Original Article http://dx.doi.org/10.3348/kjr.2012.13.2.195 pISSN 1229-6929 · eISSN 2005-8330 Korean J Radiol 2012;13(2):195-201 Effects of Arsenic Trioxide on Radiofrequency Ablation of VX2 Liver Tumor: Intraarterial versus Intravenous Administration Nak Jong Seong, MD1, Chang Jin Yoon, MD1, Sung-Gwon Kang, MD1, Jin Wook Chung, MD2, Hyo-Cheol Kim, MD2, Jae Hyung Park, MD2 1Division of Intervention, Department of Radiology, Seoul National University Bundang Hospital, Seongnam 463-707, Korea; 2Department of Radiology, Seoul National University College of Medicine, Institute of Radiation Medicine, Seoul National University Medical Research Center, and Clinical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea Objective: Arsenic trioxide (As2O3) can be used as a possible pharmaceutical alternative that augments radiofrequency (RF) ablation by reducing tumor blood flow. The aim of this study was to assess the effect of intraarterial and intravenous administration of As2O3 on RF-induced ablation in an experimentally induced liver tumor. Materials and Methods: VX2 carcinoma was grown in the livers of 30 rabbits. As2O3 (1 mg/kg) was administered through the hepatic artery (n = 10, group A) or ear vein (n = 10, group B), 30 minutes before RF ablation (125 mA ± 35; 90 ± 5°C). As a control group, 10 rabbits were treated with RF ablation alone (group C). RF was intentionally applied to the peripheral margin of the tumor so that ablation can cover the tumor and adjacent hepatic parenchyma. Ablation areas of the tumor and adjacent parenchymal changes among three groups were compared by the Kruskal-Wallis and Mann-Whitney U test. Results: The overall ablation areas were 156 ± 28.9 mm2 (group A), 119 ± 31.7 (group B), and 92 ± 17.4 (group C, p < 0.04). The ablation area of the tumor was significantly larger in group A (73 ± 19.7 mm2) than both group B (50 ± 19.4, p = 0.02) and group C (28 ± 2.2, p < 0.01). The ratios of the tumoral ablation area to the overall ablation area were larger in group A (47 ± 10.5%) than that of the other groups (42 ± 7.3% in group B and 32 ± 5.6% in group C) (p < 0.03). Conclusion: Radiofrequency-induced ablation area can be increased with intraarterial or intravenous administration of As2O3. The intraarterial administration of As2O3 seems to be helpful for the selective ablation of the tumor. Index terms: Arsenic trioxide; Radiofrequency ablation; Pharmacologic modulation; Chemotherapy; Experimental study INTRODUCTION effective treatment in unresectable malignant liver tumors (1-3). However, it has an inherent limitation in the volume Radiofrequency (RF) ablation has been proved to be an of tumors which can be effectively ablated. Consequently, Received July 10, 2011; accepted after revision August 24, 2011. clinical data demonstrated excellent local tumor control This work was supported by the Korea Research Foundation Grant (80-90%) in tumors < 3 cm in the diameter, but much less funded by the Korean Government (KRF-2005-041-e00302). satisfactory results (50-75%) in larger tumors (1-3). This Corresponding author: Chang Jin Yoon, MD, Division of limitation is mainly caused by perfusion-mediated tissue Intervention, Department of Radiology, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bungdang-gu, cooling, heat sink effect (4). Therefore, several adjunctive Seongnam 463-707, Korea. techniques have been developed to reduce regional and • Tel: (8231) 787-7609 • Fax: (8231) 787-4011 intratumoral blood flow, and increase the ablation time. • E-mail: [email protected] This is an Open Access article distributed under the terms of These include hepatic arterial occlusion by balloon catheter the Creative Commons Attribution Non-Commercial License (5), transcatheter hepatic arterial embolization (6), bipolar (http://creativecommons.org/licenses/by-nc/3.0) which permits array technique (7), saline injection (8), and pharmacologic unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. modulation (9). kjronline.org Korean J Radiol 13(2), Mar/Apr 2012 195 Seong et al. Contrary to their infamous carcinogenic properties as an (Sensation 16; Siemens, Erlangen, Germany) was performed environmental pollutant, arsenic compounds have been to confirm the presence and size of the liver tumors. On the used for medical purposes for several thousand years (10). basis of the longest diameter of the tumor, the rabbits were Recently, arsenic trioxide (As2O3) was found to be highly divided into three groups (groups A-C). The spontaneous effective for the treatment of acute promyelocytic leukemia necrosis of a VX2 liver tumor can be influenced by tumor (APL) (11, 12). Thereafter, it has been widely tested in size, which subsequently affects the results of our study. treating not only-APL leukemia but also a variety of solid Therefore, rabbits with similar sized tumors were assigned tumors including hepatocellular carcinoma (HCC) (11, 13, to each group. The longest diameter of tumors ranged from 14). The mechanism of As2O3 activity against solid tumors 13.2 to 20.5 mm (18 ± 2.0 mm; median 17.4 mm mean ± has not been completely understood. However, previous standard deviation [SD]) in group A, 13.8 to 21.3 mm (17 studies discovered As2O3 induces tumor vascular shutdown, ± 2.0 mm, 16.2 mm) in group B, and 11.7 to 20.0 mm (17 and subsequently potentiates hyperthermal therapy (15, ± 3.1 mm, 17.6 mm) in group C. Tumor volumes were not 16). Hines-Peralta et al. (17) have shown that systematic statistically different among the three groups (p = 0.687, administration of As2O3 enables larger zones of RF ablation Kruskal-Wallace test). in various experimentally induced tumor models. However, in their study, optimal results were achieved with a Arsenic Trioxide Administration and Radiofrequency relatively high dose of this toxic drug and the synergistic Ablation effect has a narrow temporary window (18). Generally the A solution of As2O3 (Sigma, St. Louis, MO, USA) was hepatic artery is a better route of drug administration than prepared by magnetic stirring for one day at room systemic veins for the treatment of liver tumors (19, 20). temperature in a glass bottle and then placed the bottle Thus, we hypothesized that hepatic arterial administration into boiling water for one hour. After the solution became of As2O3 may induce larger zones of RF ablation than crystal clear, it was sterilized using a 0.2 M bottle- intravenous administration. The purpose of this study is to top filter and stored in the dark at 4°C. Just before the assess the effects of hepatic arterial administration of As2O3 administration, the stock solution was then diluted with on RF-induced ablation and compare them with those of phosphate-buffered saline to a concentration of 1 mg/mL. systemic venous administration in a liver tumor model. In group A, the As2O3 solution was administered through the hepatic artery. Under general anesthesia, an incision MATERIALS AND METHODS was made to access the right femoral artery. The celiac angiogram was obtained to identify the hepatic arterial Liver Tumor Model and Experimental Groups anatomy and the feeder artery of the tumor using a All the experiments associated with this study were 3-Fr microcatheter (Cook, Bloomington, IN, USA). After approved by our Institutional Animal Care And Use positioning the catheter within the proper hepatic artery, 1 Committee. All rabbits were maintained according to the mL/kg of the As2O3 solution (1 mg/kg) was slowly injected Guide for the Care and Use of Laboratory Animals (21). at a rate of 180 mL/hr using an infusion pump. The catheter Thirty adult New Zealand white rabbits weighing 2.5-3.0 kg was then removed and the femoral artery was ligated. In were used. The VX2 carcinoma strain had been maintained group B, the As2O3 solution was administered into the by means of successive transplantation into the hindlimb of auricular vein. The amount of As2O3 solution and infusion the carrier rabbit. Anesthesia was induced with intravenous rate were the same in group B. In group C, the same volume ketamine hydrochloride (50 mg per kilogram of body of phosphate-buffered saline was infused into the auricular weight; Ketamine, Yuhan, Korea) and 2% xylazine (0.1 mL/ vein. kg; Rompun, Bayer, Germany). After a midline abdominal One hour after completing the As2O3 solution or incision, 0.1 mL of minced VX2 carcinoma was implanted phosphate-buffered saline injection, RF ablation of the into the subcapsular parenchyma of the left medial lobe of liver tumor was performed. Under general anesthesia, a the liver. Fourteen days after tumor implantation, when the midline incision was made to expose the liver. A 500-kHz tumors were anticipated to be 10-20 mm in diameter, the RF generator (Valley-Lab, Boulder, CO, USA) was used to rabbits were used for the experiments. apply conventional monopolar RF energy. An internally One day before RF ablation, contrast-enhanced liver CT cooled, 17-gauge electrode (Radionics) with a 1-cm active 196 Korean J Radiol 13(2), Mar/Apr 2012 kjronline.org Intraarterial vs. Intravenous Administration of As2O3 on RFA of VX2 Liver Tumor tip was placed in at peripheral margin of the tumor so staining. All the histologic evaluations were performed by a that the tumor tissue and normal parenchyma were ablated pathologist unaware of the experimental groups. simultaneously (Fig. 1A). RF energy was applied for five minutes with the generator output titrated to maintain RESULTS a designated tip temperature: a mean temperature of 90 ± 2°C. RF ablation was performed in random order by an Gross examination showed the ablation lesion in each investigator who was unaware of the treatment groups. specimen as oval-shaped paled area of ablation necrosis including the VX2 tumor and adjacent normal liver Histopathologic Examinations parenchyma, the central tissue loss areas around the needle Euthanasia of animals was performed with pentobarbital track, and peripheral thin dark-brown hemorrhagic rim (Fig.