Chemoembolization of hepatocellular carcinomas. A study of the biodistribution and pharmacokinetics of doxorubicin

Abstract

Background: This study evaluated the effects of an association of ethiodized oil (Lipiodol Ultra Fluide, Laboratoires Guerbet, Aulnay-sous-Bois, France), with or without gelatin sponge, with doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) on the biodistribution and kinetics of doxorubicin during intraarterial injection.

Methods: Eighteen patients with hepatocellular carcinoma on cirrhotic liver received a therapeutic injection into the hepatic artery of 50 mg of doxorubicin alone (Group 1; n = 4), or emulsified in 10 ml of ethiodized oil and 2.5 ml of ioxaglate (Hexabrix, Laboratoires Guerbet) with (Group 2; n = 7) or without (Group 3; n = 7) gelatin sponge embolization. Before treatment, the absence of intrahepatic shunts was verified by an injection of technetium-labeled albumin macroaggregates. The biodistribution of doxorubicin was studied on two fronts: (1) pharmacokinetic--by measurement of the doxorubicin blood level during the 48 hours after injection; and (2) scintigraphic (2 mg of doxorubicin were labeled with 2 mCi of iodine 131)--by examination of the scintigrams and calculation of the following parameters: tumours liver/nontumorous liver binding ratio (T/NT ratio), liver/liver+lungs+abdomen binding ratio, and doxorubicin half-life in tumorous tissue.

Results: Pharmacokinetics results showed the following: the peak plasma concentration was significantly higher in Group 1 as compared with Groups 2 or 3 (Group 1: 2.1 +/- 0.9 mg/ml; Group 2: 0.9 +/- 0.3 mg/ml; Group 3: 0.5 +/- 0.2 mg/ml); the area under curve calculated from time zero to 1 hour was lower in Groups 2 and 3 compared with Group 1. Examination of the scintigrams showed the following: diffuse activity throughout the organism (Group 1), diffuse activity with strong hepatic and tumorous binding (Group 2), and mostly hepatic and tumoral binding (Group 3). The liver/liver+lungs+abdomen binding ratio was 28% +/- 1% in Group 1, 36% +/- 5% in Group 2, and 63% +/- 7% in Group 3. The T/NT ratios were 1.0 +/- 0 (Group 1), 1.5 +/- 0.1 (Group 2), and 4.7 +/- 0.5 (Group 3). The doxorubicin half-lives in tumourous tissue were 0.7 +/- 0.1 days (Group 1), 1.8 +/- 0.2 days (Group 2), and 2.6 days (n = 1; Group 3).

Conclusions: This study shows (1) that the association of ethiodized oil with doxorubicin lowers the peak concentration of doxorubicin and increases the intratumoral concentration and half-life of doxorubicin, and (2) that these kinetic ameliorations are even more pronounced after embolization. Therefore, from a kinetic standpoint, the doxorubicin-ethiodized oil-gelatin sponge association is the best.