“Our solution to the limitations of ethanol ablation is the polymer ethyl cellulose,” Erika Chelales (Center for Global Women’s Health Technologies, Duke University, Durham, USA) told delegates attending the abstract presentations at the 2021 meeting of the Society of Interventional Oncology (SIO; 3–6 February, online). In a radiologic-pathologic analysis of a novel ethanol gel formulation involving the ethyl cellulose polymer, Chelales and colleagues found that their newer technique was superior to traditional ethanol for percutaneous ablation in an ex vivo rat liver model.
Comparing a world map of hepatocellular carcinoma (HCC) mortality rates by region and one of human development index (HDI) rates, Chelales showed that countries with lower HDI have higher HCC mortality rates. “This means that the countries with the highest HCC burden have lower income and fewer resources available for treatment,” she commented.
“Many regions lack routine access to safe and affordable standard of care, and can therefore not access [Barcelona Clinic Liver Cancer] BCLC-defined curative treatment options like microwave ablation, radiofrequency ablation, and cryoablation,” she continued. “Unfortunately, ablative therapies are also not easily accessible or affordable in these settings. This is due to inadequate access to supplies, like thermal ablation systems or gas tanks for cryotherapy, as well as cost. Often, the only accessible and affordable ablative therapy in these settings is ethanol ablation.”
Ethanol induces cytosis through cell membrane and cytoplasm dehydration and the disruption and irreversible denaturation of intracellular proteins, resulting in coagulative necrosis. For HCC <3cm, ethanol has comparable five-year survival to RFA, and for HCC <1.5cm, ethanol has comparable overall survival to RFA. But, most importantly, according to Chelales, it is cheaper and more readily-available than RFA. “Although it is low cost, ethanol ablation is still not widely used, and this is due to its limited efficacy,” she said, before saying that its effectiveness is limited by non-target ablation from unpredictable ethanol leak. “Off-target effects result in poor tumour coverage, and then require the patient to return for multiple subsequent treatment sessions. A treatment paradigm involving multiple treatment sessions is not suited for low and middle income settings, where patients are often lost to follow-up.
“Our solution to the limitations of ethanol ablation is the polymer ethyl cellulose”. Ethyl cellulose is an ethanol-soluble but water-insoluble polymer, and induces a phase change from liquid to fibrous gel upon injection into tissue. In the presented study, the investigators sought to compare the spatial distribution of gel, ethanol, and liquid ethanol ablation, and the correspondence of each to the results of necrosis.
“Although we envision ultrasound-guided delivery for use in settings without access to imaging techniques with a large technical footprint, for these validations we used CT [computed tomography] imaging to examine the spatial distribution of ethanol in tissue. This is because ethanol has endogenous CT contrast (pure ethanol is significantly hypodense relative to water),” Chelales explained.
Exploiting the fact that there is a linear relationship between radiodensity and ethanol concentration, the investigators used a two-point calibration equation to provides them with a method of accurately converting radiodensity units from CT images to ethanol concentration in tissue.
They first used this method to determine the optimal gel ethanol formulation in ex vivo rat liver. They injected the target tissue with 100µl of either liquid ethanol or gel ethanol, at various concentrations (6%, 8%, 10%, 12%, or 15%) of the ethyl cellulose polymer at 10mL/hr (n=six). They acquired pre- and post-ablation CT images.
“The CT images show a larger region of low radiodensity corresponding to the injected ethanol in the gel ethanol group compared to the pure ethanol groups,” Chelales noted.
The research team next created maximum intensity projections “to show a clearer picture of cytotoxic ethanol concentrations within the tissue”. For the 12% ethyl cellulose ethanol group, the regions of high ethanol concentration were located centrally within the distribution block, while for the liquid ethanol group, regions of high ethanol concentration were dispersed throughout the tissue, indicating poor localisation.
The research team then quantified the total cytotoxic ethanol volume, and found that liquid ethanol and 12% ethyl cellulose ethanol yielded the smallest and greatest distributed volumes, respectively. They also examined the shape of the distribution by measuring the aspect ratio: a lower aspect ratio was indicative of a more localised distribution, which Chelales said is more desirable for ablation planning, and more comparable to standard-of-care treatment. She reported that all the gel ethanol groups had a better distribution than the liquid ethanol, “indicating improved localisation with the use of ethyl cellulose polymer”. 12% ethyl cellulose ethanol (ECE) yielded a significantly lower aspect ratio than liquid ethanol, and also a significantly greater distribution volume. “Therefore, we determined that 12% ECE was the optimal concentration for use in rat liver tissue,” she said.
Next, the investigators performed a radiologic-pathologic comparison of liquid ethanol (0% ECE) and gel ethanol (12% ECE) ablation in ex vivo rat liver. Post-ablation CT images again showed a larger area of low radiodensity, corresponding to the injected ethanol, for the gel ethanol group compared to the liquid ethanol group. Chelales et al then excised the liver 24 hours after the ablation procedure, and used a dye that would discriminately stain viable tissue over necrotic tissue. In the gel ethanol group, they observed a greater area of necrosis compared to the liquid ethanol.
“We quantified both the distribution and the necrotic volume, and found that both were significantly greater for gel ethanol compared to liquid ethanol ablation,” Chelales summarised. “Therefore, gel ethanol ablation achieves superior CT distribution volume, and increased target treatment. We calculated the average volume of the necrotic volume to ethanol distribution volume, to quantify the correspondence of the distribution as visualised on CT, and the ablative extent. This ratio is closer to one for gel ethanol than for liquid ethanol, although this was not statistically significant. This may indicate that CT imaging provides a more accurate depiction of necrosis for ethyl cellulose ethanol compared to pure ethanol, and a possible explanation for the necessity for the need for multiple treatment sessions with traditional ethanol ablation.
“We determined that 12% ECE achieves minimal leakage and optimal control, and have demonstrated the superiority of 12% ECE ablation to traditional ethanol ablation in an in vivo rat liver model. [As such], ECE is an injectable gel formulation of ethanol that holds promise as a reliable and lower-cost ablative option, and that, compared to thermal ablation, is envisioned to be faster, delivered through a smaller needle with a smaller technological footprint, and can avoid non-target thermal injury for precarious tumour locations.”
Chelales ended by saying that these positive results mean further studies should be conducted in larger animals, and said that the development of ultrasound-based treatment criteria for necrosis is needed.
