Prospective study of lipiodol distribution as an imaging marker for doxorubicin pharmacokinetics during conventional transarterial chemoembolization of liver malignancies

To evaluate the prognostic potential of Lipiodol distribution for the pharmacokinetic (PK) profiles of doxorubicin (DOX) and doxorubicinol (DOXOL) after conventional transarterial chemoembolization (cTACE). This prospective clinical trial (ClinicalTrials.gov: NCT02753881) included 30 consecutive participants with liver malignancies treated with cTACE (5/2016-10/2018) using 50 mg DOX/10 mg mitomycin C emulsified 1:2 with ethiodized oil (Lipiodol). Peripheral blood was sampled at 10 timepoints for standard non-compartmental analysis of peak concentrations (C${}_{max}$) and area under the curve (AUC) with dose normalization (DN). Imaging markers included Lipiodol distribution on post-cTACE CT for patient stratification into 1 segment (n = 10), ≥ 2 segments (n = 10), and lobar cTACE (n = 10), and baseline enhancing tumor volume (ETV). Adverse events (AEs) and tumor response on MRI were recorded 3-4 weeks post-cTACE. Statistics included repeated measurement ANOVA (RM-ANOVA), Mann-Whitney, Kruskal-Wallis, Fisher's exact test, and Pearson correlation. Hepatocellular (n = 26), cholangiocarcinoma (n = 1), and neuroendocrine metastases (n = 3) were included. Stratified according to Lipiodol distribution, DOX-C${}_{max}$ increased from 1 segment (DOX-C${}_{max}$, 83.94 ± 75.09 ng/mL; DN-DOX-C${}_{max}$, 2.67 ± 2.02 ng/mL/mg) to ≥ 2 segments (DOX-C${}_{max}$, 139.66 ± 117.73 ng/mL; DN-DOX-C${}_{max}$, 3.68 ± 4.20 ng/mL/mg) to lobar distribution (DOX-C${}_{max}$, 334.35 ± 215.18 ng/mL; DN-DOX-C${}_{max}$, 7.11 ± 4.24 ng/mL/mg; p = 0.036). While differences in DN-DOX-AUC remained insignificant, RM-ANOVA revealed significant separation of time concentration curves for DOX (p = 0.023) and DOXOL (p = 0.041) comparing 1, ≥ 2 segments, and lobar cTACE. Additional indicators of higher DN-DOX-C${}_{max}$ were high ETV (p = 0.047) and Child-Pugh B (p = 0.009). High ETV and tumoral Lipiodol coverage also correlated with tumor response. AE occurred less frequently after segmental cTACE. This prospective clinical trial provides updated PK data revealing Lipiodol distribution as an imaging marker predictive of DOX-C${}_{max}$ and tumor response after cTACE in liver cancer.