Baseline Interleukin-6 and -8 predict response and survival in patients with advanced hepatocellular carcinoma treated with sorafenib monotherapy: an exploratory post hoc analysis of the SORAMIC trial

Osman Öcal,Juozas Kupčinskas,Kerstin Schütte,Bristi Basu,Heinz Josef Klümpen,Maciej Pech,Thomas Berg,Ricarda Seidensticker,Najib Ben Khaled,Enrico N De Toni,Jens Ricke,Daniel H Palmer ,Juan W Valle,Moritz Wildgruber,Julia Benckert,Gabija Jurkeviciute,Egidijus Morkūnas ,Peter Malfertheiner,Bruno Sangro,Antonio Gasbarrini,Christian Sengel,Max Seidensticker

doi:10.1007/s00432-021-03627-1

Abstract

PurposeTo explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib.MethodsA subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response.ResultsForty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9–8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2–4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22–7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02–4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011).ConclusionIL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.

Highlights

Hepatocellular carcinoma (HCC) develops mostly on the background of chronic inflammation of the liver (El-Serag 2012)
Univariate analysis of clinical and pathological variables conducted by stratifying patients according to these cutoff values showed that high baseline IL-6 was associated with albumin values of < 36 g/L (p = 0.013), whereas high baseline IL-8 was associated with larger maximum tumor diameter (p = 0.013)
Previous studies have shown that higher IL-6 and IL-8 levels are associated with increased HCC risk in patients with chronic liver disease (Wong et al 2009; Chien et al 2011) and correlated with advanced disease stages (Sanmamed et al 2014; Wang et al 2016; Sun et al 2019) and worse liver function in patients with HCC (Chan et al 2012; Jang et al 2012)

Summary

Introduction

Hepatocellular carcinoma (HCC) develops mostly on the background of chronic inflammation of the liver (El-Serag 2012). After a long time with sorafenib being the only systemic treatment option for HCC, several first- and second-line therapies emerged (Bruix et al 2017; Abou-Alfa et al 2018; Kudo et al 2018), and recently, atezolizumab–bevacizumab combination has been shown to be superior to sorafenib in the first-line setting (Finn et al 2020).

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