Hepatocellular carcinoma: systemic therapies and future perspectives

Abstract

Hepatocellular carcinoma is (HCC) the most common primary malignancy of the liver in adults. It is also the fifth most common solid cancer worldwide and the third leading cause of cancer-related deaths. Treatment options for HCC include liver transplantation, surgical resection, locoregional therapies and chemotherapy. The median survival time of patients following the diagnosis of unresectable disease is approximately 6–20 months, whereas the 5-year survival is less than 5%. Given the projected increase in incidence of HCC due to hepatitis C virus infection and obesity related cirrhosis, there is an urgent need for more intensive research in this cancer. In this article, we review the systemic options available for patients with HCC, its molecular pathogenesis and future therapeutic directions with special emphasis on immune-based and molecularly-targeted therapy.

Keywords::

• biomarkers
• hepatocellular carcinoma
• immune therapy
• liver transplantation
• locoregional therapy
• partial hepatectomy
• sorafenib

Financial & competing interests disclosures

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Hepatocellular carcinoma (HCC) is the fifth most common solid cancer worldwide and the third leading cause of cancer-related deaths.

• Liver transplantation and surgery are potentially curative options in patients with early HCC.

• Locoregional treatment is typically used in patients with HCC who are not candidates for resection or transplantation.

• Sorafenib remains the only systemic treatment for patients with advanced HCC.

• Several signaling pathways have been identified in HCC and include the mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt/mammalian target of rapamycin, c-MET, IGF, Wnt-β-catenin, hedgehog, VEGF and PDGF pathways.

• Angiogenesis and neovascularization are important events for HCC growth and metastasis. Most angiogenesis inhibitors (except sorafenib), however, have failed to demonstrate clinically meaningful benefits in patients with HCC.

• HCC development is typically associated with marked dysfunction in the immune surveillance of cancer development and tumor growth in the body. Mechanisms of immune dysfunction include partial antigen masking, failure of antigen processing, suppression of effector cells and inadequate co-stimulation.

• Several immune therapies are in various stages of clinical development in HCC and represent a promising treatment modality.

• Further understanding of the molecular mechanisms of HCC and development of predictive biomarkers to identify subtypes of HCC that will preferentially respond to available targeted therapies is needed to improve the outcome of patients with this dreadful tumor.

Notes