Electrochemotherapy (ECT) is a type of

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

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 A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...

. Applications for treatment of

cutaneous Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different d ...

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 , C=55 , H=84 , N=17 , O=21 , S=3 , SMI ...

cisplatin Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...

). 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 {{Infobox settlement , name = Ljubljana , official_name = , settlement_type = Capital city , image_skyline = {{multiple image , border = infobox , perrow = 1/2/2/1 , total_widt ...

. 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 {{More citations needed, date=January 2021 In surgery, a percutaneous procedurei.e. Granger et al., 2012 is any medical procedure or method where access to inner organs or other tissue is done via needle-puncture of the skin, rather than by using ...

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. It equals the interior potential minus the exterior potential. This is th ...

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 Electroporation, also known as electropermeabilization, is a microbiological and biotechnological technique in which an electric field is applied to cells to briefly increase the permeability of the cell membrane. The application of a high-vo ...

'' (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 electric current, flow of electric charge. An electrochemical cell is a prime example of DC power. Direct current may flow through a conductor (material), conductor such as a wire, but can also flow throug ...

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

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

, 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 am ...

of the pulses depends on the tissues and on the shape and position of the

electrodes An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit (e.g. a semiconductor, an electrolyte, a vacuum or a gas). In electrochemical cells, electrodes are essential parts that can consist of a variety ...

, 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, an ...

, in the case of the tumors, the amplitude of the electric pulses has to be high enough to establish an

electrical field An electric field (sometimes called E-field) is a physical field that surrounds electrically charged particles such as electrons. In classical electromagnetism, the electric field of a single charge (or group of charges) describes their capaci ...

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 Period may refer to: Common uses * Period (punctuation) * Era, a length or span of time *Menstruation, commonly referred to as a "period" Arts, entertainment, and media * Period (music), a concept in musical composition * Periodic sentence (o ...

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 chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a curat ...

(e.g.

) or low-permeant drugs (e.g.

) 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 Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...

into the

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

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 injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals. Types There is no de ...

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

Application

Electrochemotherapy (ECT) is currently primarily used for the treatment of skin cancers, such as basal cell carcinoma, squamous cell carcinoma, melanoma, and Kaposi's sarcoma, an area in which its use is increasing. Additionally, ECT is uniquely employed by a clinic in Germany for the treatment of prostate cancer, often in combination with Irreversible Electroporation (IRE).

Efficacy and clinical relevance

In a number of clinical studies ( phase II 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 is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

Kaposi sarcoma Kaposi's sarcoma (KS) is a type of cancer that can form masses on 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 carcinoma (SCC), also known as epidermoid carcinoma, comprises 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 Basal-cell carcinoma (BCC), also known as basal-cell cancer, basalioma, or rodent ulcer, is the most common type of skin cancer. It often appears as a painless, raised area of skin, which may be shiny with Telangiectasia, small blood vessels ru ...

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 a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

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 (American English) or anaesthesia (British English) 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 prev ...

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 (physics), 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 musc ...

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 ...

. 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 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, Virginia, 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

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