User:Leskovsek/electrochemotherapy

Electrochemotherapy is a therapeutic approach providing delivery into cell interior of nonpermeant drugs with intracellular targets. It is based on the local application of short and intense electric pulses that transiently permeabilize cell membrane, thus allowing transport of molecules otherwise not permitted by a cellular membrane. Presently, only anticancer applications have reached clinical use (antitumor electrochemotherapy using bleomycin or cisplatin).

Physical principle
When a biological cell is exposed to an electric field of sufficient strength, an increase in the trans-membrane voltage difference is generated, which leads to structural 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 phenomena is called cell electroporation (or electropermeabilisation) and is becoming widely used to improve anticancer drug delivery into cells, which is referred as electrochemotherapy.

Technical characteristics of physical parameters
All biomedical applications of cell electropermeabilisation use monopolar DC short and intense pulses (even though in vitro, in bacteria, time-decayed pulses can be used). Amplitude of the pulses depends on the tissues and on the shape and position of the electrodes, but, in vivo, in the case of the tumors, it has to be high enough to establish an electrical field of 400V/cm in all the cells, at least. The length of pulses is usually several hundred microseconds. In early experiments pulses where delivered with period of 1 second (i.e. at a repetition frequency of 1 Hz), nowadays however 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 a much more short treatment. Pulses are being delivered in a series of eight pulses, but can be repeated if necessary.

Description of the treatment: applicators, daily length, number of sessions
The electrochemotherapeutic treatment consists of delivering non-permeant drugs (e.g. Bleomycin) or low-permeant drugs (e.g. Cisplatin) and applying 8 electric pulses when the concentration of the drug in the area of treatment is at its peak. Many series of this treatment can be performed in a single session. Sessions should be carried out regularly until the tumor has diminished. However, it is recomended to carry out regular consultations with oncologist while treatment is being carried.

Safety
Considering that the smaller dosage of chemotherapeutic is needed than in standard chemotherapy, the method is relatively safe. The tissue close to the electrodes may become damaged, but not to the point where it would become dangerous for the patients health in general. Generaly shorter pulses introduce less adverse effects. 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 hypoxia or to defaults in glucose and other nutriments supply. In tumors, vascular lock has a longer duration and it could contribute to the effectiveness of the electrochemotherapy.

Efficacy, clinical relevance of the effect, level of evidence (study design)
A number of clinical studies (phase I and phase II) have been concluded that chemotherapy with bleomycin and cisplatin have been improved by 80% or more when combined with the abovementioned method of electroporation. Faster reduction of tumor size has been achieved with electrochemotherapy than in standard chemotherapy for both cutaneous and subcutaneous tumors. The cytoxicity of other current anticancer drugs (that can normally enter the cells by diffusion through the cell membrane) is not potentiated by the electric pulses.

Known side effects
The tissue close to the electrodes may become damaged or burned due to the high electrical current passing through. Pulses can be painful and rules for either local or general anesthesia use during the procedure have been given in the Standard Operating Procedures (nb: give references). Muscle contraction is observed for the muscles located beneath the place were electrodes are applied. They can be anticipated (for example, the extremity of the patient in case of treatments in the arms or legs can be fixed before the pulses delivery). No other side effects are being repeated.

Risk-benefit ratio
Supposing the location to be treated is easily accessible with electrodes the risk of the treatment is negligible.

Remarks (E.G. approval, etc…)
Various drug treatments benefit variously by electroporation. Bleomycin and Cisplatin are currently the best cytotoxic drugs to use with electrochemotherapy. The other important factor is the appropriate choice of electrodes and placement of electrodes in order not to damage the healthy tissue. Electrochemical treatment with the CE-marked device Cliniporator TM (Igea s.r.l. Carpy, Italy) has already been certified as the medical device and is offered on the market along with Standard Operating Procedures for electrochemotherapy of cutaneous and subcutaneous tumors. The full FDA approval is still in the phase of preparation. In spite of the recent introduction of this therapeutic approach in the clinical use, electrochemotherapy is already approved and reimbursed in several EU countries.