Radiologic-pathologic analysis of increased ethanol localization and ablative extent achieved by ethyl cellulose

Abstract

Ethanol provides a rapid, low-cost ablative solution for liver tumors with a small technological footprint but suffers from uncontrolled diffusion in target tissue, limiting treatment precision and accuracy. Incorporating the gel-forming polymer ethyl cellulose to ethanol localizes the distribution. The purpose of this study was to establish a non-invasive methodology based on CT imaging to quantitatively determine the relationship between the delivery parameters of the EC-ethanol formulation, its distribution, and the corresponding necrotic volume. The relationship of radiodensity to ethanol concentration was characterized with water–ethanol surrogates. Ex vivo EC-ethanol ablations were performed to optimize the formulation (n = 6). In vivo ablations were performed to compare the optimal EC-ethanol formulation to pure ethanol (n = 6). Ablations were monitored with CT and ethanol distribution volume was quantified. Livers were removed, sectioned and stained with NADH-diaphorase to determine the ablative extent, and a detailed time-course histological study was performed to assess the wound healing process. CT imaging of ethanol–water surrogates demonstrated the ethanol concentration-radiodensity relationship is approximately linear. A concentration of 12% EC in ethanol created the largest distribution volume, more than eight-fold that of pure ethanol, ex vivo. In vivo, 12% EC-ethanol was superior to pure ethanol, yielding a distribution volume three-fold greater and an ablation zone six-fold greater than pure ethanol. Finally, a time course histological evaluation of the liver post-ablation with 12% EC-ethanol and pure ethanol revealed that while both induce coagulative necrosis and similar tissue responses at 1–4 weeks post-ablation, 12% EC-ethanol yielded a larger ablation zone. The current study demonstrates the suitability of CT imaging to determine distribution volume and concentration of ethanol in tissue. The distribution volume of EC-ethanol is nearly equivalent to the resultant necrotic volume and increases distribution and necrosis compared to pure ethanol.

Non-Thermal Liver Ablation: Existing and New Technology

“…This was dependent on a cytotoxic concentration of 20% ethanol or more, whereby a linear relationship between radiodensity and the concentration of ethanol was observed. 29,30 Another interesting method of administering PEI aims to inject it peritumorally. High technical efficacy, upward of 89.5 to 98.5%, has been reported with this method, as well as OS rates of up to 10 years.…”

Locoregional Thermal and Chemical Tumor Ablation: Review of Clinical Applications and Potential Opportunities for Use in Low- and Middle-Income Countries

“… 126 The enhanced EC-ethanol formulation was reported to be safe and effective in the treatment of venous malformations, 129 - 131 lumbar and cervical intervertebral disk herniations, 132 - 134 and degenerative disc disease, 135 with therapeutic clinical outcomes, low complication rates, and minimal systemic side effects. Other groups have applied EC-ethanol in preclinical studies to treat oral squamous cell carcinomas in hamsters 126 and cats, 136 breast tumors in mice, 137 HCCs in rats, 138 , 139 and the cervix in swine, 140 demonstrating the ability of EC-ethanol to treat both superficial and deep tumors with limited leakage away from the injection site. These studies support further work to demonstrate the suitability and potential application of EC-ethanol ablative therapy for specific indications and unmet needs in LMICs, all in a cost-effective paradigm.…”

Determining the Relationship between Delivery Parameters and Ablation Distribution for Novel Gel Ethanol Percutaneous Therapy in Ex Vivo Swine Liver

“…EC increases ethanol viscosity [35] and leverages the endogenous polarity difference between ethanol and water to induce a phase change from liquid to fibrous gel (gelation) upon injection into tissue [36]. This mechanism of in situ gelation sequesters cytotoxic ethanol in the target region, increasing on-target coverage and reducing off-target leakage [37,38].…”

“…Upon introduction to water, the solution undergoes a phase transition as the ethanol disperses and the EC contacts the poor solvent environment (tissue). This in situ phase change creates a gradient between insoluble EC-fibrous gel-sol/gel as the ethanol diffuses over time, increasing on-target coverage and reducing off-target leakage [37,38]. The speed and degree to which the phase change occur depend on the initial concentration of EC [35].…”

“…ethanol concentration) and key injection parameters in relation to the resulting force and distribution volumes for clinically relevant (less than 5 cm in diameter as is typical for ablative therapies) tumor treatment [2]. This study followed up our previous work, which developed methodologies to relate key injection parameters to injected ECE injection volumes (50-200 µL) in ex vivo swine and rat liver [37,38]. We also investigated the force required for infusion to inform the impact that the high viscosity of ECE will have on the safety and efficacy of these injections.…”