Electrochemotherapy is a type of

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

that allows delivery of non-permeant drugs to the cell interior. It is based on the local application of short and intense electric pulses that transiently permeabilize the cell membrane, thus allowing transport of molecules otherwise not permitted by the membrane. Applications for treatment of cutaneous and subcutaneous tumors have reached clinical use by utilizing drugs such as

bleomycin -13- (1''H''-imidazol-5-yl)methyl9-hydroxy-5- 1''R'')-1-hydroxyethyl8,10-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazapentadec-1-yl}-2,4'-bi-1,3-thiazol-4-yl)carbonyl]amino}propyl)(dimethyl)sulfonium , chemical_formula = , C=55 , H=84 , N=1 ...

or cisplatin). Electrochemotherapy with bleomycin was used to treat a patient for the first time in 1991 at the Institute Gustave Roussy in France, while electrochemotherapy with cisplatin was used to treat for the first time in 1995 at the Institute of Oncology,

Ljubljana, Slovenia Ljubljana (also known by other historical names) is the capital and largest city of Slovenia. It is the country's cultural, educational, economic, political and administrative center. During antiquity, a Roman city called Emona stood in the ar ...

. Since then, more than 4000 patients were treated with electrochemotherapy all over the world (Argentina, Australia, Austria, Belgium, Bulgaria, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Mexico, Nicaragua, Poland, Portugal, Slovenia, Spain, Sweden, UK, USA). Recently, new electrochemotherapy modalities have been developed for treatment of internal tumors using surgical procedures,

endoscopic An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are insert ...

routes, or percutaneous approaches to gain access to the treatment area.

Physical principle

When a biological cell is exposed to an electric field of sufficient strength, an increase in the

transmembrane voltage Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...

is generated, which leads to rearrangements of the cell membrane structure. These changes result in an increase of the cell membrane permeability, which allows nonpermeant molecules to enter the cell. This phenomenon is called '' electroporation'' (or ''electropermeabilization'') and is becoming widely used to improve anticancer drug delivery into cells, which is being referred to as ''electrochemotherapy''. All biomedical applications of cell electropermeabilization use

direct current Direct current (DC) is one-directional flow of electric charge. An electrochemical cell is a prime example of DC power. Direct current may flow through a conductor such as a wire, but can also flow through semiconductors, insulators, or even ...

s (all unipolar) with short and intense pulses (even though

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

, time-decayed pulses can be used).

Amplitude The amplitude of a periodic variable is a measure of its change in a single period (such as time or spatial period). The amplitude of a non-periodic signal is its magnitude compared with a reference value. There are various definitions of amplit ...

of the pulses depends on the tissues and on the shape and position of the electrodes, but,

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

, in the case of the tumors, the amplitude of the electric pulses has to be high enough to establish an electrical field of 400 V/cm in the area of tumor (8 pulses with duration of 100 microseconds). The duration of pulses is usually one hundred microseconds. In early experiments, pulses were delivered with period of 1 second (i.e. at a repetition frequency of 1 Hz); today, pulses are delivered in a much shorter time period, at a repetition frequency of 5000 Hz, resulting in a much less discomfort for the patient and in the shorter duration of treatment. For treatment of deep-seated tumors in relative vicinity of the heart, pulses are synchronized with absolute refractory period of each heartbeat to minimize the probability of interaction of pulses with the heart function.

Treatment

The electrochemotherapeutic treatment consists of delivering, either systemically or locally, non-permeant

cytotoxic drugs Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

(e.g.

) or low-permeant drugs (e.g. cisplatin) and applying electric pulses to the area to be treated when the concentration of the drug in the tumor is at its peak. With the delivery of the electric pulses, cells are subjected to an electric field that causes the formation of nanoscale defects on the cell membrane, which alter the permeability of the membrane. At this stage and for some time after pulses are delivered, molecules of the cytotoxic agents can freely diffuse into the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

and exert their cytotoxic effect. Multiple positioning of the electrodes, and subsequent pulse delivery, can be performed during a session to treat the whole

lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...

, provided that drug concentration is sufficient. Treatment can be repeated over the course of weeks or months to achieve regression of large lesions.

Efficacy and clinical relevance

In a number of clinical studies (

phase II Phase II, Phase 2 or Phase Two may refer to: Media * Marvel Cinematic Universe: Phase Two, six American superhero films from 2013–2015 * ''Star Trek: Phase II'', an unrealized television series based on the characters of Gene Roddenberry's ''S ...

and phase III), investigators have concluded that electrochemotherapy of cutaneous or subcutaneous metastasis or tumours with bleomycin and cisplatin have an objective response rate of more than 80%. Reduction of tumor size has been achieved with electrochemotherapy faster and more efficiently than in standard chemotherapy for both cutaneous and subcutaneous tumors. Patients with skin metastasis from

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

Kaposi sarcoma Kaposi's sarcoma (KS) is a type of cancer that can form masses in the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limite ...

squamous cell carcinoma Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...

, basal cell carcinoma,

adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...

, or

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

have been successfully treated. First clinical results of electrochemotherapy of internal tumors (e.g. liver metastases) are also promising and encouraging. The success rate for electrochemotherapy in "human malignancies" has been stated to be more than 80% provided that a proper patient selection criteria will be performed.

Safety

Electrochemotherapy employs lower dosages of chemotherapeutic drugs than standard chemotherapy protocols; thus, the patient's burden usually associated to chemotherapy is not present. In the clinical use of electrochemotherapy, limited side effects related to bleomycin or cisplatin use are recorded. Provided that appropriate

anesthesia Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), ...

is used for alleviation of the symptoms associated with application of electric pulses, the control of the pain level during the electrochemotherapy is acceptable for the patients. Other than pain, which is limited to the treated tumor and surrounding tissue,

muscle contraction Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as ...

during electric pulse delivery is the only other discomfort. There is also induction of a vascular lock by the type of pulses used in electrochemotherapy: for a few minutes, blood flow is interrupted in the treated volume in the normal tissues. Its duration is too short to induce deleterious effects due to

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

. In tumors however, vascular lock is of a longer duration and can contribute to the effectiveness of the electrochemotherapy.

Veterinary use

Electrochemotherapy is also used in

veterinary oncology Veterinary oncology is a subspecialty of veterinary medicine that deals with cancer diagnosis and treatment in animals. Cancer is a major cause of death in pet animals. In one study, 45% of the dogs that reached 10 years of age or older died of can ...

for a variety of tumors in dogs, cats, horses, and rabbits. There are centers in Argentina, Brazil, Chile, Uruguay, Paraguay, Mexico, Peru, Bolivia, Colombia, Ecuador, Republica Dominicana, Spain, France, Italy, Ireland, Slovenia, United Arab Emirates, and the UK,. There are now multiple institutions in the US including Maine, New York, Rhode Island, Washington, Missouri, South Carolina, Hawaii, Las Vegas, Florida and the Bay Area of Northern California where this treatment is available. The success rate for electrochemotherapy has been stated to be around 90%, with an average of 3-4 treatments in the case of rabbits.

References

{{reflist, 2, refs= {{cite conference , last=Campana , first=L. G. , author2=Pasquali, S. , author3= Basso, M., author4= Mocellin, S., author5= Vecchiato, A., author6= Sileni, V. Chiarion, author7= Corti, L., author8= Nitti, D. , author9= Rossi, C. R. , display-authors=8 , title=Electrochemotherapy: clinical outcome and predictive factors from a single institution experience on 50 melanoma patients , book-title=Annals of Surgical Oncology , year=2010 , publisher=Springer , volume=17 , pages=S106 {{cite journal , vauthors=Cemazar M, Sersa G, title=Electrotransfer of therapeutic molecules into tissues , journal=Curr. Opin. Mol. Ther. , volume=9 , issue=6 , pages=554–62 , date=December 2007 , pmid=18041666 {{cite journal , vauthors=Cemazar M, Tamzali Y, Sersa G , title=Electrochemotherapy in veterinary oncology , journal=J. Vet. Intern. Med. , volume=22 , issue=4 , pages=826–31 , year=2008 , pmid=18537879 , doi=10.1111/j.1939-1676.2008.0117.x , display-authors=etal {{cite journal , vauthors=Chen C, Smye SW, Robinson MP, Evans JA, title=Membrane electroporation theories: a review , journal=Med Biol Eng Comput , volume=44 , issue=1–2 , pages=5–14 , date=March 2006 , pmid=16929916 , doi=10.1007/s11517-005-0020-2 , s2cid=6039291 {{cite journal , last=Gehl , first=Julie , author2=Geertsen, Poul F. , title=Palliation of haemorrhaging and ulcerated cutaneous tumours using electrochemotherapy , journal=European Journal of Cancer , date=November 2006 , url=http://hal.archives-ouvertes.fr/hal-00319862 , volume=4 , issue=11 , pages=35–7 , doi=10.1016/j.ejcsup.2006.07.007 {{cite journal , author=Hampton T , title=Electric pulses help with chemotherapy, may open new paths for other agents , journal=JAMA , volume=305 , issue=6 , pages=549–51 , date=February 2011 , pmid=21304073 , doi=10.1001/jama.2011.92 {{cite journal , vauthors=Heller R, Gilbert R, Jaroszeski MJ, title=Clinical applications of electrochemotherapy , journal=Adv. Drug Deliv. Rev. , volume=35 , issue=1 , pages=119–129 , date=January 1999 , pmid=10837693 , doi=10.1016/S0169-409X(98)00067-2 {{cite journal , vauthors=Jarm T, Cemazar M, Miklavcic D, Sersa G, title=Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases , journal=Expert Rev Anticancer Ther , volume=10 , issue=5 , pages=729–46 , date=May 2010 , pmid=20470005 , doi=10.1586/era.10.43 , s2cid=7626902 {{cite journal , last=Kotnik , first=Tadej , author2=Bobanović, Feda , author3=Miklavcˇicˇ, Damijian , title=Sensitivity of transmembrane voltage induced by applied electric fields—A theoretical analysis , journal=Bioelectrochemistry and Bioenergetics , date=August 1997 , volume=43 , issue=2 , pages=285–291 , doi=10.1016/S0302-4598(97)00023-8 , issn=0302-4598 {{cite journal , vauthors=Larkin JO, Collins CG, Aarons S , title=Electrochemotherapy: aspects of preclinical development and early clinical experience , journal=Ann. Surg. , volume=245 , issue=3 , pages=469–79 , date=March 2007 , pmid=17435555 , pmc=1877027 , doi=10.1097/01.sla.0000250419.36053.33 , display-authors=etal {{cite journal , vauthors=Mali B, Jarm T, Corovic S , title=The effect of electroporation pulses on functioning of the heart , journal=Med Biol Eng Comput , volume=46 , issue=8 , pages=745–57 , date=August 2008 , pmid=18415132 , pmc=2491703 , doi=10.1007/s11517-008-0346-7 , display-authors=etal {{cite journal , last=Marty , first=Michel , author2=Sersa, Gregor , author3=Garbay, Jean Rémi , author4=Gehl, Julie , author5=Collins, Christopher G. , author6= Snoj, Marko , author7=Billard, Valérie , author8=Geertsen, Poul F. , author9=Larkin, John O. , author10=Miklavcic, Damijan , author11=Pavlovic, Ivan , author12=Paulin-Kosir, Snezna M. , author13=Cemazar, Maja , author14=Morsli, Nassim , author15=Soden, Declan M. , author16=Rudolf, Zvonimir , author17=Robert, Caroline , author18=O’Sullivan, Gerald C. , author19=Mir, Lluis M. , title=Electrochemotherapy – An easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study , journal=European Journal of Cancer Supplements , date=November 2006 , volume=4 , issue=11 , pages=3–13 , doi=10.1016/j.ejcsup.2006.08.002 {{cite journal , last=Miklavcic , first=Damijan , author2=Snoj, Marko , author3=Zupanic, Anze , author4=Kos, Bor , author5= Cemazar, Maja , author6= Kropivnik, Mateja , author7= Bracko, Matej , author8= Pecnik, Tjasa , author9= Gadzijev, Eldar , author10= Sersa, Gregor , title=Towards treatment planning and treatment of deep-seated solid tumors by electrochemotherapy , journal=BioMedical Engineering OnLine , year=2010 , volume=9 , pages=10 , doi=10.1186/1475-925X-9-10 , issn=1475-925X , pmid=20178589 , pmc=2843684 , url= {{cite journal , vauthors=Mir LM, Orlowski S, Belehradek J, Paoletti C, title=Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric pulses , journal=European Journal of Cancer , volume=27 , issue=1 , pages=68–72 , year=1991 , pmid=1707289 , doi=10.1016/0277-5379(91)90064-k {{cite journal , vauthors=Mir LM, Belehradek M, Domenge C , title= lectrochemotherapy, a new antitumor treatment: first clinical trial, language=fr , journal=Comptes Rendus de l'Académie des Sciences, Série III , volume=313 , issue=13 , pages=613–8 , year=1991 , pmid=1723647 , display-authors=etal {{cite journal , vauthors=Möller MG, Salwa S, Soden DM, O'Sullivan GC, title=Electrochemotherapy as an adjunct or alternative to other treatments for unresectable or in-transit melanoma , journal=Expert Rev Anticancer Ther , volume=9 , issue=11 , pages=1611–30 , date=November 2009 , pmid=19895245 , doi=10.1586/era.09.129 , s2cid=1630835 {{cite journal , vauthors=Muñoz Madero V, Ortega Pérez G, title=Electrochemotherapy for treatment of skin and soft tissue tumours. Update and definition of its role in multimodal therapy , journal=Clin Transl Oncol , volume=13 , issue=1 , pages=18–24 , date=January 2011 , pmid=21239351 , doi=10.1007/s12094-011-0612-2 {{cite journal , vauthors=Puc M, Kotnik T, Mir LM, Miklavcic D, title=Quantitative model of small molecules uptake after in vitro cell electropermeabilization , journal=Bioelectrochemistry , volume=60 , issue=1–2 , pages=1–10 , date=August 2003 , pmid=12893304 , doi=10.1016/S1567-5394(03)00021-5 {{cite journal , vauthors=Puc M, Corovi S, Flisar K, Petkovsek M, Nastran J, Miklavcic D, title=Techniques of signal generation required for electropermeabilization. Survey of electropermeabilization devices , journal=Bioelectrochemistry , volume=64 , issue=2 , pages=113–24 , date=September 2004 , pmid=15296784 , doi=10.1016/j.bioelechem.2004.04.001 {{cite journal , vauthors=Pucihar G, Mir LM, Miklavcic D, title=The effect of pulse repetition frequency on the uptake into electropermeabilized cells in vitro with possible applications in electrochemotherapy , journal=Bioelectrochemistry , volume=57 , issue=2 , pages=167–72 , date=September 2002 , pmid=12160614 , doi=10.1016/S1567-5394(02)00116-0 , citeseerx=10.1.1.15.1614 {{cite journal , last=Rudolf , first=Zvonimir , author2=Stabuc, Borut , author3=Cemazar, Maja , author4=Miklavcic, Damijan , author5=Vodovnik, Lojze , author6= Sersa, G. , title=Electrochemotherapy with bleomycin. The first clinical experience in malignant melanoma patients , journal=Radiol Oncol , year=1995 , volume=29 , issue=6 {{cite journal , vauthors=Sersa G, Cemazar M, Miklavcic D, title=Antitumor effectiveness of electrochemotherapy with cis-diamminedichloroplatinum(II) in mice , journal=Cancer Research , volume=55 , issue=15 , pages=3450–5 , date=August 1995 , pmid=7614485 , url=http://cancerres.aacrjournals.org/content/55/15/3450.full.pdf {{cite journal , vauthors=Sersa G, Stabuc B, Cemazar M, Jancar B, Miklavcic D, Rudolf Z, title=Electrochemotherapy with cisplatin: potentiation of local cisplatin antitumour effectiveness by application of electric pulses in cancer patients , journal=Eur. J. Cancer , volume=34 , issue=8 , pages=1213–8 , date=July 1998 , pmid=9849482 , url=http://clincancerres.aacrjournals.org/content/6/3/863.long , doi=10.1016/s0959-8049(98)00025-2 {{cite journal , last=Sersa , first=Gregor , title=The state-of-the-art of electrochemotherapy before the ESOPE study; advantages and clinical uses , journal=European Journal of Cancer Supplements , year=2006 , volume=4 , issue=11 , pages=52–59 , doi=10.1016/j.ejcsup.2006.08.007 {{cite journal , vauthors=Sersa G, Miklavcic D, Cemazar M, Rudolf Z, Pucihar G, Snoj M, title=Electrochemotherapy in treatment of tumours , journal=Eur J Surg Oncol , volume=34 , issue=2 , pages=232–40 , date=February 2008 , pmid=17614247 , doi=10.1016/j.ejso.2007.05.016 , citeseerx=10.1.1.148.9258 {{cite journal , vauthors=Sersa G, Miklavcic D, title=Electrochemotherapy of tumours , journal=J Vis Exp , issue=22 , year=2008 , pmid=19229171 , pmc=2762922 , doi=10.3791/1038 {{cite journal , vauthors=Sersa G, Jarm T, Kotnik T , title=Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma , journal=Br. J. Cancer , volume=98 , issue=2 , pages=388–98 , date=January 2008 , pmid=18182988 , pmc=2361464 , doi=10.1038/sj.bjc.6604168 , display-authors=etal {{cite journal , vauthors=Soden DM, Larkin JO, Collins CG , title=Successful application of targeted electrochemotherapy using novel flexible electrodes and low dose bleomycin to solid tumours , journal=Cancer Lett. , volume=232 , issue=2 , pages=300–10 , date=February 2006 , pmid=15964138 , doi=10.1016/j.canlet.2005.03.057 , display-authors=etal {{cite journal , vauthors=Testori A, Tosti G, Martinoli C , title=Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach , journal=Dermatol Ther , volume=23 , issue=6 , pages=651–61 , year=2010 , pmid=21054709 , doi=10.1111/j.1529-8019.2010.01370.x , s2cid=46534637 , display-authors=etal {{cite journal , last=Weaver , first=James C. , author2=Chizmadzhev, Yu. A. , title=Theory of electroporation: A review , journal=Bioelectrochemistry and Bioenergetics , date=December 1996 , volume=41 , issue=2 , pages=135–160 , doi=10.1016/S0302-4598(96)05062-3 , issn=0302-4598 {{cite journal , last=Weaver , first=J.C. , title=Electroporation of cells and tissues , journal=IEEE Transactions on Plasma Science , date=February 2000 , url=http://epore.mit.edu/papers/2000_2.pdf , volume=28 , issue=1 , pages=24–33 , doi=10.1109/27.842820 , issn=0093-3813, bibcode=2000ITPS...28...24W {{cite journal , vauthors=Zupanic A, Ribaric S, Miklavcic D, title=Increasing the repetition frequency of electric pulse delivery reduces unpleasant sensations that occur in electrochemotherapy , journal=Neoplasma , volume=54 , issue=3 , pages=246–50 , year=2007 , pmid=17447858 , url=http://www.aepress.sk/_downloads/dl.php?from=pubmed&journal=NEO&file=2007_03_246.pdf {{cite journal , last=Županič , first=Anže , author2=Čorović, Selma , author3=Miklavčič, Damijan , title=Optimization of electrode position and electric pulse amplitude in electrochemotherapy , journal=Radiology and Oncology , date=1 June 2008 , url=http://ojs.szd.si/index.php/ro/article/viewFile/1206/967 , volume=42 , issue=2 , pages=93–101 , doi=10.2478/v10019-008-0005-5, doi-access=free Cancer treatments Chemotherapy

Physical principle

Treatment

Efficacy and clinical relevance

Safety

Veterinary use

See also

References