Evolution of Transarterial Chemoembolization for the Treatment of Liver Cancer

See also the article by Duran et al in this issue

Dr Kyung Won Kim is a professor in the Radiology Department as well as a cofounder of the animal imaging lab and clinical imaging core lab (www.aim-aicro.com) at Asan Medical Center. His research interests are preclinical and clinical imaging for new drug development, mainly focusing on cancer drugs. He is an editorial board member of the journal Cancer Imaging.

Dr Van den Abbeele is chair emeritus, Department of Imaging, and founding director, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute; Codirector, Tumor Imaging Metrics Core, DF/Harvard Cancer Center; senior faculty scholar; associate professor of radiology, Harvard Medical School; and co-editor-in-chief of Cancer Imaging. Her major areas of research include translational cancer research and drug development using imaging.

Transarterial chemoembolization (TACE) is one of the most popular liver-directed therapies for liver tumors, especially hepatocellular carcinoma. TACE aims to embolize the tumor and deliver chemotherapeutic agents through a catheter-based intra-arterial route. Different embolic strategies have been developed over the years; however, the basic approach is to use chemotherapeutic drugs mixed with a drug-carrying embolic material (1,2).

Conventional TACE delivers a suspension of chemotherapeutic agents mixed with Lipiodol (Guerbet, Villepinte, France). Lipiodol is an ethiodized poppyseed oil that acts as a drug-delivering carrier as well as an embolic agent. The commonly used chemotherapeutic agents are doxorubicin, cisplatin, epirubicin, and mitomycin. Theoretically, Lipiodol should be selectively retained in hepatic tumors for several months while delivering chemotherapeutic agents to the tumor. In clinical practice, however, a certain amount of the injected drug leaks into the systemic circulation during the TACE procedure. This may increase systemic toxicity. Furthermore, methods to produce the mixture of Lipiodol and therapeutic drug have not been standardized yet and differ across countries and institutions because interventional radiologists prepare the mixture during the procedure. So far, there is no standardized manufactured product for conventional TACE (1,2).

Drug-eluting beads (DEBs) have been developed to carry and release drugs in the targeted tumor in a controlled and standardized manner and reduce systemic toxicities. Several DEB materials have been applied for DEB-TACE, including DC Bead (Biocompatibles UK, a BTG International Group Company, London, England), HepaSphere/QuadraSphere microspheres (Merit Medical Systems, South Jordan, Utah), and DC Bead M1 (Biocompatibles UK). Several chemotherapeutic drugs can be loaded into these DEBs; the most commonly used drug is doxorubicin (1,2).

Most of above-mentioned DEB materials are radiolucent and invisible on radiographs. This hampers the TACE procedure and the assessment of treatment response at follow-up CT. In addition, incomplete filling of the tumor with the DEBs is associated with treatment failure (3). Recently, a new DEB material, LC Bead LUMI (Biocompatibles UK), was developed as a radiopaque product containing an iodine; this enables real-time tracking of injected beads during the TACE procedure (4). The geographic distribution information provided by visible radiopaque beads may better inform the operators with regard to successful tumor targeting and appropriate filling of the tumor with the beads during the procedure.

A major question has now emerged in the field of TACE. Embolization can induce hypoxia in the liver tissue, which upregulates several proangiogenic factors such as the vascular endothelial growth factor (VEGF) (2). VEGF is a well-known proangiogenic factor that enhances tumor angiogenesis and may enable tumor growth and metastatic spread in hepatocellular carcinoma. Indeed, a recent meta-analysis that included 782 patients with hepatocellular carcinoma (5) found that a higher serum VEGF level was directly associated with poor overall survival and disease-free survival.

On the basis of this evidence, combinations of TACE and systemic antiangiogenic agents such as sorafenib have been tested in several clinical trials, as summarized in the Table (6–9). Of these trials, only the TACTICS trial showed survival benefit with a combined conventional TACE and sorafenib regimen compared with conventional TACE alone (9). Still, there is a debate about the benefit of combined TACE and sorafenib, warranting a new innovative therapeutic strategy to overcome proangiogenic events due to VEGF increase. In this issue of Radiology, Duran et al (10) introduce new innovations that are intended to counter the proangiogenic effects of TACE treatment.

Results of Clinical Trial Evaluation of Survival Benefit for Combined TACE and Sorafenib versus TACE Alone

Duran et al evaluated the pharmacokinetics, safety, and efficacy of drug-eluting radiopaque beads loaded with vandetanib for the treatment of liver tumor using a rabbit VX2 liver tumor model. Vandetanib is an oral tyrosine kinase inhibitor targeting the VEGF receptor and the epidermal growth factor receptor and has been shown to have an antiangiogenic effect. In the preclinical study by Duran et al (10), the authors hypothesized that the local delivery of vandetanib into liver tumors using DEBs might show a direct antitumor effect through increased local tumor drug concentration and prevention of hypoxia-induced upregulation of proangiogenic factors during TACE. To prove these hypotheses, Duran et al compared the antitumor effect, drug intratumoral tissue and blood concentration, and the pharmacokinetic parameters between groups of rabbits treated with vandetanib-eluting radiopaque beads (VERBs), nonloaded radiopaque beads (ROBs), intra-arterial vandetanib suspension, or no treatment.

The results demonstrated that VERBs showed a better antitumor effect than ROBs and intra-arterial vandetanib suspension. Tumor growth at 3 weeks after treatment was lowest with VERBs, followed by ROBs, intra-arterial vandetanib suspension, and no treatment (114%, 192%, 466%, and 650% increase from baseline, respectively). Notably, bland embolization with ROBs showed better antitumor effect than intra-arterial administration of vandetanib, suggesting that embolization itself is a powerful therapeutic strategy to treat liver tumors. The exact mechanism behind the better antitumor effect seen with TACE and VERBs compared with bland embolization with ROBs was not discussed in this study. It could be related to the antitumor effect of the VERBs themselves or to the counteraction effect of proangiogenic events after TACE. Further study is required to explore the therapeutic mechanism of VERB treatment to determine whether VERBs counteract the upregulation of proangiogenic factors during TACE.

TACE with VERBs also showed better pharmacokinetic properties, with 10-times-higher intratumoral tissue drug concentration in the VERB group compared with the intra-arterial vandetanib suspension group on day 3. The peak blood drug concentration was five times lower in the VERB group relative to the intra-arterial vandetanib suspension group. These results correlate with the common properties of DEBs and coincide with results with other types of DEBs (1,2). Using univariable and multivariable logistic regression analysis, Duran et al report that the most influential factors for antitumor effect were identified as the bead volume on day 3 and the intratumoral tissue concentration at week 3 after treatment. The authors were able to measure the bead volume at CT because radiopaque LC Bead LUMI beads were used for VERB chemoembolization. These results imply that radiopaque bead volume measured at follow-up CT could be used as a predictive factor to assess treatment response. This would be helpful to guide further treatment.

In conclusion, VERBs are a novel embolic agent for DEB-TACE with the potential to prevent the upregulation of proangiogenic factors during TACE, an emerging challenge in the field of TACE research. The study by Duran et al demonstrated that VERBs have strong antitumor effects and good pharmacokinetic properties. These results suggest that the combination of antiangiogenic agents and DEBs might lead to better efficacy and safety of TACE. However, further research is required to explore the mechanism of VERB treatment at the biologic and molecular levels and to compare its efficacy and safety with that of other TACE methods to translate preclinical trials into phase I, II, and III clinical trials. Ultimately, these results may enable new drug development and offer better therapeutic options to patients with liver tumors and the clinicians taking care of these patients.