Hepatocellular carcinoma: clinical frontiers and perspectives

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death and is currently the main event leading to death in patients with cirrhosis. Evolving information suggests that the metabolic syndrome with non-alcoholic liver disease may be an important cause of HCC in addition to viral hepatitis and alcohol-induced liver disease. The molecular pathogenesis is extremely complex and heterogeneous. To date the molecular information has not impacted on treatment decisions. Periodic surveillance imaging of patients with cirrhosis is widely practiced, especially because diagnostic, radiographic criteria for early-stage HCC have been defined (including nodules between 1 and 2 cm) and effective treatment is available for tumours detected at an early stage. Worldwide the approach to resection versus transplantation varies depending upon local resources, expertise and donor availability. The criteria for transplantation are discussed, and the controversial areas highlighted with evidence-based recommendations provided. Several approaches are available for intermediate stage disease, including radiofrequency ablation, transarterial chemoembolisation and radioembolisation; the rationale for these therapies is buttressed by appropriate outcome-based studies. For advanced disease, systemic therapy with sorafenib remains the option best supported by current data. Thus, while several trials have failed to improve the benefits of established therapies, studies assessing the sequential or combined application of those already known to be beneficial are needed. Also, new concepts are provided in regards to selecting and stratifying patients for second-line studies, which may help explain the failure of prior studies.

Keywords: Hepatobiliary Surgery; Hepatocellular Carcinoma; Liver; Liver Transplantation; Molecular Mechanisms.

Conflict of interest statement

Competing interests: JB declares conflicts of interest due to consultancy/research studies with Abbott, Arqule, Bayer Shering Pharma, BTG Biocompatibles, BMS, Glaxo-Welcome, Imclone, Kowa, Lilly, Novartis, OSI, Shering-Plough (Merck) and Terumo. GJG declares conflicts of interest due to consultancy with Bayer, Bristol-Meyers Squibb, Chugai, Daiichi Sanyo, Delcath, Genentech, and Generon. VM declares conflict of interest due to consultancy with Bayer and BTG Biocompatibles.

Figures

Figure 1

Macroscopic appearance of a large hepatocellular carcinoma (HCC) resected from a patient with hepatitis C virus cirrhosis. Note the heterogeneous appearance with some necrotic areas. This macroscopic appearance translates into a heterogeneous degree of cell differentiation, as well as proliferation activity at a microscopic level. Should not be unexpected to find heterogeneous genomic profile when trying to characterise the tumour at a molecular level. As a result, efforts to profile HCC patients through biopsy sampling with the goal to refine prognosis prediction and therapeutic target identification may be an unrealistic enterprise.

Figure 2

Barcelona Clinic Liver Cancer strategy for diagnosis and staging at 2012 (1). Patients are stratified into different stages according to tumour burden, liver function and physical status. Each stage is linked to the first-line treatment option that is proposed according to the available scientific evidence. It has to be stressed that the strategy applies for patients evaluated for hepatocellular carcinoma (HCC) and not for end-stage liver cirrhosis. If this is the case, patients should be evaluated for liver transplant and HCC diagnosis could merely become a contraindication if the enlisting criteria are exceeded. If transplant is not feasible, short-term prognosis is poor and HCC treatment will be of no benefit.

Figure 3

CT of a large heterogeneous hepatocellular carcinoma treated with sorafenib. The tumour is recognised as a large hypervascular mass with heterogeneous intensity of contrast uptake (left panel). Sorafenib treatment induces a reduction in vascular supply and an area of necrosis that is reflected by absence of contrast enhancement. This reduction of tumour burden is not captured by conventional RECIST and thus novel proposals to register necrosis induction have been developed and known as EASL or mRECIST criteria. Their correlation with treatment efficacy and improved outcome has been validated for ablation and chemoembolisation, but robust validation in patients treated with sorafenib or other systemic agents is lacking. Indeed, the heterogeneity of the changes and the varying pattern in different foci may prevent a robust assessment with adequate interobserver agreement. Hence, use of the registered information to attempt correlation of changes at imaging and outcome is challenging.

Figure 4

Survival data starting follow-up at different time points. It is common to describe survival after the indication of the first treatment or when recurrence or progression are registered. In most studies, the staging of the patients just takes into account the tumour burden, liver function and physical status at the time of evaluation, while the time and events between diagnosis and first treatment, and the timing and pattern of recurrence/progression is usually dismissed. This may intensely flaw the prognostic evaluation of the patients and prevent a proper design and evaluation of therapeutic interventions.