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Electrochemotherapy as a cancer treatment option

at 09.02.2022
Most skin cancers are treated with surgery, radiation therapy, and systemic chemotherapy, which results in high rates of local control and survival. Despite significant advances in treatment, recurrence or skin metastases are frequently difficult to manage. The poor response to these treatments is frequently due to the cell membrane's relative impermeability to therapeutic agents. Electroporation, which permeabilizes the cell membrane by applying electrical impulses and allows cystostatics to be effective only in tumor tissue, has been a successful therapeutic alternative in recent decades.
Okino and Mohri [1] discovered in 1987 that cytostatics penetrate tumor cells more easily when the cell membrane is permeabilized using a technique known as electroporation. A special probe transmits an electrical impulse to the malignant tumor, changing the membrane of the cancer cell and forming pores that allow the drug to penetrate and intensify its action only on the cancer cells. In this way, a local increase in plasma membrane permeability is achieved, i.e., exposing the tumor nodule to electrical pulses (electroporation) results in increased chemotherapeutic absorption in tumor cells [2]. Belehradek et al. used the procedure for permeabilization of nodules as a new antitumor treatment strategy in 1993 [3]. As a result, electrochemotherapy has emerged as a promising treatment option for malignant tumors of cutaneous or non-cutaneous origin. This was confirmed relatively recently by a meta-analysis conducted in 2018 [4] by a team of Swiss researchers, who found that electrochemotherapy has estimated effectiveness of 84.2 %.

Applications
Electroporation is a physical phenomenon that can be used on all living cells. This is because, in addition to increased drug cytotoxicity and membrane permeability, the application of electrical pulses to the targeted tissues causes a reversible and transient decrease in tumor blood flow (reduction by about 80%). This transient vasoconstriction at the arterial level, referred to as "vascular blockade," promotes drug uptake into the target tissue. As a result, chemotherapeutic drug absorption into tumor vascular endothelial cells causes irreversible damage to tumor vessels and a further decrease in tumor blood flow a few hours after electrical treatment, disrupting nutrient intake and causing tumor cell death. The interaction of these mechanisms explains the remarkable results for the treatment of all histological types of tumors, with an average objective response to treatment of 83.91% and 80.82%, respectively, with bleomycin and cisplatin. Basal cell carcinomas, in general, demonstrated the highest objective and complete response of any tumor type.
A guide to standard operating procedures for electrochemotherapy was provided in 2006 to unify the application strategies for the convenient treatment of patients with cutaneous and subcutaneous nodules by electrochemotherapy [5] in order to resolve various controversies regarding the clinical application of this method. Before starting therapy, the guide recommends that all patients have a complete medical history, clinical examination, ECG, and the following laboratory tests: blood count, INR, sodium, potassium, chlorine, phosphate, magnesium, urea, creatinine, bilirubin, AST, ALT, AF, GT, LDH and creatinine clearance.

This method is not only effective for primary skin cancer therapy and local control, but it can also be used in patients with metastases in transit or regional diseases, or as a supplement in patients with distant metastases. The method can also be used as a first-line treatment, for example, in the treatment of inoperable primary [6] or recurrent melanoma [8], to alleviate pain or reduce palliative tumor bleeding, and as a neoadjuvant treatment before conventional treatment. In general, this method should only be used on patients who have primary skin lesions, local or locoregional metastases, or as an adjunct treatment in patients who have distant metastases. [8]

Efficiency
Electrochemotherapy has been shown to be more effective than cytostatics alone. It is a promising procedure for cutaneous and non-cutaneous malignant tumors. Small tumors respond twice as well as large tumors, according to research. Furthermore, regardless of the type of tumor, it is a much cheaper, faster, and easier to tolerate technique because, at low doses of cytostatics, it has a low level of side effects and discomfort.
According to a 2018 review [9], the average objective response to electrochemotherapy was estimated to be 84.02 %, as long as systemic chemotherapy serves only a palliative purpose, with response rates of less than 25% as monotherapy. As a result, more aggressive polychemo- or chemo-immunotherapeutic regimens have been recommended to increase response rates; however, these are associated with high toxicity, and many studies have failed to demonstrate a significant improvement in patient survival. Other issues associated with the management of skin metastases include the negative impact on patients' quality of life and the requirement for significant, time-consuming, and expensive resources. To address these issues, electroporation proves to be a life-saving solution for the more effective administration of chemotherapeutic drugs in tumor cells. Using this method, the intracellular concentration and thus toxicity of bleomycin and cisplatin can be increased up to 10,000-fold and 80-fold, respectively, significantly improving antitumor efficacy while requiring lower doses.
Several clinical trials of electrochemotherapy with bleomycin and cisplatin have been initiated in recent decades to treat skin metastases of various tumors, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma of the head and neck, Kaposi's sarcoma, adenocarcinoma of the salivary gland, hypernephroma, and transitional cell carcinoma of the bladder. The basic mechanism of electrochemotherapy, regardless of histological type, is a high response rate.
Furthermore, the administration of new drugs, such as calcium, or a combination of electrochemotherapy and immunotherapeutic compounds (such as Dabrafenib or Ipilimumab) and biological response modifiers, such as IL-2, could broaden electrochemotherapy's therapeutic recommendations [10]. In a multidisciplinary oncological approach, this could be a strategy to achieve better long-term local and systemic control of skin tumors, which can lead to an increase in overall survival and an improvement in the patient's quality of life.

Side effects and contraindications 
Electrochemotherapy appears to have mild and transient side effects. Complications such as erythema, edema, and pain appeared immediately in most studies and resolved within a few days [11]. Due to the low doses of chemotherapy drugs, late side effects and systemic toxicity were also mild. Pre-treatment moderate to severe pain, the size of the largest treated lesion, previous irradiation, and a high level of electricity appear to be associated with post-procedure pain. Patients at risk for post-procedure pain may be identified during the pre-treatment visit and/or during treatment to provide them with a pain management strategy, as the unpleasant sensation may be completely managed by local or general anesthesia. The patient and the doctor, as well as the location, condition, number, and size of the tumors, determine whether electrochemotherapy is administered under general anesthesia or only with local anesthetics. Furthermore, epinephrine is frequently administered to provide a beneficial vasoconstrictive effect. According to studies, the following are the main technical pitfalls and difficulties for optimal tumor electroporation:

(1) Electrochemotherapy is contraindicated in patients with known allergy to the drug, interstitial lung fibrosis, cumulative bleomycin dose of ≥400,000 UI/m2, and chest wall location of lesions and pacemakers.
(2) Electrochemotherapy of a large tumour might be difficult due to the required repeated time-consuming electrode applications, considering the available window after drug injection.
(3) Electrochemotherapy of large tumour size (>3 cm) might be an issue due to the technical impossibility of reaching the inner portion of the tumour at first application.
(4) Electrochemotherapy of previously irradiated fields could be problematic, due to partial electrode needle penetration and suboptimal electrical current delivery in fibrotic tissue.

However, according to the review, electrochemotherapy is a feasible, inexpensive, and easy-to-operate local treatment with no significant adverse effects or patient discomfort. Using low doses of chemotherapeutic agents, electrochemotherapy is very specific to tumour cells and causes no damage to healthy peripheral tissue. This method is not only effective for therapy and local control of primary skin cancers but can also be used in patients with only in-transit metastases or regional diseases, or as a complement to other modalities in patients with distant metastases.

References

[1] Okino M, Mohri H. Effects of a high-voltage electrical impulse and an anticancer drug on in vivo growing tumors. Jpn J Cancer Res 1987; 78: 1319-21.
[2] Sersa G, Stabuc B, Cemazar M, Miklavcic D, Rudolf Z. Electrochemotherapy with cisplatin: clinical experience in malignant melanoma patients. Clin Cancer Res 2000; 6: 863-7. Mir L, Orlowski S, Belehradek J, et al. Biomedical applications of electric pulses with special emphasis on antitumor electrochemotherapy. Bioelectrochem Bioenerg 1995; 38: 203-7. Rols M-P, Teissie J. Electropermeabilization of mammalian cells. Quantitative analysis of the phenomenon. Biophys J 1990; 58: 1089.
[3] Belehradek M, Domenge C, Luboinski B, Orlowski S, Belehradek J Jr., Mir LM. Electrochemotherapy, a new antitumor treatment. First clinical phase I-II trial. Cancer 1993; 72: 3694-700.
[4] Seyed Jafari, S.M., Jabbary Lak, F., Gazdhar, A. et al. Application of electrochemotherapy in the management of primary and metastatic cutaneous malignant tumours: a systematic review and meta-analysis. Eur J Dermatol 28, 287–313 (2018). https://doi.org/10.1684/ejd.2018.3291.
[5] Mir LM, Gehl J, Sersa G, et al. Standard operating procedures of the electrochemotherapy: instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the Cliniporator TM by means of invasive or non-invasive electrodes. EJC Suppl 2006; 4: 14-25.
[6] Snoj M, Rudolf Z, Cemazar M, Jancar B, Sersa G. Successful sphincter-saving treatment of anorectal malignant melanoma with electrochemotherapy, local excision and adjuvant brachytherapy. Anticancer Drugs 2005; 16: 345-8.
[7] Kubota Y, Tomita Y, Tsukigi M, Kurachi H, Motoyama T, Mir LM. A case of perineal malignant melanoma successfully treated with electrochemotherapy. Melanoma Res 2005; 15: 133-4.
[8] https://link.springer.com/article/10.1684/ejd.2018.3291
[9] Seyed Jafari, S.M., Jabbary Lak, F., Gazdhar, A. et al. Application of electrochemotherapy in the management of primary and metastatic cutaneous malignant tumours: a systematic review and meta-analysis. Eur J Dermatol 28, 287–313 (2018). https://doi.org/10.1684/ejd.2018.3291.
[10] Campana LG, Testori A, Mozzillo N, Rossi CR. Treatment of metastatic melanoma with electrochemotherapy. J Surg Oncol 2014; 109: 301-7. Testori A, Rossi CR, Tosti G. Utility of electrochemotherapy in melanoma treatment. Curr Opin Oncol 2012; 24: 155-61.
[11] Mir-Bonafe JM, Vilalta A, Alarcon I, et al. Electrochemotherapy in the treatment of melanoma skin metastases: a report on 31 cases. Actas Dermosifiliogr 2015; 106: 285-91.





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