A Comparative Study of Drug Pharmacokinetics in Transarterial Chemoembolization

Transarterial chemoembolization (TACE) is one of the primary treatment modalities for surgically unresectable hepatocellular carcinoma (HCC). This technique entails the delivery of chemotherapeutic agents directly into the arterial supply of a liver tumor via a catheter placed in the femoral artery. Currently, there exist two variants of this procedure based on the delivery vector used. The first variant, referred to as conventional TACE (c-TACE), involves blending the chemotherapeutic agents (doxorubicin (DOX)) into an ethiodized oil (Lipiodol; Guerbet, Villepente France) emulsion. The second variant, referred to as drug-eluting embolic TACE (DEE-TACE), involves adsorbing drug onto the surface of microspheres for intravascular delivery and elution. Both of these variants achieve efficacy through ischemic and cytotoxic effects on the tumor cells. While the second variant is more contemporary and has carved a niche for itself in the Interventional Radiology (IR) community, there is a relative paucity of evidence to suggest why one of these vectors should be utilized over the other. This study aimed to characterize tumoral uptake, temporal retention, systemic pharmacokinetics, and spatial distribution of chemotherapeutic agents in each delivery vector, as well as compare the two. In this Animal Care and Use approved study, 24 New Zealand White rabbits with single left hepatic lobe VX2 tumors underwent either c-TACE (n=12) or DEE-TACE (n=12) after which blood and tissue samples were collected. Animal sacrifice was performed at 180 minutes, 1, 2, 4, and 7 days (n=2 per time point per arm). Blood samples were drawn from the rabbits immediately prior to treatment and then at 2, 5, 10, 15, 20, 30, 45, 60, 120, and 180 minutes after treatment. Additional blood draws were performed at 1, 2, 3, 4, and 7 days depending on the subjects’ time of sacrifice. These blood samples were centrifuged to separate the blood components from the plasma, which was collected and flash frozen for later analysis. At the time of sacrifice, tumor and peritumoral tissue was collected and flash frozen for later analysis. The plasma, tumor, and peritumoral liver were then analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Peak concentration (Cmax), area-under-the-curve (AUC), half-life, and duration of drug presence were calculated. Additional outcome measures included spatial drug coverage of the tumor, intra-cellular drug concentration, and percent necrosis of the tumor. This is one of the first contemporary study that uses modern analysis modalities to assess and compare the pharmacokinetics of c- and DEE-TACE. It shows that, in rabbit VX2 tumor model, lower systemic DOX levels are evident after DEE-TACE vs. c-TACE; however, both c-TACE and DEE-TACE achieve pharmacologically meaningful, tumoricidal intra-tumoral DOX levels and high tumor-to-normal liver drug ratios. Further analysis is necessary to determine if the adverse effects (AE) due to higher systemic DOX in the c-TACE arm are offset by increased efficacy. Additionally, while percent tumor necrosis and intracellular drug concentration were not significantly different between the two arms, c-TACE resulted in sustained better coverage of the tumor.