Irreversible electroporation

Irreversible electroporation (IRE or NTIRE for non-thermal irreversible electroporation) is a soft tissue ablation technique using ultra short but strong electrical fields to create permanent and hence lethal nanopores in the cell membrane, to disrupt the cellular homeostasis. The resulting cell death results from apoptosis and not necrosis as in all other thermal or radiation based ablation techniques. The main use of IRE lies in tumor ablation in regions where precision and conservation of the extracellular matrix, blood flow and nerves are of importance. The technique is in an experimental stage and has not been approved for use outside of clinical trials. IRE is used in the NanoKnife System.

History

First observations of IRE effects go back to 1898.[1] Nollet reported the first systematic observations of the appearance of red spots on animal and human skin that was exposed to electric sparks.[2] However, its use for modern medicine began in 1982 with the seminal work of Neumann and colleagues.[3] Pulsed electric fields were used to temporarily permeabilize cell membranes to deliver foreign DNA into cells. In the following decade, the combination of high-voltage pulsed electric fields with the chemotherapeutic drug bleomycin and with DNA yielded novel clinical applications: electrochemotherapy and gene electrotransfer respectively.[4][5][6][7][8]

In these treatment modalities IRE was an unwanted side effect to reversible electroporation. In 2005, Davalos et al. described the first study of a potential use of IRE.[9]

Mechanism

Utilizing ultra short pulsed but very strong electrical fields, micropores and nanopores are induced in the phospholipid bilayers which form the outer cell membranes. Two kinds of damage can occur:

  1. Reversible electroporation (RE): Temporary and limited pathways for molecular transport via nanopores are formed, but after the end of the electric pulse, the transport ceases and the cells remain viable. Medical applications are, for example, local introduction of intracellular cytotoxic pharmaceuticals such as bleomycin (electroporation and electrochemotherapy).
  2. Irreversible electroporation (IRE): After a certain degree of damage to the cell membranes by electroporation, the leakage of intracellular contents is too severe or the resealing of the cellular membrane is too slow, leaving healthy and/or cancerous cells irreversibly damaged. They die by apoptosis, which is unique to this ablation technique, in opposition to all other ablation systems which induce necrosis either by heat or radiation.

It should be stated that even though the ablation method is generally accepted to be apoptosis, some findings seem to contradict a pure apoptotic cell death, making the exact process by which IRE causes cell death unclear.[10]

The mechanism of IRE is not completely understood. The current theory is as follows:[11]

When an electrical field of more than 0.5 V/nm[12] is applied to the resting trans-membrane potential, it is proposed that water enters the cell during this dielectric breakdown. Hydrophilic pores are formed.[13][14] A molecular dynamics simulation by Tarek[15] illustrates this proposed pore formation in two steps:[11]

  1. After the application of an electrical field, water molecules line up in single file and penetrate the hydrophobic center of the bilayer lipid membrane.
  2. These water channels continue to grow in length and diameter and expand into water-filled pores, at which point they are stabilized by the lipid head groups that move from the membrane-water interface to the middle of the bilayer.

It is proposed that as the applied electrical field increases, the greater is the perturbation of the phospholipid head groups, which in turn increases the number of water filled pores.[16] This entire process can occur within a few nanoseconds.[15] Average sizes of nanopores are likely cell-type specific. In swine livers, they average around 340-360 nm, as found using SEM.[11]

Potential advantages and disadvantages

  1. Tissue selectivity - conservation of vital structures within the treatment field. Its capability of preserving vital structures within the IRE-ablated zone. In all IRE ablated liver tissues, critical structures, such as the hepatic arteries, hepatic veins, portal veins and intrahepatic bile ducts were all preserved. In IRE the cell death is mediated by apoptosis. Structures mainly consisting of proteins like vascular elastic and collagenous structures, as well as peri-cellular matrix proteins are not affected by the currents. Vital and scaffolding structures (like large blood vessels, urethra or intrahepatic bile ducts) are conserved.[17] The electrically insulating myelin layer, surrounding nerve fibers, protects nerve bundles from the IRE effects to a certain degree. Up to what point nerves stay unaffected or can regenerate is not completely understood.[18]
  2. Sharp ablation zone margins- The transition zone between reversible electroporated area and irreversible electroporated area is accepted to be only a few cell layers. Whereas, the transition areas as in radiation or thermal based ablation techniques are non-existent. Further, the absence of the heat sink effect, which is a cause of many problems and treatment failures, is advantageous and increases the predictability of the treatment field. Geometrically, rather complex treatment fields are enabled by the multi-electrode concept.[19]
  3. Absence of thermally induced necrosis - The short pulse lengths relative to the time between the pulses prevents joule heating of the tissue. Hence, by design, no necrotic cell damage is to be expected (except possibly in very close proximity to the needle). Therefore, IRE has none of the typical short and long term side-effects associated with necrosis.[20][21]
  4. Short treatment time - A typical treatment takes less than 5 minutes. This does not include the possibly complicated electrode placement.
  5. Real time monitoring - The treatment volume can be visualized, both during and after the treatment. Possible visualization methods are ultrasound, MRI, and CT.[19]

Current technical limitations of IRE are:

  1. Strong muscle contractions - The strong electric fields created by IRE, due to direct stimulation of the neuromuscular junction, cause strong muscle contractions requiring special anesthesia and total body paralysis.[22]
  2. Incomplete ablation within targeted tumors- The originally threshold for IRE of cells was approximately 600 V/cm with 8 pulses, a pulse duration of 100 μs, and a frequency of 10 Hz.[23] Qin et al. later discovered that even at 1,300 V/cm with 99 pulses, a pulse duration of 100 μs, and 10 Hz, there were still islands of viable tumor cells within ablated regions.[24] This suggests that tumor tissue may respond differently to IRE than healthy parenchyma. The mechanism of cell death following IRE relies on cellular apoptosis, which results from the pore formation in the cellular membrane. Tumor cells, known to be resistant to apoptotic pathways, may require higher thresholds of energy to be adequately treated.
  3. Local environment - The electric fields of IRE are strongly influenced by the conductivity of the local environment. The presence of metal, for example with biliary stents, can result in variances in energy deposition. Various organs, such as the kidneys, are also subject to irregular ablation zones,due to the increased conductivity of urine.[25]

Use in medical practice

A number of electrodes, in the form of long needles, are placed around the target volume. The point of penetration for the electrodes is chosen according to anatomical conditions. Imaging is essential to the placement and can be achieved by ultrasound, magnetic resonance imaging or tomography. The needles are then connected to the IRE-generator, which then proceeds to sequentially build up a potential difference between two electrodes. The geometry of the IRE-treatment field is calculated in real time and can be influenced by the user. Depending on the treatment-field and number of electrodes used, the ablation takes between 1 and 10 minutes. In general muscle relaxants are administered, since even under general anesthetics, strong muscle contractions are induced by excitation of the motor end-plate.

Typical parameters:

The shortly pulsed, strong electrical fields are induced through thin, sterile, disposable electrodes. The potential differences are calculated and applied by a computer system between these electrodes in accordance to a previously planned treatment field.

One specific device for the IRE procedure is the NanoKnife system manufactured by AngioDynamics, which received FDA 510k clearance on October 24, 2011.[26] The NanoKnife system has also received an Investigational Device Exemption (IDE) from the FDA that allows AngioDynamics to conduct clinical trials using this device.[26] The Nanoknife system transmits a low-energy direct current from a generator to electrode probes placed in the target tissues for the surgical ablation of soft tissue. In 2011, AngioDynamics received an FDA warning letter for promoting the device for indications for which it had not received approval.[27]

In 2013, the UK National Institute for Health and Clinical Excellence issued a guidance that the safety and efficacy of the use of irreversible electroporation of the treatment of various types of cancer has not yet been established.[28]

Clinical trials

None of the potential organ systems, which may be treated for various conditions and tumors, are covered by randomized multicenter trials or long-term follow-ups.

In 2010, Ball and colleagues conducted a clinical trial evaluating IRE in 21 patients treated for metastatic or primary tumors of the liver, kidney, or lung. Two patients developed positional neuropraxia because of the extended arm position requested for CT scanning. Some patients developed self-limiting ventricular tachycardias, which are now minimized by using an electrocardiogram (ECG) synchronizer. Three patients developed pneumothoraces as a result of needle electrode insertion. The authors concluded that an ECG synchronizer should be used to minimize the risk of arrhythmias and that attention to the position of the arms is required to maximize CT scan quality but minimize brachial plexus strain.[29]

A larger, single-center, prospective, non-randomized, cohort study to investigate the safety of IRE for tumor ablation in humans evaluated 38 subjects with advanced malignancy of the liver, kidney, or lung (69 separate tumors) which were unresponsive to alternative treatment. The authors reported no mortalities within the 30 days post-procedure. Transient ventricular arrhythmia occurred in four patients; ECG synchronized delivery was subsequently used in the remaining 30 patients, with two further arrhythmias (supraventricular tachycardia and atrial fibrillation). There was one report of obstruction of the upper ureter after IRE, in addition to one report of the unintentional electroporation of an adrenal gland, resulting in a transient, severe hypertension. Two patients developed temporary neurapraxia secondary to arm extension during treatment, The authors further noted that complete target tumor ablation verified by CT was achieved in 46 of the 69 tumors treated with IRE (66%), while most treatment failures occurred in renal and lung tumors. The authors concluded that IRE appears safe for clinical use if ECG-synchronized delivery is utilized to prevent arrhythmias.[30]

Scope of applications

Kidney

While nephron-sparing surgery is the gold standard treatment for small, malignant renal masses, ablative therapies are considered a viable option in patients who are poor surgical candidates. Radiofrequency ablation (RFA) and cryoablation have been used for over a decade; however, in lesions larger than 3 cm, their efficacy is limited. The never ablation modalities, such as IRE, microwave ablation (MWA), and high-intensity focused ultrasound, may help overcome the challenges in tumor size.[31]

The first human studies have proven the safety of IRE for the ablation of renal masses; however, the effectiveness of IRE through histopathological examination of an ablated renal tumor in humans is yet to be known. Wagstaff et al. have set out to investigate the safety and effectiveness of IRE ablation of renal masses and to evaluate the efficacy of ablation using MIR and contrast-enhanced ultrasound imaging. In accordance with the prospective protocol designed by the authors, the treated patients will subsequently undergo radical nephrectomy to assess IRE ablation success.[32]

Liver

Thermal ablation techniques are very effective at treating liver tumors; however, many tumors are poorly amenable to thermal ablation due to their proximity to large blood vessels or major bile ducts, that render ablation ineffective or dangerous.[33]

In a single-center, prospective, non-randomized cohort, the safety of IRE of liver lesions was assessed in 25 patients. The authors reported a 50% tumor response rate, and noted that IRE failed to have any effect on tumors larger than 5 cm in any dimension. There were no reports of liver damage in any of the patients treated.[30] The trend of larger tumors being incompletely ablated using IRE has persisted across other studies.[34]

Pancreas

Percutaneous thermal ablation of the pancreas was first described in 1999; however, subsequent review concluded that RFA in this setting has an unacceptably high complication rate without a clear benefit in survival.[35][36] The non-thermal mechanism of cell death from IRE and the safety and feasibility seen in animal models, suggests that it may be a more reasonable option.[37]

Martin et al. evaluated overall survival in 54 patients with local pancreatic adenocarcinoma; they compared their IRE-treated cohort to matched stage III patients treated with standard therapy. They found a statistically significant increase in local progression-free survival, distant progression-free survival, and overall survival, amongst the patients treated with IRE.[38]

Lung

In a prospective, single-arm, multi-center, phase II clinical trial, the safety and efficacy of IRE on lung cancers were evaluated. The trial included patients with primary and secondary lung malignancies and preserved lung function. The expected effectiveness was not met at interim analysis and the trial was stopped prematurely. Complications included pneumothoraces (11 of 23 patients), alveolar hemorrhage not resulting in significant hemoptysis, and needle tract seeding was found in 3 cases (13%). Disease progression was seen in 14 of 23 patients (61%). Stable disease was found in 1 (4%), partial remission in 1 (4%) and complete remission in 7 (30%) patients. The authors concluded that IRE is not effective for the treatment of lung malignancies.[39] Similarly poor treatment outcomes have been observed in other studies.[30][40]

A major obstacle of IRE in the lung is the difficulty in positioning the electrodes; placing the probes in parallel alignment is made challenging by the interposition of ribs. Additionally, the planned and actual ablation zones in the lung are dramatically different due to the differences in conductivity between tumor, lung parenchyma, and air.[41]

Prostate

The idea of treating prostate cancer with IRE was first proposed by Gary Onik and Boris Rubinsky in 2007.[42] Prostate carcinomas are frequently located near sensitive structures which might be permanently damaged by thermal treatments or radiation therapy. The applicability of surgical methods is often limited by accessibility and precision. Surgery is also associated with a long healing time and high rate of side effects.[43] Using IRE, the urethra, bladder, rectum and neurovascular bundle can potentially be included in the treatment field without creating (permanent) damage. This would potentially give IRE superiority both for focal therapy and whole gland treatments, as compared to all other available methods. Though treatments using IRE have been practiced successfully for more than three years, it has to be considered experimental since there are no multi-center studies or long-term follow-ups.

The first study including 16 patients (Gleason-Score ranging from 6 to 8) was released in 2010 by G. Onik and B. Rubinsky.[44] Most publicly and broadly, IRE has been used for prostate carcinomas by M. K. Stehling in Germany.[45] In the UK, Dickson et al. have been using IRE for Gleason 6 and 7 carcinomas and reported positively about its safety and low toxicity.[46]

Coronary arteries

Maor et el have demonstrated the safety and efficiency of IRE as an ablation modality for smooth muscle cells in the walls of large vessels in rat model.[47] Therefore, IRE has been suggested as preventive treatment for coronary arteries re-stenosis after percutaneous coronary intervention.

Pulmonary veins

Numerous studies in animals have demonstrated the safety and efficiency of IRE as a non-thermal ablation modality for pulmonary veins in context of atrial fibrillation treatment. IRE's advantages in comparison with RF-ablation and cryoablation are: well defined ablation area and the lack of peripheral thermal damage. Therefore, IRE has been suggested as a part of novel treatment for atrial fibrillation.[48]

Other organs

IRE has also been investigated in ex-vivo human eye models for treatment of uveal melanoma[49] and in thyroid cancer.[50]

Successful ablations in animal tumor models have been conducted for lung,[51][52] brain,[53][54] heart,[55] skin,[56][57] bone,[58][59] head and neck cancer,[60] and blood vessels.[61]

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Further reading

  • Rubinsky B (2009). Irreversible Electroporation (Series in Biomedical Engineering). Berlin: Springer. ISBN 3-642-05419-6. 
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