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Gastrointestinal Oncology


A Review of Targeted Therapies in the Management of Advanced-stage Hepatocellular Carcinoma


Tony Hung1 and Richard S Finn2


1. Medical Student; 2. Assistant Professor of Medicine and Director, Translational Oncology Research Laboratory and Liver Cancer Research Program, Division of Hematology/Oncology, Geffen School of Medicine, University of California, Los Angeles


Abstract


Hepatocellular carcinoma (HCC) ranks third as a leading cause of cancer death worldwide and has steadily increased in incidence. Due to the asymptomatic nature of early HCC, most patients unfortunately present with advanced or unresectable tumour. While traditional cytotoxic agents have failed to demonstrate a clear survival benefit, the development of newer, molecular targeted therapies has shown promising results in the management of HCC. Notably, sorafenib, an oral multikinase inhibitor, has proven its efficacy in two randomised phase III studies and is currently the only approved systemic therapy in HCC. While the overall survival benefit for patients on sorafenib is modest, it has highlighted the unmet medical need of patients with advanced HCC. Currently, there are several agents in development as both first-line and second-line therapies. Critical to their successful development will be the study designs and the selection of patients most likely to benefit taking into account the complex interplay between underlying liver disease/cirrhosis, cancer and outcomes. The recent failure of sunitinib, a promising oral multikinase inhibitor, because of a greater incidence of adverse events and failure to extend overall survival emphasises these points. This review highlights and summarises the evidence and ongoing challenges in the development of new molecular targeted therapy in HCC.


Keywords Hepatocellular carcinoma, sorafenib, sunitinib, bevacizumab, brivanib, erlotinib, vatalanib, cediranib, linifanib, targeted therapies


Disclosure: Tony Hung has no conflicts of interest to declare. Richard S Finn is a consultant for Bayer, Onyx, and Bristol-Myers Squibb. Received: 14 April 2011 Accepted: 13 September 2011 Citation: European Oncology & Haematology, 2011;7(4):234–9 Correspondence: Richard S Finn, 10833 Le Conte Avenue, 11-934 Factor Building, Los Angeles, CA 90095, US. E: rfinn@mednet.ucla.edu


Primary liver cancer represents about 6 % of all new cancer cases worldwide and is the third leading cause of cancer-related death after lung and gastric cancers.1


Hepatocellular carcinoma (HCC)


accounts for 85–90 % of all primary liver malignancies and is the most common primary liver malignancy in adults.2


While, in Western


Europe and North America, HCC is responsible for less than 5 % of all cancer deaths, it accounts for over a third of all cancer deaths in developing countries. China alone sees more than 55 % of all HCC cases worldwide.3


In the US, HCC is a growing problem. The HCC age-adjusted incidence rate has doubled in recent decades as a consequence of a cohort effect related to infection with hepatitis B and C.4 Worldwide, hepatitis B and C account for 80–90 % of all HCC cases.3 Other risk factors for HCC include excessive alcohol consumption, smoking, non-alcoholic steatohepatitis, autoimmune hepatitis, primary biliary cirrhosis, exposure to environmental carcinogens (particularly aflatoxin B) and the presence of various genetic metabolic diseases (such as, for example, hereditary haemochromatosis, tyrosinaemia and α-1-antitrypsin deficiency).5–7 Given the diversity of the aetiologic factors implicated in the development of HCC, the complexity of hepatocyte function, and the late stage at which the disease is usually diagnosed, it is not surprising that HCC is a highly heterogeneous tumour with often a poor prognosis.8


234


Unfortunately, because of the asymptomatic nature of early HCC, up to 80 % of patients present with unresectable HCC.9


The overall


survival (OS) rates for advanced disease are only 3–5 %.10 While surgery (resection and transplantation) and percutaneous ablation (radiofrequency ablation [RFA] and percutaneous ethanol ablation) can achieve long-term control in selected patients with early HCC, recurrence rates are as high as 50 % at three years.11 Historically, even with treatments such as transarterial chemoembolisation (TACE), intra-arterial or systemic chemotherapy, radiotherapy, immunotherapy or hormonal therapy, the 5-year relative survival rate for patients with HCC is only 7 %.12


Until recently, systemic agents, including hormonal and cytotoxic agents (alone and in combination) have had no significant therapeutic success in HCC studies.13


Several reasons for this have been put


forward. Tumour biology dictates poor chemosensitivity, which is frequently mediated by the expression of drug resistance genes. Overexpression of drug efflux pumps such as P-glycoprotein and multidrug resistance protein increases the cellular outflow of cytotoxic agents. In addition, the presence of hepatic dysfunction, which contributes to the development of most HCCs (>80 %), may hinder the delivery of drug therapy. Cirrhosis not only impairs drug metabolism, but also affects the synthesis of plasma-binding proteins that influence the serum proportion of active drug. Additionally, the fluid overload that occurs with cirrhosis can alter drug distribution volumes.


© TOUCH BRIEFINGS 2011


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