Digestive Diseases and Sciences

, Volume 64, Issue 4, pp 1016–1029 | Cite as

Systemic Management for Advanced Hepatocellular Carcinoma: A Review of the Molecular Pathways of Carcinogenesis, Current and Emerging Therapies, and Novel Treatment Strategies

  • Saad Saffo
  • Tamar H. TaddeiEmail author


Hepatocellular carcinoma (HCC) arises from a number of cirrhosis-related and non-cirrhosis-related exposures and is one of the leading causes of cancer-related deaths worldwide. Achieving a durable cure currently relies on either resection or transplantation, but since most patients will be diagnosed with inoperable disease, there is great interest in achieving more effective systemic therapies. At a molecular level, HCC is heterogeneous, but initial treatment strategies, including the use of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, have been fairly homogenous, depending on general host factors and overall tumor burden rather than specific molecular signatures. Over the past 2 decades, however, there has been significant success in identifying key molecular targets, including driver mutations involving the telomerase reverse transcriptase, p53, and beta-catenin genes, and significant work is now being devoted to translating these discoveries into the development of robust and well-tolerated targeted therapies. Furthermore, multi-modal therapies have also begun to emerge, harnessing possible synergism amongst a variety of different treatment classes. As the findings of these landmark trials become available over the next several years, the landscape of the systemic management of advanced HCC will change significantly.


Hepatocellular carcinoma (HCC) Systemic therapies Molecular-targeted Multi-targeted tyrosine kinase inhibitors (TKIs) Immunotherapy Multi-modal 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Department of Internal MedicineYale School of MedicineNew HavenUSA
  2. 2.Section of Digestive Diseases, Department of Internal MedicineYale School of MedicineNew HavenUSA
  3. 3.VA Connecticut Healthcare SystemWest HavenUSA

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