In 2020, primary liver cancer was the sixth most commonly diagnosed cancer and the third most common cause of cancer-related death worldwide [1]. Based on projections, the World Health Organization estimates that, by 2040, more than 1.4 million individuals will be affected and almost 1.3 million patients will die from liver cancer annually [2].

Hepatocellular carcinoma (HCC) accounts for approximately 80%–90% of primary liver cancers and usually develops in the context of an underlying chronic liver disease caused by a hepatitis B or C viral infection, alcohol abuse or a metabolic syndrome [3].

Treatment guidelines for HCC are based on the Barcelona Clinic Liver Cancer (BCLC) algorithm, accounting for tumor burden, grade of liver dysfunction and performance status of the patient. Patients with early (BCLC 0-A) and intermediate (BCLC B) HCC are eligible for local resection, liver transplantation, local destruction methods or transarterial therapies in first-line treatment [4].

However, approximately 50% of patients with HCC are diagnosed with an advanced-stage disease (BCLC C) [5]. This stage includes patients with vascular tumor invasion or extrahepatic spread, a preserved liver function with a Child-Pugh A or B score and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 [6]. These patients were historically considered to be the optimal candidates for systemic treatment. Increasingly, systemic treatment is also considered in the BCLC B stage, more specifically for patients with multifocal, bilobar intrahepatic disease or patients with contraindications for or progressive disease after locoregional approaches.

During the last decade, major progress has been made in the arsenal of systemic treatment for unresectable HCC, resulting in a significant improvement in overall survival and quality of life [7].

The aim of this review is to give insights in the first-line treatment options for patients with advanced hepatocellular carcinoma and to provide clinical stepstones to make an individualized decision for every patient.