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Monday, September 10, 2018

Chemoembolization with Vascular Disrupting Agent CKD-516 Dissolved in Ethiodized Oil in Combination with Doxorubicin: A VX2 Tumor Model study


Summary


The authors report the findings of a translational study using a Rabbit squamous cell tumor model implanted into the left hepatic lobe. The authors sought out to evaluate the necrotic and toxic effects of CDK-516, which is a Vascular Disrupting agent (VDA). VDA’s work by disrupting immature and proliferating endothelial cells by inducing apoptosis and breakdown of the cytoskeleton. Ten rabbits where allocated into each of the 4 different groups: Lipiodol alone, Lipiodol+ CDK-516, Lipiodol + Doxorubicin, Lipiodol + CDK-516+Doxorubicin. The chemotherapeutic regimen was then injected into the left hepatic artery. Post embolization non-contrast CT was obtained to evaluated lipiodol deposition. The authors then evaluated AST and ALT levels at day 1, 3 and 7. On day 7 the rabbit was sacrificed and histologic analysis was performed by evaluating percent of tumor necrosis in the histologic slide that presented the largest portion of tumor. Ischemic changes were also evaluated on the gross specimen.

The authors found 47.1% tumor viability in group A, 27.5% in group B, 14.4% in group C and 0.7% in group D. There was a statistical difference between the 4 groups, as well as when pairwise comparisons were performed. On gross specimen evaluation there was 0% infarction rate in group A, 20% in group B, 40% in group C and 80% in group D. AST and ALT levels showed significant differences on days 1 and 3, and between group B and D on days 1, 3 and 7.

It is important to highlight that VDAs and antiangiogenic agents such as Sorafenib VDAs target established tumor vascularity that results in ischemia and necrosis in the tumor center, while Sorafenib targets new vessel formation around the tumor. The reason for which CKD-516 infusion leads to central tumor necrosis is that it targets immature tumor vessels by targeting microtubules, which deprive the tumor from oxygen and nutrients. In the tumor periphery there are immature tumor vessels and normal vessels therefore CKD-516 does not work effectively which leads to tumor survival in the periphery. Therefore, the combination of cytotoxic agents (Doxorubicin) and VDAs would seem to offer a synergistic effect where both the tumor center and periphery are treated. On the other hand, CKD-516 also showed ischemic and toxic effects as seen by the 80% gross parenchymal infarction seen in group D and the elevation in AST and ALT which did not normalize to control level. The reason for this, the authors postulate, is that systemic doses were administered intra-arterially, which may be potentially a large dose for intra-arterial injection.

The authors identified important limitations. The adequate dosage for CKD-516 is unknown. The combination strategy of CKD-516 and doxorubicin is theoretical, however actual synergy and drug interaction between the agents has not been studied. The histologic evaluations were performed without blinding which may introduce bias. Toxicity was only evaluated by studying elevation of AST and ALT and gross pathologic inspection. VX2 tumors are squamous cell tumors that present a natural course of central necrosis. And finally, tumor necrosis assessment was done by evaluating the section with the largest tumor area, instead of a volumetric analysis.

The authors concluded that the intra-arterial injection of CKD-516 and Doxorubicin showed a therapeutic benefit in a rabbit liver tumor model, and that future studies need to be undertaken to optimize the pharmacologic characteristics of the regimen so that it can eventually be used in clinical trials.



Figure- Histopathologic analysis of the 4 groups. Areas of necrosis are marked by *, tumor area is delineated by the arrows. # denotes necrosis in the adjacent liver parenchyma.

Commentary


This manuscript draws a strong argument for the use of combination therapy in targeting different pathways in the treatment of liver tumors. By using cytotoxic agents and VDAs, tumors are not only treated by inhibiting tumor growth in the periphery (Doxorubicin) but also the tumor center (CKD-516). As the authors adequately identified, there are important differences between the rabbit liver tumor model and human HCC. Therefore, definitive assumptions cannot be made, however this is a step forward in creating stronger regimens that maybe be treated with catheter directed techniques. Important studies need to follow, such as adequate dosage evaluation, pharmacokinetics, drug interaction and toxicity. As it stands, the synergistic effect of these two drugs appear to lead to high tumor necrosis (0.7% tumor viability) and high toxicity (80% ischemic changes), therefore studies are required to identify the dosage that will allow high tumor necrosis and minimize the toxic side effects.

Click here for abstract

Lee IJ, Lee M, Kim SJ, Kim YK, Won JY, Chung JW. Chemoembolization with Vascular Disrupting Agent CKD-516 Dissolved in Ethiodized Oil in Combination with Doxorubicin: A VX2 Tumor Model Study. J Vasc Interv Radiol. 2018 Aug;29(8):1078-1084. doi: 10.1016/j.jvir.2018.03.016. Epub 2018 Jun 15. PubMed PMID: 29910164.

Post Author
Carlos J. Guevara, MD
Assistant Professor
Department of Radiology, Interventional Radiology Division
University of Texas Health Sciences, Houston
@UTHouston_IR
@CarlosGuevaraIR

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