There are many new directions for research in the field of transarterial chemoembolization (TACE). After the key development of drug-eluting beads, a better understanding of the cellular mechanisms of TACE is mandatory to take the procedure further, writes Alban Denys.
Transarterial chemoembolization (TACE) is a technique invented more than 30 years ago. The rationale for this technique was to deliver chemotherapy locally at high concentration to liver tumours that were mainly fed by the hepatic artery. The technique was rapidly combined to incorporate evolving embolization techniques and to different drug carriers such as lipiodol. Until recently, TACE practice in Japan, Europe and USA was completely different for the same kind of tumours, both with regard to the chemotherapy regimen used and the embolization technique. Therefore series from different continents were hardly comparable in a world where evidence-based medicine in oncology is mandatory.
A major change took place some years ago with the development of drug-eluting beads. This development has led to a significant change and to increased homogeneity in practice. DC beads, developed by Biocompatibles (now part of BTG), has rapidly gained popularity. Clinical and experimental research on this platform has demonstrated that the doxorubicin loaded on to DC beads is delivered over time in a limited space around each bead. Results in terms of tumour response at six months have failed to demonstrate a significant benefit over conventional TACE using 300–500 microns and 500–700 microns in the PRECISION V trial.
Still, Doxorubicin-loaded beads represent a limited change. The basis of combining the chemotherapy drug effects with the ischaemic effects of embolization remains the same and is based on the same concept as conventional TACE. However, drug-eluting beads have recreated interest in the development of new platforms for TACE. These developments can be made in four main directions.
The long history of use of doxorubicin will probably end soon. The selection of a chemotherapy drug for TACE has long been made with reference to intra-venous chemotherapy. Until recently, we were missing prospective works on human culture cells for drug selection. The recent results obtained using Idarubicin in a phase I study (submitted for publication) are encouraging and will be evaluated in a phase II study soon.
In TACE, the respective role of embolization and drug has been poorly explored so far. Ischaemia promoted by embolization induces secretion of vascular endothelial growth factor (VEGF) as well as overexpression of VEGF receptors. This has led to the concept of combining TACE to anti-angiogenic agents given orally daily. Results of three phase II trials have not demonstrated significant benefit while the combination of toxicity impacts quality of life of patients. A new concept developed by Dr Pierre Bize from Lausanne, Switzerland, is to load drug-eluting beads with an anti-angiogenic agent and to deliver it locally where the angiogenic cascade is activated. Animal results have demonstrated the benefit of this concept of enhanced ischaemia.
Development of new carriers
There seems to be a trend towards developing biodegradable beads. However, the data supporting this concept is still extremely limited. Even though arteritis could potentially be reduced, this hypothesis needs more experimental work in order to be validated. The concept that a biodegradable bead will release an active drug for a longer time in vivo has to be verified and its impact on cancer cells will need to be substantiated.
New small molecules
A better understanding of what happens to cancer cells after ischaemia or after chemotherapy will open the gates for new combination therapies. Doxorubicin and other chemotherapeutic agents (such as platin-based agents) act by direct toxicity on DNA. Combination of such a chemotherapeutic agent with a DNA repair inhibitor might then enhance the effect on cancer cells and increase the number of dying cells. New agents like DNA repair inhibitor D-BA has recently been tested by our group in combination with doxorubicin-loaded beads with a significant benefit both on the treated tumour by reducing metastases and tumour vascularity.
In general, interventional radiologists will have to leave a mechanistic device-driven research and adopt a more cellular biology-based research to achieve significant improvements in the procedure.
Alban Denys is with the Department of Radiology and Interventional Radiology, Centre hospitalo-universitaire Vaudois, Université de Lausanne, Lausanne, Switzerland