Systemic Drugs for Hepatocellular Carcinoma: What Do Recent Clinical Trials Reveal About Sequencing and the Emerging Complexities of Clinical Decisions?

Liver cancer was the fourth leading cause of cancer death in 2015 with increasing incidence between 1990 and 2015. Orthotopic liver transplantation, surgical resection and ablation comprise the only curative therapy options. However, due to the late manifestation of clinical symptoms, many patients present with intermediate or advanced disease, resulting in no curative treatment option being available. Whereas intermediate-stage hepatocellular carcinoma (HCC) is usually still addressable by transarterial chemoembolization (TACE), advanced-stage HCC is amenable only to pharmacological treatments. Conventional cytotoxic agents failed demonstrating relevant effect on survival also because their use was severely limited by the mostly underlying insufficient liver function. For a decade, tyrosine kinase inhibitor (TKI) sorafenib was the only systemic therapy that proved to have a clinically relevant effect in the treatment of advanced HCC. In recent years, the number of substances for systemic treatment of advanced HCC has increased enormously. In addition to tyrosine kinase inhibitors, immune checkpoint inhibitors (ICI) and antiangiogenic drugs are increasingly being applied. The combination of anti-programmed death ligand 1 (PD-L1) antibody atezolizumab and anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has become the new standard of care for advanced HCC due to its remarkable response rates. This requires more and more complex clinical decisions regarding tumor therapy. This review aims at summarizing recent developments in systemic therapy, considering data on first- and second-line treatment, use in the neoadjuvant and adjuvant setting and combination with locoregional procedures.