Understanding emulsions could help make the ideal cocktail for conventional transarterial chemoembolization

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Kamran Ahrar

Considering the many advantages of conventional transarterial chemoembolization (cTACE) and its continued widespread use across the globe, we may want to try, one more time, to standardise the procedure. Realising that exact emulsions are nearly impossible to reproduce in the clinical setting, we need a set of simple rules to optimise emulsions for cTACE in the angiography suite, writes Kamran Ahrar.

 

Conventional transarterial chemoembolization (cTACE) is based on an emulsion of ethiodised oil (Lipiodol, Guerbet) and an aqueous chemotherapeutic solution. Lipiodol is iodinated ethyl esther of poppy seed oil. It was first synthesised by Guerbet in 1901 and was the first iodinated contrast used in a variety of different procedures such as myelography and lymphangiography. The most common chemotherapeutic agent used in cTACE is doxorubicin that is dissolved in iodinated contrast. There are many advantages of Lipiodol as the embolic agent used in cTACE. First, Lipiodol is a “plastic” embolic agent with remarkable malleability, conforming to the diameter of hepatic and tumoural arteries. This unique characteristic allows the agent to traverse the arterial supply and lodge in the distal branches of the portal vein that  provide blood supply to the tumour and the micrometastases surrounding it. Achieving this dual embolization helps reduce local recurrences and improves survival.

Second, Lipiodol demonstrates a preferential flow in the larger tumoural arteries. Third, it shows preferential uptake and retention in the tumour tissue. By some reports, Lipiodol is retained in hepatocellular carcinoma over normal liver parenchyma by a factor of 4.3. The history of cTACE dates back to the 1980s. Over the last 30 years, many of the hundreds of articles published on cTACE have left out the details of formulation of the emulsion. Realising that exact emulsions are nearly impossible to reproduce in the clinical setting, we need a set of simple rules to optimise emulsions for cTACE in the angiography suite.

An emulsion is a mixture of two liquids that are normally immiscible. Every emulsion has a continuous phase and a dispersed (discontinuous) phase. One could take two liquids, like water and oil, and make emulsions with completely opposite characteristics based on the volume of each liquid. An “oil-in-water” emulsion consists of oil droplets dispersed in a continuous phase of water. On the other hand, a “water-in-oil” emulsion is made of water droplets dispersed in a continuous phase of oil. Thierry de Baere and others have shown that “water-in-oil” emulsions have larger embolic effect compared to “oil-in-water” emulsions and are better suited for cTACE. The embolic effect of emulsion is directly related to the size of oil droplets. “Water-in-oil” emulsions inherently contain larger droplets of oil, owing to their continuous phase of iodised oil. In addition, tumour uptake of “water-in-oil” emulsions is significantly higher than tumour uptake of “oil-in-water” emulsions. Adopting the following simple rules helps optimise the emulsion for cTACE. First, choose the right volumes to promote formulation of “water-in-oil” emulsion. For best results, mix two volumes of oil with one volume of aqueous drug, keeping in mind that the maximum volume of oil to be injected in adults per session is about 15 milliliters. Second, when suspending the drug(s) in iodinated contrast, use non-ionic contrast to achieve better stability of drug-Lipiodol emulsion.

Third, start the emulsification process by pushing the aqueous drug solution into Lipiodol syringe. And finally, mix vigorously. At least 20 pumping exchanges through a 3-way stopcock help create an emulsion with oil droplets in the range of 70–100 microns. Emulsions of water-in-oil created in this fashion are fairly stable and do not break up after injection.

A major impetus for adopting drug-eluting beads in chemoembolization (DEB-TACE) was to standardise therapeutic sessions across different institutions and operators. With the current state of technology, there remains a fair amount of variability in the way interventional radiologists apply DEB-TACE to treatment of hepatocellular carcinoma. Considering many advantages of cTACE and its continued widespread use across the globe, we may want to try, one more time, to standardise the procedure. Understanding emulsions and implementing a simple algorithm for making them in cTACE go a long way in achieving that goal.


Kamran Ahrar is professor, Interventional Radiology, MD Anderson Cancer Center, Houston, USA. He has reported no disclosures pertaining to the article.