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EASL–EORTC Clinical Practice Guidelines (CPG) on the management of hepatocellular carcinoma (HCC) define the use of surveillance, diagnosis, and therapeutic strategies recommended for patients with this type of cancer. This is the first European joint effort by the European Association for the Study of the Liver (EASL) and the European Organization for Research and Treatment of Cancer (EORTC) to provide common guidelines for the management of hepatocellular carcinoma. These guidelines update the recommendations reported by the EASL panel of experts in HCC published in 2001 [
]. Several clinical and scientific advances have occurred during the past decade and, thus, a modern version of the document is urgently needed.
The purpose of this document is to assist physicians, patients, health-care providers, and health-policy makers from Europe and worldwide in the decision-making process according to evidence-based data. Users of these guidelines should be aware that the recommendations are intended to guide clinical practice in circumstances where all possible resources and therapies are available. Thus, they should adapt the recommendations to their local regulations and/or team capacities, infrastructure, and cost–benefit strategies. Finally, this document sets out some recommendations that should be instrumental in advancing the research and knowledge of this disease and ultimately contribute to improve patient care.
The EASL–EORTC CPG on the management of hepatocellular carcinoma provide recommendations based on the level of evidence and the strength of the data (the classification of evidence is adapted from National Cancer Institute [
∗The randomized, double-blinded controlled clinical trial (1i) is the gold standard of study design. Meta-analyses of randomized studies are placed in the same category of strength of evidence as are randomized studies.
∗∗This category includes trials in which treatment allocation was made by birth date, chart number (so-called quasi randomized studies) or subset analyses of randomized studies (or randomized phase II studies).
∗∗∗All other prospective (cohort studies) or retrospective studies (case–control studies, case series).
#These end-points may be subjected to investigator interpretation. More importantly, they may, but do not automatically, translate into direct patient benefit such as survival or quality of life. Nevertheless, it is rational in many circumstances to use a treatment that improves these surrogate end-points while awaiting a more definitive end-point to support its use.
The burden of cancer is increasing worldwide. Each year there are 10.9 million new cases of cancer and 6.7 million cancer-related deaths. The most commonly diagnosed cancers are lung, breast, and colorectal while the most common causes of cancer death are lung, stomach, and liver [
]. In Chinese and in black African populations, the mean age of patients with the tumor is appreciably younger. This is in sharp contrast to Japan, where the incidence of HCC is highest in the cohort of men aged 70–79 years [
]. In developed regions, the incidence is low with the exception of Southern Europe where the incidence in men (10.5 age-standardized incidence rates per 100,000) is significantly higher than in other developed regions [
There is a growing incidence of HCC worldwide. Overall, the incidence and mortality rates were of 65,000 and 60,240 cases in Europe and 21,000 and 18,400 cases in the United States in 2008, respectively. It is estimated that by 2020 the number of cases will reach 78,000 and 27,000, respectively [
]. People infected with HCV in Europe during the period 1940–60 and in the United States of America (USA) one decade later led to the current increase of HCC incidence. In Europe, the incidence and mortality rates reported are heterogeneous. HCC mortality during the last decades increased in males in most of the countries (i.e. Austria, Denmark, Germany, Greece, Ireland, Portugal, Norway, Spain, Switzerland, and United Kingdom), but decreased in others (Finland, France, Italy, Netherlands, and Sweden) [
]. In the United States, the rate of HCC deaths appears to have increased by about 40% over the period 1990–2004, whereas the overall rate of cancer deaths has declined by about 18% during this same period [
]. Besides the emergence of liver disease due to hepatitis C, this growth in incidence may be also due to an increase in HBV-related HCC, particularly among immigrants from endemic countries. Conversely, in Japan, a country where the impact of HCV-related HCC was first noticed after World War II, there has been an apparent decline in the incidence of this neoplasm for the first time since 1990 [
]. Finally, the impact of universal infant vaccination against HBV has decreased the rate of HBV-related HCC in endemic countries. So far, this has been observed among children in Taiwan, but it is expected to become more apparent as these vaccinated children grow into adults [
Approximately 90% of HCCs are associated with a known underlying risk factor (Table 2). The most frequent factors include chronic viral hepatitis (types B and C), alcohol intake and aflatoxin exposure. In Africa and East Asia, the largest attributable fraction is due to hepatitis B (60%) whereas in the developed Western world, only 20% of cases can be attributed to HBV infection, while chronic hepatitis C appears to be the major risk factor [
]. Worldwide, approximately 54% of cases can be attributed to HBV infection (which affects 400 million people globally) while 31% can be attributed to HCV infection (which affects 170 million people), leaving approximately 15% associated with other causes.
Table 2Geographical distribution of main risk factors for HCC worldwide.∗
Cirrhosis is an important risk factor for HCC, and may be caused by chronic viral hepatitis, alcohol, inherited metabolic diseases such as hemochromatosis or alpha-1-antitrypsin deficiency, and non-alcoholic fatty liver disease. All etiologic forms of cirrhosis may be complicated by tumor formation, but the risk is higher in patients with hepatitis infection. Overall, one-third of cirrhotic patients will develop HCC during their lifetime [
]. Long-term follow-up studies have demonstrated that approximately 1–8% per year of patients with cirrhosis develop HCC (e.g. 2% in HBV-infected cirrhotic patients and 3–8% in HCV-infected cirrhotic patients) [
]. In general, features of liver disease severity (low platelet count of less than 100 × 103, presence of esophageal varices), in addition to older age and male gender, correlate with HCC development among patients with cirrhosis [
Dietary exposure to aflatoxin B1, derived from the fungi Aspergillus flavus and A. parasiticus, is an important co-factor for HCC development in some parts of Africa and Asia. These molds are ubiquitous in nature and contaminate a number of staple foodstuffs in tropical and subtropical regions. Epidemiologic studies have shown a strong correlation between the dietary intake of aflatoxin B1, TP53 mutations and incidence of HCC, specifically in HBV-infected individuals [
], although the mechanisms by which these overlapping conditions contribute to cancer development remain elusive. Cirrhosis due to non-alcoholic steatohepatitis may give rise to HCC but it appears that these factors may also be additive to chronic viral hepatitis [
]. Heavy smokers have a higher risk than non-smokers. In the general population, the incidence of HCC is increased among patients with HIV infection compared to controls, and HIV appears to be an additive co-factor, exacerbating the risk of HCC in patients with chronic viral hepatitis [
Identification of mutations in germline DNA that define patients at high risk of developing cancer has become a challenge for surveillance programs and chemopreventive strategies. This is the case of mutations in BRCA1 or BRCA2 and increased risk of breast or ovarian cancer [
]. Since perinatal or early postnatal transmission is an important cause of chronic HBV infections globally, the first dose of hepatitis B vaccine should be given as soon as possible after birth, even in low-endemicity countries (those with prevalence of HBsAg carriers <2%). Vaccination is also recommended in age-specific cohorts (young adolescents) and people with risk factors for acquiring HBV infection (i.e. health workers, travellers to areas where HBV-infection is prevalent, injecting drug users, and people with multiple sex partners).
Antiviral treatment for patients with chronic hepatitis B and C infection should follow the recommendations from existing EASL guidelines [
]. Interferon, lamivudine, adefovir, entecavir, telbivudine and tenofovir are now available for HBV treatment, but long-term follow-up data assessing their effect in secondary prevention are only available with interferon and lamivudine. Observational studies assessing the effect of interferon showed a potential effect in reduction of HCC incidence [
]. Similarly, a randomized controlled trial (RCT) assessing the effect of lamivudine showed a significant reduction in HCC incidence. Nonetheless, there are some concerns regarding the effects obtained in this study as prevention of HCC occurrence was not the primary end-point of the study, and because the marginal effect obtained disappeared once adjusted for co-variables [
]. As a result, it appears prudent to conclude that surveillance for HCC should be maintained in those patients who already qualified before starting the treatment.
In hepatitis C viral infection, the results of a meta-analysis of retrospective studies suggest that the risk of HCC is reduced among patients with HCV who achieve a sustained virological response (SVR) with antiviral therapy with interferon–ribavirin [
Surveillance consists of the periodic application of a diagnostic test to subjects at risk for developing a given disease. Its usefulness and applicability are influenced by several factors, such as the incidence of the surveyed disease in the target population, the availability of efficient diagnostic test(s) at bearable costs and their acceptability by the target population, and the availability of treatments and their effectiveness [
]. The aim of surveillance is to obtain a reduction in disease-related mortality. This is usually achieved through an early diagnosis (stage migration) that, in turn, enhances the applicability and cost–effectiveness of curative therapies. Stage migration, however, cannot serve as a surrogate for the main end-point, which is patient survival.
HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified because of the presence of underlying viral hepatitis or other liver diseases. In fact, in the Western world, HCC arises in a cirrhotic background in up to 90% of cases [
], and cirrhosis itself is a progressive disease that affects patient survival. The presence of cirrhosis then influences the chances for anti-tumoral treatment and affects their results, thus rendering early diagnosis of HCC even more crucial. Moreover, many available treatments can have an adverse impact on cirrhosis, and the exact cause of death, which could be either the underlying disease or HCC, cannot be clearly defined in some instances. For this reason, a reduction in overall mortality represents a more appropriate end-point to assess the efficacy of surveillance.
Decision analysis and cost–effectiveness models suggest that an intervention is considered cost-effective if it provides gains of life expectancy of at least 3 months with a cost lower than approximately US$ 50,000 per year of life saved [
Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of hepatocarcinogenesis by interferon therapy.
] and hence exclude them from surveillance, thereby saving costs although this approach is not proven yet. Conversely, the presence of advanced cirrhosis (Child–Pugh class C) prevents potentially curative therapies from being employed, and thus surveillance is not cost-effective in these patients [
]. As an exception, patients on the waiting list for liver transplantation, regardless of the liver functional status, should be screened for HCC in order to detect tumors exceeding conventional criteria and to help define priority policies for transplantation. Finally, although it seems intuitive that surveillance might not be cost-effective above a certain age cut-off, the lack of data prevents the adoption of any specific recommendation.
Patients with chronic HBV infection are at risk of HCC development even in the absence of cirrhosis. In these cases, the recommended cut-off of annual incidence above which surveillance should be recommended cannot be applied. The cut-off of annual incidence in these patients is ill-defined, albeit expert opinion indicates that it would be warranted if HCC incidence is at least 0.2%/year [
]. Thus, cost–benefit modeling is needed in this scenario. The incidence of HCC in adult Asian or African active HBV carriers or with a family history of HCC exceeds this value, whereas HCC incidence ranges from 0.1% to 0.4%/year in Western patients with chronic HBV infection [
Unfortunately, there is scanty and sometimes contradictory information on the incidence of HCC in patients with chronic hepatitis C without cirrhosis. Data from Japan would suggest that patients with mild fibrosis have a yearly HCC incidence of 0.5% [
Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of hepatocarcinogenesis by interferon therapy.
Information about the incidence of HCC in patients with non-viral chronic liver disease without cirrhosis, such as non-alcoholic and alcoholic steatohepatitis, autoimmune liver disease, genetic hemochromatosis, α1-antitripsin deficiency, and Wilson disease is limited [
], whereas the risk of HCC development is not established in non-cirrhotic individuals.
Treated viral chronic hepatitis
Recent advances in therapy have led to relatively high rates of viral clearance or suppression among those patients being treated for chronic hepatitis B or C. Successful treatment, leading to sustained virological response in chronic hepatitis C, and HBeAg seroconversion or sustained HBV-DNA suppression in chronic hepatitis B, decreases, but does not eliminate the risk of HCC [
]. Surveillance should be offered to treated patients with chronic hepatitis B who remain at risk of HCC development due to baseline factors, or to those with HCV-induced advanced fibrosis or cirrhosis, even after achieving sustained virological response.
Tests that can be used in HCC surveillance include serological and imaging examinations. The imaging test most widely used for surveillance is ultrasonography (US). US has an acceptable diagnostic accuracy when used as a surveillance test (sensitivity ranging from 58% to 89%; specificity greater than 90%) [
]. A recent meta-analysis including 19 studies has showed that US surveillance detected the majority of HCC tumors before they presented clinically, with a pooled sensitivity of 94%. However, US was less effective for detecting early-stage HCC, with a sensitivity of only 63% [
]. In contrast, in a recent Japanese cohort including 1432 patients, careful US surveillance performed by highly skilled operators resulted in an average size of the detected tumors of 1.6 ± 0.6 cm, with less than 2% of the cases exceeding 3 cm [
The widespread popularity of US also relies on the absence of risks, non-invasiveness, good acceptance by patients and relatively moderate cost. Nonetheless, US detection of HCC on a cirrhotic background is a challenging issue. Liver cirrhosis is characterized by fibrous septa and regenerative nodules. These features produce a coarse pattern on US, which may impair identification of small tumors. Because of these limitations, the performance of US in early detection of HCC is highly dependent on the expertise of the operator and the quality of the equipment. Thus, special training for ultrasonographers is recommended. The recent introduction of US contrast agents has not proven to increase the ability of US to detect small HCC tumors [
There are no data to support the use of multidetector CT or dynamic MR imaging for surveillance. Practical experience suggests that the rate of false-positive results that will trigger further investigation is very high and non-cost-effective. These circumstances are overcome in the setting of the waiting list for liver transplantation where CT scan or MRI are alternatives to US. These techniques should be also considered when obesity, intestinal gas, and chest wall deformity prevent an adequate US assessment. Even in these circumstances, radiation risk due to repeated exposure to CT scan and high cost of MR make debatable their use in long-term surveillance.
Serological tests that have been investigated or are under investigation for early diagnosis of HCC include alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP) – also known as prothrombin induced by Vitamin K Absence II (PIVKA II) – the ratio of glycosylated AFP (L3 fraction) to total AFP, alpha-fucosidase, and glypican 3 [
]. Of note is that AFP has been mostly tested in the diagnostic mode rather than for surveillance. This is relevant, since its performance as a diagnostic test cannot be extrapolated to the surveillance setting. As a serological test for surveillance, AFP has a suboptimal performance. One randomized study [
]. However, when combined with US, AFP levels are only able to provide additional detection in 6–8% of cases not previously identified by US. Reasons for the suboptimal performance of AFP as a serological test in the surveillance mode are twofold. Firstly, fluctuating levels of AFP in patients with cirrhosis might reflect flares of HBV or HCV infection, exacerbation of underlying liver disease or HCC development [
]. Secondly, only a small proportion of tumors at an early stage (10–20%) present with abnormal AFP serum levels, a fact that has been recently correlated with a molecular subclass of aggressive HCCs (S2 class, EpCAM positive) [
]. When used as a diagnostic test, AFP levels at a value of 20 ng/ml show good sensitivity but low specificity, whereas at higher cut-offs of 200 ng/ml the sensitivity drops to 22% with high specificity [
All other serum markers have usually been evaluated, alone or in combination, in a diagnostic rather than surveillance setting. Moreover, their diagnostic performance has often been assessed at an HCC prevalence remarkably higher than that expected in the context of surveillance [
In conclusion, US can be seen as the most appropriate test to perform surveillance. The combination with AFP is not recommended, as the 6–8% gain in the detection rate does not counterbalance the increase in false positive results, ultimately leading to an about 80% increase in the cost of each small HCC diagnosed [
Two randomized controlled trials have been published on HCC surveillance. In one population-based study cluster randomization (randomizing entire villages) was performed comparing surveillance (US and AFP measurements every 6 months) versus no surveillance in a population of Chinese patients with chronic hepatitis B infection, regardless of the presence of cirrhosis [
]. Despite suboptimal adherence to the surveillance program (55%), HCC-related mortality was reduced by 37% in the surveillance arm as a result of increased applicability of resection in detected cases. The other AFP-based surveillance study carried out in Qidong (China) in high-risk individuals (males, HBsAg+) did not identify differences in overall survival [
]. However, these studies are heterogeneous as far as stage and etiology of liver disease, and surveillance protocols. Moreover, almost all suffer from methodological biases such as lead-time bias (apparent improvement of survival due to an anticipated diagnosis) and length time bias (over-representation of slower-growing tumors). While the latter is unavoidable in this type of study, lead-time bias can be minimized using correction formulas. When this was done, the advantage of surveillance remained [
The ideal interval of surveillance for HCC should be dictated by two main features: rate of tumor growth up to the limit of its detectability, and tumor incidence in the target population. Based on available knowledge on mean HCC volume doubling time [
]. In light of available knowledge, a 6-month scheduled surveillance appears the preferable choice. Further trials in this setting would be difficult to implement.
Recall policy is crucial for the success of surveillance procedures. It consists of a defined algorithm to be followed when surveillance tests show an abnormal result. This definition must take into account the ideal target of surveillance, i.e. the identification of HCC at a very early stage (2 cm or less), when radical treatments can be applied with the highest probability of long-term cure [
]. These new nodules should trigger the recall strategy for diagnosis with non-invasive or invasive (biopsy) criteria, as described in the section of diagnosis. If a diagnosis cannot be reached with non-invasive criteria due to atypical radiological appearance, then biopsy is recommended. If even biopsy provides inconclusive results, then a tight follow-up every 4 months is recommended. A second biopsy can be considered in case of growth or change in the enhancement pattern. Upon detection of a suspicious nodule, the recommended policy is to evaluate the patient in a referral center with appropriate human and technical resources [
Nowadays, early HCC diagnosis is feasible in 30–60% of cases in developed countries and this enables the application of curative treatments. In fact, while tumors less than 2 cm in diameter represented <5% of the cases in the early nineties in Europe, currently they represent up to 30% of cases in Japan. This trend is expected to continue growing in parallel to the wider implementation of surveillance policies in developed countries [
Proper definition of nodules as pre-neoplastic lesions or early HCC has critical implications. Dysplastic lesions should be followed by regular imaging studies, since at least one-third of them develop a malignant phenotype [
]. Conversely, early tumors are treated with potentially curative procedures – albeit expensive – such as resection, transplantation and percutaneous ablation. Thus, there is an urgent need to identify better tools to characterize these lesions. Otherwise, the cost–effectiveness of the recall policies applied within surveillance programs will be significantly undermined.
Accurate diagnosis of small liver nodules is of paramount importance. Until 2000, diagnosis was based on biopsy. This approach had some limitations related to feasibility due to location and risk of complications, such as bleeding or needle-track seeding [
]. In addition, achieving accuracy in differentiating between high-grade dysplastic nodules and early HCCs was complex, since stromal invasion, the most relevant criteria, is difficult to recognize even for an expert pathologist [
]. In principle, a unique dynamic radiological behavior (contrast up-take in the arterial phase by CT, MRI, angiography or US) represented the backbone of radiological diagnosis of early HCC. In cirrhotic patients with nodules >2 cm, coincidental findings by two imaging techniques were considered diagnostic, or alternatively, one imaging technique along with AFP levels above 400 ng/ml. In all other circumstances biopsy was mandatory. In 2005, the EASL panel of experts and the American Association for the Study of Liver Diseases (AASLD) guidelines adopted a new HCC radiological hallmark, i.e. contrast uptake in the arterial phase and washout in the venous/late phase [
]. Non-invasive diagnosis was established by one imaging technique in nodules above 2 cm showing the HCC radiological hallmark and two coincidental techniques with nodules of 1–2 cm in diameter (CT, MRI and US-contrast). AFP levels were dropped from the diagnostic scheme [
In order to update the EASL guidelines for non-invasive diagnostic criteria of HCC, two questions are posed. First, what data provides reliable non-invasive diagnostic accuracy for nodules of 1–2 cm in diameter taking into account that the recommendations apply to a wide range of expert physicians and radiologists. And second, what imaging techniques can be used. Regarding the first issue, two prospective studies have shown that using 2 imaging techniques is an approach with high PPV and specificity [
]. In one study including 89 consecutive cases of nodules between 0.5 and 2 cm detected within surveillance programs in cirrhotic patients showed that non-invasive criteria are accurate for the diagnosis of HCC, with a specificity of 100% [
]. Unfortunately, such an absolute specificity had the downside of a low sensitivity of 30%, meaning that two-thirds of nodules required pathological confirmation. The other study suggested that the use of a sequential algorithm would maintain an absolute specificity but increase the sensitivity, with significant savings in terms of liver biopsy procedures for nodules of 1–2 cm [
]. Finally, a recent prospective study, testing the accuracy of imaging techniques in nodules between 1 and 2 cm detected by ultrasound, showed false positive diagnosis – mostly due to high grade dysplastic nodules – above 10% with either 1 or 2 imaging techniques, with a specificity of 81% and 85%, respectively [
]. Hence, the non-invasive diagnosis of 1–2 cm lesions remains a challenging issue, with no unequivocal data in prospective validation studies. While the panel considers incorporating the 1 technique rule in order to have a consistent approach in the field, a more cautious application of this rule is recommended in suboptimal settings, where the technology at disposal or the local skills are not at the high-end level. In these circumstances, we recommended to use two coincidental techniques, since the negative consequences of high rates of false-positive diagnosis offset the benefit. Additional prospective studies to confirm the accuracy of this approach are recommended in order to support a more strong recommendation at the 1A level.
Regarding which imaging techniques should be used, it has to be pointed out the fact that the HCC radiological hallmark is based on the tumor vascular dynamic performance. This limits the usage of US-contrast – since US microbubbles are confined to the intravascular space – as opposed to iodinated contrast-CT or gadolinium-based MR imaging, in which standard contrast agents are rapidly cleared from the blood pool into the extracellular space. A recent study showed that lesions other than HCC, i.e. cholangiocarcinoma, displayed homogeneous contrast uptake at US-contrast followed by washout, i.e. the vascular pattern assumed to represent the hallmark of HCC [
], and thus biopsy or tissue biomarkers will be required in most instances. Delaying diagnosis beyond 2 cm leads to increased levels of treatment failure or recurrence, since it is known that satellites and microscopic vascular invasion rise exponentially beyond this size cut-off [
] and is recommended for all nodules occurring in non-cirrhotic livers, and for those cases with inconclusive or atypical imaging appearance in cirrhotic livers. Sensitivity of liver biopsy depends upon location, size and expertise, and might range between 70% and 90% for all tumor sizes. Pathological diagnosis is particularly complex for nodules between 1 and 2 cm [
]. Morphological criteria alone still pose problems for the differential diagnosis of high-grade dysplastic nodules versus early HCC, especially because the pathological hallmark of HCC, stromal invasion, can be absent or difficult to identify in biopsy specimens [
]. Thus, a positive tumor biopsy is clinically useful to rule in a diagnosis of HCC, but a negative biopsy does not rule out malignancy. The risk of tumor seeding after liver biopsy is 2.7% with a median time interval between biopsy and seeding of 17 months [
Tissue markers might provide a more across-the-board standardized diagnosis of these tumors. Distinct technologies such as genome-wide DNA microarray, qRT-PCR, proteomic and inmunostaining studies have been used in an attempt to identify markers of early diagnosis of HCC. Few studies, however, include a thorough analysis of several markers in a training-validation scheme and with a sufficient number of samples [
]. Similarly, a three-gene signature (the genes that encode GPC3, LYVE1, and survivin) has been proposed as an accurate molecular tool (>80% accuracy) to discriminate between dysplastic nodules and small HCCs (<2 cm) [
The diagnostic performance of some markers of early HCC identified by genomic studies has been prospectively assessed by immunohistochemistry, a low-cost technique. By examining the tissue, the pathologist can select a representative tumor sample without necrosis or inflammation and define the cell type expressing protein markers and the specific pattern. A promising marker is GPC3, which shows a sensitivity of 68–72% with a specificity superior to 92% [
Tremosini S, Forner A, Boix L, Rimola J, Rodríguez de Lope C, Reig M, et al. Biopsy diagnosis of hepatocellular carcinoma <2 cm: prospective validation of glypican 3, heat-shock protein 70 and glutamine synthetase staining in fine needle biopsy samples. ILCA book of abstracts; 2011.
]. Moreover, K19 recognizes biliary features in mixed forms of HCC/cholangiocarcinoma, which are not always detected on hematoxylin–eosin stain.
Assessment of disease extension
Assessment of tumor extension is critical for defining staging and treatment strategy. Several studies with pathological correlation have shown that dynamic contrast-enhanced MRI and 4-phase multidetector CT are the most effective imaging techniques for detecting tumors smaller than 2 cm. However, underestimation of 25–30% is expected even with the best state-of-the-art technology [
]. Pre-specified protocols should define the amount and rate of contrast given, the precise individualized timing of the image acquisition and image reconstruction with minimum slice thickness. Lipiodol contrast staining should not be used. Contrast-enhanced ultrasound is unable to compete with CT and MRI in terms of accuracy for detection of lesions. Bone scintigraphy can be used for evaluating bone metastases. PET-based imaging is not accurate to stage early tumors. Pre-operative staging prior to liver transplantation should include abdominal dynamic CT or MRI, chest CT and bone scintigraphy.
Cancer classification is intended to establish prognosis and enable the selection of the adequate treatment for the best candidates. In addition, it helps researchers to exchange information and design clinical trials with comparable criteria. In patients with HCC, unlike most solid tumors, the coexistence of two life-threatening conditions such as cancer and cirrhosis complicates prognostic assessments [
]. Thus, staging systems for this cancer should be designed with data coming from two sources. First, prognostic variables obtained from studies describing the natural history of cancer and cirrhosis. Second, treatment-dependent variables obtained from evidence-based studies providing the rationale for assigning a given therapy to patients in a given subclass.
Based on data reporting the natural history of the disease, the main clinical prognostic factors in HCC patients are related to tumor status (defined by number and size of nodules, presence of vascular invasion, extrahepatic spread), liver function (defined by Child–Pugh’s class, bilirubin, albumin, portal hypertension, ascites) and general health status (defined by ECOG classification and presence of symptoms) [
]. According to these rules, acceptable biomarkers should be obtained from randomized investigations, as is the case with KRAS status and response to cetuximab in colon cancer. Only in particularly compelling circumstances can prognostic or predictive markers tested in cohort studies be adopted in clinical practice. The panel recommends to incorporate biomarkers for the management of HCC when the following requirements are met: (1) demonstrate prognostic prediction in properly powered randomized studies or in training and validation sets from cohort studies; (2) demonstrate independent prognostic value in mutivariate analysis, including known clinico-pathological predictive variables; and (3) confirmation of results using the same technology in an external cohort reported by independent investigators. None of the biomarkers tested so far fulfil these criteria in HCC, but four just require external validation by independent groups: gene signatures or biomarkers from the tumor (EpCAM signature, G3-proliferation subclass, and miR-26a) [
]). The heterogeneity of the above studies prevents the formulation of a clear recommendation, but it is advised to test levels >200 and/or >400 ng/ml as prognostic factors of poor outcome in research investigations.
Several staging systems have been proposed to provide a clinical classification of HCC. In oncology, the standard classification of cancer is based on the TNM staging. In HCC, the 7th TNM edition in accordance with the AJCC [
]. First, pathological information is required to assess microvascular invasion, which is only available in patients treated by surgery (∼20%). In addition, it does not capture information regarding liver functional status or health status. One-dimensional systems, such as the Okuda staging and the Child–Pugh classification, albeit popular, serve purposes distinct to class prediction in HCC patients. Among more comprehensive staging systems, five have been broadly tested, three European (the French classification [
Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients.
Validation of a new prognostic staging system for hepatocellular carcinoma: a comparison of the biomarker-combined Japan Integrated Staging Score, the conventional Japan Integrated Staging Score and the BALAD Score.
]). The CUPI and CLIP scores largely subclassify patients at advanced stages, with a small number of effectively treated patients. Overall, few of the most used systems or scores have been externally validated (BCLC, CUPI, CLIP, and bm-JIS), only two include the three types of prognostic variables (BCLC, CUPI) and only one assigns treatment allocation to specific prognostic subclasses (BCLC).
The current EASL–EORTC GP guidelines endorse the Barcelona-Clínic Liver Cancer (BCLC) classification for several reasons [
]. It includes prognostic variables related to tumor status, liver function and health performance status along with treatment-dependant variables obtained from cohort studies and randomized trials. It has been externally validated in different clinical settings [
]. This is an evolving system that links tumor stage with treatment strategy in a dynamic manner enabling the incorporation of novel advancements in the understanding of the prognosis or management of HCC. In this regard, the seminal classification reported in 1999 [
]. As discussed below, further refinements in class stratification (for instance to incorporate biomarkers) or treatment allocation resulting from positive high-end trials are expected in the following years. The BCLC classification was first endorsed by the EASL [
BCLC classification: outcome prediction and treatment allocation
The Barcelona-Clínic Liver Cancer (BCLC) classification divides HCC patients in 5 stages (0, A, B, C and D) according to pre-established prognostic variables, and allocates therapies according to treatment-related status (Fig. 3). Thus, it provides information on both prognostic prediction and treatment allocation. Prognosis prediction is defined by variables related to tumor status (size, number, vascular invasion, N1, M1), liver function (Child–Pugh’s) and health status (ECOG). Treatment allocation incorporates treatment dependant variables, which have been shown to influence therapeutic outcome, such as bilirubin, portal hypertension or presence of symptoms-ECOG.
Very early HCC (BCLC stage 0) is defined as the presence of a single tumor <2 cm in diameter without vascular invasion/satellites in patients with good health status (ECOG-0) and well-preserved liver function (Child–Pugh A class). Nowadays, 5–10% of patients in the West are diagnosed at this stage while in Japan the figure is almost 30% due to the widespread implementation of surveillance programs [
]. From pathological studies, though, two subclasses of tumors have been defined: vaguely nodular type – size around 12 mm without local invasiveness – and the distinctly nodular type – mean size 16 mm which might show local invasiveness. Vaguely nodular types are very well-differentiated HCCs that contain bile ducts and portal veins, have ill-defined nodular appearance and, by definition, do not have invaded structures. Distinctly nodular type show local metastases surrounding the nodule in 10% of cases, and microscopic portal invasion in up to 25% [
]. Therefore, some tumors smaller than 2 cm are prone to locally disseminate, but others behave as carcinoma in situ and those are defined as Stage 0. Recent data have shown a 5-year survival in 80–90% of patients with resection and liver transplantation and in 70% with local ablation [
]. Whether patients at very early stage can be offered local ablation as a first line treatment option is a topic of controversy. No RCT addressing this issue have been reported so far and comparison of cohort studies suffers from selection bias.
Early HCC (BCLC stage A) is defined in patients presenting single tumors >2 cm or 3 nodules <3 cm of diameter, ECOG-0 and Child–Pugh class A or B. Median survival of patients with early HCC reaches 50–70% at 5 years after resection, liver transplantation or local ablation in selected candidates [
]. The natural outcome of these cases is ill-defined due the scarcity of reported data, but it is estimated to be a median survival of around 36 months. An improvement in survival is universal when applying the so-called treatment-dependent variables in the selection of candidates.
Tumor status is defined by size of the main nodule and multicentricity (single 2–5 cm, 3 nodules ⩽3 cm), each of these categories showing significantly different outcomes. As discussed below, single tumors beyond 5 cm are still considered for surgical resection as first option, because if modern MRI is applied in pre-operative staging, the fact that solitary large tumors remain single and with no macrovascular involvement – which might be common in HBV-related HCC – reflects a more benign biological behavior.
Variables related to liver function are relevant for candidates to resection. Absence of clinically relevant portal hypertension and normal bilirubin are key predictors of survival in patients with single tumors undergoing resection [
]. Since liver transplantation may potentially cure both the tumor and the underlying liver disease, variables mostly related with HCC have been clearly established as prognostic factors (single tumors ⩽5 cm or 3 nodules ⩽3 cm), defining the so-called Milan criteria.
Prognosis of HCC was assumed to be poor for unresectable cases, with a median survival of less than 1 year. Analysis of heterogeneous outcomes within 25 RCT (2 year survival 8–50%) [
Burrel M, Reig M, Forner A, Barrufet M, Rodríguez de Lope C, Tremosini S, et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolization (TACE) using DC beads. Implications for clinical practice and trial design. J Hepatol, in press.
Advanced HCC (BCLC stage C): Patients with cancer related-symptoms (symptomatic tumors, ECOG 1–2), macrovascular invasion (either segmental or portal invasion) or extrahepatic spread (lymph node involvement or metastases) bear a dismal prognosis, with expected median survival times of 6 months [
]. Nonetheless, it is obvious that this outcome varies according to the liver functional status and other variables. For instance, patients with preserved liver function (Child–Pugh’s A class) have a median survival of 7 months [
], while those with severe liver impairment (Child–Pugh’s B class) present 5 months of median life expectancy. In 2006, there was no FDA-approved first line treatment for patients with advanced HCC. This scenario has changed as a result of the data reported showing survival benefits from patients receiving sorafenib – a multi tyrosine kinase inhibitor – in advanced cases [
]. The results of this RCT represent a breakthrough in the management of HCC, as it is discussed in the molecular targeted therapies section of this document. Overall median survival in the sorafenib arm was 10.7 months, ranging from 14.7 months in BCLC B and 9.5 months in BCLC C patients.
End-stage HCC: Patients with end-stage disease are characterized by presenting with tumors leading to a very poor Performance Status (ECOG 3–4), which reflects a severe tumor-related disability. Their median survival is 3–4 months [
]. Similarly, Child–Pugh C patients with tumors beyond the transplantation threshold also have a very poor prognosis.
Concept of treatment stage migration
A proportion of patients in each stage do not fulfil all the criteria for the treatment allocation. In those cases, it is advised to offer the patient the next most suitable option within the same stage or the next prognostic stage. For instance, patients at BCLC A failing local ablation should be offered chemoembolization. Similarly, patients at BCLC B stage non-responding to chemoembolization – at least two cycles of treatment – should be offered sorafenib, as reported in the SHARP trial [
]. The panel of experts acknowledges that the range of survival reported for patients at BCLC B (from 45 months to 11 months) and C (from 11 months to 5 months) deserves to be addressed. Further stratification of patients within each class according to liver function (Child–Pugh A versus B, or ascites), prognostic molecular biomarkers or prognostic variables (ECOG, cancer invasiveness) should be explored.
Molecular classification of HCC
Molecular classification of cancer should aid in understanding the biological subclasses and drivers of the disease and optimize benefits from molecular therapies and enrich trial populations. Few molecular classifications have been proposed in cancer. One such is the case of breast cancer, where Her2/nu status discriminates subgroups of patients with different outcome and treatment response to trastuzumab [
In HCC, no molecular subclass has been reported as responding to specific targeted therapy. Nonetheless, clear advancements in the understanding of the pathogenesis and molecular subclasses of the disease occurred during the last decade. From the biological standpoint, different tumoral classes have been characterized including a Wnt subclass, a proliferation class (with two subclasses: S1-TGF-beta and S2-EpCAM positive) and an inflammation class [
]. Thus, a portrait of the field effect is currently available, although further studies are required to confirm the prognostic significance of these subclasses, and whether specific drivers within them can provide the rationale for a more stratified medicine.
In oncology, the benefits of treatments should be assessed through randomized controlled trials and meta-analysis. Other sources of evidence, such as non-randomized clinical trials or observational studies are considered less robust. Few medical interventions have been thoroughly tested in HCC, in contrast with other cancers with a high prevalence worldwide, such as lung, breast, colorectal and stomach cancer. As a result, the strength of evidence for most interventions in HCC is far behind the most prevalent cancers worldwide. The level of evidence for efficacy according to trial design and end-points for all available treatments in HCC and the strength of recommendations according to GRADE are summarized in Fig. 4.
In principle, recommendations in terms of selection for different treatment strategies are based on evidence-based data in circumstances where all potential efficacious interventions are available. Multidisciplinary HCC teams including hepatologists, surgeons, oncologists, radiologists, interventional radiologists, pathologists and translational researchers are encouraged to apply these guidelines. Strategic recommendations should be adapted to local regulations and/or team capacities and cost–benefit strategies.
Surgery is the mainstay of HCC treatment. Resection and transplantation achieve the best outcomes in well-selected candidates (5-year survival of 60–80%), and compete as the first option in patients with early tumors on an intention-to-treat perspective [
], where major resections can be performed with low rates of life-threatening complications and acceptable outcome (5-year survival: 30–50%).
Modern standards of HCC resection in cirrhotic patients are defined by the panel as follows: expected 5-year survival rates of 60%, with a peri-operative mortality of 2–3% and blood transfusion requirements of less than 10% [
]. Blood loss is significantly associated with patient outcome and may be controlled both by selecting patients with preserved liver functional reserve and by applying intermittent inflow occlusion during the hepatic parenchymal transection. Nowadays the selection of candidates for resection has been refined, and both the surgical technique – pre-resection imaging planning, ultrasonic dissector, intermittent Pringle maneuvre, low central venous pressure maintenance, etc. – and immediate post-operative management have been optimized. These strategies have led to a decrease in blood transfusion from 80% to 90% to less than 10% in two decades [
]. In addition, the implementation of anatomic resections according to Couinaud has ensured a surgical approach based on sound oncologic principles, although associated with modest decrease in early recurrence [
] and are recommended only in case that the maintenance of appropriate function to the remnant liver volume is ensured. Retrospective studies linking anatomic resections and better outcome should be interpreted with caution, due to the propensity of performing wider interventions in patients with well-preserved liver function. Thus, caution should be exercised as the surgical effort is aimed at preservation of adequate hepatic reserve through tailoring of the procedures to individual patients and tumor characteristics – i.e. body size, central versus peripheral location of tumor nodule and solitary large HCC (versus infiltrating tumor types).
Selection of the ideal candidates involves an adequate assessment of the liver functional reserve and tumor extension. The refinement of assessment of liver function has moved from the gross determination of Child–Pugh class to a more sophisticated measurement of indocyanine green retention rate at 15 min (ICG15) [