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) 1α, 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 µg/mL (interquartile range [IQR], 7.42-33.5 µg/mL), and its maximal plasma concentration (Cmax) was 0.164 µg/mL (IQR, 0.0798-0.528 µg/mL). The intratumoral concentration and Cmax of doxorubicin were similar between the groups: 4.08 µg/mL (IQR, 3.18-4.79 µg/mL) and 0.677 µg/mL (IQR, 0.315-1.23 µg/mL), respectively, in the DOX-TACE group and 1.68 µg/mL (IQR, 0.795-4.08 µg/mL) and 0.298 µg/mL (IQR, 0.241-0.64 µg/mL), respectively, in the SORA-DOX-TACE group. HIF-1α 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.

Conventional versus drug-eluting embolic transarterial chemoembolization with doxorubicin: comparative drug delivery, pharmacokinetics, and treatment response in a rabbit VX2 tumor model.

The purpose of this study was to compare intra-tumoral drug delivery, pharmacokinetics, and treatment response after doxorubicin (DOX) conventional (c-) versus drug-eluting embolic (DEE-) transarterial chemoembolization (TACE) in a rabbit VX2 liver tumor model. Twenty-four rabbits with solitary liver tumors underwent c-TACE (n = 12) (1:2 water-in-oil emulsion, 0.6 mL volume, 2 mg DOX) or DEE-TACE (n = 12) (130,000 70-150 µm 2 mg DOX-loaded microspheres). Systemic, intra-tumoral, and liver DOX levels were measured using mass spectrometry up to 7-day post-procedure. Intra-tumoral DOX distribution was quantified using fluorescence imaging. Percent tumor necrosis was quantified by a pathologist blinded to treatment group. Lobar TACE was successfully performed in all cases. Peak concentration (CMAX, µg/mL) for plasma, tumor tissue, and liver were 0.666, 4.232, and 0.270 for c-TACE versus 0.103, 8.988, and 0.610 for DEE-TACE. Area under the concentration versus time curve (AUC, µg/mL ∗ min) for plasma, tumor tissue, and liver were 18.3, 27,078.8, and 1339.1 for c-TACE versus 16.4, 26,204.8, and 1969.6 for DEE-TACE. A single dose of intra-tumoral DOX maintained cytotoxic levels through 7-day post-procedure for both TACE varieties, with a half-life of 1.8 (c-TACE) and 0.8 (DEE-TACE) days. Tumor-to-normal liver DOX ratio was high (c-TACE, 20.2; DEE-TACE, 13.3). c-TACE achieved significantly higher DOX coverage of tumor vs. DEE-TACE (10.8% vs. 2.3%; P = 0.003). Percent tumor necrosis was similar (39% vs. 37%; P = 0.806). In conclusion, in a rabbit VX2 liver tumor model, both c-TACE and DEE-TACE achieved tumoricidal intra-tumoral DOX levels and high tumor-to-normal liver drug ratios, though c-TACE resulted in significantly greater tumor coverage.

Development and Angiographic Use of the Rabbit VX2 Model for Liver Cancer.

The rabbit VX2 tumor is an animal model commonly utilized for translational research regarding hepatocellular carcinoma (HCC) in the field of Interventional Radiology. This model employs an anaplastic squamous cell carcinoma that is easily and reliably propagated in the skeletal muscle of donor rabbits for eventual harvest and allograft implantation into the liver of naïve recipients. This tumor graft rapidly grows within the liver of recipient rabbits into an angiographically identifiable tumor characterized by a necrotic core surrounded by a viable hypervascular capsule. The physical size of the rabbit anatomy is sufficient to facilitate vascular instrumentation allowing for the application and testing of various interventional techniques. Despite these benefits, there exists a paucity of technical resources to act as a concrete reference for researchers working with the model. Herein, we present a comprehensive visual outline for the technical aspects of development, growth, propagation, and angiographic utilization of the rabbit VX2 tumor model for use by novice and experienced researchers alike.

Endovascular Treatment for Variceal Hemorrhage: TIPS, BRTO, and Combined Approaches.

Variceal hemorrhage is a feared complication of portal hypertension, with high rates of morbidity and mortality. Optimal management requires a thoughtful, multidisciplinary approach. In cases of refractory or recurrent esophageal hemorrhage, endovascular approaches such as transjugular intrahepatic portosystemic shunt (TIPS) have a well-defined role. For hemorrhage related to gastric varices, the optimal treatment remains to be established; however, there is increasing adoption of balloon-occluded retrograde transvenous obliteration (BRTO). This article will review the concept, history, patient selection, basic technique, and outcomes for TIPS, BRTO, and combined TIPS + BRTO procedures for variceal hemorrhage.

Albumin-Bilirubin and Platelet-Albumin-Bilirubin Grades Do Not Predict Survival After Transjugular Intrahepatic Portosystemic Shunt Creation.

PURPOSE: To evaluate the capability of albumin-bilirubin (ALBI) and platelet-albumin-bilirubin (PALBI) grades in predicting transplant-free survival (TFS) in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS: This single-center retrospective study included 342 ALBI and 337 PALBI patients (62% men; age 53-54 years) with cirrhosis (median MELD 15) and portal hypertension complications (variceal bleeding, 55%; ascites, 35%; other, 10%) who underwent TIPS between 1998 and 2017. Serum albumin, bilirubin, and platelet levels within 24 h prior to TIPS were used to calculate ALBI and PALBI grades. The influence of ALBI and PALBI grade on 30-day, 90-day, and overall post-TIPS TFS was assessed using C-indices, binary logistic regression, and the Cox proportional model, adjusting for Child-Pugh (CP) and MELD scores. RESULTS: The cohort spanned 110 (32%) and 232 (68%) ALBI grades 2 and 3 patients, and 40 (12%) and 297 (88%) PALBI grades 2 and 3 patients. While there were no differences in 30-day survival between ALBI and PALBI grades 2/3 (P > 0.05), 90-day and overall TFS showed statistically significant differences in survival between ALBI and PALBI grades 2/3 (P < 0.05). Nonetheless, using univariate logistic regression, ALBI-PALBI C-indices (0.55-0.58) were inferior to the MELD score (0.81-0.84). Moreover, ALBI-PALBI did not associate with TFS on multivariable models adjusting for CP and MELD. Only MELD independently associated with TFS (P < 0.001). CONCLUSIONS: ALBI and PALBI grades do not stratify survival outcomes beyond MELD score following TIPS. MELD score remains the most robust metric for predicting post-TIPS survival outcomes.