Pharmacokinetics and Early Tumor Response to Conventional Transarterial Chemoembolization with Sorafenib and Doxorubicin in a VX2 Rabbit Tumor Model

Purpose: To investigate the pharmacokinetics (PK) and early effects of conventional transarterial chemoembolization (TACE) using sorafenib and doxorubicin on tumor necrosis, hypoxia markers, and angiogenesis in a rabbit VX2 liver tumor model. Materials and Methods: VX2 tumor-laden New Zealand White rabbits (N = 16) were divided into 2 groups: 1 group was treated with hepatic arterial administration of ethiodized oil and doxorubicin emulsion (DOX-TACE), and the other group was treated with ethiodized oil, sorafenib, and doxorubicin emulsion (SORA-DOX-TACE). Animals were killed within 3 days of the procedure. Levels of sorafenib and doxorubicin were measured in blood, tumor, and adjacent liver using mass spectrometry. Tumor necrosis was determined by histopathological examination. Intratumoral hypoxia-inducible factor (HIF) 1 alpha, vascular endothelial growth factor (VEGF), and microvessel density (MVD) were determined by immunohistochemistry. Results: The median intratumoral concentration of sorafenib in the SORA-DOX-TACE group was 17.7 mu g/mL (interquartile range [IQR], 7.42-33.5 mu g/mL), and its maximal plasma concentration (C-max) was 0.164 mu g/mL (IQR, 0.0798-0.528 mu g/mL). The intratumoral concentration and C-max of doxorubicin were similar between the groups: 4.08 mu g/mL (IQR, 3.18-4.79 mu g/mL) and 0.677 mu g/mL (IQR, 0.315-1.23 mu g/mL), respectively, in the DOX-TACE group and 1.68 mu g/mL (IQR, 0.795-4.08 mu g/mL) and 0.298 mu g/mL (IQR, 0.241-0.64 mu g/mL), respectively, in the SORA-DOX-TACE group. HIF-1 alpha expression was increased in the SORA-DOX-TACE group than in the DOX-TACE group. Tumor volume, tumor necrosis, VEGF expression, and MVD were similar between the 2 groups. Conclusions: The addition of sorafenib to DOX-TACE delivered to VX2 liver tumors resulted in high intratumoral and low systemic concentrations of sorafenib without altering the PK of doxorubicin.