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KEY CONCEPTS

  • Risk factors for liver cirrhosis and hepatocellular carcinoma (HCC) include chronic hepatitis B and C infections, metabolic syndrome, and alcohol abuse. Hepatology management of risk factors reduces the risk of cancer recurrence.

  • Treatment for HCC is multidisciplinary and involves hepatology; interventional radiology; and medical, surgical, and radiation oncology.

  • Surgical resection is considered for patients who have small-volume disease without portal hypertension. Those with portal hypertension receive locoregional and/or radiation therapy, and liver transplantation is considered.

  • Systemic therapy is recommended for patients with advanced or metastatic HCC, and locoregional and radiation therapy are combined in eligible patients.

  • Targeted therapy (anti-vascular endothelial growth factor and tyrosine kinase inhibitors) and immune checkpoint inhibitors are two main backbones of systemic therapy. These include sorafenib, lenvatinib, atezolizumab with bevacizumab, nivolumab with and without ipilimumab, pembrolizumab, cabozantinib, regorafenib, and ramucirumab.

  • There are no established guidelines for fibrolamellar HCC (FLHCC) and combined HCC-cholangiocarcinoma (cHCC-CC). Systemic therapy such as 5-fluorouracil plus interferon-α2b for FLHCC and platinum-based chemotherapy for cHCC-CC is combined with surgical resection and locoregional and radiation therapy.

INTRODUCTION

Hepatocellular carcinoma (HCC) is a malignancy of worldwide significance and has become increasingly important in the United States (US). It is the most common primary liver malignancy, the sixth most common cancer, and the third most common cause of cancer-related deaths worldwide.1 Eighty percent of new cases occur in developing countries, but the incidence is rising in economically developed regions, including Japan, Western Europe, and the US.2–5 Liver cirrhosis is the seventh leading cause of death in the world, the tenth most common cause of death in the US, and is acknowledged as a premalignant condition for developing HCC.6,7

In the US, hepatitis C virus (HCV), alcohol use, and nonalcoholic fatty liver disease (NAFLD) are the most common causes of cirrhosis.8 The incidence of HCC doubled between the years 1975 to 1995 and continued to rise through 1998.9,10 This trend was previously expected to continue because of the estimated 4 million US individuals who are HCV-seropositive and the known latency of HCC development from the initial HCV infection, which may take two to three decades.10 However, given the improved treatment regimens now available for patients with chronic HCV, HCV-related HCC incidence may decrease in the next few years.11 It is also known that NAFLD-associated cirrhosis is on the rise in the US.12–14 A majority of patients diagnosed with HCC present with advanced disease that is not amenable to curative procedures.

EPIDEMIOLOGY

Hepatocellular carcinoma represents approximately 85% of all primary liver cancers.15 The distribution of HCC varies significantly by geography; it is endemic in parts of the world where hepatitis B virus (HBV) is also endemic. In Western countries, HCV infection and alcoholic cirrhosis are the principal risk factors for HCC. Because of the rising incidence of HCV infection in American subpopulations, ...

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