getting a persistent viral response after treatment, possibly due to structural and molecular damage already found in the liver, despite successful infection elimination.<a class="elsevierStyleCrossRefs" href="#bib1090">19–21</a> Therefore, any disease that can lead to liver cirrhosis (hereditary hemochromatosis, primary biliary cirrhosis, autoimmune hepatitis) should be considered a risk factor for HCC. In recent years it has been shown that diabetes mellitus<a class="elsevierStyleCrossRefs" href="#bib1105">22–25</a> and other factors associated with a metabolic syndrome such as obesity or dyslipidemia<a class="elsevierStyleCrossRefs" href="#bib1125">26–30</a> are associated with increased mortality related to HCC, similar to smoking.<a class="elsevierStyleCrossRefs" href="#bib1150">31,32</a> Coffee consumption reduces the risk,<a class="elsevierStyleCrossRefs" href="#bib1160">33–35</a> while vitamin supplements, soy or some alternative medicine elements do not have any preventive efficacy. Preliminary studies show that prolonged use of metformin in diabetic patients<a class="elsevierStyleCrossRef" href="#bib1175">36</a> or propranolol in patients infected with HCV<a class="elsevierStyleCrossRef" href="#bib1180">37</a> could be associated with a decrease in the incidence of HCC. Also, a recent systematic review and meta-analyses have shown that the use of statins is associated with a reduction in the incidence of HCC.<a class="elsevierStyleCrossRef" href="#bib1185">38</a> Prospective studies are needed to confirm these findings and to make a recommendation on the use of these agents as preventive treatment for HCC development. Finally, coinfection with the human immunodeficiency virus in patients with chronic HBV and/or HCV seems to condition a faster progression of liver disease<a class="elsevierStyleCrossRefs" href="#bib1190">39,40</a> and, in recent years, data indicating that the incidence of HCC may be increasing in coinfected patients has been reported.<a class="elsevierStyleCrossRefs" href="#bib1200">41–44</a>Effective prevention of death by HCC can be achieved by avoiding the acquisition of risk factors. The vaccine against HBV has proved its efficiency,<a class="elsevierStyleCrossRef" href="#bib1055">12</a> while HCV infection, aflatoxin intake, alcohol or metabolic syndrome can be prevented by campaigns aimed at improving the sanitary conditions of citizens and promoting healthy lifestyles. If the risk factor has already been acquired, the only preventive option is to prevent progression to cirrhosis by administering antiviral treatment<a class="elsevierStyleCrossRefs" href="#bib1095">20,45</a> and the abandonment of habits involving increased risk. Several studies have shown that HBV replication increases the risk of HCC,<a class="elsevierStyleCrossRefs" href="#bib1220">45–49</a> therefore, the antiviral treatment should result in decreasing the progression of liver disease, thus reducing the long term development of HCC.<a class="elsevierStyleCrossRef" href="#bib1100">21</a> Regarding the use of interferon in HCV infection, if the antiviral treatment fails to eradicate the viral infection or inhibit viral replication persistently, it will not be able to effectively prevent progression to cirrhosis with the risk of HCC.<a class="elsevierStyleCrossRefs" href="#bib1245">50,51</a> Today, the availability of an effective treatment against HCV will probably determine a substantial reduction in the incidence of HCC in our country in the coming years. Therefore, primary prevention of HCC is the most effective measure.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Early diagnosticScreening in oncology is defined as the completion of a test repeatedly with the aim of reducing neoplasm-related mortality.<a class="elsevierStyleCrossRef" href="#bib1255">52</a> In our setting, more than 80% of patients with HCC have underlying liver cirrhosis and the development of HCC is nowadays a leading cause of death in patients with cirrhosis.<a class="elsevierStyleCrossRef" href="#bib1260">53</a> Given that the only possibility of treatment with curative intent is diagnosing the disease in an asymptomatic phase<a class="elsevierStyleCrossRef" href="#bib1265">54</a> and since this option is only feasible if screening of the population at risk is carried out, it is recommended to periodically scan patients with cirrhosis by abdominal ultrasound (US). Several cohort studies<a class="elsevierStyleCrossRefs" href="#bib1270">55–57</a> and cost-effectiveness analysis<a class="elsevierStyleCrossRefs" href="#bib1285">58–60</a> reinforce the usefulness of implementing US monitoring every 6 months. However, the benefit of screening techniques should be evaluated by prospective randomized studies since uncontrolled studies are affected by different biases.<a class="elsevierStyleCrossRef" href="#bib1300">61</a> There is just one single prospective randomized study available which was conducted in China. It included 18,816 patients with chronic HBV infection, being randomized to receive screening by ultrasound every 6 months by abdominal US and determination of alpha-fetoprotein (AFP) every 6 months versus no screening. Despite the low adherence (<60%), the survival of the patients included in the screening programme was 66% at one year, 53% at 3 years and 46% at 5 years versus 31, 7 and 0%, respectively, in patients without screening.<a class="elsevierStyleCrossRef" href="#bib1305">62</a> The efficacy of the programme was linked to the effectiveness of the US, while determination of AFP was not efficient.<a class="elsevierStyleCrossRef" href="#bib1310">63</a> Conducting a new validation clinical trial in developed countries is not viable; the US is part of the routine assessment of patients with chronic liver disease and the perceived benefit of the screening by physicians and patients prevents recruitment.<a class="elsevierStyleCrossRef" href="#bib1315">64</a> With all the available evidence, there is general consensus to recommend the inclusion of cirrhotic patients, who would be treated if they were diagnosed with HCC, in periodic screening programmes. In general, cirrhotic patients in functional class Child-Pugh A and B should be considered for screening. Patients in advanced class B and C or decompensation not identified by the Child-Pugh classification or by the Model for End-Stage Liver Disease (MELD) that determine poor prognosis (recurrent hepatic encephalopathy, spontaneous bacterial peritonitis, malnutrition, etc.) should be evaluated for liver transplantation. The detection of HCC in those patients will not change the indication for transplant, unless the waiting list inclusion criteria are exceeded and HCC constitutes a contraindication for transplantation. Since the transplant in these patients should be considered due to liver failure with poor short term prognosis, HCC detection and its possible treatment will have no clinically significant impact on survival. Therefore, in this subgroup of patients it is meaningless to perform early detection screening if the transplant is not feasible.Scan intervalData concerning tumour growth rates and progression to a size detectable by imaging techniques are limited. Older series show that the tumour volume doubling time is between 2 and 4 months<a class="elsevierStyleCrossRefs" href="#bib1320">65,66</a> and these results provide the basis for making rational screening every 6 months. Also, this interval was used in the only randomized clinical trial that has demonstrated the benefit of screening for HCC in patients with chronic liver disease.<a class="elsevierStyleCrossRef" href="#bib1305">62</a> In Japan an interval of 3–4 months is recommended<a class="elsevierStyleCrossRef" href="#bib1330">67</a> and some authors maintain that high-risk patients should be examined more frequently. However, there are no data available which gives evidence that a higher risk is associated with an increased tumour growth rate. A recent study shows that an interval of 12 months between scans is associated with decreased survival and reduced detection ability than the 6-month interval,<a class="elsevierStyleCrossRef" href="#bib1335">68</a> and a randomized clinical trial conducted in France on 1200 cirrhotic patients concluded that screening with ultrasound every 3 months does not improve the diagnosis or treatment of HCC compared to performing it every 6 months.<a class="elsevierStyleCrossRef" href="#bib1340">69</a> Finally, cost-effectiveness studies show that the interval of 6 months is more cost-effective than other alternatives.<a class="elsevierStyleCrossRef" href="#bib1345">70</a> Therefore, based on current scientific evidence, the 6-month interval should be considered the recommended one.Screening toolsThe HCC screening techniques can be divided into radiological and serological. The recommended radiological test is abdominal ultrasound. It is a non-invasive technique, accepted by the population, with a sensitivity of 60-80% and a specificity of over 90% for early detection of HCC.<a class="elsevierStyleCrossRef" href="#bib1350">71</a> In addition, it has a well-defined diagnostic strategy following the detection of a suspected HCC nodule. Therefore, abdominal ultrasonography, performed by skilled personnel, is currently the most suitable screening technique for early detection of HCC. In actual clinical practice a significant number of patients are not diagnosed in early stages due to the poor implementation of screening programmes or lack of lesion detection.<a class="elsevierStyleCrossRefs" href="#bib1355">72–74</a> In order to ensure the knowledge and experience to perform ultrasound based screening it would be important to consider establishing training programmes that could qualify professionals to carry out this activity. Performing computed tomography (CT) as a screening technique should be discouraged by the risk associated with irradiation<a class="elsevierStyleCrossRef" href="#bib1370">75</a> and for reasons of cost-effectiveness and reduced availability. This aspect also affects magnetic resonance imaging (MRI).Regarding the serological tests, currently there are many different tumour markers available. AFP, which until now was the only tool available, is the most widely evaluated. However, the AFP has shown poor performance because its values in many cases are normal in initial tumors<a class="elsevierStyleCrossRef" href="#bib1375">76</a> and it is well known that patients with liver cirrhosis may have transient elevations of AFP in the absence of HCC.<a class="elsevierStyleCrossRefs" href="#bib1380">77,78</a> Different retrospective analyses evaluating the diagnostic yield using ROC curves showed that using different cut-offs, between 10 and 20ng/ml, considered optimal for screening, sensitivity is 60% and specificity of 80%.<a class="elsevierStyleCrossRefs" href="#bib1390">79–81</a> When considering prospective studies which specifically evaluated the diagnostic yield of screening tests, the AFP with the same cut-off point shows a sensitivity lower than 25% and a specificity of 79%.<a class="elsevierStyleCrossRef" href="#bib1375">76</a> A retrospective study has shown that a progressive increase of AFP would be more useful,<a class="elsevierStyleCrossRef" href="#bib1405">82</a> but it must be validated prospectively. In addition, there is no study establishing that the increase of AFP should lead to HCC suspicion if the US is negative. In this regard, studies on explants show that HCC may not exist even when the AFP exceeds 500ng/ml.<a class="elsevierStyleCrossRef" href="#bib1410">83</a> Finally, there is a correlation between levels of AFP and tumour stage, with the AFP simply being an advanced disease marker. Therefore, the AFP is not a tool for effective screening and early detection and its use should be discouraged.<a class="elsevierStyleCrossRefs" href="#bib1415">84,85</a> Other markers have been proposed, such as the lectin-bound AFP fraction,<a class="elsevierStyleCrossRef" href="#bib1395">80</a>.<a class="elsevierStyleCrossRef" href="#bib1425">86</a> Des-gamma-carboxy prothrombin,<a class="elsevierStyleCrossRef" href="#bib1395">80</a>Golgi protein-73,<a class="elsevierStyleCrossRef" href="#bib1430">87</a> Glypican-3<a class="elsevierStyleCrossRef" href="#bib1435">88</a> or Dickkopf-1,<a class="elsevierStyleCrossRef" href="#bib1440">89</a> but they exhibit the same defects as the AFP and generally cannot compete with the reliability of the US.Candidates for hepatocellular carcinoma screeningSince the main risk factor for HCC is the presence of cirrhosis, all patients with cirrhosis irrespective of aetiology should be considered candidates for screening. In patients with chronic liver disease due to HCV with established cirrhosis, obtaining persistent viral response after treatment does not eliminate the risk of HCC.<a class="elsevierStyleCrossRef" href="#bib1095">20</a> Therefore, screening for HCC should also be recommended in these patients. In patients with chronic HBV infection, screening is considered cost-effective if the risk of HCC is higher than 0.2%/year. In this scenario, cost-benefit models are required to assess the screening indication. The incidence of HCC in Asian or African adults with active HBV infection, with or without a family history of HCC, clearly exceeds this cut-off point,<a class="elsevierStyleCrossRef" href="#bib1225">46</a> while the incidence of HCC ranges from 0.1 to 0.4%/year in Western patients.<a class="elsevierStyleCrossRef" href="#bib1445">90</a> Viral load is also associated with an increased risk of HCC; in Asian patients, levels of HBV DNA higher than 10,000copies/ml are associated with a HCC risk higher than 0.2%.<a class="elsevierStyleCrossRef" href="#bib1225">46</a> Regarding HCV, recent studies conducted in the USA and Japan show that there is risk of HCC in patients with bridging fibrosis in the absence of cirrhosis.<a class="elsevierStyleCrossRefs" href="#bib1450">91,92</a> Since the transition from advanced fibrosis to cirrhosis cannot be defined properly, there is consensus regarding the implementation of HCC screening to this population. Hepatic elastography seems to be a useful tool to stratify patients with different risk of HCC<a class="elsevierStyleCrossRefs" href="#bib1460">93–97</a>; this tool allows, non-invasively, to determine the presence of advanced fibrosis,<a class="elsevierStyleCrossRef" href="#bib1485">98</a> with the highest values being associated with the presence of portal hypertension,<a class="elsevierStyleCrossRefs" href="#bib1490">99,100</a> and therefore identify those patients at high risk of developing HCC in whom screening would be cost-effective. However, while high values indicate elastography cirrhosis and portal hypertension, the distinction between advanced fibrosis and liver cirrhosis without portal hypertension should be validated. The possibility of stratifying risk by genetic studies has recently been suggested,<a class="elsevierStyleCrossRefs" href="#bib1500">101,102</a> and that this information could be associated with the clinical parameters discussed above.Patients with alcoholic liver cirrhosis do not present a risk of developing homogeneous HCC. Northern European studies report a reduced incidence, but data from the rest of the world, including France<a class="elsevierStyleCrossRef" href="#bib1500">101</a> and Spain, suggest otherwise.<a class="elsevierStyleCrossRef" href="#bib1510">103</a> In the case of primary biliary cirrhosis, an incidence of 3.4 cases/1000 patients/year has been established and the main predictors of HCC development are the absence of biochemical response after medical treatment<a class="elsevierStyleCrossRef" href="#bib1515">104</a> and the presence of stage iv in the illness.<a class="elsevierStyleCrossRef" href="#bib1520">105</a> Finally, there is little information regarding the risk of HCC in patients with NASH, particularly those who have not yet developed cirrhosis, so it is not possible to make any recommendations for screening in this population. Although there are no values in the percentage of patients with NASH who develop HCC, probably those who have already developed cirrhosis should be considered for screening. The same concept applies to hereditary hemochromatosis and other entities that progress into cirrhosis.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Diagnosis of hepatocellular carcinomaIn a patient with liver cirrhosis, the probability that a node detected by US is actually HCC is very high, especially if their diameter exceeds 10mm.<a class="elsevierStyleCrossRef" href="#bib1375">76</a> Therefore, if the detected nodule exceeds this limit, additional studies to reach a conclusive diagnosis is recommended. HCC has a predominantly arterial vascularization,<a class="elsevierStyleCrossRef" href="#bib1525">106</a> unlike liver parenchyma where vascularization is mixed: arterial and portal. This determines a specific vascular pattern characterized by intense contrast uptake in the arterial phase, followed by a quick washout of contrast in venous or late portal phase. This pattern has been shown to be specific for the diagnosis of HCC when it has been correlated with the histopathologic analysis of explants, surgical resection specimens or percutaneous biopsies.<a class="elsevierStyleCrossRefs" href="#bib1375">76,107–113</a> These criteria have been refined since the first proposal for non-invasive diagnosis of HCC by imaging techniques proposed at the EASL consensus conference held in 2000 in Barcelona.<a class="elsevierStyleCrossRef" href="#bib1565">114</a> Thus, to register the dynamic pattern as specific of HCC, hypervascularisation must be detected in the early arterial phase followed by early washout in the portal venous and/or balance phase. According to these new criteria, it is possible to establish a non-invasive diagnosis of HCC if a nodule >1cm in a patient affected by chronic liver disease shows intense uptake of contrast in the arterial phase followed by early washout during the venous phase in a dynamic imaging technique (MRI or CT with contrast). The use of organ-specific contrast (gadoxetic acid) is pending specificity validation. If the vascular pattern is not typical or the nodule shows no contrast enhancement, the conclusive diagnosis of HCC should be based on pathology. Finally, in the case of nodules <1cm, given the low probability of being malignant in nature<a class="elsevierStyleCrossRef" href="#bib1375">76</a> and the difficulty of proper characterization, close ultrasound monitoring is recommended, every 3–4 months, in order to detect possible growth, and then use the above criteria (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). These non-invasive detection criteria based on specific vascular pattern detection of HCC have been externally validated in Europe,<a class="elsevierStyleCrossRefs" href="#bib1375">76,110,111</a> USA,<a class="elsevierStyleCrossRef" href="#bib1555">112</a> and Asia,<a class="elsevierStyleCrossRef" href="#bib1570">115</a> being only applicable in patients with chronic liver disease. In the case of patients with no established cirrhosis and/or absence of chronic liver disease due to HBV infection, the application of these imaging criteria is not valid and histopathologic examination is necessary to obtain a conclusive diagnosis. Detection of other imaging parameters such as the presence of intralesional fat, isolated hypointensity in venous phases or presence of pseudocapsule does not significantly increase the diagnostic yield.<a class="elsevierStyleCrossRef" href="#bib1575">116</a> The American College of Radiology(ACR) has recently proposed a system for standardizing carrying out, data collection and interpretation of liver CT scans and MRI in patients at risk of developing HCC. This system, known as Liver Imaging Reporting and Data System(LI-RADS), was published on-line in 2011 and updated in 2014.<a class="elsevierStyleCrossRef" href="#bib1580">117</a> LI-RADS categorizes the observations into 6 major categories: LR-1 (definitely benign), LR-2 (probably benign), LR-3 (intermediate probability for HCC), LR-4 (probably HCC), LR-5 (definitely HCC) and other malignancies (OM, lesions with high probability of being malignant tumours other than HCC). A recent prospective assessment of the LI-RADS system in a cohort of patients with single new onset nodules under 20mm detected by ultrasound showed that 69% of lesions categorized as LR-3 were HCC and that the criterion LR-4 was as effective as the LR-5 for the diagnosis of HCC, so joining both categories would increase sensitivity without compromising specificity.<a class="elsevierStyleCrossRef" href="#bib1585">118</a> According to these results, it has been proposed to consider as an LR-5 any nodule detected by ultrasound showing the specific vascular pattern of HCC.<a class="elsevierStyleCrossRef" href="#bib1590">119</a> The diffusion sequences have shown potential usefulness for the diagnosis of HCC, but to date there are no prospective studies that show a clear increase in diagnostic yield.<a class="elsevierStyleCrossRefs" href="#bib1595">120,121</a> Finally, the usefulness of organ-specific contrasts for the diagnosis of HCC has been investigated in recent years.<a class="elsevierStyleCrossRef" href="#bib1605">122</a> Although promising results have been described<a class="elsevierStyleCrossRefs" href="#bib1610">123,124</a> and some scientific societies have introduced their use regarding non-invasive diagnosis of HCC,<a class="elsevierStyleCrossRef" href="#bib1330">67</a> to date there are no published prospective studies that have demonstrated the superiority of organ-specific contrasts. Contrast-enhanced ultrasound is a widespread technique in the management of patients with HCC. However, its diagnostic usefulness has been questioned by its inability to differentiate HCC from intrahepatic cholangiocarcinoma,<a class="elsevierStyleCrossRefs" href="#bib1620">125,126</a> unlike MRI<a class="elsevierStyleCrossRef" href="#bib1630">127</a> and CT<a class="elsevierStyleCrossRef" href="#bib1635">128</a> that do allow their differentiation. In addition, regardless of the outcome of contrast-enhanced ultrasound, the patient must undergo an MRI or CT scan to confirm the diagnosis and complete staging.<a class="elsevierStyleCrossRef" href="#bib1640">129</a> For these reasons the contrast-enhanced ultrasound has not been kept as an imaging technique for diagnosis of HCC.<a class="elsevierStyleCrossRef" href="#bib1645">130</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Despite the improvement of imaging techniques, performing a liver nodule puncture for the diagnosis of HCC is still necessary in a significant number of cases. However, making a puncture in a liver nodule in a cirrhotic patient is not always possible. In some cases, the presence of ascites or coagulation disorders contraindicate this procedure, and in other cases, their location in the liver makes percutaneous access difficult or US fails to identify it despite its MRI detection. In addition, the diagnostic yield of a biopsy in these small nodules is not optimal, it has a false negative rate of nearly 30%.<a class="elsevierStyleCrossRefs" href="#bib1375">76,131</a> This may depend on a sampling error and the difficulty of making a differential diagnosis between very early dysplastic nodules and HCC using the small sample obtained through a percutaneous biopsy.<a class="elsevierStyleCrossRef" href="#bib1525">106</a> Therefore, a negative biopsy cannot exclude the diagnosis of HCC and the need for a new biopsy should be assessed. Regarding the technique for obtaining histological analysis samples, no studies have adequately compared the performance of fine needle puncture-aspiration with cutting needle puncture, so a general recommendation cannot be made. Cytology has a high diagnostic yield, but if what is sought is the architectural arrangement, in that case it may be better to use the cell block technique or “mini-biopsy”, as this can provide valuable information. The usefulness of a biopsy in a non-tumoral liver is controversial.In recent years there has been a breakthrough in the understanding of the molecular pathways that determine the occurring of HCC, which has allowed to evaluate molecular biology techniques that would potentially provide new diagnostic tools. Different diagnostic signatures have been proposed based on gene expression<a class="elsevierStyleCrossRef" href="#bib1655">132</a> and also immunohistochemical staining that would reflect this different expression at protein level.<a class="elsevierStyleCrossRefs" href="#bib1660">133–135</a> It is worth mentioning the panel made up of glypican 3, heat-shock protein 70 and glutamine synthetase, initially evaluated in tumours obtained after surgical resection or liver transplantation<a class="elsevierStyleCrossRef" href="#bib1660">133</a> and subsequently validated in samples obtained by percutaneous biopsy.<a class="elsevierStyleCrossRefs" href="#bib1665">134,136</a> The diagnosis can be confirmed when the stain is positive for 2 of these proteins, but the immunohistochemical panel does not replace the expert assessment and should be reserved to confirm the suspected diagnosis of HCC, particularly in those samples with little material or pathologists with little experience in assessing liver tumours.<a class="elsevierStyleCrossRef" href="#bib1675">136</a> Finally, some authors have warned of the risk of local spread (seeding) after puncturing these nodules. However, the incidence of this complication is very low, less than 0.1%,<a class="elsevierStyleCrossRefs" href="#bib1680">137,138</a> and this risk should always be assessed against the possibility of applying invasive treatments on falsely diagnosed HCC lesions by inconclusive imaging tests.<a class="elsevierStyleCrossRef" href="#bib1410">83</a> There is controversy about recommending a biopsy for diagnostic confirmation in order to obtain histological material to assess different molecular markers. While the need for samples to advance the understanding of the molecular pathways associated with HCC is indisputable, since radiological techniques can confirm the diagnosis of HCC in a significant number of patients, obtaining biopsies in a systematic manner should be done in the context of a research project with the patient's informed consent and each centre's ethics committee approval.<a class="elsevierStyleCrossRef" href="#bib1690">139</a>Finally, the use of AFP as a diagnostic tool has a very low yield.<a class="elsevierStyleCrossRefs" href="#bib1375">76,115,140</a> Different malignancies such as cholangiocarcinoma or gastrointestinal origin metastases may have increased levels of AFP.<a class="elsevierStyleCrossRefs" href="#bib1390">79,115,141,142</a> Therefore, despite finding high levels of AFP, of any magnitude, if the liver mass does not present a specific vascular pattern by imaging technique, a confirmatory biopsy should be performed.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Prognostic assessmentOnce the diagnosis is obtained, a disease extension study and prognostic assessment are necessary. This provides information for the patient and family about life expectancy, enables to choose the most appropriate treatment and to assess its response. The prognosis of solid tumours depends mainly on tumour stage. However, since, in most cases, HCC is associated with liver cirrhosis, and the degree of liver function impairment determines treatment options and survival regardless of the presence of HCC, it is essential to consider liver dysfunction severity and tumour extension jointly. There are different ratings/scores that assess the degree of liver dysfunction as the Child-Pugh classification<a class="elsevierStyleCrossRef" href="#bib1710">143</a> or the MELD system.<a class="elsevierStyleCrossRef" href="#bib1715">144</a> Recently, a multicentre study has proposed a new score that includes albumin and bilirubin values and provides a simple, objective and highly discriminatory capacity to assess the degree of liver dysfunction in patients with HCC.<a class="elsevierStyleCrossRef" href="#bib1720">145</a> Finally, the presence of cancer-related symptoms adequately assessed by validated scales such as the ECOG performance status classification<a class="elsevierStyleCrossRef" href="#bib1725">146</a> or Karnofsky index<a class="elsevierStyleCrossRef" href="#bib1730">147</a> have shown great prognostic value, and, it determines the applicability of the different treatments available, similar to the degree of hepatic functional reserve. Therefore, those prognosis systems that take into account just a single dimension of the disease (tumour size, liver function or the presence of symptoms associated with cancer) are inaccurate and are only useful for detecting terminal illness. In the last decade there have been multiple staging systems that take into account factors associated with tumour extension and liver function.<a class="elsevierStyleCrossRefs" href="#bib1735">148–162</a> Unfortunately, most of them do not consider the presence of symptoms<a class="elsevierStyleCrossRefs" href="#bib1735">148,155,157,159,161,163</a> or do not evaluate tumour extension precisely.<a class="elsevierStyleCrossRef" href="#bib1780">157</a> The only system that links staging with treatment and also has been validated externally<a class="elsevierStyleCrossRefs" href="#bib1815">164–167</a> is the Barcelona-Clinic-Liver-Cancer(BCLC) system. Since its original publication in 1999,<a class="elsevierStyleCrossRef" href="#bib1745">150</a> the system has been refined to its latest version in 2016.<a class="elsevierStyleCrossRef" href="#bib1835">168</a> Recognized for its predictive ability and its usefulness in the treatment decision process, it is the system recommended by AASLD,<a class="elsevierStyleCrossRef" href="#bib1005">2</a> EASL,<a class="elsevierStyleCrossRef" href="#bib1010">3</a>World Gastroenterology Organisation<a class="elsevierStyleCrossRef" href="#bib1840">169</a> and European Society of Medical Oncology,<a class="elsevierStyleCrossRef" href="#bib1845">170</a> as well as by different expert panels involved in the management of HCC.<a class="elsevierStyleCrossRefs" href="#bib1850">171,172</a>The BCLC system includes variables associated with tumour stage, liver function and presence of symptoms and the prognosis is established in accordance with 5 stages that are linked to the possible indication of treatment (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The very early stage (stage 0) is a particularly good prognosis group including patients with compensated liver cirrhosis (Child-Pugh A), completely asymptomatic, which present unique tumours <2cm without vascular invasion or spread. This very early stage corresponds to the carcinoma in situ<a class="elsevierStyleCrossRef" href="#bib1525">106</a> concept. In these cases, percutaneous ablation offers high cure rates, similar survival rates to those obtained with surgical resection but with less cost and morbidity, being considered the first therapeutic option, particularly in patients without future liver transplantation options. The early stage (stage A) includes asymptomatic patients with preserved liver function (Child-Pugh A and B) with solitary HCC or up to 3 nodules up to 3cm in diameter. These patients can be treated with curative intent by surgical resection, percutaneous ablation and liver transplantation, with an expected survival at 5 years of between 50 and 75%. The intermediate stage (stage B) consists of patients with multinodular tumours that exceed the criteria described before without vascular or extrahepatic invasion, with preserved liver function and general condition. The untreated expected survival in this group of patients is 49.6% (95% CI 32–75%) at one year<a class="elsevierStyleCrossRef" href="#bib1830">167</a> and the only treatment that has shown efficacy in terms of survival is transarterial chemoembolization (TACE).<a class="elsevierStyleCrossRefs" href="#bib1860">173–175</a> A stage B subclassification has recently been proposed in 4 subgroups according to tumour stage, presence of symptoms and the degree of liver dysfunction.<a class="elsevierStyleCrossRef" href="#bib1875">176</a> Unfortunately, this subclassification includes patients with severe hepatic dysfunction who should be evaluated for liver transplantation and in whom the presence of a HCC is only a contraindication when the tumour extension exceeds the criteria regarding offering this option. Further, it suggests not to distinguish between PS 0 and PS 1 when studies by the same authors demonstrate the importance of having PS 1 in patients treated with chemoembolization.<a class="elsevierStyleCrossRef" href="#bib1880">177</a> Finally, it should be noted that, according to the BCLC model, single tumours without PS compromise should be considered BCLC A, and many analyses and proposals to improve the BCLC model wrongly include them as BCLC B. Given these considerations, this subclassification has not demonstrated a prognostic discriminatory capacity in this group of patients.<a class="elsevierStyleCrossRef" href="#bib1885">178</a> Patients with preserved liver function, but having a HCC with vascular invasion and/or extrahepatic or mild malaise are classified as advanced stage (stage C). The median survival in this group of patients is 4–8 months and the only treatment to date that has shown benefits in terms of survival is sorafenib, with a median survival of about 11 months.<a class="elsevierStyleCrossRefs" href="#bib1890">179,180</a> Finally, patients with severe malaise and/or compromised liver function (Child-Pugh C or Child-Pugh B cirrhosis with decompensation associated with poor prognosis such as refractory ascites, chronic/recurrent hepatic encephalopathy or spontaneous bacterial peritonitis) who are not candidates for liver transplantation correspond to stage D or terminal. They median survival is less than 3 months<a class="elsevierStyleCrossRef" href="#bib1830">167</a> and only symptomatic treatment should be indicated.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Recent advances in understanding the molecular pathways that determine the onset and progression of HCC have defined different patterns of gene expression with possible prognostic significance.<a class="elsevierStyleCrossRefs" href="#bib1900">181–187</a> To date, no molecular pattern has been correlated with a different prognosis or that it involves a specific decision so as to select the best treatment. Therefore, current research is aimed at trying to integrate these gene expression data to existing assessment systems, enabling survival prediction and treatment indication in the molecular profile of the patient. Finally, recent research has shown that certain parameters which are identified during the course of the disease can determine its prognosis. For example, in patients with intermediate/advanced stage HCC treated with sorafenib, the type of radiological progression determines, in a statistically independent manner, postprogression survival,<a class="elsevierStyleCrossRefs" href="#bib1935">188,189</a> with the development of a new extrahepatic foci or tumour vascular invasion being the radiographic progression associated with worse survival.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Treatment of hepatocellular carcinomaIn the past, HCC was diagnosed during advanced stages, when the patient had experienced symptoms or worsening liver function. At this stage it was not possible to administer any treatment and, in most cases, the diagnosis of HCC was considered a terminal episode in the context of liver cirrhosis. In recent years, thanks to the implementation of screening programmes, HCC is increasingly being diagnosed at earlier stages, when effective treatments can still be applied. For best results, a correct assessment of tumour extension and liver function are essential, so that treatment can later be applied in adequately qualified centres. Therefore, if HCC diagnosis is confirmed or suspected, referral to reference centres with multidisciplinary teams of hepatologists, radiologists, surgeons, pathologists and oncologists with experience in the management of this disease is recommended.A treatment efficacy assessment should be based on randomized clinical trials and meta-analysis of individual data. Other sources of evidence, such as randomized clinical trials or observational studies are less reliable. In HCC, unlike other prevalent cancers such as lung, breast, stomach and colon-rectum, only a minority of therapeutic options have been properly evaluated. <a class="elsevierStyleCrossRef" href="#tbl0060">Table 3</a> summarizes the level of scientific evidence currently available regarding evaluated HCC therapeutic options.<a class="elsevierStyleCrossRef" href="#bib1265">54</a><elsevierMultimedia ident="tbl0060"></elsevierMultimedia>Treatments with curative intent can be applied during the early stages of the disease. These are surgical resection, liver transplantation and ablation. During the intermediate stage, the only treatment that has shown increased survival is TACE, when applied according to the recommended criteria. During advance HCC, the only treatment that has shown to be of benefit to date in terms of survival is sorafenib. Finally, palliative measures should be recommended during the terminal stage. Obviously, if a patient at any given stage cannot be a candidate for the recommended therapeutic option, you should consider the indication of lower priority treatment corresponding to a more advanced stage (concept known as treatment stage migration).<a class="elsevierStyleCrossRef" href="#bib1265">54</a>Surgical resectionSurgical resection is the first choice in those single tumours that appear on non-cirrhotic livers, which allow extensive resections with a low risk of complications.<a class="elsevierStyleCrossRefs" href="#bib1945">190–192</a> However, in our area, most HCC appear on chronic liver disease, usually in cirrhotic phase. In this context, it is not possible to make extensive resections due to the risk of postoperative liver failure. Therefore, this treatment option is limited. In patients with decompensated liver cirrhosis, surgical resection is formally contraindicated and the surgical treatment to consider is liver transplantation provided there are no contraindications due to age or comorbidities. In patients with compensated cirrhosis, careful assessment of liver function is essential in order to predict the type of long-term survival being offered by resection and to compare it with what other options offer, such as transplantation or ablation. This approach allows to offer each patient the option associated with the best expected survival.<a class="elsevierStyleCrossRef" href="#bib1960">193</a> The best candidates for surgical resection are patients with single tumours, which have a normal bilirubin level and absence of clinically relevant portal hypertension (CRPH).<a class="elsevierStyleCrossRefs" href="#bib1965">194,195</a> The most accurate way to evaluate the absence of CRPH is by direct measurement of the pressure gradient at the level of the hepatic vein,<a class="elsevierStyleCrossRef" href="#bib1975">196</a> considering patients whose gradient is lower than 10mmHg194 optimal for surgical resection. The presence of oesophageal varices or ascites confirm the existence of CRPH. However, detection of splenomegaly and a platelet count below 100,000/mm<a class="elsevierStyleCrossRef" href="#bib1010">3</a> does not accurately identify the presence of CRPH.<a class="elsevierStyleCrossRef" href="#bib1980">197</a> Liver stiffness determination by elastography has been evaluated in recent years as a tool for identifying CRPH and therefore predict survival and surgical liver dysfunction postresection.<a class="elsevierStyleCrossRefs" href="#bib1495">100,198</a> A recent study in Barcelona showed that elastography values above 21kPa are highly suggestive of CRPH and values less than 13.6kPa allow to rule it out.<a class="elsevierStyleCrossRef" href="#bib1495">100</a> Unfortunately, there is no unequivocal cut-off value and, to date, elastography only allows the correct evaluation of CRPH presence or absence in half the cases.<a class="elsevierStyleCrossRef" href="#bib1495">100</a> The presence of CRPH is associated with an increased risk of postoperative complications and medium-term prognosis worsens.<a class="elsevierStyleCrossRef" href="#bib1990">199</a> Thus, in multifocal tumours or in the presence of portal hypertension, resection may be technically feasible and the immediate morbidity and mortality apparently acceptable. However, 5-year survival is 50% or less,<a class="elsevierStyleCrossRef" href="#bib1970">195</a> and therefore, patients should be considered for liver transplantation if they meet the selection criteria. If liver transplantation is not feasible, percutaneous ablation has great therapeutic efficacy in small tumours, and numerous studies have shown that survival may be similar to that obtained by resection if a complete response to treatment is achieved.<a class="elsevierStyleCrossRefs" href="#bib1995">200–202</a> The same is observed in multifocal tumours non eligible for surgery treated with TACE in which median survival can exceed 4 years.<a class="elsevierStyleCrossRefs" href="#bib2010">203–205</a> Regarding the size of the lesion in single tumours, there is no cut-off point that contraindicates resection. The prevalence of additional nodules and vascular invasion increases parallel to tumour size, but, if a large tumour (>5cm) is localized, after CT or MRI confirmation, surgery should not be considered to be contraindicated. Few patients have this type of expansive tumours without spread, so each patient should be assessed individually. However, the greater the tumour size, the greater the risk of microvascular invasion and satellitosis, whereby the risk of recurrence increases<a class="elsevierStyleCrossRefs" href="#bib2025">206–208</a> and other alternatives can potentially get equal or better survival.Despite advances in diagnostic capacity, underestimation of tumour extension continues to be a problem.<a class="elsevierStyleCrossRef" href="#bib1540">109</a> It is therefore essential to have an intraoperative ultrasound in order to detect nodules between 0.5 and 1cm and optimize the surgical resection efficacy. Anatomic resections should be performed with a margin free of disease.<a class="elsevierStyleCrossRefs" href="#bib2040">209,210</a> The benefits of getting a resection margin is based on the ability to eliminate potential sources of tumour spread in peritumoral liver tissue. If the tumour is very small (<15mm) and has not yet reached a significant invasiveness with potential microscopic vascular invasion, the possibility of tumour spread beyond the resected segment is very low and anatomical resection will not provide any benefit. In larger tumours, where vascular invasion is more likely even though it might not be recognizable, anatomical resection may reduce the risk of recurrence. Finally, if microscopic vascular invasion is already present, the likelihood of distant spread is very high and therefore, an anatomic resection with clear margins may not have an impact on recurrence/survival.<a class="elsevierStyleCrossRef" href="#bib2050">211</a> In these rigorously selected patients, operated by experienced teams, perioperative mortality in conventional patients (not those with high risk in experimental programmes) should be less than 10%, the transfusion rate lower than 1% and survival at 5 years 50%.<a class="elsevierStyleCrossRefs" href="#bib1960">193,195</a> Advances in laparoscopic surgery allow a less invasive surgical treatment and provide the same results in survival with lower perioperative morbidity and shorter hospital stays.<a class="elsevierStyleCrossRefs" href="#bib2055">212,213</a> Its application requires a careful assessment of the resection to be carried out depending on location, and obviously a specific training is necessary.Adjuvant therapy to prevent recurrence of hepatocellular carcinomaDespite a strict selection of candidates and the excellent results obtained in terms of survival, the rate of disease recurrence is very high and may reach 70% at 5 years.<a class="elsevierStyleCrossRef" href="#bib2065">214</a> It has been proposed that 60–70% of recurrences correspond to intrahepatic metastasis undetected at the time of resection, and 30–40% are de novo HCC.<a class="elsevierStyleCrossRefs" href="#bib2040">209,215</a> The first type would appear during the first 2 years of follow-up and would often be multifocal. Its main risk factors are the presence of microvascular invasion or satellitosis and a low degree of histological differentiation.<a class="elsevierStyleCrossRefs" href="#bib1970">195,207,209,210</a> In contrast, metachronous tumours would have a late onset and be usually unifocal. However, the classification between metachronous HCC and recurrence due to spread cannot be based simply on the pattern of recurrence and the time of onset, since tumours with less proliferative or metastatic capacity, or livers with less capacity to host metastases can lead to long term unifocal spread. This possibility is verified in extrahepatic relapse beyond 2 years in patients with liver transplantation.Since the presence of microvascular invasion and/or satellitosis on histological examination of the surgical specimen correlates with early recurrence and poor prognosis, some groups have proposed assessing the patient's inclusion in the list of liver transplantation once the spread in the resected segment is known, before the onset of the relapse<a class="elsevierStyleCrossRefs" href="#bib2035">208,216</a> and the results of this strategy are positive.<a class="elsevierStyleCrossRef" href="#bib2080">217</a> Multiple adjuvant therapies to prevent recurrence have been evaluated, aimed at both, preventing recurrence due to spread (Chemoembolization–Lipiodolization,<a class="elsevierStyleCrossRefs" href="#bib2085">218,219</a> intrahepatic radiation,<a class="elsevierStyleCrossRef" href="#bib2095">220</a> systemic agents<a class="elsevierStyleCrossRefs" href="#bib2100">221,222</a> or immunotherapy<a class="elsevierStyleCrossRef" href="#bib2110">223</a>) as well as preventing recurrences de novo (retinoids<a class="elsevierStyleCrossRef" href="#bib2115">224</a> and interferon).<a class="elsevierStyleCrossRefs" href="#bib2120">225–227</a> Despite encouraging results at first, the efficacy of these strategies has not been reproduced by more consistent studies and at the present time they cannot be considered part of routine clinical practice. Recent studies evaluating vitamin K2 analogs<a class="elsevierStyleCrossRef" href="#bib2135">228</a> or heparinase inhibitors (PI-88)<a class="elsevierStyleCrossRef" href="#bib2140">229</a> have proved negative. Finally, a phase 3 multicentre randomized study evaluated sorafenib versus placebo as adjuvant treatment after complete ablation or hepatic resection (STORM study), also obtaining a negative result.<a class="elsevierStyleCrossRef" href="#bib2145">230</a><elsevierMultimedia ident="tbl0025"></elsevierMultimedia>Liver transplantationIn the 80s, the results obtained after liver transplantation, with recurrence rates of 50% and 5-year survival rates lower than 40%, questioned the acceptance of liver transplantation as a valid treatment option for HCC. These data were the result of the selection of candidates with large tumours or even presence of vascular invasion or extrahepatic spread. However, those patients in whom HCC was found incidentally in the explant showed a low likelihood of recurrence and a survival similar to that of patients transplanted without HCC. This was the rationale used to show that when liver transplantation was limited to patients with single tumours <5cm or up to 3 nodules under 3cm without vascular invasion or extrahepatic spread (Milan criteria), a survival rate at 4 years of 75% and a recurrence rate of 8% was obtained.<a class="elsevierStyleCrossRef" href="#bib2150">231</a> These results have been validated by different groups<a class="elsevierStyleCrossRefs" href="#bib2155">232–235</a> and constitute the criteria for liver transplantation accepted by AASLD,<a class="elsevierStyleCrossRef" href="#bib1005">2</a> UNOS/OPTN (<a id="intr0035" class="elsevierStyleInterRef" href="http://www.optn.org/">www.optn.org</a>), EASL/EORTC,<a class="elsevierStyleCrossRef" href="#bib1010">3</a> SETH<a class="elsevierStyleCrossRef" href="#bib2175">236</a> and a panel of international experts under the auspices of several scientific societies directly involved in the management of HCC.<a class="elsevierStyleCrossRef" href="#bib1855">172</a> Therefore, liver transplantation is the treatment of choice in patients with HCC who are not optimal candidates for surgical resection, who have no extrahepatic disease that contraindicates the procedure and who have a HCC compatible with the Milan criteria.<a class="elsevierStyleCrossRef" href="#bib1265">54</a>Transplantation applicability is limited. The number of candidates exceeds the number of organs available and, therefore, there is a waiting time between indication and transplantation. During this time the tumour can progress and reach intervention contraindication. This may reach 25% of patients if the wait is 12 months and therefore survival according to intention to treat may be significantly deteriorated.<a class="elsevierStyleCrossRef" href="#bib2180">237</a> The following strategies have been proposed to reduce the risk of progression during the waiting time:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Increasing the number of donors: This would be the most effective strategy but its impact is limited. Despite using high risk donors (steatotic livers, elderly, non heart-beating donors), or develop the domino effect transplant, the number of candidates still exceeds the available donors. This leads to the conclusion that a potentially more effective option is the development of transplant programmes from living donors.<a class="elsevierStyleCrossRef" href="#bib2185">238</a> The latter alternative has shown similar results to cadaveric transplantation<a class="elsevierStyleCrossRefs" href="#bib2190">239–245</a> and cost-effectiveness studies have shown its usefulness when the waiting list exceeds 7 months.<a class="elsevierStyleCrossRef" href="#bib2225">246</a> However, its applicability in routine clinical practice in Spain is low.<a class="elsevierStyleCrossRef" href="#bib2230">247</a> Furthermore, the donor's morbidity and mortality<a class="elsevierStyleCrossRef" href="#bib2235">248</a> possibility and the highest rate of postoperative complications of biliary origin in the receiver needs to be considered, particularly in those centres with limited experience.<a class="elsevierStyleCrossRef" href="#bib2240">249</a></li><li class="elsevierStyleListItem" id="lsti0010">-Prioritization systems: The goal is to transplant as soon as possible those patients with a high progression probability during the time they are on the waiting list and delay those with less aggressive disease. The MELD system for patients with advanced liver disease has been implemented in recent years. Granting some MELD points to patients with HCC has also been proposed, with the purpose of balancing the risk of exclusion/death on the waiting list among all categories of patients. Since the proportion of patients with advanced liver disease and the intensity of it is neither stable nor homogeneous between different areas, the use of the same point value for patients with HCC implies that the probability of delisting is hardly comparable between the different geographical areas. This heterogeneity has been found in the United States, where this system was implemented years ago.<a class="elsevierStyleCrossRefs" href="#bib2245">250–252</a> Therefore, for the time being, an optimal prioritization strategy is not available.<a class="elsevierStyleCrossRef" href="#bib2260">253</a></li><li class="elsevierStyleListItem" id="lsti0015">-Application of treatments during the waiting time: There is no randomized clinical trial demonstrating that the application of locoregional treatments during the waiting time increases survival. However, different observational studies have suggested that treatment with radiofrequency<a class="elsevierStyleCrossRefs" href="#bib2265">254,255</a> or TACE<a class="elsevierStyleCrossRefs" href="#bib2275">256–258</a> while on the waiting list decreases the rate of exclusion and cost-effectiveness analyses have suggested its usefulness when the waiting list exceeds 6 months.<a class="elsevierStyleCrossRef" href="#bib2290">259</a> Therefore, the administration of locoregional treatment is indicated to be considered in those centres where the waiting time exceeds this period. Probably, if the waiting time is over 18–24 months, there will be no significant benefit regarding treatment application because the probability of progression exceeds the probability of success.<a class="elsevierStyleCrossRef" href="#bib2295">260</a></li></ul>Despite the lack of donors, many groups have proposed that the criteria for inclusion in the list could be expanded without increasing the recurrence rate or decreasing long-term survival. This suggestion is based on the fact that some patients in whom the explant analysis showed they discreetly exceeding the HCC Milan criteria had an acceptable survival and recurrence rate.<a class="elsevierStyleCrossRefs" href="#bib2170">235,261–268</a> However, many of these series included a small number of patients with expanded criteria, which were based in many cases on retrospective analysis, definition of tumour stage is based on explant findings or imaging techniques findings without a homogeneous criterion at the time of inclusion, and do not consider or register the decrease in the rate while on the list. Moreover, there are studies in which the analysis of patients who discretely exceed the Milan limits show worse survival.<a class="elsevierStyleCrossRefs" href="#bib2340">269,270</a> Finally, the follow-up time is short, and therefore the 5-year survival according to the principle of intention to treat is not well known. In addition to these data, it should be noted that the expansion of criteria will increase the number of patients on the list, so that the shortage of donors will increase, and therefore, some organs will be used in patients with a lower life expectancy, while other patients with excellent post-transplant survival prospects will not be transplanted. Cost-effectiveness analysis taking into account the impact that the expansion of criteria would have in organ shortage transplant programmes advise against this strategy.<a class="elsevierStyleCrossRef" href="#bib2350">271</a> Furthermore, recent studies question the Milan criteria and have proposed different criteria to optimize the selection of patients based on the calculation of the total tumour volume,<a class="elsevierStyleCrossRefs" href="#bib2355">272,273</a> determination of AFP<a class="elsevierStyleCrossRefs" href="#bib2365">274–276</a> or the association of both,<a class="elsevierStyleCrossRef" href="#bib2380">277</a> among others.Other groups have shown that patients with HCC exceeding the Milan criteria with objective response after application of a locoregional treatment (Downstaging) have an excellent outcome after performing a liver transplant.<a class="elsevierStyleCrossRefs" href="#bib2385">278–283</a> This recommendation is based on the fact that response to treatment with decreased tumour stage could be a marker of less neoplastic aggressiveness, allowing the selection of patients with tumours that would have a satisfactory outcome after liver transplantation. However, all these series include a low number of patients,<a class="elsevierStyleCrossRef" href="#bib2415">284</a> the proposed expansion is not uniform, the imaging criteria to define tumour extension are not detailed, the treatments applied are heterogeneous, and the definition of downstaging is not homogeneous. Finally, follow-up is limited and establishing a recommendation is not feasible.Considering the available scientific evidence at this time, it is recommended not to expand the liver transplant eligibility criteria except in areas where there is no shortage of donors or in the context of a research protocol.Finally, taking into account the unrestricted availability of organs and the minimum waiting time when considering living donor liver transplantation, some authors have suggested that the transplantation selection criteria of patients with HCC could be expanded.<a class="elsevierStyleCrossRefs" href="#bib2190">239,285–289</a> This proposal should not be regarded as conventional clinical practice until its efficacy in research studies is established with an adequate number of cases analyzed according to intention to treat from the moment of its assessment and sufficient follow-up.<elsevierMultimedia ident="tbl0030"></elsevierMultimedia>Ablative techniquesPercutaneous ablation is the treatment of choice for those patients with HCC in early stage where surgical resection is not possible and liver transplantation is contraindicated due to an associated disease. At the same time, it is a therapeutic option to try to prevent tumour progression during the liver transplantation waiting time.Tumour ablation may be performed through instillation of chemicals, mainly ethanol and acetic acid, or by intratumoral temperature modification, as in the case of RF, cryoablation, microwaves or laser.<a class="elsevierStyleCrossRef" href="#bib2445">290</a> At present, radiofrequency ablation (RFA) is the reference technique, while the percutaneous ethanol injection(PEI) has been reserved for very special indications due to location or to complete ablation when there is a minimal residual activity. However, it should be noted that in tumours <2cm, the effectiveness of PEI is not different from RFA,<a class="elsevierStyleCrossRef" href="#bib2450">291</a> but in larger tumours their efficacy is lost due to the presence of intratumoral fibrous septa that prevent the correct diffusion of ethanol.<a class="elsevierStyleCrossRefs" href="#bib2455">292–294</a> The RFA has more ablative capacity, obtaining a higher response rate than PEI in tumours >3cm with fewer sessions.<a class="elsevierStyleCrossRef" href="#bib2470">295</a> However, it has drawbacks, such as an increased frequency and severity of adverse effects,<a class="elsevierStyleCrossRefs" href="#bib2475">296–298</a> higher cost and lower applicability since its use is not recommended in subcapsular tumours or tumours that are adjacent to the gallbladder, hepatic hilum or heart due to the risk of complications, or those in close contact with blood vessels by a thermal energy dissipation phenomenon hindering the complete ablation of the lesion. PEI and RFA ablation have been directly compared in recent years.<a class="elsevierStyleCrossRefs" href="#bib2490">299–303</a> In all these trials, RFA has shown greater ablation capacity, obtaining a higher complete response rate and a lower chance of local recurrence. Although only one of the clinical trials conducted in Japan demonstrated RFA superiority compared to PEI in terms of survival,<a class="elsevierStyleCrossRef" href="#bib2510">303</a> 3 metaanalysis published recently have shown that RFA provides survival advantage compared to PEI, especially in tumours >2cm.<a class="elsevierStyleCrossRefs" href="#bib2450">291,304,305</a> Microwave ablation has shown a great ablative capacity, and unlike RFA, its ablative capacity is not affected by the presence of blood vessels adjacent to the tumour.<a class="elsevierStyleCrossRef" href="#bib2525">306</a> However, to date, no prospective randomized study has demonstrated the superiority of this technique over RFA.As surgical resection, the main drawback of percutaneous ablation is the high recurrence (80% at 5 years) despite getting a complete response, initially.<a class="elsevierStyleCrossRefs" href="#bib2065">214,297</a>Given the great therapeutic efficacy of ablation in tumours <2cm and the low probability of side effects, several groups have directly compared the percutaneous ablation with surgical resection<a class="elsevierStyleCrossRef" href="#bib2065">214</a>.<a class="elsevierStyleCrossRefs" href="#bib2530">307–312</a> with conflicting results. Unfortunately, these studies have methodological problems, particularly in the allocation of treatment and selection bias, invalidating the results. Recently, two cost-effectiveness analysis exploring which of these two options is more cost-effective have been published.<a class="elsevierStyleCrossRefs" href="#bib2560">313,314</a> Using different methodology, both studies concluded that radiofrequency can offer a similar survival to resection but with a lower cost. The advantage of surgical resection is the availability of the histological analysis of the surgical specimen, which allows obtaining information about the risk of recurrence and the possible desirability of considering entering the waiting list for liver transplantation at high risk of recurrence.<a class="elsevierStyleCrossRefs" href="#bib2035">208,216</a> If the transplant is not feasible and given the current evidence, percutaneous ablation may be the treatment of choice in patients with HCC at very early stage.<a class="elsevierStyleCrossRef" href="#bib1265">54</a><elsevierMultimedia ident="tbl0035"></elsevierMultimedia>Chemoembolization and other locoregional treatmentsThe only treatment that has shown benefit in terms of survival in patients with intermediate HCC (stage B of the BCLC classification) is TACE. This treatment is based on the predominantly arterial vascularization of HCC. It involves selective catheterization of the hepatic artery and supraselective of tumour feeding arteries, and injecting a chemotherapeutic agent together with blood flow occlusion through an embolizing substance.<a class="elsevierStyleCrossRef" href="#bib2570">315</a> TACE is contraindicated in patients with decompensated cirrhosis (Child-Pugh B≥8, including jaundice, encephalopathy, refractory ascites), extensive involvement of both lobes, reduced portal flow (thrombosis or hepatofugal flow), untreatable arteriovenous fistula, biliary-enteric anastomosis or biliary stent and creatinine clearance <30ml/min. In these cases, there is a high risk of decompensated liver disease and, although an objective tumour response can be achieved, survival benefit is marginal.<a class="elsevierStyleCrossRef" href="#bib2570">315</a> Furthermore, despite the strict selection of patients and careful technique, TACE is not exempt from side effects and complications, which may vary from a simple embolization syndrome (the most common, consisting of fever, ileus and abdominal pain) to liver failure, abscesses, ischaemic cholecystitis or even death. Fever is a tumour necrosis marker and prophylactic antibiotic treatment has not demonstrated to avoid the risk of infection.<a class="elsevierStyleCrossRef" href="#bib2575">316</a> The benefit of TACE in terms of survival is based on 2 randomized controlled trials<a class="elsevierStyleCrossRefs" href="#bib1860">173,174</a> and then a meta-analysis of accumulated data,<a class="elsevierStyleCrossRef" href="#bib1870">175</a> which showed that TACE is superior to placebo in patients with intermediate HCC, obtaining a median survival with the treatment of approximately 20 months. A recently published meta-analysis by the Cochrane group showed that the scientific evidence supporting the efficacy of TACE was still limited.<a class="elsevierStyleCrossRef" href="#bib2580">317</a> However, this meta-analysis has important methodological problems, particularly caused by the inclusion of a study exploring the combination of TACE with percutaneous ablation in early stage HCC and the exclusion of a positive clinical trial published by Lo et al. in 2002,<a class="elsevierStyleCrossRef" href="#bib1865">174</a> invalidating their findings.<a class="elsevierStyleCrossRefs" href="#bib2585">318,319</a>TACE is a treatment that has evolved in recent years and there are still many aspects to be investigated.<a class="elsevierStyleCrossRef" href="#bib2595">320</a> The treatment modality which demonstrated a survival benefit is based on the administration of a chemotherapeutic agent together with lipiodol as carrier vehicle followed by vascular occlusion with Spongostan particles; this treatment modality is now known as conventional TACE. The safety and efficacy of synthetic microspheres charged with adriamycin has been evaluated in recent years. These spheres slowly release chemotherapy once injected. With these spheres, vascular occlusion is achieved simultaneously with the administration of the chemotherapeutic agent, preventing the washout of the same, whereby the passage of it to the systemic circulation is reduced, minimizing side effects.<a class="elsevierStyleCrossRef" href="#bib2600">321</a> Besides, the calibre can be chosen depending on the vessel to be embolized and increase the homogeneity of the resulting embolization. Regarding which is the best chemotherapeutic and/or embolizing agent, this is not known since to date no study has correctly compared the different technical modalities. An objective radiological response close to 80% has been obtained with charged particles TACE, apparently higher than that published with conventional TACE. However, a randomized study whose primary objective was to demonstrate superiority in terms of radiological response compared with conventional TACE showed no significant differences,<a class="elsevierStyleCrossRef" href="#bib2605">322</a> possibly due to the excellent objective responses obtained with conventional TACE when a superselective treatment is performed,<a class="elsevierStyleCrossRef" href="#bib2610">323</a> although tolerance was significantly better in patients treated with charged particles. Median survivals between 40–50 months have been reported in selected patients with a treatment protocol using these spheres.<a class="elsevierStyleCrossRefs" href="#bib2010">203,204</a> Moreover, it is necessary to assess what is the best treatment regimen (fixed regimen or re-treat only when revascularization of lesions or progression is detected) and how the response has to be evaluated, or more importantly, when to consider that TACE has failed and therefore look at other treatment options. In this regard, the concept of untreatable progression has been suggested, defined as progression associated with a profile that prevents new treatment, such as a significant progression with excessive tumour burden or a less significant progression but associated with liver or general condition dysfunction or a contraindication to the pulmonary angiography technique.<a class="elsevierStyleCrossRefs" href="#bib2570">315,324</a> Furthermore, although radiological responses are achieved over half of the cases, the main drawback of TACE is that most patients experience disease progression despite an initial response. Therefore, an area of interest is to investigate how to prevent or slow the progression of the disease after treatment. The association of TACE with molecular agents such as sorafenib or brivanib has not improved the response rate, time to tumour progression or survival.<a class="elsevierStyleCrossRefs" href="#bib2620">325,326</a> Finally, combined locoregional treatments are actively being researched in order to increase tumour necrosis, and indirectly, patient survival. Pilot studies<a class="elsevierStyleCrossRef" href="#bib2630">327</a> and several meta-analyses including retrospective studies with methodological limitations (low number of patients, risk of selection bias, in many cases the control group was percutaneous ablation and not TACE, etc.) show the combination's benefit,<a class="elsevierStyleCrossRefs" href="#bib2635">328–330</a> but prospective randomized studies are needed to confirm these preliminary results.In recent years there have been other potentially useful locoregional treatments. Among them, we highlight radioembolization with Yttrium-90 microspheres.<a class="elsevierStyleCrossRef" href="#bib2650">331</a> Multiple prospective studies including patients at different stages of the disease have shown positive results in terms of radiological response, good clinical tolerance to treatment with a survival seemingly comparable to that obtained in patients treated with TACE or sorafenib.<a class="elsevierStyleCrossRefs" href="#bib2655">332–336</a> These data have provided the rationale for conducting randomized clinical trials in well-defined patients comparing radioembolisation combined or not with sorafenib versus sorafenib. These would confirm its benefit in terms of survival and its validity in conventional clinical practice.The new radiotherapy techniques such as three-dimensional conformal radiotherapy, intensity modulated radiation therapy, stereotactic image-guided radiotherapy or proton pump radiotherapy allow to administer high doses of radiation on the tumour lesion without damaging the surrounding tissue. Research is being conducted on its possible role in the treatment of those patients where local treatment has failed and the lesion has a small tumour volume, there is no distant disease and maintain good liver function. They could also be useful for tumours located in difficult areas such as the liver dome or close to the vessels. Their administration is also being researched in patients with invasion of the inferior vena cava or portal vein tumour thrombosis. In any case, the results look promising, and its efficacy must be confirmed in larger studies and randomized studies.<a class="elsevierStyleCrossRef" href="#bib2680">337</a><elsevierMultimedia ident="tbl0040"></elsevierMultimedia>Systemic treatment: sorafenibConventional chemotherapy with cytotoxic purpose (usually doxorubicin<a class="elsevierStyleCrossRefs" href="#bib2685">338,339</a> and oxaliplatin<a class="elsevierStyleCrossRef" href="#bib2695">340</a>) has never shown a significant survival benefit. Therefore, its use is not recommended outside clinical trials.<a class="elsevierStyleCrossRefs" href="#bib1870">175,341</a> Treatments such as tamoxifen,<a class="elsevierStyleCrossRefs" href="#bib1870">175,342–345</a> megestrol,<a class="elsevierStyleCrossRefs" href="#bib2725">346,347</a> octreotride,<a class="elsevierStyleCrossRefs" href="#bib2735">348–350</a> antiandrogenic derivatives<a class="elsevierStyleCrossRefs" href="#bib2750">351,352</a> and seocalcitol<a class="elsevierStyleCrossRef" href="#bib2760">353</a> have not demonstrated efficacy in HCC.In recent years there has been great progress in understanding the molecular alterations that influence tumour progression.<a class="elsevierStyleCrossRefs" href="#bib2765">354–356</a> This has allowed us to develop multiple agents acting specifically at the level of the altered molecular pathways. Multiple molecular therapies have been evaluated, with negative results in most cases.<a class="elsevierStyleCrossRef" href="#bib2780">357</a><a class="elsevierStyleCrossRef" href="#tbl0065">Table 4</a> summarizes the main drugs assessed. To date, the only agent that has shown efficacy in terms of survival in phase 3 placebo-controlled studies is sorafenib. This molecule is a low molecular weight multikinase inhibitor with high oral bioavailability which acts by blocking different signalling pathways associated with hepatocarcinogenesis, particularly the RAF/MEK/ERK pathway by inhibiting Raf kinase and different tyrosine kinases (VEGFR2, PDGFR, c-Kit receptors).<a class="elsevierStyleCrossRef" href="#bib2785">358</a> Its main actions are to reduce angiogenesis and slow cell proliferation. Following the positive results of preclinical studies<a class="elsevierStyleCrossRef" href="#bib2790">359</a> and a phase ii clinical trial,<a class="elsevierStyleCrossRef" href="#bib2795">360</a> 2 international, multicentre, randomized, controlled, double-blind clinical trials were carried out evaluating sorafenib 400mg/12h compared to placebo in patients with advanced HCC and compensated liver function, one conducted in Europe and America (SHARP trial)<a class="elsevierStyleCrossRef" href="#bib1890">179</a> and another in Southeast Asia (Asia-Pacific Study).<a class="elsevierStyleCrossRef" href="#bib1895">180</a> In both studies, sorafenib showed a significant increase in survival and time to radiographic progression. In addition, an exploratory subset analysis showed that sorafenib's efficacy was maintained regardless of the aetiology of cirrhosis, baseline tumour stage, performance status and previous treatments.<a class="elsevierStyleCrossRef" href="#bib2800">361</a> The most common side effects were diarrhoea, weight loss and hand-foot reaction (exclusive alteration of palms and/or soles that can vary from erythema to the occurring of blisters and areas of necrosis). In most cases the side effects were mild and easily controlled.<a class="elsevierStyleCrossRef" href="#bib2805">362</a> These results have been replicated in different clinical trials where sorafenib was the treatment in the control arm<a class="elsevierStyleCrossRefs" href="#bib2695">340,363–366</a> and multiple prospective studies in routine clinical practice.<a class="elsevierStyleCrossRefs" href="#bib1935">188,367,368</a> Sorafenib has been evaluated in patients with compensated liver function (Child-Pugh A) and data regarding its usefulness in Child-Pugh B patients is limited. The pharmacokinetic profile is not significantly modified and a significant increase in side effects has not been reported. However, it should be noted that the Child-Pugh B stage comprises a broad clinical spectrum and the potential impact on tumour progression may not modify patient survival in relation to impaired liver function.<a class="elsevierStyleCrossRefs" href="#bib2835">368,369</a> Therefore, the use of sorafenib in Child-Pugh B patients should be evaluated individually.<a class="elsevierStyleCrossRef" href="#bib2805">362</a> The results published in Child-Pugh C patients show little benefit in terms of survival and its use in these patients should be discouraged.<a class="elsevierStyleCrossRefs" href="#bib2805">362,368,370,371</a> Finally, various biological and clinical markers that could predict response to sorafenib and identify the lack of efficacy at baseline or during treatment have been suggested. Biomarkers such as AFP, vascular endothelial growth factor, angiopoietin-2, hepatocyte growth factor or c-Kit have shown a prognostic value in patients with advanced HCC,<a class="elsevierStyleCrossRef" href="#bib2855">372</a> but they do not contribute to treatment decision. By contrast, the development of certain adverse effects such as diarrhoea,<a class="elsevierStyleCrossRef" href="#bib2860">373</a> hypertension<a class="elsevierStyleCrossRef" href="#bib2865">374</a> or dermatologic conditions<a class="elsevierStyleCrossRefs" href="#bib2870">375–377</a> are associated with better survival. This association between adverse effects and greater efficacy is relevant given that indicates the need for careful monitoring of patients in order to adjust the dose if side effects are detected, and thus avoid unnecessary treatment interruptions that could lead to loss of efficacy.<elsevierMultimedia ident="tbl0065"></elsevierMultimedia>Sorafenib showed that molecular therapies may be useful in the treatment of HCC and opened the way to evaluate blocking multiple signalling pathways in the same way that has been done for years in the case of other neoplasms. Unfortunately, so far, no other agent assessed in phase 3 clinical trials alone in first-line (sunitinib, linifanib, brivanib)<a class="elsevierStyleCrossRefs" href="#bib2810">363,364,366</a> or second-line (brivanib, everolimus, ramucirumab),<a class="elsevierStyleCrossRefs" href="#bib2885">378–380</a> or associated with sorafenib in first-line (erlotinib),<a class="elsevierStyleCrossRef" href="#bib2820">365</a> has managed to demonstrate benefit in terms of survival. At present there are ongoing clinical trials evaluating different molecules that have shown promising results in preliminary studies (regorafenib, lenvatinib, cabozantinib and tivantinib, among others) that could change the management of advanced HCC in coming years.<elsevierMultimedia ident="tbl0045"></elsevierMultimedia>Future perspectives. Objectives in hepatocellular carcinoma researchBreakthroughs are still needed in the field of liver cancer. In addition to implementing the preventive strategies mentioned earlier, progress is needed in the area of early detection and increasing therapeutic efficacy. It is imperative, at different healthcare settings, to change the view that HCC is a neoplasm which is impossible to detect at an early stage and for which there is no treatment. Thus, the number of patients eligible for radical treatment will increase and access to treatment will be allowed to patients who are currently detected only when they are in the final stage of the disease. Since the population at risk is fully identified, it is essential that screening recommendations are implemented correctly and by properly trained personnel. Research in imaging techniques and tumour markers will be of paramount importance to increase the efficacy of the monitoring plans. Therefore, an intense research activity should be developed in the area of detection, diagnosis and staging. Translational research should allow incorporating laboratory findings on the criteria for the characterization and prognostic assessment of patients. In addition, a better understanding of the biological alterations involved in hepatic oncogenesis will lead to the identification of new treatment targets. These should be assessed according to a specific analysis for HCC patients since tumour coexistence with base liver disease requires a different development to the one followed conventionally in other neoplasms. In this regard, an international panel of experts from different specialties promoted by AASLD has developed a consensus document with recommendations to follow in the field of HCC treatment.<a class="elsevierStyleCrossRef" href="#bib1850">171</a> In the case of phase i clinical trials, it is necessary to include Child-Pugh A patients with compensated liver cirrhosis to assess the exact dose, toxicity and specific episodes associated with liver disease that would not be recorded in traditional phase i studies that include patients with different neoplasms. In the case of phase ii trials, the panel of experts recommended the use of phase ii randomized trials designed to evaluate a time-dependent surrogate episode such as time to progression. Overall survival should be reported as a secondary objective, along with safety data. Also, the use of composite variables such as disease/progression free survival as primary objectives should be avoided in these studies. In clinical trials on new therapies, it is advisable to include a biomarker analysis so as to determine response predictors. According to the results of the SHARP trial, sorafenib should be the standard treatment in all those trials evaluating first-line treatment in advanced HCC. The new agents being evaluated as a second line treatment for advanced HCC should be compared to placebo/maintenance therapy and only those drugs that have shown efficacy as a second-line treatment in phase iii trials can be considered to be directly compared with sorafenib in phase ii studies. For the assessment of first-line treatment in advanced HCC, the ideal design would be the new agent associated with sorafenib compared to sorafenib. For second-line treatments, patients with contraindications or failure after treatment with sorafenib should be included and the control arm should be placebo/maintenance treatment. Recent studies have shown that the development of some side effects in patients treated with sorafenib, particularly dermatological, are associated with greater survival.<a class="elsevierStyleCrossRefs" href="#bib2870">375–377</a> In addition, the type of radiological progression determines, in a statistically independent manner, the post-progression survival.<a class="elsevierStyleCrossRefs" href="#bib1935">188,189</a> Thus, those studies evaluating new second line agents after failure and/or intolerance to sorafenib should record this information and possibly stratify this population prior to randomization to obtain homogeneous group comparisons. In addition, those agents evaluated as adjuvant or neoadjuvant treatment should be compared with placebo/maintenance treatment in phase ii studies. In the case of phase iii trials, the primary goal should be overall survival. Time-dependent episodes, such as time to progression, should be considered as secondary objectives, and again, the use of composite measures such as disease/progression free survival should be avoided since it has already been demonstrated that these parameters are not related to survival in HCC.<a class="elsevierStyleCrossRef" href="#bib2810">363</a> Phase iii studies of adjuvant treatments should use survival or time to recurrence as primary objectives. A composite objective (recurrence-free survival) should only be considered if the study population is very selective and mortality unrelated to cancer is almost entirely avoided.Another important aspect is the assessment of the radiological response and its ability to predict the efficacy of a therapeutic agent. Considering that the main objective of locoregional treatments available in HCC is to obtain complete lesion necrosis, simple diameter change measurement of the treated lesions is insufficient to assess response<a class="elsevierStyleCrossRef" href="#bib2900">381</a> and it is necessary to incorporate in the assessment the presence of tumour necrosis identified as lack of contrast uptake in the arterial phase.<a class="elsevierStyleCrossRef" href="#bib2615">324</a> Measurement of tumour necrosis through imaging was initially established in 2000 by the EASL<a class="elsevierStyleCrossRef" href="#bib1565">114</a> and subsequently incorporated into conventional RECIST criteria by an expert group, leading to the modified RECIST (mRECIST) criteria.<a class="elsevierStyleCrossRefs" href="#bib1850">171,382</a> The application of mRECIST criteria for the assessment of systemic treatments is more controversial. Recent studies have shown that a higher objective response according to mRECIST criteria is not associated with survival improvement.<a class="elsevierStyleCrossRefs" href="#bib2890">379,383</a> Determining the time to radiographic progression has been suggested as a possible benefit surrogate marker in terms of survival based on the findings of the 2 phase iii studies of sorafenib in advanced HCC.<a class="elsevierStyleCrossRefs" href="#bib1890">179,180</a> Unfortunately, other studies evaluating other agents such as brivanib have shown that increased time to radiographic progression was not associated with increased survival.<a class="elsevierStyleCrossRef" href="#bib2885">378</a>The detailed knowledge of the altered molecular pathways in HCC could allow to change the management of this disease. In this sense, future research is needed regarding markers that can help identify patients who may benefit from a particular systemic treatment. There are studies in which inclusion is based on the presence of specific molecular alterations in tissue.<a class="elsevierStyleCrossRef" href="#bib2915">384</a> Furthermore, the molecular analysis would help in selecting the most appropriate therapeutic option for a given patient according to the molecular profile of the tumour (a la carte treatment). Although this approach is very attractive, at present we have no biomarker with clinical applicability. Moreover, the determination of molecular alterations in histologic tissue is limited by tumour heterogeneity, both in the same node, as well as in different nodes and along the progression.<a class="elsevierStyleCrossRefs" href="#bib2920">385,386</a> Great efforts are being made to identify tumour products in peripheral blood (liquid biopsy) in order to overcome the limitations described above.Conflict of interestsJordi Bruix (coordinator). He has received remuneration from Bayer HealthCare and BTG for participating in educational activities, conducting research and consulting activities, and Daichi, Bristol-Myers Squibb, Novartis, Gilead, Abbvie, Arquile, Sytex and Roche for consulting activities.Alejandro Forner. Has received remuneration from Bayer HealthCare for participating in educational activities and/or conducting consulting activities.Maria Reig. Has received remuneration from Bayer HealthCare for participating in educational activities and/or conducting consulting activities.Maria Varela. Has received remuneration from Bayer HealthCare for participating in educational activities and research and/or performing consulting activities.Marta Burrel. He has received remuneration from BTG to participate in educational activities and conducting consulting activities.Jaime Feliu. He has received remuneration from Amgen, Sanofi-Aventis, Lilly and Bayer for participating in educational activities and/or conducting consulting activities.Javier Briceño. Absence of conflicts of interest.Javier Sastre. Absence of conflicts of interest.Luis Martí-Bonmatí. Absence of conflicts of interest.Josep M. Llovet. He has received remuneration from Bayer HealthCare, Bristol Myers Squibb and Boehringer Ingelheim for participating in teaching, research and consultancy activities, and Novartis, Celsion, Lilly Pharmaceuticals, GlaxoSmithKline, BTG and Blueprint Medicines for consulting activities.Jose Ignacio Bilbao. He has received remuneration from BTG and SIRTEX to participate in educational activities and/or conducting consulting activities.Bruno Sangro. He has received remuneration from Bayer HealthCare, BTG and SIRTEX to participate in educational activities and/or conducting consulting activities.Fernando Pardo. He has received remuneration from Bayer HealthCare, BTG and SIRTEX to participate in educational activities and/or conducting consulting activities.Carmen Ayuso. Absence of conflicts of interest.Concepció Bru. Absence of conflicts of interest.Josep Tabernero. He has received remuneration from Amgen, Boehringer-Ingelheim, Celgene, Chugai, ImClone, Lilly, Merck, Merck Serono, Millennium, Novartis, Roche, Sanofi and Taiho for participating in educational activities and/or conducting consulting activities." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres733944" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec737699" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres733943" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec737698" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology and prevention" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Early diagnostic" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Scan interval" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Screening tools" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Candidates for hepatocellular carcinoma screening" ] ] ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Diagnosis of hepatocellular carcinoma" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Prognostic assessment" ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Treatment of hepatocellular carcinoma" ] 10 => array:3 [ "identificador" => "sec0050" "titulo" => "Surgical resection" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Adjuvant therapy to prevent recurrence of hepatocellular carcinoma" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Liver transplantation" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Ablative techniques" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Chemoembolization and other locoregional treatments" ] 4 => array:2 [ "identificador" => "sec0075" "titulo" => "Systemic treatment: sorafenib" ] ] ] 11 => array:2 [ "identificador" => "sec0080" "titulo" => "Future perspectives. Objectives in hepatocellular carcinoma research" ] 12 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflict of interests" ] 13 => array:2 [ "identificador" => "xack244042" "titulo" => "Acknowledgement" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-12-03" "fechaAceptado" => "2016-01-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec737699" "palabras" => array:3 [ 0 => "Hepatocellular carcinoma" 1 => "Liver" 2 => "Liver cirrhosis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec737698" "palabras" => array:3 [ 0 => "Carcinoma hepatocelular" 1 => "Hígado" 2 => "Cirrosis hepática" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Hepatocellular carcinoma is the most common primary malignancy of the liver and one of the most frequent causes of death in patients with liver cirrhosis. Simultaneously with the recognition of the clinical relevance of this neoplasm, in recent years there have been important developments in the diagnosis, staging and treatment of HCC. Consequently, the Asociación Española para el Estudio del Hígado has driven the need to update clinical practice guidelines, continuing to invite all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document (Sociedad Española de Trasplante Hepático, Sociedad Española de Radiología Médica, Sociedad Española de Radiología Vascular e Intervencionista y Sociedad Española de Oncología Médica). The clinical practice guidelines published in 2009 accepted as Clinical Practice Guidelines of the National Health System has been taken as reference document, incorporating the most important advances that have been made in recent years. The scientific evidence for the treatment of HCC has been evaluated according to the recommendations of the National Cancer Institute (<a class="elsevierStyleInterRef" id="intr0015" href="http://www.cancer.gov/">www.cancer.gov</a>) and the strength of recommendation is based on the GRADE system." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El carcinoma hepatocelular es la neoplasia primaria de hígado más común y una de las causas de muerte más frecuentes en los pacientes afectos de cirrosis hepática. Simultáneamente al reconocimiento de la relevancia clínica de esta neoplasia, en los últimos años han aparecido novedades importantes en el diagnóstico, estadificación y tratamiento del carcinoma hepatocelular. Por tal motivo, desde la Asociación Española para el Estudio del Hígado se ha impulsado la necesidad de actualizar las guías de práctica clínica, invitando de nuevo a todas las sociedades involucradas en el diagnóstico y tratamiento de esta enfermedad a participar en la redacción y aprobación del documento (la Sociedad Española de Trasplante Hepático, la Sociedad Española de Radiología Médica, la Sociedad Española de Radiología Vascular e Intervencionista y la Sociedad Española de Oncología Médica). Se ha tomado como documento de referencia las guías de práctica clínica publicadas en 2009 aceptadas como Guía de Práctica Clínica del Sistema Nacional de Salud, incorporando los avances más importantes que se han obtenido en los últimos años. La evidencia científica en el tratamiento del carcinoma hepatocelular se ha evaluado de acuerdo con las recomendaciones del National Cancer Institute (<a class="elsevierStyleInterRef" id="intr0020" href="http://www.cancer.gov/">www.cancer.gov</a>) y la fuerza de la recomendación se basa en el sistema GRADE." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Forner A, Reig M, Varela M, Burrel M, Feliu J, Briceño J, et al. Diagnóstico y tratamiento del carcinoma hepatocelular. Actualización del documento de consenso de la AEEH, SEOM, SERAM, SERVEI y SETH. Med Clin (Barc). 2016;146:511." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "Spanish Association for the Study of the Liver (AEEH): Alejandro Forner, Maria Reig, María Varela, Josep Maria Llovet, Bruno Sangro, Jordi Bruix. Spanish Liver Transplant Society (SETH): Javier Briceño, Fernando Pardo. Spanish Society of Medical Radiology (SERAM): Luis Martí-Bonmatí, Carmen Ayuso, Conxita Bru. Spanish Society of Vascular and Interventional Radiology (SERVEI): Marta Burrel, Jose Ignacio Bilbao. Spanish Society of Medical Oncology (SEOM): Jaime Feliu, Javier Sastre, Josep Tabernero." ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "Systematic search in MELDLINE repository using the following search terms: (“carcinoma, hepatocellular”[MeSH Terms] OR “carcinoma” [All Fields] AND “hepatocellular” [All Fields]) AND (“surgery” [Subheading] OR “surgery” [All Fields] OR (“surgical” [All Fields] AND “procedures” [All Fields] AND “operative” [All Fields]) OR resection[All Fields]) (“carcinoma, hepatocellular” [MeSH Terms] OR “carcinoma” [All Fields] AND “hepatocellular” [All Fields]) AND ablation[All Fields] (“carcinoma, hepatocellular” [MeSH Terms] OR “carcinoma” [All Fields] AND “hepatocellular” [All Fields]) AND (“liver transplantation” [MeSH Terms] OR (“liver” [All Fields] AND “transplantation” [All Fields]) OR “liver transplantation” [All Fields]) (“carcinoma, hepatocellular” [MeSH Terms] OR “carcinoma” [All Fields] AND “hepatocellular” [All Fields]) AND transarterial[All Fields] AND (“drug therapy” [Subheading] OR (“drug” [All Fields] AND “therapy” [All Fields]) OR “drug therapy” [All Fields] OR “chemotherapy” [All Fields] OR “drug therapy” [MeSH Terms] OR (“drug” [All Fields] AND “therapy” [All Fields]) OR “chemotherapy” [All Fields]) (“carcinoma, hepatocellular” [MeSH Terms] OR “carcinoma” [All Fields] AND “hepatocellular” [All Fields]) AND systemic[All Fields] AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “therapeutics” [MeSH Terms] OR “therapeutics” [All Fields]) (“carcinoma, hepatocellular” [MeSH Terms] OR “carcinoma” [All Fields] AND “hepatocellular” [All Fields]) AND (“imaging” [All Fields]) AND “diagnosis” [MeSH Terms]) The following types of documents were included in the search: systematic reviews, clinical practice guidelines, observational studies, meta-analysis, cost-effectiveness analysis (Markov model) and randomized clinical trials: The search range included January 1995 to August 2015." "etiqueta" => "Annex 1" "titulo" => "Literature search criteria" "identificador" => "sec0090" ] ] ] ] "multimedia" => array:15 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Bruix and Sherman.<a class="elsevierStyleCrossRef" href="#bib1005">2</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1494 "Ancho" => 2322 "Tamanyo" => 183447 ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithm for the study of a liver nodule detected on abdominal ultrasound." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Bruix et al.<a class="elsevierStyleCrossRef" href="#bib1835">168</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2020 "Ancho" => 3204 "Tamanyo" => 314170 ] ] "descripcion" => array:1 [ "en" => "Barcelona-Clinic Liver-Cancer (BCLC) Staging System. BSC:best supportive care; HCC: hepatocellular carcinoma; PS: performance status. *The Child-Pugh classification does not identify all patients with severe hepatic dysfunction requiring to be considered for liver transplantation. ** Patients with end-stage cirrhosis due to severe hepatic impairment (Child-Pugh C or earlier stages with episodes predicting poor prognosis, high MELD score) should be considered for liver transplantation. In these patients, the presence of HCC can be a contraindication for liver transplantation if it exceeds the inclusion criteria." ] ] 2 => array:8 [ "identificador" => "tbl0050" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Strength of evidence according to study design \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Level 1: Randomized clinical trials or meta-analysis of randomized trials \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(i) Double blind \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(ii) Non-blind treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Level 2: Non-randomized clinical trials \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Level 3: Case Series<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(i) Population, consecutive series \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(ii) Consecutive cases (non-population) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(iii) Non-consecutive cases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Strength of evidence according to the study objectives \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">A. Overall mortality (or survival according to a defined time point) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">B. Specific mortality of the disease (or disease-specific mortality according to a defined time point) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">C. Quality of life assessment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">D. Indirect surrogates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(i) Episode-free survival \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(ii) Disease-free survival \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(iii) Progression-free survival \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(iv) Tumour response \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211125.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "It includes prospective studies (cohort studies) and retrospective studies (case-control studies, case series)." ] ] ] "descripcion" => array:1 [ "en" => "Levels of evidence according to the study design." ] ] 3 => array:8 [ "identificador" => "tbl0055" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Notes \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Symbol \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Degree of evidence</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">High quality of evidence \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">New studies are unlikely to change our confidence on effect estimation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Moderate quality of evidence \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">New studies are likely to have a significant impact on effect estimation and may change our estimation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">B \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Low or very low quality of evidence \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">New studies will have an important impact on effect estimation and is likely to change our estimation. Any effect estimation is uncertain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Grade of recommendation</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Strong \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Factors that influence the strength of the recommendation include quality of the evidence, presumed importance of patient outcomes and cost \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Variability in preferences and values, or greater insecurity; more likely to make a weak recommendation The recommendation is made with less security: higher cost or resource consumption \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211126.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Level of evidence and level of recommendation (adapted from the GRADE system)." ] ] 4 => array:8 [ "identificador" => "tbl0060" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "HCC: hepatocellular carcinoma.Classification of scientific evidence adapted from NCI (<a class="elsevierStyleInterRef" id="intr0005" href="http://www.cancer.gov/">www.cancer.gov</a>) (<a class="elsevierStyleCrossRef" href="#tbl0050">Table 1</a>a)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Benefit \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Level of evidence \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Surgical treatments</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Surgical resection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increases survival \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3iiA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Adjuvant therapies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Controversial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1A-D \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Adjuvant Sorafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No DFS increase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1iD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liver transplantation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increases survival \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3iiA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neoadjuvant therapies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Therapeutic response \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3Diii \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Locoregional treatments</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Percutaneous treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increases survival \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3iiA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Radiofrequency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Better local control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1iiD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chemoembolization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increases survival \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1iiA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lipiodolization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Therapeutic response \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3iiDiii \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Internal radiation (131I,90Y0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Therapeutic response \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3iiDiii \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Systemic treatments</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sorafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increases survival \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1iA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hormonal compounds \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No survival increase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1iA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tamoxifen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antiandrogens \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Seocalcitiol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Systemic chemotherapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No survival increase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1iiA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Immunotherapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No survival increase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1iiA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Other systemic agents \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No survival increase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1iA \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211130.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Scientific evidence of HCC treatments according to the quality of the study design." ] ] 5 => array:8 [ "identificador" => "tbl0065" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "HCC: hepatocellular carcinoma; ns: not significant; TTP: time to progression (time to radiographic progression)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author, year \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Randomization \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No. \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TTP (months) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p value \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Survival (months) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p value \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top">First-line</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Sorafenib</td><td class="td" title="table-entry " align="left" valign="top">Llovet et al., 2008<a class="elsevierStyleCrossRef" href="#bib1890">179</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Sorafenib vs placebo</td><td class="td" title="table-entry " align="left" valign="top">299/303 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.5 vs 2.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.7 vs 7.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cheng et al., 2009<a class="elsevierStyleCrossRef" href="#bib1895">180</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">150/76 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.8 vs 1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.5 vs 4.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sorafenib+erlotinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Zhu et al., 2012<a class="elsevierStyleCrossRef" href="#bib2820">365</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sorafenib+erlotinib vs sorafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">362/358 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.2 vs 4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.5 vs 8.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sunitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cheng et al., 2013<a class="elsevierStyleCrossRef" href="#bib2810">363</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sunitinib vs sorafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">530/544 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.6 vs 3.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.9 vs 10.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Linifanib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cainap et al., 2012<a class="elsevierStyleCrossRef" href="#bib2825">366</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Linifanib vs sorafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">514/521 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.4 vs 4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.1 vs 9.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Brivanib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Johnson et al., 2013<a class="elsevierStyleCrossRef" href="#bib2815">364</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Brivanib vs sorafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">577/578 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.2 vs 4.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.5 vs 9.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FOLFOX-4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Qin et al., 2013<a class="elsevierStyleCrossRef" href="#bib2695">340</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FOLFOX-4 vs doxorubicin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">184/187 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.9 vs 1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.4 vs 4.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="8" align="left" valign="top">Second-line</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Everolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Zhu et al., 2014<a class="elsevierStyleCrossRef" href="#bib2890">379</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Everolimus vs placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">362/184 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.9 vs 2.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.6 vs 7.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Brivanib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Llovet et al., 2013<a class="elsevierStyleCrossRef" href="#bib2885">378</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Brivanib vs placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">263/132 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.2 vs 2.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.4 vs 8.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ramucirumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Zhu et al., 2015<a class="elsevierStyleCrossRef" href="#bib2895">380</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ramucirumab vs placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">283/282 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.5 vs 2.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.2 vs 7.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211132.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Molecular therapies evaluated in HCC." ] ] 6 => array:5 [ "identificador" => "tbl0005" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommendations: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1. Universal HBV vaccination reduces the incidence of HCC (evidence 2D, recommendation 1A). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2. In patients with chronic hepatitis, antiviral treatments are recommended as they have proven to be able to prevent progression to cirrhosis and therefore prevent the development of HCC (evidence 1A, recommendation 1A). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3. Once the oncogenic liver damage is established (cirrhosis, or even without reaching cirrhosis in patients with HBV infection), removal of the etiological agent reduces the risk of HCC, but it does not eliminate it (evidence 1D, recommendation 2B). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211129.png" ] ] ] ] ] 7 => array:5 [ "identificador" => "tbl0010" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommendations: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4. The patients with liver cirrhosis should be considered for participation in screening programmes (evidence 1B, recommendation 1A/B). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5. The most appropriate screening technique is abdominal ultrasound performed by expert staff (evidence 2B, recommendation 1B). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6. AFP use is not recommended as a screening technique (evidence 3D, recommendation 2B). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">7. Abdominal ultrasound screening should be performed every 6 months. The screening interval need not be shortened in patients at increased risk of HCC (evidence 2B, recommendation 2B). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211127.png" ] ] ] ] ] 8 => array:5 [ "identificador" => "tbl0015" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommendations: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">8. Nodules<1cm detected by ultrasound screening should be monitored by ultrasound every 3–6 months. If no growth is detected after two years, the patient should return to routine screening every 6 months (evidence 3D, recommendation 2B). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">9. Nodules>1cm detected by ultrasound in cirrhotic patients may be diagnosed with HCC without being histologically confirmed if they present with a contrast enhancement in the arterial phase followed by washout in venous phases in an imaging technique (Dynamic CT and MRI) (evidence 2D, recommendation 1A). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">10. If the vascular pattern is not HCC-specific a diagnostic nodule puncture should be recommended (evidence 2D, recommendation 1A). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">11. If the pathological analysis is negative, the diagnosis of HCC cannot be ruled out. Performing a new diagnostic puncture or close monitoring of the lesion should be assessed (evidence 2D, recommendation 1A). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">12. In the case of patients without established cirrhosis, the application of these imaging criteria is not valid and puncture for diagnosis would be necessary (evidence 2D, recommendation 2A). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">13. The determination of AFP is not useful for the diagnosis of HCC (evidence 2D, recommendation 2A). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211134.png" ] ] ] ] ] 9 => array:5 [ "identificador" => "tbl0020" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommendation: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">14. Tumour stage, liver function and the presence of symptoms must be considered in order to assess HCC prognosis. The BCLC system takes into account these parameters and is the only system that relates the prognostic prediction with the recommended therapeutic option (evidence 2A; recommendation 1B). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211135.png" ] ] ] ] ] 10 => array:5 [ "identificador" => "tbl0025" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommendations: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">15. Surgical resection is recommended in patients with single HCC on non-cirrhotic livers or cirrhotic patients with preserved liver function, normal bilirubin and portal pressure gradient below 10mmHg. If these criteria are exceeded, survival is significantly lower (evidence 2A, recommendation 1B). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">16. At present there is no adjuvant treatment proven effective in preventing recurrence (evidence 1D, recommendation 2C). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211128.png" ] ] ] ] ] 11 => array:5 [ "identificador" => "tbl0030" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommendations: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">17. Liver transplantation is an effective option for patients presenting with HCC that meets the Milan criteria: single tumour≤5cm or up to 3nodules<3cm (evidence 2A, recommendation 1A). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">18. The living donor liver transplantation is a valid option if the waiting time is long enough to consider that there may be risk of exclusion due to tumour progression (evidence 2A, recommendation 2B). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">19.- No recommendation can be made regarding the expansion of the inclusion criteria beyond the conventional Milan criteria (evidence 2B, recomendación2B). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">20. The preoperative locoregional treatment may be considered when the expected waiting time is greater than 6 months (evidence 2D, recommendation 2B). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211123.png" ] ] ] ] ] 12 => array:5 [ "identificador" => "tbl0035" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommendations: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">21. Tumour ablation is an effective treatment for patients with early HCC who are not candidates for surgical resection or as a treatment during the waiting time for liver transplantation (evidence 2A, recommendation 1B). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">22. The ethanol injection and radiofrequency possess similar efficacy in tumours <2cm. Radiofrequency has more ablative capacity and its effectiveness is clearly superior to the ethanol injection in tumours >2cm (evidence 1iD, recommendation 1A). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">23. In tumours smaller than 2cm percutaneous ablation presents a therapeutic efficacy a similar to surgical resection (Evidence 1iA, recommendation 2B). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211124.png" ] ] ] ] ] 13 => array:5 [ "identificador" => "tbl0040" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommendations: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">24. TACE is the treatment of choice in patients without cancer associated symptoms, with preserved liver function, which have a multinodular HCC without vascular or extrahepatic invasion (evidence 1iiA, recommendation 1A). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">25. Other treatments such as intratumoral locoregional radiotherapy with Yttrium-90 have shown efficacy in preliminary studies and its assessment is recommended in the context of clinical trials (evidence 2A, recommendation 2B). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211131.png" ] ] ] ] ] 14 => array:5 [ "identificador" => "tbl0045" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => false "mostrarDisplay" => true "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommendations: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">26. Sorafenib is the treatment of choice in patients with advanced HCC (evidence 1iA, recommendation 1A). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">27. Chemotherapy has been shown ineffective in HCC and its use is not recommended (evidence 1-2A, recommendation 1A/B). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1211133.png" ] ] ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:386 [ 0 => array:3 [ "identificador" => "bib1000" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ …2] ] ] 1 => array:3 [ "identificador" => "bib1005" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ …2] ] ] 2 => array:3 [ "identificador" => "bib1010" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ …2] ] ] 3 => array:3 [ "identificador" => "bib1015" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:1 [ …1] ] ] 4 => array:3 [ "identificador" => "bib1020" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ …2] ] ] 5 => array:3 [ "identificador" => "bib1025" 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"referencia" => array:1 [ …1] ] 77 => array:3 [ "identificador" => "bib1385" "etiqueta" => "78" "referencia" => array:1 [ …1] ] 78 => array:3 [ "identificador" => "bib1390" "etiqueta" => "79" "referencia" => array:1 [ …1] ] 79 => array:3 [ "identificador" => "bib1395" "etiqueta" => "80" "referencia" => array:1 [ …1] ] 80 => array:3 [ "identificador" => "bib1400" "etiqueta" => "81" "referencia" => array:1 [ …1] ] 81 => array:3 [ "identificador" => "bib1405" "etiqueta" => "82" "referencia" => array:1 [ …1] ] 82 => array:3 [ "identificador" => "bib1410" "etiqueta" => "83" "referencia" => array:1 [ …1] ] 83 => array:3 [ "identificador" => "bib1415" "etiqueta" => "84" "referencia" => array:1 [ …1] ] 84 => array:3 [ "identificador" => "bib1420" "etiqueta" => "85" "referencia" => array:1 [ …1] ] 85 => array:3 [ "identificador" => "bib1425" "etiqueta" => "86" "referencia" => array:1 [ …1] ] 86 => array:3 [ "identificador" => "bib1430" "etiqueta" => "87" "referencia" => array:1 [ …1] ] 87 => 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Consensus statement

Diagnosis and treatment of hepatocellular carcinoma. Update consensus document from the AEEH, SEOM, SERAM, SERVEI and SETH

Diagnóstico y tratamiento del carcinoma hepatocelular. Actualización del documento de consenso de la AEEH, SEOM, SERAM, SERVEI y SETH

Alejandro Fornera,b, María Reiga,b, María Varelac, Marta Burreld, Jaime Feliue, Javier Briceñof, Javier Sastreg, Luis Martí-Bonmatih, Josep María Lloveta,b,i, José Ignacio Bilbaoj, Bruno Sangrob,k, Fernando Pardol, Carmen Ayusod, Concepció Brud, Josep Tabernerom, Jordi Bruixa,b,

Corresponding author

jbruix@clinic.ub.es

Corresponding author.

a Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, Spain

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

c Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, Spain

d Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, Spain

e Servicio de Oncología Médica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Sociedad Española de Oncología Médica, Madrid, Spain

f Unidad de Trasplante Hepático, Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, Spain

g Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain

h Departamento de Radiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain

i Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, United States

j Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, Spain

k Unidad de Hepatología, Departamento de Medicina Interna, Clínica Universidad de Navarra, Pamplona, Spain

l Servicio de Cirugi¿a Hepatobliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, Spain

m Servicio de Oncología Médica, Hospital Universitario Vall d’Hebrón, Barcelona, Universidad Autónoma de Barcelona, Barcelona, Spain

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May 2008&#41; and simultaneously proposed the development of a consensus document was prepared by an expert panel&#46; In order to achieve maximum acceptance and validity&#44; the Spanish Society of Liver Transplantation &#40;SETH&#41;&#44; the Spanish Society of Medical Radiology &#40;SERAM&#41;&#44; the Spanish Society of Vascular and Interventional Radiology &#40;SERVEI&#41; and the Spanish Society of Medical Oncology &#40;SEOM&#41; were invited to participate in the preparation of this document&#46; Thus&#44; this proposal is integrated into all fields of knowledge involved in the diagnosis and treatment of this neoplasm&#46; In this sense&#44; one of the main conclusions of the expert panel was the need for the diagnosis and treatment of these patients to be carried out in multidisciplinary groups based in reference centres involving all specialties involved&#58; hepatology&#47;gastroenterology&#44; radiology &#40;including interventional radiology&#41;&#44; surgery&#44; anatomical pathology and medical oncology&#46; This need encompasses all developmental stages and should be considered a key requirement in the advancement of HCC diagnosis and treatment&#46; The occurring of this neoplasm within a diseased liver involves high complexity&#44; while the entire process of diagnosis&#44; staging and follow-up requires a close relationship between the various specialists and the application of the latest technology&#46; This document was published in 2009<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">1</span></a> and subsequently accepted as Clinical Practice Guideline of the National Health System &#40;<a id="intr0025" class="elsevierStyleInterRef" href="http://portal.guiasalud.es/web/guest/catalogo-gpclud">http&#58;&#47;&#47;portal&#46;guiasalud&#46;es&#47;web&#47;guest&#47;catalogo-gpclud</a>&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In recent years there have been important developments in the diagnosis&#44; staging and treatment of HCC&#46; 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Scientific evidence in the treatment of HCC has been evaluated in accordance with the recommendations of the <span class="elsevierStyleItalic">National Cancer Institute</span>&#40;NCI&#41; &#40;<a id="intr0030" class="elsevierStyleInterRef" href="http://www.cancer.gov/">www&#46;cancer&#46;gov</a>&#41; and the strength of the recommendation is based on the GRADE system &#40;<a class="elsevierStyleCrossRefs" href="#tbl0050">Tables 1 and 2</a>&#41;&#46; Ultimately&#44; these guidelines aim to show what is the current diagnostic and therapeutic procedure according to the latest scientific evidence&#44; and provide a basis from which to implement research projects to improve existing tools&#46; There has been no external funding for the preparation of this document&#46;</p><elsevierMultimedia ident="tbl0050"></elsevierMultimedia><elsevierMultimedia ident="tbl0055"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology and prevention</span><p id="par0015" class="elsevierStylePara elsevierViewall">HCC is an important medical problem&#46; Currently the sixth most common malignancy worldwide and the third leading cause of cancer deaths&#46;<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">4</span></a> Its global distribution is very heterogeneous and is closely related to the variable prevalence of the different risk factors associated with the development of this disease&#46; The highest incidence affects Southeast Asia and sub-Saharan Africa&#46; Most cases occurring in those areas are related to the hepatitis B virus &#40;HBV&#41;&#44; associated or not with aflatoxin&#44; and the incidence exceeds 15 cases&#47;100&#44;000 inhabitants&#47;year&#46;<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">4</span></a> Southern Europe&#44; including Spain&#44; has an intermediate incidence of 5&#8211;10 cases&#47;100&#44;000 inhabitants&#47;year&#44; and finally northern Europe and America have the lowest incidence&#44; approximately 5 cases&#47;100&#44;000 inhabitants&#47;year&#46;<a class="elsevierStyleCrossRefs" href="#bib1020"><span class="elsevierStyleSup">5&#44;6</span></a> Hepatitis C virus &#40;HCV&#41; infection<a class="elsevierStyleCrossRef" href="#bib1030"><span class="elsevierStyleSup">7</span></a> and alcoholism<a class="elsevierStyleCrossRef" href="#bib1035"><span class="elsevierStyleSup">8</span></a> play a predominant role in both areas&#46; However&#44; in recent years&#44; some epidemiological changes have been observed in various areas&#46;<a class="elsevierStyleCrossRefs" href="#bib1040"><span class="elsevierStyleSup">9&#44;10</span></a> Thus&#44; in countries where chronic HBV infection is the leading cause of HCC&#44; such as Taiwan&#44; the incidence has decreased due to the implementation of universal vaccination against HBV&#46;<a class="elsevierStyleCrossRefs" href="#bib1050"><span class="elsevierStyleSup">11&#44;12</span></a> By contrast&#44; the incidence of HCC has increased in countries such as the UK&#44;<a class="elsevierStyleCrossRef" href="#bib1060"><span class="elsevierStyleSup">13</span></a> Canada<a class="elsevierStyleCrossRef" href="#bib1065"><span class="elsevierStyleSup">14</span></a> and the US&#44;<a class="elsevierStyleCrossRef" href="#bib1070"><span class="elsevierStyleSup">15</span></a> probably reflecting the spread of chronic HCV infection&#46; Finally&#44; those countries where the HCV epidemic appeared early&#44; such as Japan&#44; the incidence has reached its plateau&#46;<a class="elsevierStyleCrossRef" href="#bib1075"><span class="elsevierStyleSup">16</span></a> In Spain&#44; HCV is at present the main risk factor associated with the development of HCC&#44; and although the data are heterogeneous&#44; since in many cases liver metastases are recorded as primary liver tumours&#44; there is evidence that the incidence of HCC has increased in recent years&#46;<a class="elsevierStyleCrossRefs" href="#bib1080"><span class="elsevierStyleSup">17&#44;18</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The risk of HCC varies in all geographic areas according to the degree of liver involvement&#44; being less than 1&#37; annually in patients with chronic hepatitis without significant fibrosis&#44; increasing to 3&#8211;7&#37; annually when the patient develops cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib1030"><span class="elsevierStyleSup">7</span></a> The major risk is acquired when liver cirrhosis is established and it is obvious that the intensity of liver inflammation &#40;related to viral load or genotype&#41; is responsible for the chronic process of necrosis&#47;regeneration which results in cirrhosis&#44; and therefore this is the parameter to be used to establish a clinically significant risk acquisition&#46; In this sense&#44; once liver cirrhosis is established&#44; the risk of developing HCC remains despite getting a persistent viral response after treatment&#44; possibly due to structural and molecular damage already found in the liver&#44; despite successful infection elimination&#46;<a class="elsevierStyleCrossRefs" href="#bib1090"><span class="elsevierStyleSup">19&#8211;21</span></a> Therefore&#44; any disease that can lead to liver cirrhosis &#40;hereditary hemochromatosis&#44; primary biliary cirrhosis&#44; autoimmune hepatitis&#41; should be considered a risk factor for HCC&#46; In recent years it has been shown that diabetes mellitus<a class="elsevierStyleCrossRefs" href="#bib1105"><span class="elsevierStyleSup">22&#8211;25</span></a> and other factors associated with a metabolic syndrome such as obesity or dyslipidemia<a class="elsevierStyleCrossRefs" href="#bib1125"><span class="elsevierStyleSup">26&#8211;30</span></a> are associated with increased mortality related to HCC&#44; similar to smoking&#46;<a class="elsevierStyleCrossRefs" href="#bib1150"><span class="elsevierStyleSup">31&#44;32</span></a> Coffee consumption reduces the risk&#44;<a class="elsevierStyleCrossRefs" href="#bib1160"><span class="elsevierStyleSup">33&#8211;35</span></a> while vitamin supplements&#44; soy or some alternative medicine elements do not have any preventive efficacy&#46; Preliminary studies show that prolonged use of metformin in diabetic patients<a class="elsevierStyleCrossRef" href="#bib1175"><span class="elsevierStyleSup">36</span></a> or propranolol in patients infected with HCV<a class="elsevierStyleCrossRef" href="#bib1180"><span class="elsevierStyleSup">37</span></a> could be associated with a decrease in the incidence of HCC&#46; Also&#44; a recent systematic review and meta-analyses have shown that the use of statins is associated with a reduction in the incidence of HCC&#46;<a class="elsevierStyleCrossRef" href="#bib1185"><span class="elsevierStyleSup">38</span></a> Prospective studies are needed to confirm these findings and to make a recommendation on the use of these agents as preventive treatment for HCC development&#46; Finally&#44; coinfection with the human immunodeficiency virus in patients with chronic HBV and&#47;or HCV seems to condition a faster progression of liver disease<a class="elsevierStyleCrossRefs" href="#bib1190"><span class="elsevierStyleSup">39&#44;40</span></a> and&#44; in recent years&#44; data indicating that the incidence of HCC may be increasing in coinfected patients has been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib1200"><span class="elsevierStyleSup">41&#8211;44</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Effective prevention of death by HCC can be achieved by avoiding the acquisition of risk factors&#46; The vaccine against HBV has proved its efficiency&#44;<a class="elsevierStyleCrossRef" href="#bib1055"><span class="elsevierStyleSup">12</span></a> while HCV infection&#44; aflatoxin intake&#44; alcohol or metabolic syndrome can be prevented by campaigns aimed at improving the sanitary conditions of citizens and promoting healthy lifestyles&#46; If the risk factor has already been acquired&#44; the only preventive option is to prevent progression to cirrhosis by administering antiviral treatment<a class="elsevierStyleCrossRefs" href="#bib1095"><span class="elsevierStyleSup">20&#44;45</span></a> and the abandonment of habits involving increased risk&#46; Several studies have shown that HBV replication increases the risk of HCC&#44;<a class="elsevierStyleCrossRefs" href="#bib1220"><span class="elsevierStyleSup">45&#8211;49</span></a> therefore&#44; the antiviral treatment should result in decreasing the progression of liver disease&#44; thus reducing the long term development of HCC&#46;<a class="elsevierStyleCrossRef" href="#bib1100"><span class="elsevierStyleSup">21</span></a> Regarding the use of interferon in HCV infection&#44; if the antiviral treatment fails to eradicate the viral infection or inhibit viral replication persistently&#44; it will not be able to effectively prevent progression to cirrhosis with the risk of HCC&#46;<a class="elsevierStyleCrossRefs" href="#bib1245"><span class="elsevierStyleSup">50&#44;51</span></a> Today&#44; the availability of an effective treatment against HCV will probably determine a substantial reduction in the incidence of HCC in our country in the coming years&#46; Therefore&#44; primary prevention of HCC is the most effective measure&#46;<elsevierMultimedia ident="tbl0005"></elsevierMultimedia></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Early diagnostic</span><p id="par0030" class="elsevierStylePara elsevierViewall">Screening in oncology is defined as the completion of a test repeatedly with the aim of reducing neoplasm-related mortality&#46;<a class="elsevierStyleCrossRef" href="#bib1255"><span class="elsevierStyleSup">52</span></a> In our setting&#44; more than 80&#37; of patients with HCC have underlying liver cirrhosis and the development of HCC is nowadays a leading cause of death in patients with cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib1260"><span class="elsevierStyleSup">53</span></a> Given that the only possibility of treatment with curative intent is diagnosing the disease in an asymptomatic phase<a class="elsevierStyleCrossRef" href="#bib1265"><span class="elsevierStyleSup">54</span></a> and since this option is only feasible if screening of the population at risk is carried out&#44; it is recommended to periodically scan patients with cirrhosis by abdominal ultrasound &#40;US&#41;&#46; Several cohort studies<a class="elsevierStyleCrossRefs" href="#bib1270"><span class="elsevierStyleSup">55&#8211;57</span></a> and cost-effectiveness analysis<a class="elsevierStyleCrossRefs" href="#bib1285"><span class="elsevierStyleSup">58&#8211;60</span></a> reinforce the usefulness of implementing US monitoring every 6 months&#46; However&#44; the benefit of screening techniques should be evaluated by prospective randomized studies since uncontrolled studies are affected by different biases&#46;<a class="elsevierStyleCrossRef" href="#bib1300"><span class="elsevierStyleSup">61</span></a> There is just one single prospective randomized study available which was conducted in China&#46; It included 18&#44;816 patients with chronic HBV infection&#44; being randomized to receive screening by ultrasound every 6 months by abdominal US and determination of alpha-fetoprotein &#40;AFP&#41; every 6 months versus no screening&#46; Despite the low adherence &#40;&#60;60&#37;&#41;&#44; the survival of the patients included in the screening programme was 66&#37; at one year&#44; 53&#37; at 3 years and 46&#37; at 5 years versus 31&#44; 7 and 0&#37;&#44; respectively&#44; in patients without screening&#46;<a class="elsevierStyleCrossRef" href="#bib1305"><span class="elsevierStyleSup">62</span></a> The efficacy of the programme was linked to the effectiveness of the US&#44; while determination of AFP was not efficient&#46;<a class="elsevierStyleCrossRef" href="#bib1310"><span class="elsevierStyleSup">63</span></a> Conducting a new validation clinical trial in developed countries is not viable&#59; the US is part of the routine assessment of patients with chronic liver disease and the perceived benefit of the screening by physicians and patients prevents recruitment&#46;<a class="elsevierStyleCrossRef" href="#bib1315"><span class="elsevierStyleSup">64</span></a> With all the available evidence&#44; there is general consensus to recommend the inclusion of cirrhotic patients&#44; who would be treated if they were diagnosed with HCC&#44; in periodic screening programmes&#46; In general&#44; cirrhotic patients in functional class Child-Pugh A and B should be considered for screening&#46; Patients in advanced class B and C or decompensation not identified by the Child-Pugh classification or by the <span class="elsevierStyleItalic">Model for End-Stage Liver Disease</span> &#40;MELD&#41; that determine poor prognosis &#40;recurrent hepatic encephalopathy&#44; spontaneous bacterial peritonitis&#44; malnutrition&#44; etc&#46;&#41; should be evaluated for liver transplantation&#46; The detection of HCC in those patients will not change the indication for transplant&#44; unless the waiting list inclusion criteria are exceeded and HCC constitutes a contraindication for transplantation&#46; Since the transplant in these patients should be considered due to liver failure with poor short term prognosis&#44; HCC detection and its possible treatment will have no clinically significant impact on survival&#46; Therefore&#44; in this subgroup of patients it is meaningless to perform early detection screening if the transplant is not feasible&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Scan interval</span><p id="par0035" class="elsevierStylePara elsevierViewall">Data concerning tumour growth rates and progression to a size detectable by imaging techniques are limited&#46; Older series show that the tumour volume doubling time is between 2 and 4 months<a class="elsevierStyleCrossRefs" href="#bib1320"><span class="elsevierStyleSup">65&#44;66</span></a> and these results provide the basis for making rational screening every 6 months&#46; Also&#44; this interval was used in the only randomized clinical trial that has demonstrated the benefit of screening for HCC in patients with chronic liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib1305"><span class="elsevierStyleSup">62</span></a> In Japan an interval of 3&#8211;4 months is recommended<a class="elsevierStyleCrossRef" href="#bib1330"><span class="elsevierStyleSup">67</span></a> and some authors maintain that high-risk patients should be examined more frequently&#46; However&#44; there are no data available which gives evidence that a higher risk is associated with an increased tumour growth rate&#46; A recent study shows that an interval of 12 months between scans is associated with decreased survival and reduced detection ability than the 6-month interval&#44;<a class="elsevierStyleCrossRef" href="#bib1335"><span class="elsevierStyleSup">68</span></a> and a randomized clinical trial conducted in France on 1200 cirrhotic patients concluded that screening with ultrasound every 3 months does not improve the diagnosis or treatment of HCC compared to performing it every 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib1340"><span class="elsevierStyleSup">69</span></a> Finally&#44; cost-effectiveness studies show that the interval of 6 months is more cost-effective than other alternatives&#46;<a class="elsevierStyleCrossRef" href="#bib1345"><span class="elsevierStyleSup">70</span></a> Therefore&#44; based on current scientific evidence&#44; the 6-month interval should be considered the recommended one&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Screening tools</span><p id="par0040" class="elsevierStylePara elsevierViewall">The HCC screening techniques can be divided into radiological and serological&#46; The recommended radiological test is abdominal ultrasound&#46; It is a non-invasive technique&#44; accepted by the population&#44; with a sensitivity of 60-80&#37; and a specificity of over 90&#37; for early detection of HCC&#46;<a class="elsevierStyleCrossRef" href="#bib1350"><span class="elsevierStyleSup">71</span></a> In addition&#44; it has a well-defined diagnostic strategy following the detection of a suspected HCC nodule&#46; Therefore&#44; abdominal ultrasonography&#44; performed by skilled personnel&#44; is currently the most suitable screening technique for early detection of HCC&#46; In actual clinical practice a significant number of patients are not diagnosed in early stages due to the poor implementation of screening programmes or lack of lesion detection&#46;<a class="elsevierStyleCrossRefs" href="#bib1355"><span class="elsevierStyleSup">72&#8211;74</span></a> In order to ensure the knowledge and experience to perform ultrasound based screening it would be important to consider establishing training programmes that could qualify professionals to carry out this activity&#46; Performing computed tomography &#40;CT&#41; as a screening technique should be discouraged by the risk associated with irradiation<a class="elsevierStyleCrossRef" href="#bib1370"><span class="elsevierStyleSup">75</span></a> and for reasons of cost-effectiveness and reduced availability&#46; This aspect also affects magnetic resonance imaging &#40;MRI&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Regarding the serological tests&#44; currently there are many different tumour markers available&#46; AFP&#44; which until now was the only tool available&#44; is the most widely evaluated&#46; However&#44; the AFP has shown poor performance because its values in many cases are normal in initial tumors<a class="elsevierStyleCrossRef" href="#bib1375"><span class="elsevierStyleSup">76</span></a> and it is well known that patients with liver cirrhosis may have transient elevations of AFP in the absence of HCC&#46;<a class="elsevierStyleCrossRefs" href="#bib1380"><span class="elsevierStyleSup">77&#44;78</span></a> Different retrospective analyses evaluating the diagnostic yield using ROC curves showed that using different cut-offs&#44; between 10 and 20<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#44; considered optimal for screening&#44; sensitivity is 60&#37; and specificity of 80&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib1390"><span class="elsevierStyleSup">79&#8211;81</span></a> When considering prospective studies which specifically evaluated the diagnostic yield of screening tests&#44; the AFP with the same cut-off point shows a sensitivity lower than 25&#37; and a specificity of 79&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib1375"><span class="elsevierStyleSup">76</span></a> A retrospective study has shown that a progressive increase of AFP would be more useful&#44;<a class="elsevierStyleCrossRef" href="#bib1405"><span class="elsevierStyleSup">82</span></a> but it must be validated prospectively&#46; In addition&#44; there is no study establishing that the increase of AFP should lead to HCC suspicion if the US is negative&#46; In this regard&#44; studies on explants show that HCC may not exist even when the AFP exceeds 500<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46;<a class="elsevierStyleCrossRef" href="#bib1410"><span class="elsevierStyleSup">83</span></a> Finally&#44; there is a correlation between levels of AFP and tumour stage&#44; with the AFP simply being an advanced disease marker&#46; Therefore&#44; the AFP is not a tool for effective screening and early detection and its use should be discouraged&#46;<a class="elsevierStyleCrossRefs" href="#bib1415"><span class="elsevierStyleSup">84&#44;85</span></a> Other markers have been proposed&#44; such as the lectin-bound AFP fraction&#44;<a class="elsevierStyleCrossRef" href="#bib1395"><span class="elsevierStyleSup">80</span></a><span class="elsevierStyleSup">&#46;</span><a class="elsevierStyleCrossRef" href="#bib1425"><span class="elsevierStyleSup">86</span></a> Des-gamma-carboxy prothrombin&#44;<a class="elsevierStyleCrossRef" href="#bib1395"><span class="elsevierStyleSup">80</span></a><span class="elsevierStyleItalic">Golgi protein-73</span>&#44;<a class="elsevierStyleCrossRef" href="#bib1430"><span class="elsevierStyleSup">87</span></a> Glypican-3<a class="elsevierStyleCrossRef" href="#bib1435"><span class="elsevierStyleSup">88</span></a> or Dickkopf-1&#44;<a class="elsevierStyleCrossRef" href="#bib1440"><span class="elsevierStyleSup">89</span></a> but they exhibit the same defects as the AFP and generally cannot compete with the reliability of the US&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Candidates for hepatocellular carcinoma screening</span><p id="par0050" class="elsevierStylePara elsevierViewall">Since the main risk factor for HCC is the presence of cirrhosis&#44; all patients with cirrhosis irrespective of aetiology should be considered candidates for screening&#46; In patients with chronic liver disease due to HCV with established cirrhosis&#44; obtaining persistent viral response after treatment does not eliminate the risk of HCC&#46;<a class="elsevierStyleCrossRef" href="#bib1095"><span class="elsevierStyleSup">20</span></a> Therefore&#44; screening for HCC should also be recommended in these patients&#46; In patients with chronic HBV infection&#44; screening is considered cost-effective if the risk of HCC is higher than 0&#46;2&#37;&#47;year&#46; In this scenario&#44; cost-benefit models are required to assess the screening indication&#46; The incidence of HCC in Asian or African adults with active HBV infection&#44; with or without a family history of HCC&#44; clearly exceeds this cut-off point&#44;<a class="elsevierStyleCrossRef" href="#bib1225"><span class="elsevierStyleSup">46</span></a> while the incidence of HCC ranges from 0&#46;1 to 0&#46;4&#37;&#47;year in Western patients&#46;<a class="elsevierStyleCrossRef" href="#bib1445"><span class="elsevierStyleSup">90</span></a> Viral load is also associated with an increased risk of HCC&#59; in Asian patients&#44; levels of HBV DNA higher than 10&#44;000<span class="elsevierStyleHsp" style=""></span>copies&#47;ml are associated with a HCC risk higher than 0&#46;2&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib1225"><span class="elsevierStyleSup">46</span></a> Regarding HCV&#44; recent studies conducted in the USA and Japan show that there is risk of HCC in patients with bridging fibrosis in the absence of cirrhosis&#46;<a class="elsevierStyleCrossRefs" href="#bib1450"><span class="elsevierStyleSup">91&#44;92</span></a> Since the transition from advanced fibrosis to cirrhosis cannot be defined properly&#44; there is consensus regarding the implementation of HCC screening to this population&#46; Hepatic elastography seems to be a useful tool to stratify patients with different risk of HCC<a class="elsevierStyleCrossRefs" href="#bib1460"><span class="elsevierStyleSup">93&#8211;97</span></a>&#59; this tool allows&#44; non-invasively&#44; to determine the presence of advanced fibrosis&#44;<a class="elsevierStyleCrossRef" href="#bib1485"><span class="elsevierStyleSup">98</span></a> with the highest values being associated with the presence of portal hypertension&#44;<a class="elsevierStyleCrossRefs" href="#bib1490"><span class="elsevierStyleSup">99&#44;100</span></a> and therefore identify those patients at high risk of developing HCC in whom screening would be cost-effective&#46; However&#44; while high values indicate elastography cirrhosis and portal hypertension&#44; the distinction between advanced fibrosis and liver cirrhosis without portal hypertension should be validated&#46; The possibility of stratifying risk by genetic studies has recently been suggested&#44;<a class="elsevierStyleCrossRefs" href="#bib1500"><span class="elsevierStyleSup">101&#44;102</span></a> and that this information could be associated with the clinical parameters discussed above&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Patients with alcoholic liver cirrhosis do not present a risk of developing homogeneous HCC&#46; Northern European studies report a reduced incidence&#44; but data from the rest of the world&#44; including France<a class="elsevierStyleCrossRef" href="#bib1500"><span class="elsevierStyleSup">101</span></a> and Spain&#44; suggest otherwise&#46;<a class="elsevierStyleCrossRef" href="#bib1510"><span class="elsevierStyleSup">103</span></a> In the case of primary biliary cirrhosis&#44; an incidence of 3&#46;4 cases&#47;1000 patients&#47;year has been established and the main predictors of HCC development are the absence of biochemical response after medical treatment<a class="elsevierStyleCrossRef" href="#bib1515"><span class="elsevierStyleSup">104</span></a> and the presence of stage <span class="elsevierStyleSmallCaps">iv</span> in the illness&#46;<a class="elsevierStyleCrossRef" href="#bib1520"><span class="elsevierStyleSup">105</span></a> Finally&#44; there is little information regarding the risk of HCC in patients with NASH&#44; particularly those who have not yet developed cirrhosis&#44; so it is not possible to make any recommendations for screening in this population&#46; Although there are no values in the percentage of patients with NASH who develop HCC&#44; probably those who have already developed cirrhosis should be considered for screening&#46; The same concept applies to hereditary hemochromatosis and other entities that progress into cirrhosis&#46;<elsevierMultimedia ident="tbl0010"></elsevierMultimedia></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Diagnosis of hepatocellular carcinoma</span><p id="par0060" class="elsevierStylePara elsevierViewall">In a patient with liver cirrhosis&#44; the probability that a node detected by US is actually HCC is very high&#44; especially if their diameter exceeds 10<span class="elsevierStyleHsp" style=""></span>mm&#46;<a class="elsevierStyleCrossRef" href="#bib1375"><span class="elsevierStyleSup">76</span></a> Therefore&#44; if the detected nodule exceeds this limit&#44; additional studies to reach a conclusive diagnosis is recommended&#46; HCC has a predominantly arterial vascularization&#44;<a class="elsevierStyleCrossRef" href="#bib1525"><span class="elsevierStyleSup">106</span></a> unlike liver parenchyma where vascularization is mixed&#58; arterial and portal&#46; This determines a specific vascular pattern characterized by intense contrast uptake in the arterial phase&#44; followed by a quick washout of contrast in venous or late portal phase&#46; This pattern has been shown to be specific for the diagnosis of HCC when it has been correlated with the histopathologic analysis of explants&#44; surgical resection specimens or percutaneous biopsies&#46;<a class="elsevierStyleCrossRefs" href="#bib1375"><span class="elsevierStyleSup">76&#44;107&#8211;113</span></a> These criteria have been refined since the first proposal for non-invasive diagnosis of HCC by imaging techniques proposed at the EASL consensus conference held in 2000 in Barcelona&#46;<a class="elsevierStyleCrossRef" href="#bib1565"><span class="elsevierStyleSup">114</span></a> Thus&#44; to register the dynamic pattern as specific of HCC&#44; hypervascularisation must be detected in the early arterial phase followed by early washout in the portal venous and&#47;or balance phase&#46; According to these new criteria&#44; it is possible to establish a non-invasive diagnosis of HCC if a nodule &#62;1<span class="elsevierStyleHsp" style=""></span>cm in a patient affected by chronic liver disease shows intense uptake of contrast in the arterial phase followed by early washout during the venous phase in a dynamic imaging technique &#40;MRI or CT with contrast&#41;&#46; The use of organ-specific contrast &#40;gadoxetic acid&#41; is pending specificity validation&#46; If the vascular pattern is not typical or the nodule shows no contrast enhancement&#44; the conclusive diagnosis of HCC should be based on pathology&#46; Finally&#44; in the case of nodules &#60;1<span class="elsevierStyleHsp" style=""></span>cm&#44; given the low probability of being malignant in nature<a class="elsevierStyleCrossRef" href="#bib1375"><span class="elsevierStyleSup">76</span></a> and the difficulty of proper characterization&#44; close ultrasound monitoring is recommended&#44; every 3&#8211;4 months&#44; in order to detect possible growth&#44; and then use the above criteria &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; These non-invasive detection criteria based on specific vascular pattern detection of HCC have been externally validated in Europe&#44;<a class="elsevierStyleCrossRefs" href="#bib1375"><span class="elsevierStyleSup">76&#44;110&#44;111</span></a> USA&#44;<a class="elsevierStyleCrossRef" href="#bib1555"><span class="elsevierStyleSup">112</span></a> and Asia&#44;<a class="elsevierStyleCrossRef" href="#bib1570"><span class="elsevierStyleSup">115</span></a> being only applicable in patients with chronic liver disease&#46; In the case of patients with no established cirrhosis and&#47;or absence of chronic liver disease due to HBV infection&#44; the application of these imaging criteria is not valid and histopathologic examination is necessary to obtain a conclusive diagnosis&#46; Detection of other imaging parameters such as the presence of intralesional fat&#44; isolated hypointensity in venous phases or presence of pseudocapsule does not significantly increase the diagnostic yield&#46;<a class="elsevierStyleCrossRef" href="#bib1575"><span class="elsevierStyleSup">116</span></a> The <span class="elsevierStyleItalic">American College of Radiology</span>&#40;<span class="elsevierStyleItalic">ACR</span>&#41; has recently proposed a system for standardizing carrying out&#44; data collection and interpretation of liver CT scans and MRI in patients at risk of developing HCC&#46; This system&#44; known as <span class="elsevierStyleItalic">Liver Imaging Reporting and Data System</span>&#40;LI-RADS&#41;&#44; was published <span class="elsevierStyleItalic">on-line</span> in 2011 and updated in 2014&#46;<a class="elsevierStyleCrossRef" href="#bib1580"><span class="elsevierStyleSup">117</span></a> LI-RADS categorizes the observations into 6 major categories&#58; LR-1 &#40;definitely benign&#41;&#44; LR-2 &#40;probably benign&#41;&#44; LR-3 &#40;intermediate probability for HCC&#41;&#44; LR-4 &#40;probably HCC&#41;&#44; LR-5 &#40;definitely HCC&#41; and <span class="elsevierStyleItalic">other malignancies</span> &#40;OM&#44; lesions with high probability of being malignant tumours other than HCC&#41;&#46; A recent prospective assessment of the LI-RADS system in a cohort of patients with single new onset nodules under 20<span class="elsevierStyleHsp" style=""></span>mm detected by ultrasound showed that 69&#37; of lesions categorized as LR-3 were HCC and that the criterion LR-4 was as effective as the LR-5 for the diagnosis of HCC&#44; so joining both categories would increase sensitivity without compromising specificity&#46;<a class="elsevierStyleCrossRef" href="#bib1585"><span class="elsevierStyleSup">118</span></a> According to these results&#44; it has been proposed to consider as an LR-5 any nodule detected by ultrasound showing the specific vascular pattern of HCC&#46;<a class="elsevierStyleCrossRef" href="#bib1590"><span class="elsevierStyleSup">119</span></a> The diffusion sequences have shown potential usefulness for the diagnosis of HCC&#44; but to date there are no prospective studies that show a clear increase in diagnostic yield&#46;<a class="elsevierStyleCrossRefs" href="#bib1595"><span class="elsevierStyleSup">120&#44;121</span></a> Finally&#44; the usefulness of organ-specific contrasts for the diagnosis of HCC has been investigated in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib1605"><span class="elsevierStyleSup">122</span></a> Although promising results have been described<a class="elsevierStyleCrossRefs" href="#bib1610"><span class="elsevierStyleSup">123&#44;124</span></a> and some scientific societies have introduced their use regarding non-invasive diagnosis of HCC&#44;<a class="elsevierStyleCrossRef" href="#bib1330"><span class="elsevierStyleSup">67</span></a> to date there are no published prospective studies that have demonstrated the superiority of organ-specific contrasts&#46; Contrast-enhanced ultrasound is a widespread technique in the management of patients with HCC&#46; However&#44; its diagnostic usefulness has been questioned by its inability to differentiate HCC from intrahepatic cholangiocarcinoma&#44;<a class="elsevierStyleCrossRefs" href="#bib1620"><span class="elsevierStyleSup">125&#44;126</span></a> unlike MRI<a class="elsevierStyleCrossRef" href="#bib1630"><span class="elsevierStyleSup">127</span></a> and CT<a class="elsevierStyleCrossRef" href="#bib1635"><span class="elsevierStyleSup">128</span></a> that do allow their differentiation&#46; In addition&#44; regardless of the outcome of contrast-enhanced ultrasound&#44; the patient must undergo an MRI or CT scan to confirm the diagnosis and complete staging&#46;<a class="elsevierStyleCrossRef" href="#bib1640"><span class="elsevierStyleSup">129</span></a> For these reasons the contrast-enhanced ultrasound has not been kept as an imaging technique for diagnosis of HCC&#46;<a class="elsevierStyleCrossRef" href="#bib1645"><span class="elsevierStyleSup">130</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Despite the improvement of imaging techniques&#44; performing a liver nodule puncture for the diagnosis of HCC is still necessary in a significant number of cases&#46; However&#44; making a puncture in a liver nodule in a cirrhotic patient is not always possible&#46; In some cases&#44; the presence of ascites or coagulation disorders contraindicate this procedure&#44; and in other cases&#44; their location in the liver makes percutaneous access difficult or US fails to identify it despite its MRI detection&#46; In addition&#44; the diagnostic yield of a biopsy in these small nodules is not optimal&#44; it has a false negative rate of nearly 30&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib1375"><span class="elsevierStyleSup">76&#44;131</span></a> This may depend on a sampling error and the difficulty of making a differential diagnosis between very early dysplastic nodules and HCC using the small sample obtained through a percutaneous biopsy&#46;<a class="elsevierStyleCrossRef" href="#bib1525"><span class="elsevierStyleSup">106</span></a> Therefore&#44; a negative biopsy cannot exclude the diagnosis of HCC and the need for a new biopsy should be assessed&#46; Regarding the technique for obtaining histological analysis samples&#44; no studies have adequately compared the performance of fine needle puncture-aspiration with cutting needle puncture&#44; so a general recommendation cannot be made&#46; Cytology has a high diagnostic yield&#44; but if what is sought is the architectural arrangement&#44; in that case it may be better to use the cell block technique or &#8220;mini-biopsy&#8221;&#44; as this can provide valuable information&#46; The usefulness of a biopsy in a non-tumoral liver is controversial&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In recent years there has been a breakthrough in the understanding of the molecular pathways that determine the occurring of HCC&#44; which has allowed to evaluate molecular biology techniques that would potentially provide new diagnostic tools&#46; Different diagnostic signatures have been proposed based on gene expression<a class="elsevierStyleCrossRef" href="#bib1655"><span class="elsevierStyleSup">132</span></a> and also immunohistochemical staining that would reflect this different expression at protein level&#46;<a class="elsevierStyleCrossRefs" href="#bib1660"><span class="elsevierStyleSup">133&#8211;135</span></a> It is worth mentioning the panel made up of glypican <span class="elsevierStyleItalic">3&#44; heat-shock protein 70</span> and <span class="elsevierStyleItalic">glutamine synthetase</span>&#44; initially evaluated in tumours obtained after surgical resection or liver transplantation<a class="elsevierStyleCrossRef" href="#bib1660"><span class="elsevierStyleSup">133</span></a> and subsequently validated in samples obtained by percutaneous biopsy&#46;<a class="elsevierStyleCrossRefs" href="#bib1665"><span class="elsevierStyleSup">134&#44;136</span></a> The diagnosis can be confirmed when the stain is positive for 2 of these proteins&#44; but the immunohistochemical panel does not replace the expert assessment and should be reserved to confirm the suspected diagnosis of HCC&#44; particularly in those samples with little material or pathologists with little experience in assessing liver tumours&#46;<a class="elsevierStyleCrossRef" href="#bib1675"><span class="elsevierStyleSup">136</span></a> Finally&#44; some authors have warned of the risk of local spread <span class="elsevierStyleItalic">&#40;seeding&#41;</span> after puncturing these nodules&#46; However&#44; the incidence of this complication is very low&#44; less than 0&#46;1&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib1680"><span class="elsevierStyleSup">137&#44;138</span></a> and this risk should always be assessed against the possibility of applying invasive treatments on falsely diagnosed HCC lesions by inconclusive imaging tests&#46;<a class="elsevierStyleCrossRef" href="#bib1410"><span class="elsevierStyleSup">83</span></a> There is controversy about recommending a biopsy for diagnostic confirmation in order to obtain histological material to assess different molecular markers&#46; While the need for samples to advance the understanding of the molecular pathways associated with HCC is indisputable&#44; since radiological techniques can confirm the diagnosis of HCC in a significant number of patients&#44; obtaining biopsies in a systematic manner should be done in the context of a research project with the patient&#39;s informed consent and each centre&#39;s ethics committee approval&#46;<a class="elsevierStyleCrossRef" href="#bib1690"><span class="elsevierStyleSup">139</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Finally&#44; the use of AFP as a diagnostic tool has a very low yield&#46;<a class="elsevierStyleCrossRefs" href="#bib1375"><span class="elsevierStyleSup">76&#44;115&#44;140</span></a> Different malignancies such as cholangiocarcinoma or gastrointestinal origin metastases may have increased levels of AFP&#46;<a class="elsevierStyleCrossRefs" href="#bib1390"><span class="elsevierStyleSup">79&#44;115&#44;141&#44;142</span></a> Therefore&#44; despite finding high levels of AFP&#44; of any magnitude&#44; if the liver mass does not present a specific vascular pattern by imaging technique&#44; a confirmatory biopsy should be performed&#46;<elsevierMultimedia ident="tbl0015"></elsevierMultimedia></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Prognostic assessment</span><p id="par0080" class="elsevierStylePara elsevierViewall">Once the diagnosis is obtained&#44; a disease extension study and prognostic assessment are necessary&#46; This provides information for the patient and family about life expectancy&#44; enables to choose the most appropriate treatment and to assess its response&#46; The prognosis of solid tumours depends mainly on tumour stage&#46; However&#44; since&#44; in most cases&#44; HCC is associated with liver cirrhosis&#44; and the degree of liver function impairment determines treatment options and survival regardless of the presence of HCC&#44; it is essential to consider liver dysfunction severity and tumour extension jointly&#46; There are different ratings&#47;scores that assess the degree of liver dysfunction as the Child-Pugh classification<a class="elsevierStyleCrossRef" href="#bib1710"><span class="elsevierStyleSup">143</span></a> or the MELD system&#46;<a class="elsevierStyleCrossRef" href="#bib1715"><span class="elsevierStyleSup">144</span></a> Recently&#44; a multicentre study has proposed a new score that includes albumin and bilirubin values and provides a simple&#44; objective and highly discriminatory capacity to assess the degree of liver dysfunction in patients with HCC&#46;<a class="elsevierStyleCrossRef" href="#bib1720"><span class="elsevierStyleSup">145</span></a> Finally&#44; the presence of cancer-related symptoms adequately assessed by validated scales such as the <span class="elsevierStyleItalic">ECOG performance status classification</span><a class="elsevierStyleCrossRef" href="#bib1725"><span class="elsevierStyleSup">146</span></a> or Karnofsky index<a class="elsevierStyleCrossRef" href="#bib1730"><span class="elsevierStyleSup">147</span></a> have shown great prognostic value&#44; and&#44; it determines the applicability of the different treatments available&#44; similar to the degree of hepatic functional reserve&#46; Therefore&#44; those prognosis systems that take into account just a single dimension of the disease &#40;tumour size&#44; liver function or the presence of symptoms associated with cancer&#41; are inaccurate and are only useful for detecting terminal illness&#46; In the last decade there have been multiple staging systems that take into account factors associated with tumour extension and liver function&#46;<a class="elsevierStyleCrossRefs" href="#bib1735"><span class="elsevierStyleSup">148&#8211;162</span></a> Unfortunately&#44; most of them do not consider the presence of symptoms<a class="elsevierStyleCrossRefs" href="#bib1735"><span class="elsevierStyleSup">148&#44;155&#44;157&#44;159&#44;161&#44;163</span></a> or do not evaluate tumour extension precisely&#46;<a class="elsevierStyleCrossRef" href="#bib1780"><span class="elsevierStyleSup">157</span></a> The only system that links staging with treatment and also has been validated externally<a class="elsevierStyleCrossRefs" href="#bib1815"><span class="elsevierStyleSup">164&#8211;167</span></a> is the <span class="elsevierStyleItalic">Barcelona-Clinic-Liver-Cancer</span>&#40;BCLC&#41; system&#46; Since its original publication in 1999&#44;<a class="elsevierStyleCrossRef" href="#bib1745"><span class="elsevierStyleSup">150</span></a> the system has been refined to its latest version in 2016&#46;<a class="elsevierStyleCrossRef" href="#bib1835"><span class="elsevierStyleSup">168</span></a> Recognized for its predictive ability and its usefulness in the treatment decision process&#44; it is the system recommended by AASLD&#44;<a class="elsevierStyleCrossRef" href="#bib1005"><span class="elsevierStyleSup">2</span></a> EASL&#44;<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleItalic">World Gastroenterology Organisation</span><a class="elsevierStyleCrossRef" href="#bib1840"><span class="elsevierStyleSup">169</span></a> and <span class="elsevierStyleItalic">European Society of Medical Oncology</span>&#44;<a class="elsevierStyleCrossRef" href="#bib1845"><span class="elsevierStyleSup">170</span></a> as well as by different expert panels involved in the management of HCC&#46;<a class="elsevierStyleCrossRefs" href="#bib1850"><span class="elsevierStyleSup">171&#44;172</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The BCLC system includes variables associated with tumour stage&#44; liver function and presence of symptoms and the prognosis is established in accordance with 5 stages that are linked to the possible indication of treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The very early stage &#40;stage 0&#41; is a particularly good prognosis group including patients with compensated liver cirrhosis &#40;Child-Pugh A&#41;&#44; completely asymptomatic&#44; which present unique tumours &#60;2<span class="elsevierStyleHsp" style=""></span>cm without vascular invasion or spread&#46; This very early stage corresponds to the carcinoma <span class="elsevierStyleItalic">in situ</span><a class="elsevierStyleCrossRef" href="#bib1525"><span class="elsevierStyleSup">106</span></a> concept&#46; In these cases&#44; percutaneous ablation offers high cure rates&#44; similar survival rates to those obtained with surgical resection but with less cost and morbidity&#44; being considered the first therapeutic option&#44; particularly in patients without future liver transplantation options&#46; The early stage &#40;stage A&#41; includes asymptomatic patients with preserved liver function &#40;Child-Pugh A and B&#41; with solitary HCC or up to 3 nodules up to 3<span class="elsevierStyleHsp" style=""></span>cm in diameter&#46; These patients can be treated with curative intent by surgical resection&#44; percutaneous ablation and liver transplantation&#44; with an expected survival at 5 years of between 50 and 75&#37;&#46; The intermediate stage &#40;stage B&#41; consists of patients with multinodular tumours that exceed the criteria described before without vascular or extrahepatic invasion&#44; with preserved liver function and general condition&#46; The untreated expected survival in this group of patients is 49&#46;6&#37; &#40;95&#37; CI 32&#8211;75&#37;&#41; at one year<a class="elsevierStyleCrossRef" href="#bib1830"><span class="elsevierStyleSup">167</span></a> and the only treatment that has shown efficacy in terms of survival is <span class="elsevierStyleItalic">transarterial chemoembolization</span> &#40;TACE&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib1860"><span class="elsevierStyleSup">173&#8211;175</span></a> A stage B subclassification has recently been proposed in 4 subgroups according to tumour stage&#44; presence of symptoms and the degree of liver dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib1875"><span class="elsevierStyleSup">176</span></a> Unfortunately&#44; this subclassification includes patients with severe hepatic dysfunction who should be evaluated for liver transplantation and in whom the presence of a HCC is only a contraindication when the tumour extension exceeds the criteria regarding offering this option&#46; Further&#44; it suggests not to distinguish between PS 0 and PS 1 when studies by the same authors demonstrate the importance of having PS 1 in patients treated with chemoembolization&#46;<a class="elsevierStyleCrossRef" href="#bib1880"><span class="elsevierStyleSup">177</span></a> Finally&#44; it should be noted that&#44; according to the BCLC model&#44; single tumours without PS compromise should be considered BCLC A&#44; and many analyses and proposals to improve the BCLC model wrongly include them as BCLC B&#46; Given these considerations&#44; this subclassification has not demonstrated a prognostic discriminatory capacity in this group of patients&#46;<a class="elsevierStyleCrossRef" href="#bib1885"><span class="elsevierStyleSup">178</span></a> Patients with preserved liver function&#44; but having a HCC with vascular invasion and&#47;or extrahepatic or mild malaise are classified as advanced stage &#40;stage C&#41;&#46; The median survival in this group of patients is 4&#8211;8 months and the only treatment to date that has shown benefits in terms of survival is sorafenib&#44; with a median survival of about 11 months&#46;<a class="elsevierStyleCrossRefs" href="#bib1890"><span class="elsevierStyleSup">179&#44;180</span></a> Finally&#44; patients with severe malaise and&#47;or compromised liver function &#40;Child-Pugh C or Child-Pugh B cirrhosis with decompensation associated with poor prognosis such as refractory ascites&#44; chronic&#47;recurrent hepatic encephalopathy or spontaneous bacterial peritonitis&#41; who are not candidates for liver transplantation correspond to stage D or terminal&#46; They median survival is less than 3 months<a class="elsevierStyleCrossRef" href="#bib1830"><span class="elsevierStyleSup">167</span></a> and only symptomatic treatment should be indicated&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Recent advances in understanding the molecular pathways that determine the onset and progression of HCC have defined different patterns of gene expression with possible prognostic significance&#46;<a class="elsevierStyleCrossRefs" href="#bib1900"><span class="elsevierStyleSup">181&#8211;187</span></a> To date&#44; no molecular pattern has been correlated with a different prognosis or that it involves a specific decision so as to select the best treatment&#46; Therefore&#44; current research is aimed at trying to integrate these gene expression data to existing assessment systems&#44; enabling survival prediction and treatment indication in the molecular profile of the patient&#46; Finally&#44; recent research has shown that certain parameters which are identified during the course of the disease can determine its prognosis&#46; For example&#44; in patients with intermediate&#47;advanced stage HCC treated with sorafenib&#44; the type of radiological progression determines&#44; in a statistically independent manner&#44; postprogression survival&#44;<a class="elsevierStyleCrossRefs" href="#bib1935"><span class="elsevierStyleSup">188&#44;189</span></a> with the development of a new extrahepatic foci or tumour vascular invasion being the radiographic progression associated with worse survival&#46;<elsevierMultimedia ident="tbl0020"></elsevierMultimedia></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Treatment of hepatocellular carcinoma</span><p id="par0095" class="elsevierStylePara elsevierViewall">In the past&#44; HCC was diagnosed during advanced stages&#44; when the patient had experienced symptoms or worsening liver function&#46; At this stage it was not possible to administer any treatment and&#44; in most cases&#44; the diagnosis of HCC was considered a terminal episode in the context of liver cirrhosis&#46; In recent years&#44; thanks to the implementation of screening programmes&#44; HCC is increasingly being diagnosed at earlier stages&#44; when effective treatments can still be applied&#46; For best results&#44; a correct assessment of tumour extension and liver function are essential&#44; so that treatment can later be applied in adequately qualified centres&#46; Therefore&#44; if HCC diagnosis is confirmed or suspected&#44; referral to reference centres with multidisciplinary teams of hepatologists&#44; radiologists&#44; surgeons&#44; pathologists and oncologists with experience in the management of this disease is recommended&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">A treatment efficacy assessment should be based on randomized clinical trials and meta-analysis of individual data&#46; Other sources of evidence&#44; such as randomized clinical trials or observational studies are less reliable&#46; In HCC&#44; unlike other prevalent cancers such as lung&#44; breast&#44; stomach and colon-rectum&#44; only a minority of therapeutic options have been properly evaluated&#46; <a class="elsevierStyleCrossRef" href="#tbl0060">Table 3</a> summarizes the level of scientific evidence currently available regarding evaluated HCC therapeutic options&#46;<a class="elsevierStyleCrossRef" href="#bib1265"><span class="elsevierStyleSup">54</span></a></p><elsevierMultimedia ident="tbl0060"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Treatments with curative intent can be applied during the early stages of the disease&#46; These are surgical resection&#44; liver transplantation and ablation&#46; During the intermediate stage&#44; the only treatment that has shown increased survival is TACE&#44; when applied according to the recommended criteria&#46; During advance HCC&#44; the only treatment that has shown to be of benefit to date in terms of survival is sorafenib&#46; Finally&#44; palliative measures should be recommended during the terminal stage&#46; Obviously&#44; if a patient at any given stage cannot be a candidate for the recommended therapeutic option&#44; you should consider the indication of lower priority treatment corresponding to a more advanced stage &#40;concept known as <span class="elsevierStyleItalic">treatment stage migration</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1265"><span class="elsevierStyleSup">54</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Surgical resection</span><p id="par0110" class="elsevierStylePara elsevierViewall">Surgical resection is the first choice in those single tumours that appear on non-cirrhotic livers&#44; which allow extensive resections with a low risk of complications&#46;<a class="elsevierStyleCrossRefs" href="#bib1945"><span class="elsevierStyleSup">190&#8211;192</span></a> However&#44; in our area&#44; most HCC appear on chronic liver disease&#44; usually in cirrhotic phase&#46; In this context&#44; it is not possible to make extensive resections due to the risk of postoperative liver failure&#46; Therefore&#44; this treatment option is limited&#46; In patients with decompensated liver cirrhosis&#44; surgical resection is formally contraindicated and the surgical treatment to consider is liver transplantation provided there are no contraindications due to age or comorbidities&#46; In patients with compensated cirrhosis&#44; careful assessment of liver function is essential in order to predict the type of long-term survival being offered by resection and to compare it with what other options offer&#44; such as transplantation or ablation&#46; This approach allows to offer each patient the option associated with the best expected survival&#46;<a class="elsevierStyleCrossRef" href="#bib1960"><span class="elsevierStyleSup">193</span></a> The best candidates for surgical resection are patients with single tumours&#44; which have a normal bilirubin level and absence of clinically relevant portal hypertension &#40;CRPH&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib1965"><span class="elsevierStyleSup">194&#44;195</span></a> The most accurate way to evaluate the absence of CRPH is by direct measurement of the pressure gradient at the level of the hepatic vein&#44;<a class="elsevierStyleCrossRef" href="#bib1975"><span class="elsevierStyleSup">196</span></a> considering patients whose gradient is lower than 10<span class="elsevierStyleHsp" style=""></span>mmHg<span class="elsevierStyleSup">194</span> optimal for surgical resection&#46; The presence of oesophageal varices or ascites confirm the existence of CRPH&#46; However&#44; detection of splenomegaly and a platelet count below 100&#44;000&#47;mm<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">3</span></a> does not accurately identify the presence of CRPH&#46;<a class="elsevierStyleCrossRef" href="#bib1980"><span class="elsevierStyleSup">197</span></a> Liver stiffness determination by elastography has been evaluated in recent years as a tool for identifying CRPH and therefore predict survival and surgical liver dysfunction postresection&#46;<a class="elsevierStyleCrossRefs" href="#bib1495"><span class="elsevierStyleSup">100&#44;198</span></a> A recent study in Barcelona showed that elastography values above 21<span class="elsevierStyleHsp" style=""></span>kPa are highly suggestive of CRPH and values less than 13&#46;6<span class="elsevierStyleHsp" style=""></span>kPa allow to rule it out&#46;<a class="elsevierStyleCrossRef" href="#bib1495"><span class="elsevierStyleSup">100</span></a> Unfortunately&#44; there is no unequivocal cut-off value and&#44; to date&#44; elastography only allows the correct evaluation of CRPH presence or absence in half the cases&#46;<a class="elsevierStyleCrossRef" href="#bib1495"><span class="elsevierStyleSup">100</span></a> The presence of CRPH is associated with an increased risk of postoperative complications and medium-term prognosis worsens&#46;<a class="elsevierStyleCrossRef" href="#bib1990"><span class="elsevierStyleSup">199</span></a> Thus&#44; in multifocal tumours or in the presence of portal hypertension&#44; resection may be technically feasible and the immediate morbidity and mortality apparently acceptable&#46; However&#44; 5-year survival is 50&#37; or less&#44;<a class="elsevierStyleCrossRef" href="#bib1970"><span class="elsevierStyleSup">195</span></a> and therefore&#44; patients should be considered for liver transplantation if they meet the selection criteria&#46; If liver transplantation is not feasible&#44; percutaneous ablation has great therapeutic efficacy in small tumours&#44; and numerous studies have shown that survival may be similar to that obtained by resection if a complete response to treatment is achieved&#46;<a class="elsevierStyleCrossRefs" href="#bib1995"><span class="elsevierStyleSup">200&#8211;202</span></a> The same is observed in multifocal tumours non eligible for surgery treated with TACE in which median survival can exceed 4 years&#46;<a class="elsevierStyleCrossRefs" href="#bib2010"><span class="elsevierStyleSup">203&#8211;205</span></a> Regarding the size of the lesion in single tumours&#44; there is no cut-off point that contraindicates resection&#46; The prevalence of additional nodules and vascular invasion increases parallel to tumour size&#44; but&#44; if a large tumour &#40;&#62;5<span class="elsevierStyleHsp" style=""></span>cm&#41; is localized&#44; after CT or MRI confirmation&#44; surgery should not be considered to be contraindicated&#46; Few patients have this type of expansive tumours without spread&#44; so each patient should be assessed individually&#46; However&#44; the greater the tumour size&#44; the greater the risk of microvascular invasion and satellitosis&#44; whereby the risk of recurrence increases<a class="elsevierStyleCrossRefs" href="#bib2025"><span class="elsevierStyleSup">206&#8211;208</span></a> and other alternatives can potentially get equal or better survival&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Despite advances in diagnostic capacity&#44; underestimation of tumour extension continues to be a problem&#46;<a class="elsevierStyleCrossRef" href="#bib1540"><span class="elsevierStyleSup">109</span></a> It is therefore essential to have an intraoperative ultrasound in order to detect nodules between 0&#46;5 and 1<span class="elsevierStyleHsp" style=""></span>cm and optimize the surgical resection efficacy&#46; Anatomic resections should be performed with a margin free of disease&#46;<a class="elsevierStyleCrossRefs" href="#bib2040"><span class="elsevierStyleSup">209&#44;210</span></a> The benefits of getting a resection margin is based on the ability to eliminate potential sources of tumour spread in peritumoral liver tissue&#46; If the tumour is very small &#40;&#60;15<span class="elsevierStyleHsp" style=""></span>mm&#41; and has not yet reached a significant invasiveness with potential microscopic vascular invasion&#44; the possibility of tumour spread beyond the resected segment is very low and anatomical resection will not provide any benefit&#46; In larger tumours&#44; where vascular invasion is more likely even though it might not be recognizable&#44; anatomical resection may reduce the risk of recurrence&#46; Finally&#44; if microscopic vascular invasion is already present&#44; the likelihood of distant spread is very high and therefore&#44; an anatomic resection with clear margins may not have an impact on recurrence&#47;survival&#46;<a class="elsevierStyleCrossRef" href="#bib2050"><span class="elsevierStyleSup">211</span></a> In these rigorously selected patients&#44; operated by experienced teams&#44; perioperative mortality in conventional patients &#40;not those with high risk in experimental programmes&#41; should be less than 10&#37;&#44; the transfusion rate lower than 1&#37; and survival at 5 years 50&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib1960"><span class="elsevierStyleSup">193&#44;195</span></a> Advances in laparoscopic surgery allow a less invasive surgical treatment and provide the same results in survival with lower perioperative morbidity and shorter hospital stays&#46;<a class="elsevierStyleCrossRefs" href="#bib2055"><span class="elsevierStyleSup">212&#44;213</span></a> Its application requires a careful assessment of the resection to be carried out depending on location&#44; and obviously a specific training is necessary&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Adjuvant therapy to prevent recurrence of hepatocellular carcinoma</span><p id="par0120" class="elsevierStylePara elsevierViewall">Despite a strict selection of candidates and the excellent results obtained in terms of survival&#44; the rate of disease recurrence is very high and may reach 70&#37; at 5 years&#46;<a class="elsevierStyleCrossRef" href="#bib2065"><span class="elsevierStyleSup">214</span></a> It has been proposed that 60&#8211;70&#37; of recurrences correspond to intrahepatic metastasis undetected at the time of resection&#44; and 30&#8211;40&#37; are de <span class="elsevierStyleItalic">novo HCC</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib2040"><span class="elsevierStyleSup">209&#44;215</span></a> The first type would appear during the first 2 years of follow-up and would often be multifocal&#46; Its main risk factors are the presence of microvascular invasion or satellitosis and a low degree of histological differentiation&#46;<a class="elsevierStyleCrossRefs" href="#bib1970"><span class="elsevierStyleSup">195&#44;207&#44;209&#44;210</span></a> In contrast&#44; metachronous tumours would have a late onset and be usually unifocal&#46; However&#44; the classification between metachronous HCC and recurrence due to spread cannot be based simply on the pattern of recurrence and the time of onset&#44; since tumours with less proliferative or metastatic capacity&#44; or livers with less capacity to host metastases can lead to long term unifocal spread&#46; This possibility is verified in extrahepatic relapse beyond 2 years in patients with liver transplantation&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Since the presence of microvascular invasion and&#47;or satellitosis on histological examination of the surgical specimen correlates with early recurrence and poor prognosis&#44; some groups have proposed assessing the patient&#39;s inclusion in the list of liver transplantation once the spread in the resected segment is known&#44; before the onset of the relapse<a class="elsevierStyleCrossRefs" href="#bib2035"><span class="elsevierStyleSup">208&#44;216</span></a> and the results of this strategy are positive&#46;<a class="elsevierStyleCrossRef" href="#bib2080"><span class="elsevierStyleSup">217</span></a> Multiple adjuvant therapies to prevent recurrence have been evaluated&#44; aimed at both&#44; preventing recurrence due to spread &#40;Chemoembolization&#8211;Lipiodolization&#44;<a class="elsevierStyleCrossRefs" href="#bib2085"><span class="elsevierStyleSup">218&#44;219</span></a> intrahepatic radiation&#44;<a class="elsevierStyleCrossRef" href="#bib2095"><span class="elsevierStyleSup">220</span></a> systemic agents<a class="elsevierStyleCrossRefs" href="#bib2100"><span class="elsevierStyleSup">221&#44;222</span></a> or immunotherapy<a class="elsevierStyleCrossRef" href="#bib2110"><span class="elsevierStyleSup">223</span></a>&#41; as well as preventing recurrences de novo &#40;retinoids<a class="elsevierStyleCrossRef" href="#bib2115"><span class="elsevierStyleSup">224</span></a> and interferon&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib2120"><span class="elsevierStyleSup">225&#8211;227</span></a> Despite encouraging results at first&#44; the efficacy of these strategies has not been reproduced by more consistent studies and at the present time they cannot be considered part of routine clinical practice&#46; Recent studies evaluating vitamin K2 analogs<a class="elsevierStyleCrossRef" href="#bib2135"><span class="elsevierStyleSup">228</span></a> or heparinase inhibitors &#40;PI-88&#41;<a class="elsevierStyleCrossRef" href="#bib2140"><span class="elsevierStyleSup">229</span></a> have proved negative&#46; Finally&#44; a phase 3 multicentre randomized study evaluated sorafenib versus placebo as adjuvant treatment after complete ablation or hepatic resection &#40;STORM study&#41;&#44; also obtaining a negative result&#46;<a class="elsevierStyleCrossRef" href="#bib2145"><span class="elsevierStyleSup">230</span></a><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Liver transplantation</span><p id="par0130" class="elsevierStylePara elsevierViewall">In the 80s&#44; the results obtained after liver transplantation&#44; with recurrence rates of 50&#37; and 5-year survival rates lower than 40&#37;&#44; questioned the acceptance of liver transplantation as a valid treatment option for HCC&#46; These data were the result of the selection of candidates with large tumours or even presence of vascular invasion or extrahepatic spread&#46; However&#44; those patients in whom HCC was found incidentally in the explant showed a low likelihood of recurrence and a survival similar to that of patients transplanted without HCC&#46; This was the rationale used to show that when liver transplantation was limited to patients with single tumours &#60;5<span class="elsevierStyleHsp" style=""></span>cm or up to 3 nodules under 3<span class="elsevierStyleHsp" style=""></span>cm without vascular invasion or extrahepatic spread &#40;Milan criteria&#41;&#44; a survival rate at 4 years of 75&#37; and a recurrence rate of 8&#37; was obtained&#46;<a class="elsevierStyleCrossRef" href="#bib2150"><span class="elsevierStyleSup">231</span></a> These results have been validated by different groups<a class="elsevierStyleCrossRefs" href="#bib2155"><span class="elsevierStyleSup">232&#8211;235</span></a> and constitute the criteria for liver transplantation accepted by AASLD&#44;<a class="elsevierStyleCrossRef" href="#bib1005"><span class="elsevierStyleSup">2</span></a> UNOS&#47;OPTN &#40;<a id="intr0035" class="elsevierStyleInterRef" href="http://www.optn.org/">www&#46;optn&#46;org</a>&#41;&#44; EASL&#47;EORTC&#44;<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">3</span></a> SETH<a class="elsevierStyleCrossRef" href="#bib2175"><span class="elsevierStyleSup">236</span></a> and a panel of international experts under the auspices of several scientific societies directly involved in the management of HCC&#46;<a class="elsevierStyleCrossRef" href="#bib1855"><span class="elsevierStyleSup">172</span></a> Therefore&#44; liver transplantation is the treatment of choice in patients with HCC who are not optimal candidates for surgical resection&#44; who have no extrahepatic disease that contraindicates the procedure and who have a HCC compatible with the Milan criteria&#46;<a class="elsevierStyleCrossRef" href="#bib1265"><span class="elsevierStyleSup">54</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Transplantation applicability is limited&#46; The number of candidates exceeds the number of organs available and&#44; therefore&#44; there is a waiting time between indication and transplantation&#46; During this time the tumour can progress and reach intervention contraindication&#46; This may reach 25&#37; of patients if the wait is 12 months and therefore survival according to intention to treat may be significantly deteriorated&#46;<a class="elsevierStyleCrossRef" href="#bib2180"><span class="elsevierStyleSup">237</span></a> The following strategies have been proposed to reduce the risk of progression during the waiting time&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0140" class="elsevierStylePara elsevierViewall">Increasing the number of donors&#58; This would be the most effective strategy but its impact is limited&#46; Despite using high risk donors &#40;steatotic livers&#44; elderly&#44; non heart-beating donors&#41;&#44; or develop the domino effect transplant&#44; the number of candidates still exceeds the available donors&#46; This leads to the conclusion that a potentially more effective option is the development of transplant programmes from living donors&#46;<a class="elsevierStyleCrossRef" href="#bib2185"><span class="elsevierStyleSup">238</span></a> The latter alternative has shown similar results to cadaveric transplantation<a class="elsevierStyleCrossRefs" href="#bib2190"><span class="elsevierStyleSup">239&#8211;245</span></a> and cost-effectiveness studies have shown its usefulness when the waiting list exceeds 7 months&#46;<a class="elsevierStyleCrossRef" href="#bib2225"><span class="elsevierStyleSup">246</span></a> However&#44; its applicability in routine clinical practice in Spain is low&#46;<a class="elsevierStyleCrossRef" href="#bib2230"><span class="elsevierStyleSup">247</span></a> Furthermore&#44; the donor&#39;s morbidity and mortality<a class="elsevierStyleCrossRef" href="#bib2235"><span class="elsevierStyleSup">248</span></a> possibility and the highest rate of postoperative complications of biliary origin in the receiver needs to be considered&#44; particularly in those centres with limited experience&#46;<a class="elsevierStyleCrossRef" href="#bib2240"><span class="elsevierStyleSup">249</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0145" class="elsevierStylePara elsevierViewall">Prioritization systems&#58; The goal is to transplant as soon as possible those patients with a high progression probability during the time they are on the waiting list and delay those with less aggressive disease&#46; The MELD system for patients with advanced liver disease has been implemented in recent years&#46; Granting some MELD points to patients with HCC has also been proposed&#44; with the purpose of balancing the risk of exclusion&#47;death on the waiting list among all categories of patients&#46; Since the proportion of patients with advanced liver disease and the intensity of it is neither stable nor homogeneous between different areas&#44; the use of the same point value for patients with HCC implies that the probability of delisting is hardly comparable between the different geographical areas&#46; This heterogeneity has been found in the United States&#44; where this system was implemented years ago&#46;<a class="elsevierStyleCrossRefs" href="#bib2245"><span class="elsevierStyleSup">250&#8211;252</span></a> Therefore&#44; for the time being&#44; an optimal prioritization strategy is not available&#46;<a class="elsevierStyleCrossRef" href="#bib2260"><span class="elsevierStyleSup">253</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0150" class="elsevierStylePara elsevierViewall">Application of treatments during the waiting time&#58; There is no randomized clinical trial demonstrating that the application of locoregional treatments during the waiting time increases survival&#46; However&#44; different observational studies have suggested that treatment with radiofrequency<a class="elsevierStyleCrossRefs" href="#bib2265"><span class="elsevierStyleSup">254&#44;255</span></a> or TACE<a class="elsevierStyleCrossRefs" href="#bib2275"><span class="elsevierStyleSup">256&#8211;258</span></a> while on the waiting list decreases the rate of exclusion and cost-effectiveness analyses have suggested its usefulness when the waiting list exceeds 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib2290"><span class="elsevierStyleSup">259</span></a> Therefore&#44; the administration of locoregional treatment is indicated to be considered in those centres where the waiting time exceeds this period&#46; Probably&#44; if the waiting time is over 18&#8211;24 months&#44; there will be no significant benefit regarding treatment application because the probability of progression exceeds the probability of success&#46;<a class="elsevierStyleCrossRef" href="#bib2295"><span class="elsevierStyleSup">260</span></a></p></li></ul></p><p id="par0155" class="elsevierStylePara elsevierViewall">Despite the lack of donors&#44; many groups have proposed that the criteria for inclusion in the list could be expanded without increasing the recurrence rate or decreasing long-term survival&#46; This suggestion is based on the fact that some patients in whom the explant analysis showed they discreetly exceeding the HCC Milan criteria had an acceptable survival and recurrence rate&#46;<a class="elsevierStyleCrossRefs" href="#bib2170"><span class="elsevierStyleSup">235&#44;261&#8211;268</span></a> However&#44; many of these series included a small number of patients with expanded criteria&#44; which were based in many cases on retrospective analysis&#44; definition of tumour stage is based on explant findings or imaging techniques findings without a homogeneous criterion at the time of inclusion&#44; and do not consider or register the decrease in the rate while on the list&#46; Moreover&#44; there are studies in which the analysis of patients who discretely exceed the Milan limits show worse survival&#46;<a class="elsevierStyleCrossRefs" href="#bib2340"><span class="elsevierStyleSup">269&#44;270</span></a> Finally&#44; the follow-up time is short&#44; and therefore the 5-year survival according to the principle of intention to treat is not well known&#46; In addition to these data&#44; it should be noted that the expansion of criteria will increase the number of patients on the list&#44; so that the shortage of donors will increase&#44; and therefore&#44; some organs will be used in patients with a lower life expectancy&#44; while other patients with excellent post-transplant survival prospects will not be transplanted&#46; Cost-effectiveness analysis taking into account the impact that the expansion of criteria would have in organ shortage transplant programmes advise against this strategy&#46;<a class="elsevierStyleCrossRef" href="#bib2350"><span class="elsevierStyleSup">271</span></a> Furthermore&#44; recent studies question the Milan criteria and have proposed different criteria to optimize the selection of patients based on the calculation of the total tumour volume&#44;<a class="elsevierStyleCrossRefs" href="#bib2355"><span class="elsevierStyleSup">272&#44;273</span></a> determination of AFP<a class="elsevierStyleCrossRefs" href="#bib2365"><span class="elsevierStyleSup">274&#8211;276</span></a> or the association of both&#44;<a class="elsevierStyleCrossRef" href="#bib2380"><span class="elsevierStyleSup">277</span></a> among others&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Other groups have shown that patients with HCC exceeding the Milan criteria with objective response after application of a locoregional treatment <span class="elsevierStyleItalic">&#40;Downstaging&#41;</span> have an excellent outcome after performing a liver transplant&#46;<a class="elsevierStyleCrossRefs" href="#bib2385"><span class="elsevierStyleSup">278&#8211;283</span></a> This recommendation is based on the fact that response to treatment with decreased tumour stage could be a marker of less neoplastic aggressiveness&#44; allowing the selection of patients with tumours that would have a satisfactory outcome after liver transplantation&#46; However&#44; all these series include a low number of patients&#44;<a class="elsevierStyleCrossRef" href="#bib2415"><span class="elsevierStyleSup">284</span></a> the proposed expansion is not uniform&#44; the imaging criteria to define tumour extension are not detailed&#44; the treatments applied are heterogeneous&#44; and the definition of <span class="elsevierStyleItalic">downstaging</span> is not homogeneous&#46; Finally&#44; follow-up is limited and establishing a recommendation is not feasible&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Considering the available scientific evidence at this time&#44; it is recommended not to expand the liver transplant eligibility criteria except in areas where there is no shortage of donors or in the context of a research protocol&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Finally&#44; taking into account the unrestricted availability of organs and the minimum waiting time when considering living donor liver transplantation&#44; some authors have suggested that the transplantation selection criteria of patients with HCC could be expanded&#46;<a class="elsevierStyleCrossRefs" href="#bib2190"><span class="elsevierStyleSup">239&#44;285&#8211;289</span></a> This proposal should not be regarded as conventional clinical practice until its efficacy in research studies is established with an adequate number of cases analyzed according to intention to treat from the moment of its assessment and sufficient follow-up&#46;<elsevierMultimedia ident="tbl0030"></elsevierMultimedia></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ablative techniques</span><p id="par0175" class="elsevierStylePara elsevierViewall">Percutaneous ablation is the treatment of choice for those patients with HCC in early stage where surgical resection is not possible and liver transplantation is contraindicated due to an associated disease&#46; At the same time&#44; it is a therapeutic option to try to prevent tumour progression during the liver transplantation waiting time&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Tumour ablation may be performed through instillation of chemicals&#44; mainly ethanol and acetic acid&#44; or by intratumoral temperature modification&#44; as in the case of RF&#44; cryoablation&#44; microwaves or laser&#46;<a class="elsevierStyleCrossRef" href="#bib2445"><span class="elsevierStyleSup">290</span></a> At present&#44; <span class="elsevierStyleItalic">radiofrequency ablation</span> &#40;RFA&#41; is the reference technique&#44; while the <span class="elsevierStyleItalic">percutaneous ethanol injection</span>&#40;PEI&#41; has been reserved for very special indications due to location or to complete ablation when there is a minimal residual activity&#46; However&#44; it should be noted that in tumours &#60;2<span class="elsevierStyleHsp" style=""></span>cm&#44; the effectiveness of PEI is not different from RFA&#44;<a class="elsevierStyleCrossRef" href="#bib2450"><span class="elsevierStyleSup">291</span></a> but in larger tumours their efficacy is lost due to the presence of intratumoral fibrous septa that prevent the correct diffusion of ethanol&#46;<a class="elsevierStyleCrossRefs" href="#bib2455"><span class="elsevierStyleSup">292&#8211;294</span></a> The RFA has more ablative capacity&#44; obtaining a higher response rate than PEI in tumours &#62;3<span class="elsevierStyleHsp" style=""></span>cm with fewer sessions&#46;<a class="elsevierStyleCrossRef" href="#bib2470"><span class="elsevierStyleSup">295</span></a> However&#44; it has drawbacks&#44; such as an increased frequency and severity of adverse effects&#44;<a class="elsevierStyleCrossRefs" href="#bib2475"><span class="elsevierStyleSup">296&#8211;298</span></a> higher cost and lower applicability since its use is not recommended in subcapsular tumours or tumours that are adjacent to the gallbladder&#44; hepatic hilum or heart due to the risk of complications&#44; or those in close contact with blood vessels by a thermal energy dissipation phenomenon hindering the complete ablation of the lesion&#46; PEI and RFA ablation have been directly compared in recent years&#46;<a class="elsevierStyleCrossRefs" href="#bib2490"><span class="elsevierStyleSup">299&#8211;303</span></a> In all these trials&#44; RFA has shown greater ablation capacity&#44; obtaining a higher complete response rate and a lower chance of local recurrence&#46; Although only one of the clinical trials conducted in Japan demonstrated RFA superiority compared to PEI in terms of survival&#44;<a class="elsevierStyleCrossRef" href="#bib2510"><span class="elsevierStyleSup">303</span></a> 3 metaanalysis published recently have shown that RFA provides survival advantage compared to PEI&#44; especially in tumours &#62;2<span class="elsevierStyleHsp" style=""></span>cm&#46;<a class="elsevierStyleCrossRefs" href="#bib2450"><span class="elsevierStyleSup">291&#44;304&#44;305</span></a> Microwave ablation has shown a great ablative capacity&#44; and unlike RFA&#44; its ablative capacity is not affected by the presence of blood vessels adjacent to the tumour&#46;<a class="elsevierStyleCrossRef" href="#bib2525"><span class="elsevierStyleSup">306</span></a> However&#44; to date&#44; no prospective randomized study has demonstrated the superiority of this technique over RFA&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">As surgical resection&#44; the main drawback of percutaneous ablation is the high recurrence &#40;80&#37; at 5 years&#41; despite getting a complete response&#44; initially&#46;<a class="elsevierStyleCrossRefs" href="#bib2065"><span class="elsevierStyleSup">214&#44;297</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Given the great therapeutic efficacy of ablation in tumours &#60;2<span class="elsevierStyleHsp" style=""></span>cm and the low probability of side effects&#44; several groups have directly compared the percutaneous ablation with surgical resection<a class="elsevierStyleCrossRef" href="#bib2065"><span class="elsevierStyleSup">214</span></a><span class="elsevierStyleSup">&#46;</span><a class="elsevierStyleCrossRefs" href="#bib2530"><span class="elsevierStyleSup">307&#8211;312</span></a> with conflicting results&#46; Unfortunately&#44; these studies have methodological problems&#44; particularly in the allocation of treatment and selection bias&#44; invalidating the results&#46; Recently&#44; two cost-effectiveness analysis exploring which of these two options is more cost-effective have been published&#46;<a class="elsevierStyleCrossRefs" href="#bib2560"><span class="elsevierStyleSup">313&#44;314</span></a> Using different methodology&#44; both studies concluded that radiofrequency can offer a similar survival to resection but with a lower cost&#46; The advantage of surgical resection is the availability of the histological analysis of the surgical specimen&#44; which allows obtaining information about the risk of recurrence and the possible desirability of considering entering the waiting list for liver transplantation at high risk of recurrence&#46;<a class="elsevierStyleCrossRefs" href="#bib2035"><span class="elsevierStyleSup">208&#44;216</span></a> If the transplant is not feasible and given the current evidence&#44; percutaneous ablation may be the treatment of choice in patients with HCC at very early stage&#46;<a class="elsevierStyleCrossRef" href="#bib1265"><span class="elsevierStyleSup">54</span></a><elsevierMultimedia ident="tbl0035"></elsevierMultimedia></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Chemoembolization and other locoregional treatments</span><p id="par0195" class="elsevierStylePara elsevierViewall">The only treatment that has shown benefit in terms of survival in patients with intermediate HCC &#40;stage B of the BCLC classification&#41; is TACE&#46; This treatment is based on the predominantly arterial vascularization of HCC&#46; It involves selective catheterization of the hepatic artery and supraselective of tumour feeding arteries&#44; and injecting a chemotherapeutic agent together with blood flow occlusion through an embolizing substance&#46;<a class="elsevierStyleCrossRef" href="#bib2570"><span class="elsevierStyleSup">315</span></a> TACE is contraindicated in patients with decompensated cirrhosis &#40;Child-Pugh B<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>8&#44; including jaundice&#44; encephalopathy&#44; refractory ascites&#41;&#44; extensive involvement of both lobes&#44; reduced portal flow &#40;thrombosis or hepatofugal flow&#41;&#44; untreatable arteriovenous fistula&#44; biliary-enteric anastomosis or biliary <span class="elsevierStyleItalic">stent</span> and creatinine clearance &#60;30<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#46; In these cases&#44; there is a high risk of decompensated liver disease and&#44; although an objective tumour response can be achieved&#44; survival benefit is marginal&#46;<a class="elsevierStyleCrossRef" href="#bib2570"><span class="elsevierStyleSup">315</span></a> Furthermore&#44; despite the strict selection of patients and careful technique&#44; TACE is not exempt from side effects and complications&#44; which may vary from a simple embolization syndrome &#40;the most common&#44; consisting of fever&#44; ileus and abdominal pain&#41; to liver failure&#44; abscesses&#44; ischaemic cholecystitis or even death&#46; Fever is a tumour necrosis marker and prophylactic antibiotic treatment has not demonstrated to avoid the risk of infection&#46;<a class="elsevierStyleCrossRef" href="#bib2575"><span class="elsevierStyleSup">316</span></a> The benefit of TACE in terms of survival is based on 2 randomized controlled trials<a class="elsevierStyleCrossRefs" href="#bib1860"><span class="elsevierStyleSup">173&#44;174</span></a> and then a meta-analysis of accumulated data&#44;<a class="elsevierStyleCrossRef" href="#bib1870"><span class="elsevierStyleSup">175</span></a> which showed that TACE is superior to placebo in patients with intermediate HCC&#44; obtaining a median survival with the treatment of approximately 20 months&#46; A recently published meta-analysis by the Cochrane group showed that the scientific evidence supporting the efficacy of TACE was still limited&#46;<a class="elsevierStyleCrossRef" href="#bib2580"><span class="elsevierStyleSup">317</span></a> However&#44; this meta-analysis has important methodological problems&#44; particularly caused by the inclusion of a study exploring the combination of TACE with percutaneous ablation in early stage HCC and the exclusion of a positive clinical trial published by Lo et al&#46; in 2002&#44;<a class="elsevierStyleCrossRef" href="#bib1865"><span class="elsevierStyleSup">174</span></a> invalidating their findings&#46;<a class="elsevierStyleCrossRefs" href="#bib2585"><span class="elsevierStyleSup">318&#44;319</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">TACE is a treatment that has evolved in recent years and there are still many aspects to be investigated&#46;<a class="elsevierStyleCrossRef" href="#bib2595"><span class="elsevierStyleSup">320</span></a> The treatment modality which demonstrated a survival benefit is based on the administration of a chemotherapeutic agent together with lipiodol as carrier vehicle followed by vascular occlusion with Spongostan particles&#59; this treatment modality is now known as conventional TACE&#46; The safety and efficacy of synthetic microspheres charged with adriamycin has been evaluated in recent years&#46; These spheres slowly release chemotherapy once injected&#46; With these spheres&#44; vascular occlusion is achieved simultaneously with the administration of the chemotherapeutic agent&#44; preventing the washout of the same&#44; whereby the passage of it to the systemic circulation is reduced&#44; minimizing side effects&#46;<a class="elsevierStyleCrossRef" href="#bib2600"><span class="elsevierStyleSup">321</span></a> Besides&#44; the calibre can be chosen depending on the vessel to be embolized and increase the homogeneity of the resulting embolization&#46; Regarding which is the best chemotherapeutic and&#47;or embolizing agent&#44; this is not known since to date no study has correctly compared the different technical modalities&#46; An objective radiological response close to 80&#37; has been obtained with charged particles TACE&#44; apparently higher than that published with conventional TACE&#46; However&#44; a randomized study whose primary objective was to demonstrate superiority in terms of radiological response compared with conventional TACE showed no significant differences&#44;<a class="elsevierStyleCrossRef" href="#bib2605"><span class="elsevierStyleSup">322</span></a> possibly due to the excellent objective responses obtained with conventional TACE when a superselective treatment is performed&#44;<a class="elsevierStyleCrossRef" href="#bib2610"><span class="elsevierStyleSup">323</span></a> although tolerance was significantly better in patients treated with charged particles&#46; Median survivals between 40&#8211;50 months have been reported in selected patients with a treatment protocol using these spheres&#46;<a class="elsevierStyleCrossRefs" href="#bib2010"><span class="elsevierStyleSup">203&#44;204</span></a> Moreover&#44; it is necessary to assess what is the best treatment regimen &#40;fixed regimen or re-treat only when revascularization of lesions or progression is detected&#41; and how the response has to be evaluated&#44; or more importantly&#44; when to consider that TACE has failed and therefore look at other treatment options&#46; In this regard&#44; the concept of untreatable progression has been suggested&#44; defined as progression associated with a profile that prevents new treatment&#44; such as a significant progression with excessive tumour burden or a less significant progression but associated with liver or general condition dysfunction or a contraindication to the pulmonary angiography technique&#46;<a class="elsevierStyleCrossRefs" href="#bib2570"><span class="elsevierStyleSup">315&#44;324</span></a> Furthermore&#44; although radiological responses are achieved over half of the cases&#44; the main drawback of TACE is that most patients experience disease progression despite an initial response&#46; Therefore&#44; an area of interest is to investigate how to prevent or slow the progression of the disease after treatment&#46; The association of TACE with molecular agents such as sorafenib or brivanib has not improved the response rate&#44; time to tumour progression or survival&#46;<a class="elsevierStyleCrossRefs" href="#bib2620"><span class="elsevierStyleSup">325&#44;326</span></a> Finally&#44; combined locoregional treatments are actively being researched in order to increase tumour necrosis&#44; and indirectly&#44; patient survival&#46; Pilot studies<a class="elsevierStyleCrossRef" href="#bib2630"><span class="elsevierStyleSup">327</span></a> and several meta-analyses including retrospective studies with methodological limitations &#40;low number of patients&#44; risk of selection bias&#44; in many cases the control group was percutaneous ablation and not TACE&#44; etc&#46;&#41; show the combination&#39;s benefit&#44;<a class="elsevierStyleCrossRefs" href="#bib2635"><span class="elsevierStyleSup">328&#8211;330</span></a> but prospective randomized studies are needed to confirm these preliminary results&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">In recent years there have been other potentially useful locoregional treatments&#46; Among them&#44; we highlight radioembolization with Yttrium-90 microspheres&#46;<a class="elsevierStyleCrossRef" href="#bib2650"><span class="elsevierStyleSup">331</span></a> Multiple prospective studies including patients at different stages of the disease have shown positive results in terms of radiological response&#44; good clinical tolerance to treatment with a survival seemingly comparable to that obtained in patients treated with TACE or sorafenib&#46;<a class="elsevierStyleCrossRefs" href="#bib2655"><span class="elsevierStyleSup">332&#8211;336</span></a> These data have provided the rationale for conducting randomized clinical trials in well-defined patients comparing radioembolisation combined or not with sorafenib versus sorafenib&#46; These would confirm its benefit in terms of survival and its validity in conventional clinical practice&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">The new radiotherapy techniques such as three-dimensional conformal radiotherapy&#44; intensity modulated radiation therapy&#44; stereotactic image-guided radiotherapy or proton pump radiotherapy allow to administer high doses of radiation on the tumour lesion without damaging the surrounding tissue&#46; Research is being conducted on its possible role in the treatment of those patients where local treatment has failed and the lesion has a small tumour volume&#44; there is no distant disease and maintain good liver function&#46; They could also be useful for tumours located in difficult areas such as the liver dome or close to the vessels&#46; Their administration is also being researched in patients with invasion of the inferior vena cava or portal vein tumour thrombosis&#46; In any case&#44; the results look promising&#44; and its efficacy must be confirmed in larger studies and randomized studies&#46;<a class="elsevierStyleCrossRef" href="#bib2680"><span class="elsevierStyleSup">337</span></a><elsevierMultimedia ident="tbl0040"></elsevierMultimedia></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Systemic treatment&#58; sorafenib</span><p id="par0215" class="elsevierStylePara elsevierViewall">Conventional chemotherapy with cytotoxic purpose &#40;usually doxorubicin<a class="elsevierStyleCrossRefs" href="#bib2685"><span class="elsevierStyleSup">338&#44;339</span></a> and oxaliplatin<a class="elsevierStyleCrossRef" href="#bib2695"><span class="elsevierStyleSup">340</span></a>&#41; has never shown a significant survival benefit&#46; Therefore&#44; its use is not recommended outside clinical trials&#46;<a class="elsevierStyleCrossRefs" href="#bib1870"><span class="elsevierStyleSup">175&#44;341</span></a> Treatments such as tamoxifen&#44;<a class="elsevierStyleCrossRefs" href="#bib1870"><span class="elsevierStyleSup">175&#44;342&#8211;345</span></a> megestrol&#44;<a class="elsevierStyleCrossRefs" href="#bib2725"><span class="elsevierStyleSup">346&#44;347</span></a> octreotride&#44;<a class="elsevierStyleCrossRefs" href="#bib2735"><span class="elsevierStyleSup">348&#8211;350</span></a> antiandrogenic derivatives<a class="elsevierStyleCrossRefs" href="#bib2750"><span class="elsevierStyleSup">351&#44;352</span></a> and seocalcitol<a class="elsevierStyleCrossRef" href="#bib2760"><span class="elsevierStyleSup">353</span></a> have not demonstrated efficacy in HCC&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">In recent years there has been great progress in understanding the molecular alterations that influence tumour progression&#46;<a class="elsevierStyleCrossRefs" href="#bib2765"><span class="elsevierStyleSup">354&#8211;356</span></a> This has allowed us to develop multiple agents acting specifically at the level of the altered molecular pathways&#46; Multiple molecular therapies have been evaluated&#44; with negative results in most cases&#46;<a class="elsevierStyleCrossRef" href="#bib2780"><span class="elsevierStyleSup">357</span></a><a class="elsevierStyleCrossRef" href="#tbl0065">Table 4</a> summarizes the main drugs assessed&#46; To date&#44; the only agent that has shown efficacy in terms of survival in phase 3 placebo-controlled studies is sorafenib&#46; This molecule is a low molecular weight multikinase inhibitor with high oral bioavailability which acts by blocking different signalling pathways associated with hepatocarcinogenesis&#44; particularly the RAF&#47;MEK&#47;ERK pathway by inhibiting Raf kinase and different tyrosine kinases &#40;VEGFR2&#44; PDGFR&#44; c-Kit receptors&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib2785"><span class="elsevierStyleSup">358</span></a> Its main actions are to reduce angiogenesis and slow cell proliferation&#46; Following the positive results of preclinical studies<a class="elsevierStyleCrossRef" href="#bib2790"><span class="elsevierStyleSup">359</span></a> and a phase <span class="elsevierStyleSmallCaps">ii clinical trial</span>&#44;<a class="elsevierStyleCrossRef" href="#bib2795"><span class="elsevierStyleSup">360</span></a> 2 international&#44; multicentre&#44; randomized&#44; controlled&#44; double-blind clinical trials were carried out evaluating sorafenib 400<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h compared to placebo in patients with advanced HCC and compensated liver function&#44; one conducted in Europe and America &#40;SHARP trial&#41;<a class="elsevierStyleCrossRef" href="#bib1890"><span class="elsevierStyleSup">179</span></a> and another in Southeast Asia &#40;Asia-Pacific Study&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1895"><span class="elsevierStyleSup">180</span></a> In both studies&#44; sorafenib showed a significant increase in survival and time to radiographic progression&#46; In addition&#44; an exploratory subset analysis showed that sorafenib&#39;s efficacy was maintained regardless of the aetiology of cirrhosis&#44; baseline tumour stage&#44; <span class="elsevierStyleItalic">performance status</span> and previous treatments&#46;<a class="elsevierStyleCrossRef" href="#bib2800"><span class="elsevierStyleSup">361</span></a> The most common side effects were diarrhoea&#44; weight loss and hand-foot reaction &#40;exclusive alteration of palms and&#47;or soles that can vary from erythema to the occurring of blisters and areas of necrosis&#41;&#46; In most cases the side effects were mild and easily controlled&#46;<a class="elsevierStyleCrossRef" href="#bib2805"><span class="elsevierStyleSup">362</span></a> These results have been replicated in different clinical trials where sorafenib was the treatment in the control arm<a class="elsevierStyleCrossRefs" href="#bib2695"><span class="elsevierStyleSup">340&#44;363&#8211;366</span></a> and multiple prospective studies in routine clinical practice&#46;<a class="elsevierStyleCrossRefs" href="#bib1935"><span class="elsevierStyleSup">188&#44;367&#44;368</span></a> Sorafenib has been evaluated in patients with compensated liver function &#40;Child-Pugh A&#41; and data regarding its usefulness in Child-Pugh B patients is limited&#46; The pharmacokinetic profile is not significantly modified and a significant increase in side effects has not been reported&#46; However&#44; it should be noted that the Child-Pugh B stage comprises a broad clinical spectrum and the potential impact on tumour progression may not modify patient survival in relation to impaired liver function&#46;<a class="elsevierStyleCrossRefs" href="#bib2835"><span class="elsevierStyleSup">368&#44;369</span></a> Therefore&#44; the use of sorafenib in Child-Pugh B patients should be evaluated individually&#46;<a class="elsevierStyleCrossRef" href="#bib2805"><span class="elsevierStyleSup">362</span></a> The results published in Child-Pugh C patients show little benefit in terms of survival and its use in these patients should be discouraged&#46;<a class="elsevierStyleCrossRefs" href="#bib2805"><span class="elsevierStyleSup">362&#44;368&#44;370&#44;371</span></a> Finally&#44; various biological and clinical markers that could predict response to sorafenib and identify the lack of efficacy at baseline or during treatment have been suggested&#46; Biomarkers such as AFP&#44; <span class="elsevierStyleItalic">vascular endothelial growth factor</span>&#44; <span class="elsevierStyleItalic">angiopoietin-2</span>&#44; <span class="elsevierStyleItalic">hepatocyte growth factor</span> or c-Kit have shown a prognostic value in patients with advanced HCC&#44;<a class="elsevierStyleCrossRef" href="#bib2855"><span class="elsevierStyleSup">372</span></a> but they do not contribute to treatment decision&#46; By contrast&#44; the development of certain adverse effects such as diarrhoea&#44;<a class="elsevierStyleCrossRef" href="#bib2860"><span class="elsevierStyleSup">373</span></a> hypertension<a class="elsevierStyleCrossRef" href="#bib2865"><span class="elsevierStyleSup">374</span></a> or dermatologic conditions<a class="elsevierStyleCrossRefs" href="#bib2870"><span class="elsevierStyleSup">375&#8211;377</span></a> are associated with better survival&#46; This association between adverse effects and greater efficacy is relevant given that indicates the need for careful monitoring of patients in order to adjust the dose if side effects are detected&#44; and thus avoid unnecessary treatment interruptions that could lead to loss of efficacy&#46;</p><elsevierMultimedia ident="tbl0065"></elsevierMultimedia><p id="par0225" class="elsevierStylePara elsevierViewall">Sorafenib showed that molecular therapies may be useful in the treatment of HCC and opened the way to evaluate blocking multiple signalling pathways in the same way that has been done for years in the case of other neoplasms&#46; Unfortunately&#44; so far&#44; no other agent assessed in phase 3 clinical trials alone in first-line &#40;sunitinib&#44; linifanib&#44; brivanib&#41;<a class="elsevierStyleCrossRefs" href="#bib2810"><span class="elsevierStyleSup">363&#44;364&#44;366</span></a> or second-line &#40;brivanib&#44; everolimus&#44; ramucirumab&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib2885"><span class="elsevierStyleSup">378&#8211;380</span></a> or associated with sorafenib in first-line &#40;erlotinib&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib2820"><span class="elsevierStyleSup">365</span></a> has managed to demonstrate benefit in terms of survival&#46; At present there are ongoing clinical trials evaluating different molecules that have shown promising results in preliminary studies &#40;regorafenib&#44; lenvatinib&#44; cabozantinib and tivantinib&#44; among others&#41; that could change the management of advanced HCC in coming years&#46;<elsevierMultimedia ident="tbl0045"></elsevierMultimedia></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Future perspectives&#46; Objectives in hepatocellular carcinoma research</span><p id="par0230" class="elsevierStylePara elsevierViewall">Breakthroughs are still needed in the field of liver cancer&#46; In addition to implementing the preventive strategies mentioned earlier&#44; progress is needed in the area of early detection and increasing therapeutic efficacy&#46; It is imperative&#44; at different healthcare settings&#44; to change the view that HCC is a neoplasm which is impossible to detect at an early stage and for which there is no treatment&#46; Thus&#44; the number of patients eligible for radical treatment will increase and access to treatment will be allowed to patients who are currently detected only when they are in the final stage of the disease&#46; Since the population at risk is fully identified&#44; it is essential that screening recommendations are implemented correctly and by properly trained personnel&#46; Research in imaging techniques and tumour markers will be of paramount importance to increase the efficacy of the monitoring plans&#46; Therefore&#44; an intense research activity should be developed in the area of detection&#44; diagnosis and staging&#46; Translational research should allow incorporating laboratory findings on the criteria for the characterization and prognostic assessment of patients&#46; In addition&#44; a better understanding of the biological alterations involved in hepatic oncogenesis will lead to the identification of new treatment targets&#46; These should be assessed according to a specific analysis for HCC patients since tumour coexistence with base liver disease requires a different development to the one followed conventionally in other neoplasms&#46; In this regard&#44; an international panel of experts from different specialties promoted by AASLD has developed a consensus document with recommendations to follow in the field of HCC treatment&#46;<a class="elsevierStyleCrossRef" href="#bib1850"><span class="elsevierStyleSup">171</span></a> In the case of phase <span class="elsevierStyleSmallCaps">i</span> clinical trials&#44; it is necessary to include Child-Pugh A patients with compensated liver cirrhosis to assess the exact dose&#44; toxicity and specific episodes associated with liver disease that would not be recorded in traditional phase <span class="elsevierStyleSmallCaps">i</span> studies that include patients with different neoplasms&#46; In the case of phase <span class="elsevierStyleSmallCaps">ii</span> trials&#44; the panel of experts recommended the use of phase <span class="elsevierStyleSmallCaps">ii</span> randomized trials designed to evaluate a time-dependent surrogate episode such as time to progression&#46; Overall survival should be reported as a secondary objective&#44; along with safety data&#46; Also&#44; the use of composite variables such as disease&#47;progression free survival as primary objectives should be avoided in these studies&#46; In clinical trials on new therapies&#44; it is advisable to include a biomarker analysis so as to determine response predictors&#46; According to the results of the SHARP trial&#44; sorafenib should be the standard treatment in all those trials evaluating first-line treatment in advanced HCC&#46; The new agents being evaluated as a second line treatment for advanced HCC should be compared to placebo&#47;maintenance therapy and only those drugs that have shown efficacy as a second-line treatment in phase <span class="elsevierStyleSmallCaps">iii</span> trials can be considered to be directly compared with sorafenib in phase <span class="elsevierStyleSmallCaps">ii</span> studies&#46; For the assessment of first-line treatment in advanced HCC&#44; the ideal design would be the new agent associated with sorafenib compared to sorafenib&#46; For second-line treatments&#44; patients with contraindications or failure after treatment with sorafenib should be included and the control arm should be placebo&#47;maintenance treatment&#46; Recent studies have shown that the development of some side effects in patients treated with sorafenib&#44; particularly dermatological&#44; are associated with greater survival&#46;<a class="elsevierStyleCrossRefs" href="#bib2870"><span class="elsevierStyleSup">375&#8211;377</span></a> In addition&#44; the type of radiological progression determines&#44; in a statistically independent manner&#44; the post-progression survival&#46;<a class="elsevierStyleCrossRefs" href="#bib1935"><span class="elsevierStyleSup">188&#44;189</span></a> Thus&#44; those studies evaluating new second line agents after failure and&#47;or intolerance to sorafenib should record this information and possibly stratify this population prior to randomization to obtain homogeneous group comparisons&#46; In addition&#44; those agents evaluated as adjuvant or neoadjuvant treatment should be compared with placebo&#47;maintenance treatment in phase <span class="elsevierStyleSmallCaps">ii</span> studies&#46; In the case of phase <span class="elsevierStyleSmallCaps">iii</span> trials&#44; the primary goal should be overall survival&#46; Time-dependent episodes&#44; such as time to progression&#44; should be considered as secondary objectives&#44; and again&#44; the use of composite measures such as disease&#47;progression free survival should be avoided since it has already been demonstrated that these parameters are not related to survival in HCC&#46;<a class="elsevierStyleCrossRef" href="#bib2810"><span class="elsevierStyleSup">363</span></a> Phase <span class="elsevierStyleSmallCaps">iii</span> studies of adjuvant treatments should use survival or time to recurrence as primary objectives&#46; A composite objective &#40;recurrence-free survival&#41; should only be considered if the study population is very selective and mortality unrelated to cancer is almost entirely avoided&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Another important aspect is the assessment of the radiological response and its ability to predict the efficacy of a therapeutic agent&#46; Considering that the main objective of locoregional treatments available in HCC is to obtain complete lesion necrosis&#44; simple diameter change measurement of the treated lesions is insufficient to assess response<a class="elsevierStyleCrossRef" href="#bib2900"><span class="elsevierStyleSup">381</span></a> and it is necessary to incorporate in the assessment the presence of tumour necrosis identified as lack of contrast uptake in the arterial phase&#46;<a class="elsevierStyleCrossRef" href="#bib2615"><span class="elsevierStyleSup">324</span></a> Measurement of tumour necrosis through imaging was initially established in 2000 by the EASL<a class="elsevierStyleCrossRef" href="#bib1565"><span class="elsevierStyleSup">114</span></a> and subsequently incorporated into conventional RECIST criteria by an expert group&#44; leading to the modified RECIST &#40;mRECIST&#41; criteria&#46;<a class="elsevierStyleCrossRefs" href="#bib1850"><span class="elsevierStyleSup">171&#44;382</span></a> The application of mRECIST criteria for the assessment of systemic treatments is more controversial&#46; Recent studies have shown that a higher objective response according to mRECIST criteria is not associated with survival improvement&#46;<a class="elsevierStyleCrossRefs" href="#bib2890"><span class="elsevierStyleSup">379&#44;383</span></a> Determining the time to radiographic progression has been suggested as a possible benefit surrogate marker in terms of survival based on the findings of the 2 phase <span class="elsevierStyleSmallCaps">iii</span> studies of sorafenib in advanced HCC&#46;<a class="elsevierStyleCrossRefs" href="#bib1890"><span class="elsevierStyleSup">179&#44;180</span></a> Unfortunately&#44; other studies evaluating other agents such as brivanib have shown that increased time to radiographic progression was not associated with increased survival&#46;<a class="elsevierStyleCrossRef" href="#bib2885"><span class="elsevierStyleSup">378</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">The detailed knowledge of the altered molecular pathways in HCC could allow to change the management of this disease&#46; In this sense&#44; future research is needed regarding markers that can help identify patients who may benefit from a particular systemic treatment&#46; There are studies in which inclusion is based on the presence of specific molecular alterations in tissue&#46;<a class="elsevierStyleCrossRef" href="#bib2915"><span class="elsevierStyleSup">384</span></a> Furthermore&#44; the molecular analysis would help in selecting the most appropriate therapeutic option for a given patient according to the molecular profile of the tumour &#40;<span class="elsevierStyleItalic">a la carte</span> treatment&#41;&#46; Although this approach is very attractive&#44; at present we have no biomarker with clinical applicability&#46; Moreover&#44; the determination of molecular alterations in histologic tissue is limited by tumour heterogeneity&#44; both in the same node&#44; as well as in different nodes and along the progression&#46;<a class="elsevierStyleCrossRefs" href="#bib2920"><span class="elsevierStyleSup">385&#44;386</span></a> Great efforts are being made to identify tumour products in peripheral blood <span class="elsevierStyleItalic">&#40;liquid biopsy&#41;</span> in order to overcome the limitations described above&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interests</span><p id="par0245" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Jordi Bruix &#40;coordinator&#41;</span>&#46; He has received remuneration from Bayer HealthCare and BTG for participating in educational activities&#44; conducting research and consulting activities&#44; and Daichi&#44; Bristol-Myers Squibb&#44; Novartis&#44; Gilead&#44; Abbvie&#44; Arquile&#44; Sytex and Roche for consulting activities&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Alejandro Forner</span>&#46; Has received remuneration from Bayer HealthCare for participating in educational activities and&#47;or conducting consulting activities&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Maria Reig&#46;</span> Has received remuneration from Bayer HealthCare for participating in educational activities and&#47;or conducting consulting activities&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Maria Varela&#46;</span> Has received remuneration from Bayer HealthCare for participating in educational activities and research and&#47;or performing consulting activities&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Marta Burrel&#46;</span> He has received remuneration from BTG to participate in educational activities and conducting consulting activities&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Jaime Feliu&#46;</span> He has received remuneration from Amgen&#44; Sanofi-Aventis&#44; Lilly and Bayer for participating in educational activities and&#47;or conducting consulting activities&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Javier Brice&#241;o&#46;</span> Absence of conflicts of interest&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Javier Sastre&#46;</span> Absence of conflicts of interest&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Luis Mart&#237;-Bonmat&#237;</span>&#46; Absence of conflicts of interest&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Josep M&#46; Llovet</span>&#46; He has received remuneration from Bayer HealthCare&#44; Bristol Myers Squibb and Boehringer Ingelheim for participating in teaching&#44; research and consultancy activities&#44; and Novartis&#44; Celsion&#44; Lilly Pharmaceuticals&#44; GlaxoSmithKline&#44; BTG and Blueprint Medicines for consulting activities&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Jose Ignacio Bilbao</span>&#46; He has received remuneration from BTG and SIRTEX to participate in educational activities and&#47;or conducting consulting activities&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Bruno Sangro&#46;</span> He has received remuneration from Bayer HealthCare&#44; BTG and SIRTEX to participate in educational activities and&#47;or conducting consulting activities&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Fernando Pardo</span>&#46; He has received remuneration from Bayer HealthCare&#44; BTG and SIRTEX to participate in educational activities and&#47;or conducting consulting activities&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Carmen Ayuso</span>&#46; Absence of conflicts of interest&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Concepci&#243; Bru</span>&#46; Absence of conflicts of interest&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Josep Tabernero&#46;</span> He has received remuneration from Amgen&#44; Boehringer-Ingelheim&#44; Celgene&#44; Chugai&#44; ImClone&#44; Lilly&#44; Merck&#44; Merck Serono&#44; Millennium&#44; Novartis&#44; Roche&#44; Sanofi and Taiho for participating in educational activities and&#47;or conducting consulting activities&#46;</p></span></span>"
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          "titulo" => "Future perspectives&#46; Objectives in hepatocellular carcinoma research"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hepatocellular carcinoma is the most common primary malignancy of the liver and one of the most frequent causes of death in patients with liver cirrhosis&#46; Simultaneously with the recognition of the clinical relevance of this neoplasm&#44; in recent years there have been important developments in the diagnosis&#44; staging and treatment of HCC&#46; Consequently&#44; the <span class="elsevierStyleItalic">Asociaci&#243;n Espa&#241;ola para el Estudio del H&#237;gado</span> has driven the need to update clinical practice guidelines&#44; continuing to invite all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document &#40;<span class="elsevierStyleItalic">Sociedad Espa&#241;ola de Trasplante Hep&#225;tico</span>&#44; <span class="elsevierStyleItalic">Sociedad Espa&#241;ola de Radiolog&#237;a M&#233;dica</span>&#44; <span class="elsevierStyleItalic">Sociedad Espa&#241;ola de Radiolog&#237;a Vascular e Intervencionista</span> y <span class="elsevierStyleItalic">Sociedad Espa&#241;ola de Oncolog&#237;a M&#233;dica</span>&#41;&#46; The clinical practice guidelines published in 2009 accepted as Clinical Practice Guidelines of the National Health System has been taken as reference document&#44; incorporating the most important advances that have been made in recent years&#46; The scientific evidence for the treatment of HCC has been evaluated according to the recommendations of the National Cancer Institute &#40;<a class="elsevierStyleInterRef" id="intr0015" href="http://www.cancer.gov/">www&#46;cancer&#46;gov</a>&#41; and the strength of recommendation is based on the GRADE system&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El carcinoma hepatocelular es la neoplasia primaria de h&#237;gado m&#225;s com&#250;n y una de las causas de muerte m&#225;s frecuentes en los pacientes afectos de cirrosis hep&#225;tica&#46; Simult&#225;neamente al reconocimiento de la relevancia cl&#237;nica de esta neoplasia&#44; en los &#250;ltimos a&#241;os han aparecido novedades importantes en el diagn&#243;stico&#44; estadificaci&#243;n y tratamiento del carcinoma hepatocelular&#46; Por tal motivo&#44; desde la Asociaci&#243;n Espa&#241;ola para el Estudio del H&#237;gado se ha impulsado la necesidad de actualizar las gu&#237;as de pr&#225;ctica cl&#237;nica&#44; invitando de nuevo a todas las sociedades involucradas en el diagn&#243;stico y tratamiento de esta enfermedad a participar en la redacci&#243;n y aprobaci&#243;n del documento &#40;la Sociedad Espa&#241;ola de Trasplante Hep&#225;tico&#44; la Sociedad Espa&#241;ola de Radiolog&#237;a M&#233;dica&#44; la Sociedad Espa&#241;ola de Radiolog&#237;a Vascular e Intervencionista y la Sociedad Espa&#241;ola de Oncolog&#237;a M&#233;dica&#41;&#46; Se ha tomado como documento de referencia las gu&#237;as de pr&#225;ctica cl&#237;nica publicadas en 2009 aceptadas como Gu&#237;a de Pr&#225;ctica Cl&#237;nica del Sistema Nacional de Salud&#44; incorporando los avances m&#225;s importantes que se han obtenido en los &#250;ltimos a&#241;os&#46; La evidencia cient&#237;fica en el tratamiento del carcinoma hepatocelular se ha evaluado de acuerdo con las recomendaciones del <span class="elsevierStyleItalic">National Cancer Institute</span> &#40;<a class="elsevierStyleInterRef" id="intr0020" href="http://www.cancer.gov/">www&#46;cancer&#46;gov</a>&#41; y la fuerza de la recomendaci&#243;n se basa en el sistema GRADE&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Forner A&#44; Reig M&#44; Varela M&#44; Burrel M&#44; Feliu J&#44; Brice&#241;o J&#44; et al&#46; Diagn&#243;stico y tratamiento del carcinoma hepatocelular&#46; Actualizaci&#243;n del documento de consenso de la AEEH&#44; SEOM&#44; SERAM&#44; SERVEI y SETH&#46; Med Clin &#40;Barc&#41;&#46; 2016&#59;146&#58;511&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Spanish Association for the Study of the Liver &#40;AEEH&#41;&#58; Alejandro Forner&#44; Maria Reig&#44; Mar&#237;a Varela&#44; Josep Maria Llovet&#44; Bruno Sangro&#44; Jordi Bruix&#46;</p> <p class="elsevierStyleNotepara" id="npar0020">Spanish Liver Transplant Society &#40;SETH&#41;&#58; Javier Brice&#241;o&#44; Fernando Pardo&#46;</p> <p class="elsevierStyleNotepara" id="npar0025">Spanish Society of Medical Radiology &#40;SERAM&#41;&#58; Luis Mart&#237;-Bonmat&#237;&#44; Carmen Ayuso&#44; Conxita Bru&#46;</p> <p class="elsevierStyleNotepara" id="npar0030">Spanish Society of Vascular and Interventional Radiology &#40;SERVEI&#41;&#58; Marta Burrel&#44; Jose Ignacio Bilbao&#46;</p> <p class="elsevierStyleNotepara" id="npar0035">Spanish Society of Medical Oncology &#40;SEOM&#41;&#58; Jaime Feliu&#44; Javier Sastre&#44; Josep Tabernero&#46;</p>"
      ]
    ]
    "apendice" => array:1 [
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          0 => array:4 [
            "apendice" => "<p id="par0330" class="elsevierStylePara elsevierViewall">Systematic search in MELDLINE repository using the following search terms&#58;</p> <p id="par0335" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">&#40;&#8220;carcinoma&#44; hepatocellular</span>&#8221;<span class="elsevierStyleItalic">&#91;MeSH Terms&#93; OR &#8220;carcinoma</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; AND &#40;&#8220;surgery</span>&#8221; <span class="elsevierStyleItalic">&#91;Subheading&#93; OR &#8220;surgery</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; OR &#40;&#8220;surgical</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;procedures</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;operative</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; OR resection&#91;All Fields&#93;&#41;</span></p> <p id="par0340" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">&#40;&#8220;carcinoma&#44; hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;MeSH Terms&#93; OR &#8220;carcinoma</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; AND ablation&#91;All Fields&#93;</span></p> <p id="par0345" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">&#40;&#8220;carcinoma&#44; hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;MeSH Terms&#93; OR &#8220;carcinoma</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; AND &#40;&#8220;liver transplantation</span>&#8221; <span class="elsevierStyleItalic">&#91;MeSH Terms&#93; OR &#40;&#8220;liver</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;transplantation</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; OR &#8220;liver transplantation</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41;</span></p> <p id="par0350" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">&#40;&#8220;carcinoma&#44; hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;MeSH Terms&#93; OR &#8220;carcinoma</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; AND transarterial&#91;All Fields&#93; AND &#40;&#8220;drug therapy</span>&#8221; <span class="elsevierStyleItalic">&#91;Subheading&#93; OR &#40;&#8220;drug</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;therapy</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; OR &#8220;drug therapy</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; OR &#8220;chemotherapy</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; OR &#8220;drug therapy</span>&#8221; <span class="elsevierStyleItalic">&#91;MeSH Terms&#93; OR &#40;&#8220;drug</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;therapy</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; OR &#8220;chemotherapy</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41;</span></p> <p id="par0355" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">&#40;&#8220;carcinoma&#44; hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;MeSH Terms&#93; OR &#8220;carcinoma</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; AND systemic&#91;All Fields&#93; AND &#40;&#8220;therapy</span>&#8221; <span class="elsevierStyleItalic">&#91;Subheading&#93; OR &#8220;therapy</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; OR &#8220;therapeutics</span>&#8221; <span class="elsevierStyleItalic">&#91;MeSH Terms&#93; OR &#8220;therapeutics</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41;</span></p> <p id="par0360" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">&#40;&#8220;carcinoma&#44; hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;MeSH Terms&#93; OR &#8220;carcinoma</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93; AND &#8220;hepatocellular</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; AND &#40;&#8220;imaging</span>&#8221; <span class="elsevierStyleItalic">&#91;All Fields&#93;&#41; AND &#8220;diagnosis</span>&#8221; <span class="elsevierStyleItalic">&#91;MeSH Terms&#93;&#41;</span></p> <p id="par0365" class="elsevierStylePara elsevierViewall">The following types of documents were included in the search&#58; systematic reviews&#44; clinical practice guidelines&#44; observational studies&#44; meta-analysis&#44; cost-effectiveness analysis &#40;Markov model&#41; and randomized clinical trials&#58;</p> <p id="par0370" class="elsevierStylePara elsevierViewall">The search range included January 1995 to August 2015&#46;</p>"
            "etiqueta" => "Annex 1"
            "titulo" => "Literature search criteria"
            "identificador" => "sec0090"
          ]
        ]
      ]
    ]
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        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from Bruix and Sherman&#46;<a class="elsevierStyleCrossRef" href="#bib1005"><span class="elsevierStyleSup">2</span></a>"
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            "imagen" => "gr1.jpeg"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Diagnostic algorithm for the study of a liver nodule detected on abdominal ultrasound&#46;</p>"
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        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from Bruix et al&#46;<a class="elsevierStyleCrossRef" href="#bib1835"><span class="elsevierStyleSup">168</span></a>"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 2020
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        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Barcelona-Clinic Liver-Cancer</span> &#40;BCLC&#41; Staging System&#46; BSC&#58;<span class="elsevierStyleItalic">best supportive care</span>&#59; HCC&#58; hepatocellular carcinoma&#59; PS&#58; <span class="elsevierStyleItalic">performance status</span>&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">&#42;The Child-Pugh classification does not identify all patients with severe hepatic dysfunction requiring to be considered for liver transplantation&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42; Patients with end-stage cirrhosis due to severe hepatic impairment &#40;Child-Pugh C or earlier stages with episodes predicting poor prognosis&#44; high MELD score&#41; should be considered for liver transplantation&#46; In these patients&#44; the presence of HCC can be a contraindication for liver transplantation if it exceeds the inclusion criteria&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Strength of evidence according to study design</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Level 1&#58; Randomized clinical trials or meta-analysis of randomized trials</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#40;i&#41; Double blind&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#40;ii&#41; Non-blind treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Level 2&#58; Non-randomized clinical trials</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Level 3&#58; Case Series</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#40;i&#41; Population&#44; consecutive series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#40;ii&#41; Consecutive cases &#40;non-population&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#40;iii&#41; Non-consecutive cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Strength of evidence according to the study objectives</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">A&#46; Overall mortality &#40;or survival according to a defined time point&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">B&#46; Specific mortality of the disease &#40;or disease-specific mortality according to a defined time point&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">C&#46; Quality of life assessment</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">D&#46; Indirect surrogates</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#40;i&#41; Episode-free survival&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#40;ii&#41; Disease-free survival&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#40;iii&#41; Progression-free survival&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#40;iv&#41; Tumour response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">It includes prospective studies &#40;cohort studies&#41; and retrospective studies &#40;case-control studies&#44; case series&#41;&#46;</p>"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Levels of evidence according to the study design&#46;</p>"
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      3 => array:8 [
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        "etiqueta" => "Table 2"
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        "detalles" => array:1 [
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        "tabla" => array:1 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Notes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Symbol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Degree of evidence</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>High quality of evidence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">New studies are unlikely to change our confidence on effect estimation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Moderate quality of evidence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">New studies are likely to have a significant impact on effect estimation and may change our estimation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Low or very low quality of evidence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">New studies will have an important impact on effect estimation and is likely to change our estimation&#46; Any effect estimation is uncertain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Grade of recommendation</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Strong&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Factors that influence the strength of the recommendation include quality of the evidence&#44; presumed importance of patient outcomes and cost&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Weak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Variability in preferences and values&#44; or greater insecurity&#59; more likely to make a weak recommendation<br>The recommendation is made with less security&#58; higher cost or resource consumption&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Level of evidence and level of recommendation &#40;adapted from the GRADE system&#41;&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0060"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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          0 => array:3 [
            "identificador" => "at3"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">HCC&#58; hepatocellular carcinoma&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Classification of scientific evidence adapted from NCI &#40;<a class="elsevierStyleInterRef" id="intr0005" href="http://www.cancer.gov/">www&#46;cancer&#46;gov</a>&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0050">Table 1</a>a&#41;&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Benefit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Level of evidence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleBold">Surgical treatments</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Surgical resection</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increases survival&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3iiA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Adjuvant therapies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Controversial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1A-D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Adjuvant Sorafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No DFS increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1iD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Liver transplantation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increases survival&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3iiA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Neoadjuvant therapies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Therapeutic response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3Diii&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleBold">Locoregional treatments</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Percutaneous treatment</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increases survival&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3iiA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Radiofrequency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Better local control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1iiD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Chemoembolization</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increases survival&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1iiA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Lipiodolization</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Therapeutic response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3iiDiii&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Internal radiation &#40;</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">131</span></span><span class="elsevierStyleItalic">I</span>&#44;<span class="elsevierStyleSup"><span class="elsevierStyleItalic">90</span></span><span class="elsevierStyleItalic">Y</span><span class="elsevierStyleSup">0</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Therapeutic response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3iiDiii&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleBold">Systemic treatments</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Sorafenib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increases survival&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1iA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hormonal compounds</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No survival increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1iA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Tamoxifen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Antiandrogens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Seocalcitiol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Systemic chemotherapy</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No survival increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1iiA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Immunotherapy</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No survival increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1iiA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Other systemic agents</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No survival increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1iA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Scientific evidence of HCC treatments according to the quality of the study design&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0065"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">HCC&#58; hepatocellular carcinoma&#59; ns&#58; not significant&#59; TTP&#58; <span class="elsevierStyleItalic">time to progression</span> &#40;time to radiographic progression&#41;&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author&#44; year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Randomization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TTP &#40;months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Survival &#40;months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">First-line</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sorafenib</td><td class="td" title="table-entry  " align="left" valign="top">Llovet et al&#46;&#44; 2008<a class="elsevierStyleCrossRef" href="#bib1890"><span class="elsevierStyleSup">179</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Sorafenib vs placebo</td><td class="td" title="table-entry  " align="left" valign="top">299&#47;303&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;5 vs 2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;7 vs 7&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cheng et al&#46;&#44; 2009<a class="elsevierStyleCrossRef" href="#bib1895"><span class="elsevierStyleSup">180</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">150&#47;76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;8 vs 1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;5 vs 4&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sorafenib<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>erlotinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Zhu et al&#46;&#44; 2012<a class="elsevierStyleCrossRef" href="#bib2820"><span class="elsevierStyleSup">365</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sorafenib<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>erlotinib vs sorafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">362&#47;358&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;2 vs 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#46;5 vs 8&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sunitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cheng et al&#46;&#44; 2013<a class="elsevierStyleCrossRef" href="#bib2810"><span class="elsevierStyleSup">363</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sunitinib vs sorafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">530&#47;544&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;6 vs 3&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;9 vs 10&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Linifanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cainap et al&#46;&#44; 2012<a class="elsevierStyleCrossRef" href="#bib2825"><span class="elsevierStyleSup">366</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Linifanib vs sorafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">514&#47;521&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;4 vs 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#46;1 vs 9&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Brivanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Johnson et al&#46;&#44; 2013<a class="elsevierStyleCrossRef" href="#bib2815"><span class="elsevierStyleSup">364</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Brivanib vs sorafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">577&#47;578&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;2 vs 4&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#46;5 vs 9&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FOLFOX-4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Qin et al&#46;&#44; 2013<a class="elsevierStyleCrossRef" href="#bib2695"><span class="elsevierStyleSup">340</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">FOLFOX-4 vs doxorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">184&#47;187&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;9 vs 1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;4 vs 4&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">Second-line</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Everolimus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Zhu et al&#46;&#44; 2014<a class="elsevierStyleCrossRef" href="#bib2890"><span class="elsevierStyleSup">379</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Everolimus vs placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">362&#47;184&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;9 vs 2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;6 vs 7&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Brivanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Llovet et al&#46;&#44; 2013<a class="elsevierStyleCrossRef" href="#bib2885"><span class="elsevierStyleSup">378</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Brivanib vs placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">263&#47;132&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;2 vs 2&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#46;4 vs 8&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ramucirumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Zhu et al&#46;&#44; 2015<a class="elsevierStyleCrossRef" href="#bib2895"><span class="elsevierStyleSup">380</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ramucirumab vs placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">283&#47;282&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;5 vs 2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#46;2 vs 7&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1211132.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Molecular therapies evaluated in HCC&#46;</p>"
        ]
      ]
      6 => array:5 [
        "identificador" => "tbl0005"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Recommendations</span>&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">1&#46; Universal HBV vaccination reduces the incidence of HCC &#40;evidence 2D&#44; recommendation 1A&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">2&#46; In patients with chronic hepatitis&#44; antiviral treatments are recommended as they have proven to be able to prevent progression to cirrhosis and therefore prevent the development of HCC &#40;evidence 1A&#44; recommendation 1A&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">3&#46; Once the oncogenic liver damage is established &#40;cirrhosis&#44; or even without reaching cirrhosis in patients with HBV infection&#41;&#44; removal of the etiological agent reduces the risk of HCC&#44; but it does not eliminate it &#40;evidence 1D&#44; recommendation 2B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1211129.png"
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        ]
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      7 => array:5 [
        "identificador" => "tbl0010"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Recommendations</span>&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">4&#46; The patients with liver cirrhosis should be considered for participation in screening programmes &#40;evidence 1B&#44; recommendation 1A&#47;B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">5&#46; The most appropriate screening technique is abdominal ultrasound performed by expert staff &#40;evidence 2B&#44; recommendation 1B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">6&#46; AFP use is not recommended as a screening technique &#40;evidence 3D&#44; recommendation 2B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">7&#46; Abdominal ultrasound screening should be performed every 6 months&#46; The screening interval need not be shortened in patients at increased risk of HCC &#40;evidence 2B&#44; recommendation 2B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1211127.png"
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            ]
          ]
        ]
      ]
      8 => array:5 [
        "identificador" => "tbl0015"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Recommendations</span>&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">8&#46; Nodules<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>cm detected by ultrasound screening should be monitored by ultrasound every 3&#8211;6 months&#46; If no growth is detected after two years&#44; the patient should return to routine screening every 6 months &#40;evidence 3D&#44; recommendation 2B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">9&#46; Nodules<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>cm detected by ultrasound in cirrhotic patients may be diagnosed with HCC without being histologically confirmed if they present with a contrast enhancement in the arterial phase followed by washout in venous phases in an imaging technique &#40;Dynamic CT and MRI&#41; &#40;evidence 2D&#44; recommendation 1A&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">10&#46; If the vascular pattern is not HCC-specific a diagnostic nodule puncture should be recommended &#40;evidence 2D&#44; recommendation 1A&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">11&#46; If the pathological analysis is negative&#44; the diagnosis of HCC cannot be ruled out&#46; Performing a new diagnostic puncture or close monitoring of the lesion should be assessed &#40;evidence 2D&#44; recommendation 1A&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">12&#46; In the case of patients without established cirrhosis&#44; the application of these imaging criteria is not valid and puncture for diagnosis would be necessary &#40;evidence 2D&#44; recommendation 2A&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">13&#46; The determination of AFP is not useful for the diagnosis of HCC &#40;evidence 2D&#44; recommendation 2A&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1211134.png"
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      ]
      9 => array:5 [
        "identificador" => "tbl0020"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Recommendation&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">14&#46; Tumour stage&#44; liver function and the presence of symptoms must be considered in order to assess HCC prognosis&#46; The BCLC system takes into account these parameters and is the only system that relates the prognostic prediction with the recommended therapeutic option &#40;evidence 2A&#59; recommendation 1B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1211135.png"
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        ]
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      10 => array:5 [
        "identificador" => "tbl0025"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Recommendations</span>&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">15&#46; Surgical resection is recommended in patients with single HCC on non-cirrhotic livers or cirrhotic patients with preserved liver function&#44; normal bilirubin and portal pressure gradient below 10<span class="elsevierStyleHsp" style=""></span>mmHg&#46; If these criteria are exceeded&#44; survival is significantly lower &#40;evidence 2A&#44; recommendation 1B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">16&#46; At present there is no adjuvant treatment proven effective in preventing recurrence &#40;evidence 1D&#44; recommendation 2C&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1211128.png"
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            ]
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        ]
      ]
      11 => array:5 [
        "identificador" => "tbl0030"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Recommendations</span>&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">17&#46; Liver transplantation is an effective option for patients presenting with HCC that meets the Milan criteria&#58; single tumour<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>cm or up to 3<span class="elsevierStyleHsp" style=""></span>nodules<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>cm &#40;evidence 2A&#44; recommendation 1A&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">18&#46; The living donor liver transplantation is a valid option if the waiting time is long enough to consider that there may be risk of exclusion due to tumour progression &#40;evidence 2A&#44; recommendation 2B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">19&#46;- No recommendation can be made regarding the expansion of the inclusion criteria beyond the conventional Milan criteria &#40;evidence 2B&#44; recomendaci&#243;n2B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">20&#46; The preoperative locoregional treatment may be considered when the expected waiting time is greater than 6 months &#40;evidence 2D&#44; recommendation 2B&#41;&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1211123.png"
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        ]
      ]
      12 => array:5 [
        "identificador" => "tbl0035"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => false
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