Review Article: Systemic Treatment of Hepatocellular Carcinoma

Matthias Pinter; Markus Peck-Radosavljevic


Aliment Pharmacol Ther. 2018;48(6):598-609. 

In This Article

Abstract and Introduction


Background: The approval of the tyrosine kinase inhibitor sorafenib in 2007 marked a milestone in the treatment of hepatocellular carcinoma, as sorafenib was the first systemic therapy to show a survival benefit in patients with advanced hepatocellular carcinoma. Since then many drugs failed in the first- and second-line setting and it took almost another decade until further tyrosine kinase inhibitors succeeded in phase III trials.

Aim: To summarise the evolving field of systemic therapy of hepatocellular carcinoma.

Methods: We reviewed recently published studies identified from PubMed and data presented at recent meetings. Main search terms included hepatocellular carcinoma, tyrosine kinase inhibitors, immunotherapy, immune checkpoint inhibitors, sorafenib, regorafenib, lenvatinib, cabozantinib, ramucirumab, and nivolumab.

Results: We discuss the evolution of targeted therapies since the approval of sorafenib including failures and recent advances. We also elaborate the unmet need of biomarkers to guide treatment decisions and discuss the emerging field of immunotherapy in hepatocellular carcinoma.

Conclusions: The tyrosine kinase inhibitors sorafenib (first line) and regorafenib (second line) have been approved for hepatocellular carcinoma, and the immune checkpoint inhibitor nivolumab obtained conditional approval for sorafenib-experienced patients in the United States. With lenvatinib in the first line, and cabozantinib and ramucirumab in sorafenib-experienced patients, three more targeted therapies reached their primary endpoint in phase III trials and may soon be added to the treatment armamentarium.


Hepatocellular carcinoma (HCC) is the most common primary liver cancer,[1] usually develops in patients with liver cirrhosis,[2,3] and represents the second most common cause of cancer-related death.[4]

Potential curative therapies include resection, liver transplantation, and local ablative therapies, but these are reserved for early stages, characterised by small tumours limited to the liver. Transarterial chemoembolzation (TACE) and systemic therapies are the only available treatment options in the palliative setting,[5] while transarterial radioembilisation is struggling (and currently unable) to find a place in the evidence-based treatment landscape.[6–8] Patients with either symptomatic disease (performance status 1–2), macrovascular tumour invasion, or extrahepatic metastases (advanced stage HCC) are classical candidates for systemic treatment according to current guidelines.[5] Patients with multifocal HCC and compensated liver disease (intermediate stage HCC) should be treated with TACE.[5] However, these patients may become candidates for systemic therapies under certain circumstances (Figure 1): if they fail to respond to TACE (failure of 2 rounds of TACE), develop untreatable progression (major intrahepatic progression, macrovascular invasion, metastasis, symptomatic progression), show deterioration of liver function (ascites, decompensation),[9,10] or show unfavourable disease characteristics at baseline (Hepatoma arterial-embolisation prognostic score C or D; Barcelona-Clinic Liver Cancer B subclass 3 or 4; STATE score <18).[11–13] Liver function in particular should be monitored cautiously as even discrete subclinical worsening of liver function is associated with poorer outcome after repeated TACE.[14,15]

Figure 1.

Candidates for systemic therapy. HCC, hepatocellular carcinoma; EHM, extrahepatic metastases; MVI, macrovascular invasion; PS, Performance Status; TACE, transarterial chemoembolisation

To date, only tyrosine kinase inhibitors have been approved globally and additionally an immune checkpoint inhibitor in the United States only.[16] Conventional chemotherapy is not recommended in HCC due to lack of efficacy,[5] and only recently two phase III studies testing chemotherapy in advanced HCC again failed.[17,18] Whether a subset of patients with HCC may have some benefit from chemotherapy[19] needs to be confirmed in larger studies.

This review focuses on the evolution of targeted therapies since the approval of sorafenib, including failures and recent advances, and discusses the unmet need of biomarker-driven treatment strategies as well as the emerging field of immunotherapy in HCC.