Irreversible Electroporation: Background, Theory, and Review of Recent Developments in Clinical Oncology

Abstract

Irreversible electroporation (IRE) has established a clinical niche as an alternative to thermal ablation for the eradication of unresectable tumors, particularly those near critical vascular structures. IRE has been used in over 50 independent clinical trials and has shown clinical success when used as a standalone treatment and as a single component within combinatorial treatment paradigms. Recently, many studies evaluating IRE in larger patient cohorts and alongside other novel therapies have been reported. Here, we present the basic principles of reversible electroporation and IRE followed by a review of preclinical and clinical data with a focus on tumors in three organ systems in which IRE has shown great promise: the prostate, pancreas, and liver. Finally, we discuss alternative and future developments, which will likely further advance the use of IRE in the clinic.

Keywords: electroporation; interventional oncology; irreversible electroporation; pulsed electric field.

FIG. 1.

Pore formation is a stochastic process manifested in the lipid bilayer. The behavior of a cell exposed to an external electrical stimulus (a) depends on the amplitude and temporal characteristics of the field. Under physiological conditions (I), the lipid bilayer is a stable barrier exhibiting permeability only to select molecules. After exposure to an intense electric field, hydrophobic pores appear immediately (II) and stabilize after reorientation of lipid head groups (III), allowing for passage of previously impermeable molecules. The asymptotic model proposed by Neu and Krassowska shows that (b) the free energy of induced pores decreases with increasing transmembrane potential beyond a critical radius.

FIG. 2.

IRE is delivered through 25- or 15-cm long monopolar electrodes with varying degrees of exposure. IRE, irreversible electroporation.

FIG. 3.

Pretreatment planning allows for prediction of ablation outcomes. For a canine case of multifocal liver cancer, this consists of (a) locating malignant tissue (red arrow) on diagnostic imaging, (b) reconstructing patient anatomy to assess tumor proximity to relevant structures, (c) identifying suitable electrode insertion pathway and estimating ablation volume (pink), and (d) using the pretreatment planning model to inform insertion tracts for optimal ablation outcomes.

FIG. 4.

(a) Temporal trends in the cumulative number of interventional clinical trials investigating IRE and the corresponding number of patients associated with them. (b) Distribution of clinical trials based on cancer localization. Data acquired from ClinicalTrials.org on August 31, 2019.

FIG. 5.

Ablation regions visualized on transrectal ultrasound correlate with those quantified histologically. (a) Perioperative ultrasound shows (b) the area circumscribed by the electrode configuration within the hypoechoic prostatic tissue. (c) Histology obtained after radical prostatectomy 4 weeks post-treatment shows (d) the area of ablation, which closely resembles the size, shape, and location of that visualized intraoperatively. Image originally found in van den Bos et al. reprinted under Creative Commons Attribution 4.0 International License.

FIG. 6.

Schematic depicting generalized electrode placement and resulting treatment zone for a pancreatic tumor encasing the superior mesenteric vessels. The proximity of the pancreas to these vessels and other vasculature limits interventional options for a large number of patients. In such cases, IRE has shown promise as it allows for focal ablation of the tumor without long-term injury to these critical proteinaceous structures. Additionally, the zone of reversible electroporation could be used in the future to increase uptake of adjuvant molecules and/or chemotherapeutics in the periphery of the ablation, further increasing efficacy.

FIG. 7.

H-FIRE selectively targets malignant cells. IRE and H-FIRE employ voltage waveforms (a) with different characteristic frequencies, which result in unique biological effects. IRE-treated malignant (U251) and healthy (NHA) astrocytes (b, top) exhibit similar electric field thresholds for cell death. However, lethal electric field thresholds for H-FIRE (b, bottom) are much lower for U251 cells than NHAs, demonstrating the capacity of H-FIRE to target malignant phenotypes. (b) Published in Ivey et al. reprinted under Creative Commons Attribution 4.0 International License. H-FIRE, high-frequency irreversible electroporation. Scale bar represents 1 mm.