Every process and every binding force in our body is based on electromagnetic interactions on a microscopic level. Hormones, proteins, DNA cell walls, etc. - it is all being held together, binding and interacting by smartly arranged differences in potential of carbon based molecules. Hence it is not astounding that external electrical fields can cause a multitude of effects. Strongly pulsed electric fields start to prove to be an extremely potent tool for interacting with our biological matrix, among the applications is tissue selective cancer treatment.

Non-Thermal Irreversible Electroporation is a special case of the so called pulsed electric field treatment. Pulsed Electric Fields (PEFs) provide local field strengths so high that the binding forces on cell walls break, causing nanometer sized pores. This disrupts the very purpose of the cell design - homeostasis. Normally, the cell recovers form these wall disruptions in seconds to minutes. However, if the amount and size of the pores reach a certain threshold, the damage done by the homeostasis loss is too severe and becomes irreversible - hence Irreversible Electroporation (IRE). Still, the timing of the pulses is short enough to not cause significant joules heating (depending on tissue conductivity, number of pulses and volumetric configuration), hence the term Non-Thermal Irreversible Electroporation (NT-IRE).


Irreversible Electroporation (IRE) for cancer treatment - from macroscopic to microscopic and back

Step 1: The tools
There are several ways to reach the high electrical field threshold required for permanent membrane breakdown (several hundred volts per centimeter). Different application systems for different purposes have been designed over the years. Clinically, the two most common commercial systems able to produce the parameters required for IRE are the AngioDynamics NanoKnife IRE ablation system and the IGEA Cliniporator system, while only the NanoKnife has CE and FDA for IRE specifically and the Cliniporator was designed for Electrochemotherapy (ECT).
The NanoKnife exclusively uses needle type electrodes to build up the field strength threshold required for IRE.

 

A

B

C

D

 

Fig.1: The tools for (Irreversible) electroporation in clinical environment. A: The NanoKnife is the only medical device currently labelled for IRE. B: The Cliniporator Vitae does have the technical ability to do IRE, however it was designed for Electrochemotherapy (ECT), which is based on Reversible Electroporation. C: Sterile Electrode pairs are brought into the cancerous area, normally without any cuts or surgery (depending on the type of intervention). D: Electrical fields between each two electrodes determine the treatment field. Strength and length of the pulses determine whether it is Reversible Electroporation, Non Thermal Irreversible Electroporation or others.


Step 2: Localization / Diagnostics

The high local electrical field strengths required for IRE can never be applied on very large areas or the whole body. It needs to be a localizable treatment field. Localizing the area you want to treat is a science of itself, normally done by diagnostic and/or interventional radiologists with many years of experience. Once an agreement has been reached between the specialists physicians, electrodes are inserted into the cancerous area.

Fig.2: Image based diagnostic is the essential tool for planning a treatment. A: A focal prostate cancer lesion B: Computer simulation of the electrical field using a defined electrode setup to ensure full coverage of the cancer.


Step 3: Pulse application parameters

While the placing of the electrodes is normally the most time intensive part of the procedure, the electrodes themselves do nothing without proper controlling of correct potential differences and timing done by a microprocessor inside the pulse generator (i.e. NanoKnife or Cliniporator). The process itself is incredibly simple and immensely complex at the same time: One electrode is being put on an electrical positive potential relative to ground (body) and the other electrode equals negative potential. Table 1 shows a list of the recommended parameters by AngioDynamics (NanoKnife) while even small variations can influence a plethora of mechanisms, from electrochemistry to immunology.

 

Typical voltage  3000 Volt (anode +1500V, cathode -1500V) 
Typical time per pulse  90 microseconds 
Typical number of pulses  90 
Typical interval between pulses  1 second 
Typical distance between electrodes  2 cm 
Typical exposure length of electrodes  2 cm 

Table 1: List of typical parameters for Irreversible Electroporation in clinical use.

The problem of local field distribution is described by Laplace equation. The complexity of the problems is manifold. At first, solving Laplace equation in 3 dimensions is not in every case intuitive, especially when a superposition of several sequences needs to be taken into account. Also, D(Vector) is not constant but tissue has an inhomogeneous conductivity both in terms of spatial dimension and in time. Next, the process is not fully described by using Laplace equation. At least electrochemistry and bioheat with its effect on pore formation (next step) needs to be taken into account. Only very powerful computer can make approximations. This is not a tragedy, Magnetic Resonance Imaging, Positron Emission Tomography or focused radiation therapies run into similar mathematical/physical problems where solutions can only be approximated. Still, they are some of the most valuable tools medicine has to offer. This is similar in Electroporation: Whilst exact treatment field calculations elude our current computational power, this is not necessary to use IRE efficiently for cancer because it is  not possible to treat cancer with a micrometer precision. It is more important to understand the effects involved and know which structures react in which way to the different effects involved in IRE.

Fig.3: Strong local electrical fields and currents cause a plethora of effects in the body. Among others, Reversible Electroporation (RE), Irreversible Electroporation (IRE), thermal damage by joules heating and electrochemical effects. It is a fine balance between field strength, conductivity and timing to reach the desired effect at the right place.

Fig.4: Computer simulation of the electrical field distribution in a default two electrode setup. Red are approximately areas where Irreversible Electroporation would take place when using 8 pulses. The colour gradient area is the region where one would expect Reversible Electroporation and hence the possibility to bring in Electrochemotherapy or Gene Therapy. Though the electrical field is the primary source of cell death, several coupled physical and chemical phenomenon happen simultaneously in PEFs, all relevant to the treatment volume and treatment effect approximations.


Step 4: Pore formations

Once the local field is above a threshold, the phospholipid layers defining the cellular membrane can not withstand the exterior force exhibited by the (I)RE field. In details this process is explained in Fig.6.


Fig.5 shows electron microscope images of these pore formation. Homeostasis is lost. The whole evolutionary design of cells is towards (selective) homeostasis. The state of (temporarily) broken homeostasis is a special but also instable state. During this state a wide variety of molecules can be inserted into the cell which normally can not or hardly penetrate into the cell. The cell walls will close afterwards. Most prominent examples are Bleomycin or Cisplatin for ECT or CRISPR based Gentherapy. This is known as Reversible Electroporation. However, if the membrane is disrupted to severely and can not be repaired, the cell will die. This is the phenomenon known as Irreversible Electroporation described here.

Fig.5: Electron microscope images showing pores on the cell surface. The diameter of these pores is usually several hundreds nanometre in diameter (billionth of a meter).

Fig.6: Phases of electroporation. When in neutral state, the cell keeps homeostasis by stable membranes which consist of phosholipid layer, bound together mainly by van-der-waals forces. An equal transmembrane potential exists between inner and out cells. Now, an external electrical field is applied (PHASE 1) the transmembrane potential builds up towards the end of the cell opposite to the E field vector (left image). Depending of the net field strength, The cell membrane can withstand this force for a short period, nanoseconds or few microseconds (Molecular Dynamic Simulation middle (side view) and right image (top view)). If the field and with it the force is applied for a longer time (PHASE 2) (few microseconds), water pores start to form in the membrane. If applied for tens of microseconds (PHASE 3), the pores reach a size where they stabilize even if the external field is switched off. Depending on size and count of the pores, one is now talking about reversible electroporation (RE, cell will fully recover in seconds or minutes) or irreversible electroporation (IRE, cell will die).
Many thanks to Dr. Mounir Tarek for generating these simulations for us and "Spektrum der Wissenschaft".


Step 5: Macroscopic outcome

The mechanism of pore formation happens to every single cell where this excessive external electrical field is present. But while only cells die, the amino acid structure "collagen", which makes up 25-30% of our body proteins by forming the so-called extra cellular matrix, stay unaffected, among other bodily structures. This allows nerves and larger vessels to be preserved or gives them the ability to regenerate by not denaturizing their structural matrix. This makes up the essential difference of IRE compared to other ablation modalities: Selectively sparing infrastructure, especially blood vessels and nerves, means that for the first time these structures can be included into the treatment field without causing permanent damage to them. Depending on the cancer location, this selectivity can make the essential difference between sever permanent damage (i.e. Prostate cancer: incontinence and impotence) or even live and death as for cancer close to mayor vessels and vital structures (frequently the case i.e. in pancreatic cancer). Additionally, the penumbra around the area of irreversible electroporation (See Fig.4, rainbow area), can additionally be used for treatments based on reversible electroporation like ECT.

Fig.7: An ablated area in the prostate. Vessel wall and nerve trunk are in tact. Rubinsky 2007


Step 6: Immunological mechanisms

In the following hours, days, weeks and month several different immunological mechanisms take place.
Most importantly, the dead cells attract macrophages which "eat" them in a apoptotic-like manner.
An alive cancer has several hiding mechanisms which makes cancer cells either invisible to the immune system, deactivates the fighting mechanisms or build barriers against the fighting cells. All these mechanisms are disrupted after the irreversible damage was done to a cancerous area.
However, the surface of the cancer cells are mostly damaged. This makes an important difference, because this way the cleaning macrophages "see" the cancerous structures and build systemic and tumour specific T-Killer cells. This mechanism is known as Danger-Signal immune response to cancer.
Whilst this is a property of extreme interest for cancer therapies, it is not yet clear how the response can be optimized for a significant impact every time. Just like other groups of physicians and scientists involved in this, we have observed cases where this response was drastic and lasting like in Fig.8. In other cases this effect seems to cause less or no systemic response. Dendritic cell injections and modulated antibodies might  multiply this effect, also low-dose cyclophosphamide shows promising properties.
Summarized, the response appears highly individual which is not astonishing: The largest differing part of our Genome is immune system related and also cancer can have a rather versatile genetic expression profile rendering every case different.
Over the following weeks the necrotic areas are fully removed. Depending on the structure, healthy cells repopulate the intact extra cellular matrix, i.e. smooth muscle cells, endothelia cells and axons. Scaring and side effects are minimized compared to all thermal or radiation based procedures.

 

Fig.8: Immunological response which had a positive effect on the lymph nodes after treatment with IRE.


Combination of Irreversible Electroporation (IRE) and Electro Chemo Therapy (ECT)

As shown in Fig.4, with every IRE type field comes a much larger RE type field. The seconds and minutes when the cell membrane is open and the cell is accessible can be used for a large variety of molecules and protein structures. It is being done in laboratories dealing with cells, i.e. to transfer genes, every day around the world. One very powerful drug which can be inserted is Bleomycin or Cisplatin, both chemotherapeutics with a long and positive track record. Both are up to 10000 times more effective if the cell underwent RE. The drug needs to be only administered once, eliminating almost all of the usual side effects of prolonged chemotherapy treatment plans, but is effective only locally where the RE was done. This is known as Electrochemotherapy (ECT).
Though obvious, combining both, IRE and ECT, strangely is not a very common treatment method yet, which is probably due to the fact that both are relatively new methods and based on different patents owned by different companies. The advantages are manifold. Of course the area of effects is much larger, but the advantages go beyond this fact. The properties are very symbiotic in that sense that IRE and ECT have quite different kill mechanisms. IRE induces a reliable but almost instantaneous cell death with a selectivity limited to tissue types. Bleomycin based ECT is cell selective (mitosis selective), fighting the always dividing cancer cells even more effectively, while sparing cells that are not currently in the phase of mitosis. So the combination of the two yields a treatment with large treatment volumes with a selectivity profile that allows to include areas that could not have been touched with any other known ablation technology, radiation or surgery. We present the combination for prostate cancer more in detail here.


Clinical evidence

Clinical evidence is frequently misunderstood by the patients. Clinical evidence means that a treatment or a drug has a proven benefit for a specific purpose or disease. When experts talk about low or no clinical evidence for a certain intervention, that does not necessarily mean that it is not effective. Normally effectiveness is already proven a decade ahead in lab models and is usually the very reason why a medical product was made out of it. However, the body is complicated and "effectiveness"  for a certain goal (i.e. tumour removal) does not mean "beneficial", where "beneficial" itself is often hard to define. Medicine has literally dozens of examples where interventions are being done effectively and still, it has no benefit, depending on the definition. Many of those are even in the guidelines which themselves are on average based far below 10% based on class 1 evidence. Not every common practice in medicine is proven. Infamous examples with (hardly) no proven benefit are several orthopaedic interventions, cardiological interventions but also holds true for several oncological interventions. A highly discussed example is prostate cancer itself: In many guidelines (like in Germany) radical ectomy for low-risk Gleason 6 prostate cancer is still recommended explicitly: it is effective (prostate is gone afterwards with the usual problems) but the clinical evidence shows that the patient does not live longer.

So, now let's take a look at IRE:
Is IRE effective to remove cancer cells locally? Yes.

Is IRE evidence based for survival benefit in cancer? For some cancers yes, for prostate cancer no. The reason is simple: Quickly lethal cancers are easy to make statistics on, slow developing cancers (like prostate cancer) are extremely complicated and multifactorial. The most prominent result of IRE was shown in 2015 by Martin et al. for locally advanced pancreatic cancer: specific patients treated had twice the mean survival time compared to the state of the art chemotherapy + surgery treatment if IRE is included into the concept to reduce the tumour mass. This has never been reported before and is a milestone both for pancreatic cancer treatment and for proving that IRE as a technology can treat cancer very efficiently.

So where does IRE for prostate cancer stand? IRE can remove prostate cancer lesions. This can be seen on the MRI after 1 day or latest after 1 week in every case. It can also be proven by re-biopsy if the patient wishes. Also, we and others have published results form up to 5 years of follow up and "recurrence free survival" (which is very different from survival benefit) and pathology (ectomy after IRE) exsists with good results. But: does this yield a statistical survival benefit (lowers prostate cancer specific mortality) after the decades is normally takes a prostate adenocarcinoma to be lethal? That can naturally only be found after a long time and large studies. And even this will not tell much about IRE as an ablation technology, because there are great discrepancies in every step along the way: Selection of patient, diagnostic workup quality, treatment planning, pulse sequence, probe placements, skill of the performing doctor, tumour margin planning, follow up intervals and quality, patient compliance, re-treatment, combination treatments (ADT, immunotherapys or even nutrition and lifestyle changes) and so on. Practically, for every permutation of these factors a large decade long trial would be required to prove which one is the best, very little of it has to do with IRE as an ablation modality. This will take millions of patients undergoing trials.

Is this necessary? Partly yes, partly no. It is an ongoing debate and can not be fully presented here. What is most important when deciding for an experimental method is a good partner who will do multimodal follow-ups and monitor you closely and guide you through the decades. For prostate cancer with IRE, we highly recommend our experience with both, IRE and state of the art MRI cancer diagnostic is unmatched worldwide

Has these long trials been done for radical prostate ectomy and/or radiation treatment? Again, partly yes, partly no. These treatments are decades old and millions of patients have been treated this way. Therefore many combinations have been tried with debatable success and quality of evidence. However, even these treatments are constantly being refined: Robotic surgeries, more focused radiation beams and so on. Sticking to the standards of evidence based medicine, one would need to prove survival benefit for every single change. Which would be of course ridiculous in some cases. There always is and needs to be a balance between strict evidence requirement and using facts known from physics and biology, logic and deductive reasoning to develop better treatments without decade long delays for the patients who need it now.

How good is radical prostatectomy and/or radiation therapy? Medicine's usual answer: It depends. It depends greatly on the grade and stage of the cancer as well as on what you expect from it. The absolute survival benefit is somewhere between 0-30% in most cases, to extremely simplify the numbers. The side effect profile is known. Get in touch with us if you would like to have a more in detail analysis of your survival benefit for your case.

Where does this leave the patient? Is "new" good or bad? Maybe the most important part of the equation is the patient's feeling about it: Would you be comfortable using a treatment which is found medically safe with likely better properties than other treatments but is not "evidence based" for your specific illness and has only some years of follow up with good results?

Where can I get scientific literature about IRE? We try to keep our Bibliography up do date with the more relevant scientific publications on IRE. Or we recommend using scholar.google.com to search for the latest scientific literature.

 

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Stefan Zapf, MA, MD

Stefan Zapf

 

Stefan Zapf, MA, MD, studied Biology and Medicine at the University of Mainz, Germany. Specializing in diagnostic and interventional radiology he was in leading position in radiation therapy and radiology at university hospital in Mainz. Specializing on novel minimally invasive therapies, he has been managing the interventional radiology unit at the Institut fuer Bildgebende Diagnostik and Prostate Center since 2005. Together with Prof. Stehling he is leading in the field of Pulsed Electric Field therapies with most interventions of inner organs worldwide.

Michael K. Stehling, MD, PhD

Michael Stehling

 

Michael K. Stehling, MD, PhD - University Professor of Radiology, Jerusalem University Visiting Scholar, University of California in Berkeley, Privatdozent an der LMU München

 

Prof. Stehling served as Research Assistant to Sir Peter Mansfield, Prof of Physics and Nobel Prize winner in Medicine in 2003 (for discoveries concerning magnetic resonance imaging). The Prostate-Center was founded in 2010 by Prof. Michael K. Stehling. At the Prostate-Center physicians, scientists and engineers collaborate closely to offer state of the art diagnostics and the most promising and innovative minimally invasive treatment technologies.

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