Prognostic impact of extracellular volume fraction derived from equilibrium contrast-enhanced CT in HCC patients receiving immune checkpoint inhibitors

Abstract

This study aimed to investigate whether extracellular volume (ECV) fraction derived from equilibration contrast-enhanced computed tomography (CECT) affects prognosis in HCC patients receiving ICIs. This retrospective study ultimately included 211 HCC patients undergoing ICIs, of whom 60 were included in an internal validation to assess the reproducibility of the results. Baseline unenhanced and equilibrated CECT were used to measure CT values of the tumor, liver and aorta, which were combined with hematocrit to calculate the ECV fraction. Correlation analysis was used to investigate the association between tumor ECV and liver ECV fractions. The effects of clinical variables and ECV fraction on progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards models and Kaplan-Meier curves. Of these 151 patients, tumor ECV fraction positively correlated with liver ECV fraction. In the Lower tumor ECV group, PFS (5.6 vs. 7.6 months) and OS (10.5 vs. 15.5 months) were notably shorter than in the Higher tumor ECV group, while no significant differences were found between the Higher and Lower liver ECV groups. Furthermore, the multivariable Cox regression model demonstrated that higher tumor ECV fraction level was an independent protective factor for PFS and OS (all P < 0.001). Internal validation cohort preliminary demonstrated reproducibility of results. The tumor ECV fraction is expected to become a routine indicator before ICIs therapy for HCC patients in contrast to liver ECV fraction, contributing to their subsequent management.

Keywords: Extracellular volume fraction; Hepatocellular carcinoma; Immune checkpoint inhibitors; Prognosis.

Fig. 1

ECV fraction position of a 79 years old male with hepatocellular carcinoma receiving immune checkpoint inhibitors. Axial unenhanced (A) and equilibration contrast-enhanced CT (B) show ROIs on the 4.5 centimeters tumor (black circle) and aorta (black dashed circle). Axial unenhanced (C) and equilibration contrast-enhanced CT (D) show ROIs on the anterior and posterior segments of the right lobe and lateral segment of the left lobe of the liver (white circle) and the aorta (white dashed circle). The tumor ECV fraction was 38.48%, liver ECV fraction was 28.07%.

Fig. 2

Correlation analysis of tumor ECV fraction with liver ECV fraction.

Fig. 3

Kaplan-Meier curves of PFS (A) and OS (B) for Lower tumor ECV group (blue) and Higher tumor ECV group (red). PFS progression-free survival, OS overall survival, ECV extracellular volume.

Fig. 4

Heatmap showed the relationship between tumor, liver ECV fraction and clinical characteristics with OS for each patient. ECV extracellular volume, HBV hepatitis B virus, ICIs immune checkpoint inhibitors, PVTT portal vein tumor thrombosis, BCLC Barcelona clinic liver cancer, ECOG PS eastern cooperative oncology group physical status, NLR neutrophil to lymphocyte ratio, PLR platelet to lymphocyte ratio, ALT alanine transaminase, AST aspartate transaminase, TB total bilirubin, PT prothrombin time, AFP alpha-fetoprotein.

Fig. 5

Forest plot of subgroup analysis of overall survival between Lower tumor ECV and Higher tumor ECV groups. The dashed line indicates a risk ratio of 1. ECV extracellular volume, HBV hepatitis B virus, ICIs immune checkpoint inhibitors, TKIs tyrosine kinase inhibitors, PVTT portal vein tumor thrombosis, BCLC stage Barcelona clinic liver cancer stage, ECOG PS eastern cooperative oncology group physical status, AFP alpha-fetoprotein.