Sequential Systemic Treatment in Patients With Hepatocellular Carcinoma

Martha M. Kirstein; Bernhard Scheiner; Tristan Marwede; Caroline Wolf; Torsten Voigtländer; Georg Semmler; Frank Wacker; Michael P. Manns; Jan B. Hinrichs; Matthias Pinter; Arndt Vogel


Aliment Pharmacol Ther. 2020;52(1):205-212. 

In This Article

Abstract and Introduction


Background: Hepatocellular carcinoma (HCC) is one of the most lethal cancers. After many years of stagnation, there are now several systemic treatments available for patients with HCC.

Aim: To analyse the feasibility and efficacy of sequential systemic treatments in patients with HCC in clinical practice.

Methods: In this multicentre study, patients who were treated with novel systemic therapies for HCC between 2014 and 2019 at two referral centres, Hannover Medical School, Germany, and Medical University of Vienna, Austria, were included.

Results: Overall, 85 patients were included of which 76 patients (89.4%) received more than one and a maximum of five systemic treatment lines. The most common therapy sequence was sorafenib (n = 72; 84.7%) followed by regorafenib (n = 37; 48.7%), whereas 11 patients were initially treated with lenvatinib (12.9%). Other second-line treatments included pembrolizumab, nivolumab, cabozantinib and ramucirumab. Hepatic function deteriorated during sequential systemic treatment in 48.6% of the patients as defined by an increase in at least one Child-Pugh point. Median overall survival (mOS) from the start of first systemic treatment was 35 months for patients with sequential systemic treatment compared to 9 months for patients with one systemic treatment line (P < 0.001). Patients previously treated with surgical/locoregional therapies had a longer mOS compared to patients with initial systemic treatment (66 vs 25 months; P = 0.020).

Conclusions: Sequential systemic treatment is feasible and effective in selected patients with HCC in clinical practice. Our study underlines the critical importance of well-preserved liver function for successful administration of sequential systemic therapy.


Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second leading cause of cancer-related death. The prognosis is still dismal.[1,2] The multityrosine kinase inhibitor sorafenib has been the only approved agent for patients with advanced HCC for almost a decade based on a prolongation of median overall survival (mOS) from 7.9 to 10.7 months.[3] In the last few years, several systemic treatment options have emerged including the tyrosine kinase inhibitors (TKIs) lenvatinib, regorafenib, cabozantinib and the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab.[4–7] Immune checkpoint inhibitor monotherapies have failed to show a statistically significant improvement in overall survival (OS) in the first- and second-line setting in phase III trials.[8,9] In contrast, the combined immunotherapy/VEGF inhibition with atezolizumab and bevacizumab has recently shown superior activity in first-line treatment compared to sorafenib in the phase III IMbrave150 trial and will likely become the new standard of care in first line.[10]

These numerous novel systemic agents approved in the first- and second-line setting offer a variety of sequential treatment opportunities, which are already being implemented in current guidelines.[11] So far, there are no prospective clinical studies investigating sequential therapy in HCC, but post hoc analysis from phase-III trials and some real-life studies provided first evidence that sequential treatment will improve mOS in HCC.[4,12–16]

In this multicentre study, we aimed to investigate the feasibility and efficacy of sequential systemic treatments with the currently available and recently approved drugs in a real life cohort.