Professor Irene Krämer, Pharmacy Director, Johannes Gutenberg-University Hospital, Mainz, Germany, began the session with an analysis of the scientific rationale for TACE and the health and safety considerations.
Krämer began by stating that the conventional TACE (cTACE) method was two fold: the first step is to embolise the tumour with gelfoam, polyvinyl alcohol (PVA) particles or spherical embolic agents (embolic microspheres) to occlude arterial blood supply to the tumour causing ischaemia, and subsequent necrosis of the tumour (mechanical occlusion); the second step is to deliver a high concentration of the cytotoxic drugs (doxorubicin, mitomycin and cisplatin with the contrast agent lipiodol) into the tumour.
It has been well documented that the advantage of cTACE is that higher concentrations of the drug can be delivered to the tumour with decreased systemic exposure compared with systemic chemotherapy. With this targeted delivery method, cTACE does not cause extensive damage to the genuine liver parenchyma.
Krämer explained that the mixtures of Lipiodol and cytotoxic drug solutions are not very stable and there is also limited pharmaceutical data to issues surrounding compatibility. She also commented that there was handling safety concerns regarding contamination when delivering the anticancer drugs and performing embolisation in this two stage process.
Drug-Eluting Bead TACE However, Drug-Eluting Bead TACE (DC Bead) products combine the delivery of the cytotoxic drugs as well as embolising the artery with the beads (primary action). She stated that there is valid pharmaceutical data regarding the formulation and stability of the Drug-Eluting Bead as well as instructions for preparation, and no issue surrounding the handling safety.
These PVA hydrogel microspheres are composed of non-degradable polymers, with a spherical hydrophilic polymer network ie. dispersible in hydrophilic solutions, and the size, morphology and compressibility means they are easy to deliver. Their permeability to water causes the microspheres to swell, which results in embolus formation and subsequent long-lasting endovascular occlusion. DC Bead is tinted blue for easy visualisation and is supplied in colour-coded vials for added procedural safety and efficiency.
Irene Krämer
Preparation and loading Krämer explained that the beads are modified in their chemical structure by cross linkages containing free sulfonate (SO3-) moeities, which are negatively charged. This enables the beads to be loaded with and release cationic drugs, as the drugs are positively charged (ionic exchange mechanism). The water content of the beads is >90% and the interaction of doxorubicin with sulfonate groups on DC Bead displaces water from the hydration shells, which subsequently shrink 20-30%. The beads are available in four sizes (average diameters 181µm, 355µm, 525µm and 778µm). The loading time of doxorubicin is concentration dependent, at a concentration of 25mg/mL, 20-100 minutes; at 2mg/mL, 8-11 hours. During the loading phase, it is possible to see the doxorubicin becoming absorbed by the microspheres as the mixture becomes lighter and by 30 minutes, 95% of the doxorubicin is loaded (Figure 1 and Figure 2).
The preparation of the loading of cytotoxic Drug-Eluting Beads should be performed in a pharmaceutical setting to ensure the safety for both personnel and the product. To prepare the loaded beads suspensions with an equal volume of contrast medium takes approximately 12 minutes and is a nine step procedure, with a waiting time of 20-100 minutes. With the pre-loaded PRECISION beads, the process takes six minutes (five steps) and the mixture is ready to use immediately. The beads are usually delivered through a 2.7F micro-catheter (Figure 3).
When loaded the DC Bead is stable for seven days and the beads mixed with contrast medium stable for 24 hours. This extended stability of loaded beads allows for suitable operative planning times. Krämer stressed the importance of having good supply logistics in order to co-ordinate the treatment.
Controlled drug delivery In discussing the delivery of the drug, Krämer said that there had been extensive in vitro and in vivo studies that showed Drug-Eluting Bead TACE has both superior control of delivery and reproducibility of delivery compared with cTACE. The release of the drug is sustained and is delivered to the organ and is not eluted to the rest of the body. As the drug is trapped in the tumour there is a maximisation of the tumour dose as well as a minimisation of peak and total systemic exposure (Figure 4), resulting in less adverse events.
Conclusion Krämer concluded her talk by summarising the relative drug distributions of the various treatments. She said that doxorubicin arterial injection (inter-arterial chemotherapy) results in distribution throughout the entire body, whilst cTACE (doxorubicin and embolisation) allows a high concentration in the tumour but also an infusion throughout the entire body. In contrast, the Drug-Eluting Beads provides a local/regional embolisation and drug delivery, thereby maximising the dosage at the site of target tissue. She finished by outlining future DC Bead platforms that could also be successful in treating metastases of the colon (PARAGON Bead), managing post embolisation pain (ibuprofen bead), a long-term biologic drug delivery (cell bead) and a delivery solution where biodegradability of the bead is a requirement or an advantage (biodegradable bead)(Figure 5).
