Irreversible electroporation#Mechanism

First observations of IRE effects go back to 1754. Nollet reported the first systematic observations of the appearance of red spots on animal and human skin that was exposed to electric sparks.{{cite book | vauthors = Nollet JA | date = 1754 | title = Recherches sur les causes particulieres des phe ́nome ́nes e ́lectriques | location = Paris | publisher = Guerin & Delatour }} However, its use for modern medicine began in 1982 with the seminal work of Neumann and colleagues.{{cite journal | vauthors = Neumann E, Schaefer-Ridder M, Wang Y, Hofschneider PH | title = Gene transfer into mouse lyoma cells by electroporation in high electric fields | journal = The EMBO Journal | volume = 1 | issue = 7 | pages = 841–5 | year = 1982 | pmid = 6329708 | pmc = 553119 | doi = 10.1002/j.1460-2075.1982.tb01257.x }} 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.{{cite journal | vauthors = Mir LM, Belehradek M, Domenge C, Orlowski S, Poddevin B, Belehradek J, Schwaab G, Luboinski B, Paoletti C | title = [Electrochemotherapy, a new antitumor treatment: first clinical trial] | journal = Comptes Rendus de l'Académie des Sciences, Série III | volume = 313 | issue = 13 | pages = 613–8 | year = 1991 | pmid = 1723647 }}{{cite journal | vauthors = Okino M, Mohri H | title = Effects of a high-voltage electrical impulse and an anticancer drug on in vivo growing tumors | journal = Japanese Journal of Cancer Research | volume = 78 | issue = 12 | pages = 1319–21 | date = December 1987 | pmid = 2448275 }}{{cite journal | vauthors = Orlowski S, Belehradek J, Paoletti C, Mir LM | title = Transient electropermeabilization of cells in culture. Increase of the cytotoxicity of anticancer drugs | journal = Biochemical Pharmacology | volume = 37 | issue = 24 | pages = 4727–33 | date = December 1988 | pmid = 2462423 | doi = 10.1016/0006-2952(88)90344-9 }}{{cite journal | vauthors = Daud AI, DeConti RC, Andrews S, Urbas P, Riker AI, Sondak VK, Munster PN, Sullivan DM, Ugen KE, Messina JL, Heller R | title = Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma | journal = Journal of Clinical Oncology | volume = 26 | issue = 36 | pages = 5896–903 | date = December 2008 | pmid = 19029422 | pmc = 2645111 | doi = 10.1200/JCO.2007.15.6794 }}{{cite journal | vauthors = Titomirov AV, Sukharev S, Kistanova E | title = In vivo electroporation and stable transformation of skin cells of newborn mice by plasmid DNA | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1088 | issue = 1 | pages = 131–4 | date = January 1991 | pmid = 1703441 | doi = 10.1016/0167-4781(91)90162-f | url = https://zenodo.org/record/1258377 }} The use of irreversible electroporation for therapeutic applications was first suggested by Davalos, Mir, and Rubinsky.{{cite journal | vauthors = Davalos RV, Mir IL, Rubinsky B | title = Tissue ablation with irreversible electroporation | journal = Annals of Biomedical Engineering | volume = 33 | issue = 2 | pages = 223–31 | date = February 2005 | pmid = 15771276 | doi = 10.1007/s10439-005-8981-8 | s2cid = 11325715 }}

{{further|Electroporation#Physical 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.{{citation needed|date=March 2021}} 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).{{citation needed|date=March 2021}}
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 either apoptosis or via cell-internally induced necrotic pathways, which is unique to this ablation technique.{{citation needed|date=March 2021}}

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.{{cite journal | vauthors = Golberg A, Yarmush ML | s2cid = 16034684 | title = Nonthermal irreversible electroporation: fundamentals, applications, and challenges | journal = IEEE Transactions on Bio-Medical Engineering | volume = 60 | issue = 3 | pages = 707–14 | date = March 2013 | pmid = 23314769 | doi = 10.1109/TBME.2013.2238672 }} In any case, all studies agree that the cell death is an induced one with the cells dying over a varying time period of hours to days and does not rely on local extreme heating and melting of tissue via high energy deposition like most ablation technologies (see radiofrequency ablation, microwave ablation, High-intensity focused ultrasound).{{citation needed|date=March 2021}}

When an electrical field of more than 0.5 V/nm{{cite journal | vauthors = Tieleman DP, Leontiadou H, Mark AE, Marrink SJ | title = Simulation of pore formation in lipid bilayers by mechanical stress and electric fields | journal = Journal of the American Chemical Society | volume = 125 | issue = 21 | pages = 6382–3 | date = May 2003 | pmid = 12785774 | doi = 10.1021/ja029504i | url = https://www.rug.nl/research/portal/en/publications/simulation-of-pore-formation-in-lipid-bilayers-by-mechanical-stress-and-electric-fields(d8724ecd-cef4-4c40-a688-14c45ce87547).html | hdl = 11370/d8724ecd-cef4-4c40-a688-14c45ce87547 | hdl-access = free }} is applied to the resting trans-membrane potential, it is proposed that water enters the cell during this dielectric breakdown. Hydrophilic pores are formed.{{cite journal | vauthors = Weaver JC | title = Molecular basis for cell membrane electroporation | journal = Annals of the New York Academy of Sciences | volume = 720 | issue = 1 | pages = 141–52 | date = May 1994 | pmid = 8010633 | doi = 10.1111/j.1749-6632.1994.tb30442.x | bibcode = 1994NYASA.720..141W | s2cid = 32594522 }}{{cite journal | vauthors = Neumann E, Kakorin S, Toensing K | title = Fundamentals of electroporative delivery of drugs and genes | journal = Bioelectrochemistry and Bioenergetics | volume = 48 | issue = 1 | pages = 3–16 | date = February 1999 | pmid = 10228565 | doi = 10.1016/s0302-4598(99)00008-2 }} A molecular dynamics simulation by Tarek{{cite journal | vauthors = Tarek M | title = Membrane electroporation: a molecular dynamics simulation | journal = Biophysical Journal | volume = 88 | issue = 6 | pages = 4045–53 | date = June 2005 | pmid = 15764667 | pmc = 1305635 | doi = 10.1529/biophysj.104.050617 | bibcode = 2005BpJ....88.4045T }} illustrates this proposed pore formation in two steps:{{cite journal | vauthors = Lee EW, Wong D, Prikhodko SV, Perez A, Tran C, Loh CT, Kee ST | title = Electron microscopic demonstration and evaluation of irreversible electroporation-induced nanopores on hepatocyte membranes | journal = Journal of Vascular and Interventional Radiology | volume = 23 | issue = 1 | pages = 107–13 | date = January 2012 | pmid = 22137466 | doi = 10.1016/j.jvir.2011.09.020 }}

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.{{cite journal | vauthors = Chen C, Smye SW, Robinson MP, Evans JA | s2cid = 6039291 | title = Membrane electroporation theories: a review | journal = Medical & Biological Engineering & Computing | volume = 44 | issue = 1–2 | pages = 5–14 | date = March 2006 | pmid = 16929916 | doi = 10.1007/s11517-005-0020-2 }} This entire process can occur within a few nanoseconds. Average sizes of nanopores are likely cell-type specific. In swine livers, they average around 340-360 nm, as found using SEM.

A secondary described mode of cell death was described to be from a breakdown of the membrane due to transmembrane transfer of electrolytes and adenosine triphosphate. Other effects like heat{{cite journal | vauthors = van Gemert MJ, Wagstaff PG, de Bruin DM, van Leeuwen TG, van der Wal AC, Heger M, van der Geld CW | title = Irreversible electroporation: just another form of thermal therapy? | journal = The Prostate | volume = 75 | issue = 3 | pages = 332–5 | date = February 2015 | pmid = 25327875 | pmc = 4305196 | doi = 10.1002/pros.22913 }} or electrolysis{{cite journal | vauthors = Rubinsky L, Guenther E, Mikus P, Stehling M, Rubinsky B | s2cid = 31700711 | title = Electrolytic Effects During Tissue Ablation by Electroporation | journal = Technology in Cancer Research & Treatment | volume = 15 | issue = 5 | pages = NP95–NP103 | date = October 2016 | pmid = 26323571 | doi = 10.1177/1533034615601549 | doi-access = free }}{{cite journal | vauthors = Klein N, Mercadal B, Stehling M, Ivorra A | title = In vitro study on the mechanisms of action of electrolytic electroporation (E2) | journal = Bioelectrochemistry | volume = 133 | pages = 107482 | date = June 2020 | pmid = 32062417 | doi = 10.1016/j.bioelechem.2020.107482 | s2cid = 211135921 }} were also shown to play a role in the currently clinically applied IRE pulse protocols.

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. As IRE targets the bilipid membranes of cells, 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.{{cite journal | vauthors = Maor E, Rubinsky B | title = Endovascular nonthermal irreversible electroporation: a finite element analysis | journal = Journal of Biomechanical Engineering | volume = 132 | issue = 3 | pages = 031008 | date = March 2010 | pmid = 20459196 | doi = 10.1115/1.4001035 }} 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.{{cite journal | vauthors = Schoellnast H, Monette S, Ezell PC, Maybody M, Erinjeri JP, Stubblefield MD, Single G, Solomon SB | s2cid = 19251168 | title = The delayed effects of irreversible electroporation ablation on nerves | journal = European Radiology | volume = 23 | issue = 2 | pages = 375–80 | date = February 2013 | pmid = 23011210 | doi = 10.1007/s00330-012-2610-3 | pmc = 9377791 }}
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.{{cite journal | vauthors = Lee EW, Thai S, Kee ST | title = Irreversible electroporation: a novel image-guided cancer therapy | journal = Gut and Liver | volume = 4 | issue = Suppl. 1 | pages = S99–S104 | date = September 2010 | pmid = 21103304 | pmc = 2989557 | doi = 10.5009/gnl.2010.4.s1.s99 }}
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.{{cite journal | vauthors = Neal RE, Davalos RV | s2cid = 985854 | title = The feasibility of irreversible electroporation for the treatment of breast cancer and other heterogeneous systems | journal = Annals of Biomedical Engineering | volume = 37 | issue = 12 | pages = 2615–25 | date = December 2009 | pmid = 19757056 | doi = 10.1007/s10439-009-9796-9 | citeseerx = 10.1.1.679.1068 }}{{cite journal | vauthors = Edd JF, Horowitz L, Davalos RV, Mir LM, Rubinsky B | s2cid = 8269394 | title = In vivo results of a new focal tissue ablation technique: irreversible electroporation | journal = IEEE Transactions on Bio-Medical Engineering | volume = 53 | issue = 7 | pages = 1409–15 | date = July 2006 | pmid = 16830945 | doi = 10.1109/TBME.2006.873745 }}
4. Short treatment time - A typical treatment takes less than 5 minutes. This does not include the possibly complicated electrode placement which might require the use of many electrode and re-position of the electrodes during the procedure.
5. Real time monitoring - The treatment volume can be to a certain degree be visualized, both during and after the treatment. Possible visualization methods are ultrasound, MRI, and CT.
6. Immunological response - IRE appears to provoke a stronger immunological response than other ablation methods which is currently being studied for use in conjunction with cancer immunotheraputic approaches.

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.{{cite journal | vauthors = Arena CB, Sano MB, Rossmeisl JH, Caldwell JL, Garcia PA, Rylander MN, Davalos RV | title = High-frequency irreversible electroporation (H-FIRE) for non-thermal ablation without muscle contraction | language = En | journal = BioMedical Engineering OnLine | volume = 10 | issue = 1 | pages = 102 | date = November 2011 | pmid = 22104372 | pmc = 3258292 | doi = 10.1186/1475-925x-10-102 | doi-access = free }}
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.{{cite journal | vauthors = Rubinsky B, Onik G, Mikus P | title = Irreversible electroporation: a new ablation modality--clinical implications | journal = Technology in Cancer Research & Treatment | volume = 6 | issue = 1 | pages = 37–48 | date = February 2007 | pmid = 17241099 | doi = 10.1177/153303460700600106 | doi-access = free }} 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.{{cite journal | vauthors = Qin Z, Jiang J, Long G, Lindgren B, Bischof JC | s2cid = 9514520 | title = Irreversible electroporation: an in vivo study with dorsal skin fold chamber | journal = Annals of Biomedical Engineering | volume = 41 | issue = 3 | pages = 619–29 | date = March 2013 | pmid = 23180025 | doi = 10.1007/s10439-012-0686-1 }} 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 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. However, the recurrence rated found in clinical studies suggest a rather low recurrence rate and often superior overall survival when compared with other ablation modalities.{{cite journal | vauthors = Geboers B, Scheffer HJ, Graybill PM, Ruarus AH, Nieuwenhuizen S, Puijk RS, van den Tol PM, Davalos RV, Rubinsky B, de Gruijl TD, Miklavčič D, Meijerink MR | display-authors = 6 | title = High-Voltage Electrical Pulses in Oncology: Irreversible Electroporation, Electrochemotherapy, Gene Electrotransfer, Electrofusion, and Electroimmunotherapy | journal = Radiology | volume = 295 | issue = 2 | pages = 254–272 | date = May 2020 | pmid = 32208094 | doi = 10.1148/radiol.2020192190 | s2cid = 214645288 }}{{cite journal| vauthors = Aycock KN, Davalos RV |date=2019-12-01|title=Irreversible Electroporation: Background, Theory, and Review of Recent Developments in Clinical Oncology |journal=Bioelectricity |volume=1|issue=4|pages=214–234|doi=10.1089/bioe.2019.0029 |pmid=34471825|pmc=8370296|doi-access=free}}
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.{{cite journal | vauthors = Ben-David E, Ahmed M, Faroja M, Moussa M, Wandel A, Sosna J, Appelbaum L, Nissenbaum I, Goldberg SN | title = Irreversible electroporation: treatment effect is susceptible to local environment and tissue properties | journal = Radiology | volume = 269 | issue = 3 | pages = 738–47 | date = December 2013 | pmid = 23847254 | pmc = 4228712 | doi = 10.1148/radiol.13122590 }}

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.{{citation needed|date=March 2021}}

Typical parameters (1st generation IRE system):{{citation needed|date=March 2021}}

• Number of pulses per treatment: 90
• Pulse length: 100 μs
• Intermission between pulses: 100 to 1000 ms
• Field strength: 1500 volt/cm
• Current: ca. 50 A (tissue- and geometry dependent)
• Max ablation volume using two electrodes: 4 × 3 × 2 cm³

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.{{cite journal | vauthors = Wagstaff PG, Buijs M, van den Bos W, de Bruin DM, Zondervan PJ, de la Rosette JJ, Laguna Pes MP | title = Irreversible electroporation: state of the art | journal = OncoTargets and Therapy | volume = 9 | pages = 2437–2446 | date = 2016 | pmid = 27217767 | pmc = 4853139 | doi = 10.2147/OTT.S88086 | doi-access = free }}

One specific device for the IRE procedure is the NanoKnife system manufactured by AngioDynamics, which received FDA 510k clearance on October 24, 2011.{{cite web | title = FDA Grants Prostate IDE Approval for AngioDynamics' NanoKnife System | url = https://investors.angiodynamics.com/news-releases/news-release-details/fda-grants-prostate-ide-approval-angiodynamics-nanoknife-system?releaseid=772028 | work = Press Release | publisher = AngioDynamics | date = 13 June 2013 }} The NanoKnife system has also received an Investigational Device Exemption (IDE) from the FDA that allows AngioDynamics to conduct clinical trials using this device. 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.{{cite web | url = https://www.fdanews.com/ext/resources/files/archives/u/uc/ucm/ucm2/ucm26/ucm269607.pdf | work = Public Health Service | date = 2011-01-21 | title = Angiodynamics, Inc. Enforcement Actions: Warning Letter. | publisher = United States Food and Drug Administration }}

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.{{cite journal | vauthors = Vroomen LG, Petre EN, Cornelis FH, Solomon SB, Srimathveeravalli G | title = Irreversible electroporation and thermal ablation of tumors in the liver, lung, kidney and bone: What are the differences? | journal = Diagnostic and Interventional Imaging | volume = 98 | issue = 9 | pages = 609–617 | date = September 2017 | pmid = 28869200 | doi = 10.1016/j.diii.2017.07.007 | quote = Current evidence on the safety and efficacy of irreversible electroporation for treating primary lung cancer and metastases in the lung is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. | doi-access = free }}

Newer generations of Electroporation-based ablation systems are being developed specifically to address the shortcomings of the first generation of IRE but, as of June 2020, none of the technologies are available as a medical device.{{cite journal | vauthors = Siddiqui IA, Kirks RC, Latouche EL, DeWitt MR, Swet JH, Baker EH, Vrochides D, Iannitti DA, Davalos RV, McKillop IH | s2cid = 4056858 | display-authors = 6 | title = High-Frequency Irreversible Electroporation: Safety and Efficacy of Next-Generation Irreversible Electroporation Adjacent to Critical Hepatic Structures | journal = Surgical Innovation | volume = 24 | issue = 3 | pages = 276–283 | date = June 2017 | pmid = 28492356 | doi = 10.1177/1553350617692202 }}{{cite book | vauthors = Nuccitelli R |chapter=Tissue Ablation Using Nanosecond Electric Pulses |date=2017 | title =Handbook of Electroporation|pages=1787–1797| veditors = Miklavčič O |place=Cham |publisher= Springer International Publishing |language=en |doi=10.1007/978-3-319-32886-7_93 |isbn=978-3-319-32885-0 }}

Potential organ systems, where IRE might have a significant impact due to its properties include the pancreas, liver, prostate and the kidneys, which were the main focus of the studies listed in Table 1-3 (state: June 2020).

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 (state. June 2020).

Hepatic IRE appears to be safe, even when performed near vessels and bile ducts{{cite journal | vauthors = Kourounis G, Paul Tabet P, Moris D, Papalambros A, Felekouras E, Georgiades F, Astras G, Petrou A | display-authors = 6 | title = Irreversible electroporation (Nanoknife® treatment) in the field of hepatobiliary surgery: Current status and future perspectives | journal = Journal of B.U.On. | volume = 22 | issue = 1 | pages = 141–149 | date = 2017 | pmid = 28365947 | url = https://jbuon.com/archive/22-1-141.pdf }}{{cite journal | vauthors = Silk MT, Wimmer T, Lee KS, Srimathveeravalli G, Brown KT, Kingham PT, Fong Y, Durack JC, Sofocleous CT, Solomon SB | display-authors = 6 | title = Percutaneous ablation of peribiliary tumors with irreversible electroporation | journal = Journal of Vascular and Interventional Radiology | volume = 25 | issue = 1 | pages = 112–8 | date = January 2014 | pmid = 24262034 | doi = 10.1016/j.jvir.2013.10.012 }} with an overall complication rate of 16%, with most complications being needle related (pneumothorax and hemorrhage).The COLDFIRE-2 trial with 50 patients showed 76% local tumor progression-free survival after 1 year.{{cite journal | vauthors = Scheffer HJ, Vroomen LG, Nielsen K, van Tilborg AA, Comans EF, van Kuijk C, van der Meijs BB, van den Bergh J, van den Tol PM, Meijerink MR | display-authors = 6 | title = Colorectal liver metastatic disease: efficacy of irreversible electroporation--a single-arm phase II clinical trial (COLDFIRE-2 trial) | journal = BMC Cancer | volume = 15 | issue = 1 | pages = 772 | date = October 2015 | pmid = 26497813 | pmc = 4619419 | doi = 10.1186/s12885-015-1736-5 | doi-access = free }} Whilst there are no studies comparing IRE to other ablative therapies yet, thermal ablations have shown a higher efficacy in that matter with around 96% progression free survival. Therefor Bart et al. concluded that IRE should currently only be performed for only truly unresectable and non-ablatable tumors.

Animal studies have shown the safety and efficacy of IRE on pancreatic tissue.{{cite journal | vauthors = Lee EW, Shahrouki P, Peterson S, Tafti BA, Ding PX, Kee ST | title = Safety of Irreversible Electroporation Ablation of the Pancreas | journal = Pancreas | volume = 50 | issue = 9 | pages = 1281–1286 | date = October 2021 | pmid = 34860812 | doi = 10.1097/MPA.0000000000001916 | s2cid = 244872230 }} The overall survival rates in studies on the use of IRE for pancreatic cancer provide an encouraging nonvariable endpoint and show an additive beneficial effect of IRE compared with standard-of care chemotherapeutic treatment with FOLFIRINOX (a combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) (median OS, 12–14months).{{cite journal | vauthors = Rombouts SJ, Walma MS, Vogel JA, van Rijssen LB, Wilmink JW, Mohammad NH, van Santvoort HC, Molenaar IQ, Besselink MG | display-authors = 6 | title = Systematic Review of Resection Rates and Clinical Outcomes After FOLFIRINOX-Based Treatment in Patients with Locally Advanced Pancreatic Cancer | journal = Annals of Surgical Oncology | volume = 23 | issue = 13 | pages = 4352–4360 | date = December 2016 | pmid = 27370653 | pmc = 5090009 | doi = 10.1245/s10434-016-5373-2 }}{{cite journal | vauthors = Vincent A, Herman J, Schulick R, Hruban RH, Goggins M | title = Pancreatic cancer | journal = Lancet | volume = 378 | issue = 9791 | pages = 607–620 | date = August 2011 | pmid = 21620466 | pmc = 3062508 | doi = 10.1016/S0140-6736(10)62307-0 }} However, IRE appears to be more effective in conjunction with systemic therapy and is not suggested as first-line treatment. Despite that IRE makes adjuvant tumor mass reduction therapy for LAPC possible, IRE remains, in its current state, a high risk procedure requiring additional safety data before it can be used widely.{{cite journal | vauthors = Shahrouki P, Lee EW | title = Irreversible Electroporation: A Novel Treatment Modality in Locally Advanced and Unresectable Pancreatic Adenocarcinoma | journal = Pancreas | volume = 50 | issue = 9 | pages = e79–e80 | date = October 2021 | pmid = 34860823 | doi = 10.1097/MPA.0000000000001915 | s2cid = 244886899 }}

The concept of treating prostate cancer with IRE was first proposed by Gary Onik and Boris Rubinsky in 2007.{{cite journal | vauthors = Onik G, Mikus P, Rubinsky B | title = Irreversible electroporation: implications for prostate ablation | journal = Technology in Cancer Research & Treatment | volume = 6 | issue = 4 | pages = 295–300 | date = August 2007 | pmid = 17668936 | doi = 10.1177/153303460700600405 | doi-access = free }} 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.{{cite journal | vauthors = Kasivisvanathan V, Emberton M, Ahmed HU | title = Focal therapy for prostate cancer: rationale and treatment opportunities | journal = Clinical Oncology | volume = 25 | issue = 8 | pages = 461–73 | date = August 2013 | pmid = 23759249 | pmc = 4042323 | doi = 10.1016/j.clon.2013.05.002 }} Using IRE, the urethra, bladder, rectum and neurovascular bundle and lower urinary sphincter can potentially be included in the treatment field without creating (permanent) damage.{{citation needed|date=March 2021}}

IRE has been in use against prostate cancer since 2011, partly in form of clinical trials, compassionate care or individualized treatment approach. As for all other ablation technologies and also most conventional methods, no studies employed a randomized multi-center approach or targeted cancer-specific mortality as endpoint. Cancer-specific mortality or overall survival are notoriously hard to assess for prostate cancer, as the trials require more than a decade and usually several treatment types are performed during the years making treatment-specific survival advantages difficult to quantify. Therefore, the results of ablation-based treatments and focal treatments in general usually use local recurrences and functional outcome (quality of life) as endpoint. In that regard, the clinical results collected so far and listed in Table 3 shown encouraging results and uniformly state IRE as a safe and effective treatment (at least for focal ablation) but all warrant further studies. The largest cohort presented by Guenther et al. with up to 6-year follow-up is limited as a heterogeneous retrospective analysis and no prospective clinical trial. Therefore, despite that several hospitals in Europe have been employing the method for many years with one private clinic even listing more than one thousand treatments as of June 2020,{{Cite web| vauthors = Stehling M |title=Vitus Prostate Center - Privately owned Radiology Clinic|url=https://vitusprostate.com/}} IRE for prostate cancer is currently not recommended in treatment guidelines.

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 since the 1990s; however, in lesions larger than 3 cm, their efficacy is limited. The newer ablation modalities, such as IRE, microwave ablation (MWA), and high-intensity focused ultrasound, may help overcome the challenges in tumor size.{{cite journal | vauthors = Olweny EO, Cadeddu JA | title = Novel methods for renal tissue ablation | journal = Current Opinion in Urology | volume = 22 | issue = 5 | pages = 379–84 | date = September 2012 | pmid = 22706069 | doi = 10.1097/mou.0b013e328355ecf5 | s2cid = 43528999 }}

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 MRI 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.{{cite journal | vauthors = Wagstaff PG, de Bruin DM, Zondervan PJ, Savci Heijink CD, Engelbrecht MR, van Delden OM, van Leeuwen TG, Wijkstra H, de la Rosette JJ, Laguna Pes MP | display-authors = 6 | title = The efficacy and safety of irreversible electroporation for the ablation of renal masses: a prospective, human, in-vivo study protocol | language = En | journal = BMC Cancer | volume = 15 | issue = 1 | pages = 165 | date = March 2015 | pmid = 25886058 | pmc = 4376341 | doi = 10.1186/s12885-015-1189-x | doi-access = free }}

Later phase 2 prospective trials showed good results in terms of safety and feasibility {{cite journal | vauthors = Wendler JJ, Pech M, Köllermann J, Friebe B, Siedentopf S, Blaschke S, Schindele D, Porsch M, Baumunk D, Jürgens J, Fischbach F, Ricke J, Schostak M, Böhm M, Liehr UB | s2cid = 5024881 | display-authors = 6 | title = Upper-Urinary-Tract Effects After Irreversible Electroporation (IRE) of Human Localised Renal-Cell Carcinoma (RCC) in the IRENE Pilot Phase 2a Ablate-and-Resect Study | journal = CardioVascular and Interventional Radiology | volume = 41 | issue = 3 | pages = 466–476 | date = March 2018 | pmid = 28929209 | doi = 10.1007/s00270-017-1795-x }}{{cite journal | vauthors = Buijs M, Zondervan PJ, de Bruin DM, van Lienden KP, Bex A, van Delden OM | title = Feasibility and safety of irreversible electroporation (IRE) in patients with small renal masses: Results of a prospective study | journal = Urologic Oncology | volume = 37 | issue = 3 | pages = 183.e1–183.e8 | date = March 2019 | pmid = 30509869 | doi = 10.1016/j.urolonc.2018.11.008 | s2cid = 54523926 }} for small renal masses but the cohort was limited in numbers (7 and 10 patients respectively), hence efficacy is not yet sufficiently determined. IRE appears safe for small renal masses up to 4 cm. However, the consensus is that current evidence is still inadequate in quality and quantity.

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.{{cite journal | vauthors = Ricke J, Jürgens JH, Deschamps F, Tselikas L, Uhde K, Kosiek O, De Baere T | s2cid = 34055662 | title = Irreversible electroporation (IRE) fails to demonstrate efficacy in a prospective multicenter phase II trial on lung malignancies: the ALICE trial | journal = CardioVascular and Interventional Radiology | volume = 38 | issue = 2 | pages = 401–8 | date = April 2015 | pmid = 25609208 | doi = 10.1007/s00270-014-1049-0 }} Similarly poor treatment outcomes have been observed in other studies.{{cite journal|vauthors=Thomson KR, Cheung W, Ellis SJ, Federman D, Kavnoudias H, Loader-Oliver D, Roberts S, Evans P, Ball C, Haydon A|date=May 2011|title=Investigation of the safety of irreversible electroporation in humans|journal=Journal of Vascular and Interventional Radiology|volume=22|issue=5|pages=611–21|doi=10.1016/j.jvir.2010.12.014|pmid=21439847}}{{cite journal | vauthors = Usman M, Moore W, Talati R, Watkins K, Bilfinger TV | title = Irreversible electroporation of lung neoplasm: a case series | journal = Medical Science Monitor | volume = 18 | issue = 6 | pages = CS43-7 | date = June 2012 | pmid = 22648257 | pmc = 3560719 | doi = 10.12659/msm.882888 }}

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.{{cite journal | vauthors = Srimathveeravalli G, Wimmer T, Silk M|display-authors=etal | year = 2013 | title = Treatment planning considerations for IRE in the lung: placement of needle electrodes is critical | journal = J Vasc Interv Radiol | volume = 24 | issue = 4| page = S22 | doi=10.1016/j.jvir.2013.01.047}}

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.{{cite journal | vauthors = Maor E, Ivorra A, Rubinsky B | title = Non thermal irreversible electroporation: novel technology for vascular smooth muscle cells ablation | journal = PLOS ONE | volume = 4 | issue = 3 | pages = e4757 | date = 2009-03-09 | pmid = 19270746 | pmc = 2650260 | doi = 10.1371/journal.pone.0004757 | bibcode = 2009PLoSO...4.4757M | doi-access = free }} Therefore, IRE has been suggested as preventive treatment for coronary artery re-stenosis after percutaneous coronary intervention.{{citation needed|date=March 2021}}

Numerous studies in animals have demonstrated the safety and efficiency of IRE as a non-thermal ablation modality for pulmonary veins in the context of atrial fibrillation treatment.{{cite journal | vauthors = Xie F, Varghese F, Pakhomov AG, Semenov I, Xiao S, Philpott J, Zemlin C | title = Ablation of Myocardial Tissue With Nanosecond Pulsed Electric Fields | journal = PLOS ONE | volume = 10 | issue = 12 | pages = e0144833 | date = 2015-12-14 | pmid = 26658139 | pmc = 4687652 | doi = 10.1371/journal.pone.0144833 | bibcode = 2015PLoSO..1044833X | doi-access = free }} In 2023, irreversible electroporation is being widely used and evaluated in humans, as cardiac ablation therapy to kill very small areas of heart muscle. This is done to treat irregularities of heart rhythm. A cardiac catheter delivers trains of high-voltage ultra-rapid electrical pulses that form irreversible pores in cell membranes, resulting in cell death. It is thought to allow better selectivity than the previous techniques, which used heat or cold to kill larger volumes of muscle.{{cite journal |last1=Tabaja |first1=Chadi |last2=Younis |first2=Arwa |last3=Hussein |first3=Ayman A. |last4=Taigen |first4=Tyler L. |last5=Nakagawa |first5=Hiroshi |last6=Saliba |first6=Walid I. |last7=Sroubek |first7=Jakub |last8=Santangeli |first8=Pasquale |last9=Wazni |first9=Oussama M. |title=Catheter-Based Electroporation |journal=JACC: Clinical Electrophysiology |date=September 2023 |volume=9 |issue=9 |pages=2008–2023 |doi=10.1016/j.jacep.2023.03.014 |pmid=37354168 }}

IRE has also been investigated in ex-vivo human eye models for treatment of uveal melanoma{{cite journal | vauthors = Mandel Y, Laufer S, Belkin M, Rubinsky B, Pe'er J, Frenkel S | title = Irreversible electroporation of human primary uveal melanoma in enucleated eyes | journal = PLOS ONE | volume = 8 | issue = 9 | pages = e71789 | date = 2013-01-01 | pmid = 24039721 | pmc = 3764134 | doi = 10.1371/journal.pone.0071789 | bibcode = 2013PLoSO...871789M | doi-access = free }} and in thyroid cancer.{{cite journal | vauthors = Meijerink MR, Scheffer HJ, de Bree R, Sedee RJ | title = Percutaneous Irreversible Electroporation for Recurrent Thyroid Cancer--A Case Report | journal = Journal of Vascular and Interventional Radiology | volume = 26 | issue = 8 | pages = 1180–2 | date = August 2015 | pmid = 26210244 | doi = 10.1016/j.jvir.2015.05.004 }}

Successful ablations in animal tumor models have been conducted for lung,{{cite journal | vauthors = Deodhar A, Monette S, Single GW, Hamilton WC, Thornton RH, Sofocleous CT, Maybody M, Solomon SB | s2cid = 13294844 | title = Percutaneous irreversible electroporation lung ablation: preliminary results in a porcine model | journal = CardioVascular and Interventional Radiology | volume = 34 | issue = 6 | pages = 1278–87 | date = December 2011 | pmid = 21455641 | doi = 10.1007/s00270-011-0143-9 }}{{cite journal | vauthors = Dupuy DE, Aswad B, Ng T | s2cid = 1233259 | title = Irreversible electroporation in a Swine lung model | journal = CardioVascular and Interventional Radiology | volume = 34 | issue = 2 | pages = 391–5 | date = April 2011 | pmid = 21191587 | doi = 10.1007/s00270-010-0091-9 }} brain,{{cite journal | vauthors = Garcia PA, Pancotto T, Rossmeisl JH, Henao-Guerrero N, Gustafson NR, Daniel GB, Robertson JL, Ellis TL, Davalos RV | title = Non-thermal irreversible electroporation (N-TIRE) and adjuvant fractionated radiotherapeutic multimodal therapy for intracranial malignant glioma in a canine patient | journal = Technology in Cancer Research & Treatment | volume = 10 | issue = 1 | pages = 73–83 | date = February 2011 | pmid = 21214290 | pmc = 4527477 | doi = 10.7785/tcrt.2012.500181 }}{{cite journal | vauthors = Garcia PA, Rossmeisl JH, Neal RE, Ellis TL, Olson JD, Henao-Guerrero N, Robertson J, Davalos RV | s2cid = 10958480 | title = Intracranial nonthermal irreversible electroporation: in vivo analysis | journal = The Journal of Membrane Biology | volume = 236 | issue = 1 | pages = 127–36 | date = July 2010 | pmid = 20668843 | doi = 10.1007/s00232-010-9284-z | citeseerx = 10.1.1.679.527 }} heart,{{cite journal | vauthors = Lavee J, Onik G, Mikus P, Rubinsky B | title = A novel nonthermal energy source for surgical epicardial atrial ablation: irreversible electroporation | journal = The Heart Surgery Forum | volume = 10 | issue = 2 | pages = E162-7 | year = 2007 | pmid = 17597044 | doi = 10.1532/hsf98.20061202 }} skin,{{cite journal | vauthors = Al-Sakere B, André F, Bernat C, Connault E, Opolon P, Davalos RV, Rubinsky B, Mir LM | title = Tumor ablation with irreversible electroporation | journal = PLOS ONE | volume = 2 | issue = 11 | pages = e1135 | date = November 2007 | pmid = 17989772 | pmc = 2065844 | doi = 10.1371/journal.pone.0001135 | bibcode = 2007PLoSO...2.1135A | doi-access = free }}{{cite journal | vauthors = Calmels L, Al-Sakere B, Ruaud JP, Leroy-Willig A, Mir LM | title = In vivo MRI follow-up of murine tumors treated by electrochemotherapy and other electroporation-based treatments | journal = Technology in Cancer Research & Treatment | volume = 11 | issue = 6 | pages = 561–70 | date = December 2012 | pmid = 22712607 | doi = 10.7785/tcrt.2012.500270 | doi-access = free }} bone,{{cite journal | vauthors = Fini M, Tschon M, Ronchetti M, Cavani F, Bianchi G, Mercuri M, Alberghini M, Cadossi R | title = Ablation of bone cells by electroporation | journal = The Journal of Bone and Joint Surgery. British Volume | volume = 92 | issue = 11 | pages = 1614–20 | date = November 2010 | pmid = 21037363 | doi = 10.1302/0301-620X.92B11.24664 | hdl = 11380/646548 | doi-access = free }}{{cite book | vauthors = Fini M, Tschon M, Alberghini M, Bianchi G, Mercuri M, Campanacci L, Cavani F, Ronchetti M, de Terlizzi F, Cadossi R | display-authors = 6 | chapter = Cell electroporation in bone tissue. | veditors = Lee E, Kee S, Gehl J | title = Clinical aspects of electroporation | date = 2011 | pages = 115–127 | publisher = Springer | location = New York, NY. | isbn = 978-1-4419-8362-6}} head and neck cancer,{{cite book | vauthors = Wong D, Lee EW, Kee ST | date = 2011 | chapter = Translational research on irreversible electroporation: VX2 rabbit head and neck. | veditors = Lee E, Kee S, Gehl J | title = Clinical Aspects of Electroporation. | location = Berlin | publisher = Springer | pages = 231–236 | isbn = 978-1-4419-8362-6}} and blood vessels.{{cite journal | vauthors = Maor E, Ivorra A, Rubinsky B | title = Non thermal irreversible electroporation: novel technology for vascular smooth muscle cells ablation | journal = PLOS ONE | volume = 4 | issue = 3 | pages = e4757 | date = 2009-01-01 | pmid = 19270746 | pmc = 2650260 | doi = 10.1371/journal.pone.0004757 | bibcode = 2009PLoSO...4.4757M | doi-access = free }}

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• {{cite book | author = Rubinsky B | title = Irreversible Electroporation (Series in Biomedical Engineering) | publisher = Springer | location = Berlin | year = 2009 | isbn = 978-3-642-05419-8 }}

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Category:Interventional radiology

Category:Medical physics

Category:Vascular procedures

Category:Surgical oncology

Category:Medical technology