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CANCER ABLATION

While surgery and radiation is at the foundation for cancer treatment in developed countries, they are often not viable options for many in developing countries due to shortages in infrastructure, personnel and cost. Because of these obstacles, nine out of ten people in developing countries do not have access to local cancer treatment. Ethanol ablation is especially appealing for use in developing countries because it can be locally available and ultra-low-cost (<$5 per treatments), requires no specialized equipment, is highly portable, and can effectively treat relatively large lesions up to 5 cm in diameter. In high-resource settings ethanol ablation is sometimes preferred over radiofrequency ablation or surgery because it requires less operating time, fewer supplies, and results in fewer complications.

 

However, ethanol ablation’s clinical use has been limited to certain tumor locations due to the unpredictable delivery of pure ethanol. Pure ethanol can leak into porous tissue and vasculature leading to non-specific toxicity and incomplete tumor necrosis. We have developed a method for delivering ethanol that results in more precise delivery and greater safety than pure ethanol ablations. The beauty of our solution lies in its simplicity: combining ethanol, a cytotoxic agent, with ethyl cellulose, a water-insoluble/ethanol-soluble polymer, and intratumorally injecting the solution results in a slow-release ethanol-rich gel. We use intratumoral injections of ethanol and the polymer ethyl-cellulose delivered at a controlled injection rate to further control the size and distribution of the gel. Thus, ethyl cellulose creates a high concentration ethanol cavity, or depot, at the injection site.

When a mixture of ethanol and ethylcellulose (EECF) is mixed with water, the solution undergoes a liquid to solid phase transition resulting in an ethanol-rich, cotton-like gel.

When we translated this to localized treatment of tumors, the ethyl cellulose-ethanol mixture was completely retained within the tumor, i.e., no leakage was observed. The ethanol and ethyl cellulose treatment completely annihilated the tumors one week after a single injection. In fact, 7/7 tumors injected with ethanol-ethyl cellulose completely regressed seven days after the initial injection, while none of the tumors regressed in the control (ethanol only) group.

Spontaneously grown tumors in a hamster cheek pouch were treated with an intratumoral injection of either ethanol alone or ethanol plus ethyl cellulose (gel ethanol). Representative images of the effect of ethanol only and gel ethanol injections on a tumor are shown over 7 days. By day 7, all tumors treated with gel ethanol were completely gone, while tumors treated with ethanol-only showed little response.

For local tumor control, the goal is to kill as much of the diseased tissue as possible while preserving nearby healthy tissue. Ablation modalities are characterized by their zone of necrosis and the degree of peripheral damage compared to surgery. In order to produce a consistent well defined ablation zone we have developed an ethanol-ethyl cellulose mixture termed “gel ethanol” which is both low-cost and easily accessible. Ethylcellulose has unique physical properties that make it liquid when dissolved in pure ethanol and solid once injected into tissue which limits ethanol leakage into peripheral vessels and tissues. Fluorescein was added to an mixture of gel ethanol and to ethanol alone (control) to allow visualization of the injectate. Twenty-four hours after injection, tumors were excised and stained for cell viability. A mouse was considered to have an adverse event if it showed signs of functional impairment, bleeding, or inflammation/edema at any time during a 4-week monitoring period. In preliminary experiments, we demonstrated that gel ethanol distributed over a volume roughly twice the injection volume (Fig. 1A,B) and achieved a zone of necrosis of a volume similar to the distribution volume(Fig. 1 C,D). Importantly, and collateral tissue damage, bleeding, and inflammation were reduced (Fig. 1E) when using gel ethanol compared to using ethanol alone.

A) Tumor cross-section following injection of liquid or gel ethanol with fluorescein added. B) The fluorescent volume is largest for gel ethanol. C) Cell viability staining of large tumors after treatment with liquid or gel ethanol compared with no treatment. D) The necrotic volume is greatest following treatment with gel ethanol. E) Percent of mice with adverse events within four weeks of treatment.

We are currently optimizing the delivery strategy for gel ethanol by examining how injectate infusion rate and formulation affect ethanol depot formation and tumor growth in pre-clinical models. We further hope to harness the power of the immune system through the abscopal effect to fight current and future tumor growths by using ethanol to activate the body’s own defense mechanisms to systemically fight disease with a single treatment.

References

Nief C, Morhard R, Adrianzen Alvarez D, Chelales E, Bourla I, Lam C, Crouch B, Mueller J, Katz D, Dewhirst M, Everitt J, Ramanujam N. A Simple, Precise, and Immunogenic Ablation Technique for Local Treatment of Solid Tumors. Science Advances. In Review, June 2019.

 

Morhard R, Nief C, Castedo CB, Hu F, Madonna M, Mueller JL, Dewhirst MW, Katz DF, Ramanujam N. Development of enhanced ethanol ablation as an alternative to surgery in treatment of superficial solid tumors. Scientific reports. 2017 Aug 18;7(1):8750.