Introduction

Electrochemotherapy, a local treatment of various neoplasms, utilizes electroporation to change the permeability of cell membranes to facilitate the uptake of cytotoxic drugs. These drugs, injected directly into the tissue, would otherwise be unable to pass through the cell membrane efficiently. Bleomycin and cisplatin are the two drugs shown to be effective with this treatment modality, although other drugs are being researched. Electrochemotherapy’s mechanisms of action include: increased membrane permeability and intracellular drug accumulation; vascular effects; and involvement of immune response.¹ Electrochemotherapy has been shown to be an effective treatment for a variety of neoplastic processes and has been shown to be completely effective in as little as 1 treatment. It is best utilized to treat superficial tumors or areas where surgical excision was incomplete or unable to be performed at all. Side effects are typically limited to local tissue inflammation and necrosis. Performing electrochemotherapy requires heavy sedation or, ideally, general anesthesia. Proper safety protocols must be used to protect not only the patient, but all staff involved to reduce risk of exposure. Overall, electrochemotherapy can be an effective treatment for various malignancies with minimal side effects.

Electroporation

Electroporation is the process of introducing a substance into a cell using a pulse of electricity to temporarily open the pores in the cell membranes. Application of electrical current to the cells causes relocation of the charges on the cell membrane. This relocation of charges alters the cells membrane potential allowing the formation of pores through which water, charged molecules, and larger molecules may pass into the cell. Various levels of electrical pulses have been studied and the standard dose of 8, 1,000–1,500 V/cm, 100-μs-long pulses.^1,3 This process is what makes electrochemotherapy successful. By allowing the drug to directly enter the cell, intracellular drug concentrations are 2–4 times higher than traditional IV administration techniques.³

Vascular Lock

Vascular lock is the term used to encompass two vascular effects caused by the electrical pulses applied in electrochemotherapy. Applied electrical fields assist stromal cells with drug uptake and effect endothelial cells of the tumor’s vessels. This effect, termed vascular disrupting effect of electrochemotherapy, leads to endothelial cell apoptosis and therefore disruption of tumor blood flow. The second effect is vasoconstriction in the area the electrical field is applied. These two effects combined “lock” the administered drug within the applied electrical field area creating further exposure to the desired tissue. If a chemotherapeutic is administered after the electrical pulses have been applied, it can block the drug from entering the tumor.¹

Immune Response

Studies have shown a difference in electrochemotherapy’s effectiveness between immunocompetent and immunocompromised patients. This difference implied an immune response is key to electrochemotherapy being a successful treatment. After electrochemotherapy, tumors shed immense amounts of tumor antigen which can induce a systemic immune response. This immune response can be up-regulated by biological response modifiers like IL-2, GM-CSF and TNF-α.³

Bleomycin

Bleomycin is an antitumor antibiotic. It exerts its action by inducing DNA strand breaks, although the exact mechanism of action is yet to be fully understood. Bleomycin is most commonly used in electrochemotherapy as it has a higher potentiation of cytotoxicity when an electrical pulse is applied. Bleomycin can be given intratumorally and intravenously during an electrochemotherapy procedure. Dosing parameters range from clinician to clinician but a sufficient maximum dose of 15 U/m² per treatment is commonly utilized. Dilution of the bleomycin should be done according to manufacturer specifications. Depending on the size of the area being treated, most of this dose may be given intratumorally with the remainder being administered IV. The IV administration should be performed first, then the intratumoral (IT) injection due to the vascular lock effect. The IV portion of the drug, if applicable, should be given 4–8 minutes prior to the IT injection. Electrical pulses should be applied within 1 minute of the IT injections.

Cisplatin

Cisplatin is the second most commonly used drug in relation to electrochemotherapy. Cisplatin, a platinum-agent chemotherapeutic, binds to DNA and interferes with replication. Cisplatin is contraindicated in cats due to severe renal toxicity and typically fatal pulmonary toxicity. Studies have been done however using electrochemotherapy with cisplatin in cats that have had mild toxicity concerns and positive treatment outcomes.⁴ Dosing parameters for cisplatin also vary between clinicians, but a sufficient maximum dose per treatment is 15 mg/m². In dogs, the cisplatin dose may also be given IV and/or IT, with IV administration occurring first.

Malignancies

A variety of malignancies have been proven to be sensitive to electrochemotherapy treatment on both canines and felines. Squamous cell carcinoma, fibrosarcoma, localized lymphoma, mammary adenocarcinoma, anal sac carcinoma, apocrine gland carcinoma, mast cell tumors, melanoma, and perianal tumors have all shown promising responses to electrochemotherapy treatment. A meta-analysis of 1,894 tumors from 44 eligible clinical studies published before October 2011 demonstrated that the effectiveness of single-session electrochemotherapy on cutaneous and subcutaneous tumors is 59.4% for complete response and 84.1% for objective response.¹

Procedure

Electrochemotherapy is a relatively quick, inexpensive treatment for a variety of tumor types. For the procedure patients should be under general anesthesia. Deep sedation can be used as an alternative but is less ideal. Anesthesia induction and maintenance protocols may vary due to clinician preference. The patient should be positioned as necessary on a table that allows easy access for the anesthetist as well as the clinician and their technician. The clinician will be responsible for the IT injections as well as the application of the electrodes. The technician assisting will be responsible for containing any rogue chemotherapeutic agent as well as operating the electroporator as instructed by the clinician. Isolation of the area being treated is necessary to prevent unnecessary drug exposure.

The area being treated should be clean and free of debris. The chemotherapeutic of choice should be injected into the area of treatment to sufficiently encompass all potentially malignant tissue. Recall that any portion of the drug to be given IV should be done so before the IT injections. Once the chemotherapeutic has been adequately administered into the tissue, electrical pulses should be applied within 1 minute. For the use of plate electrodes, a water-based gel should be applied to the tissue in question before applying an electrical pulse. The application of the electrode should start from the safety margin of the tumor and progress towards the center in a circular motion. Applying the electrode twice in a perpendicular pattern will ensure the most complete application of electrical field. Gel application is not necessary when using a needle electrode. All needles should be inserted into the tissue to ensure proper electrical field application. The pattern described above for the plate electrode also applies to the needle electrode. The application of electrical pulses will cause a muscle contraction in the patient. Depending on the area of pulse application measures should be taken to restrain areas of the patient’s body to protect the patient and those around it.²

Safety

As with all chemotherapy administration techniques, extreme care must be taken to protect all persons involved in the procedure from exposure to the drug in question. Full personal protective equipment must be utilized. This includes a non-permeable gown, chemotherapy approved gloves, eye protection (preferably goggles) and at least an N-95 filter mask. The procedure should take place in a dedicated chemotherapy administration suite as contamination risks are high. Ideally the suite should have negative air pressure to prevent flow of contaminated air into other parts of the building. Chemotherapeutic agents should be prepared in a class II laminar flow biologic safety cabinet to collect any aerosolized particles that may be produced during preparation.

The area being treated should be isolated as much as possible using non-permeable chemotherapy pads, gauze, or other absorbent material to collect any leaking chemotherapeutic. Care should be taken on the part of the clinician to limit unnecessary injection, leakage, or spray of the chemotherapeutic agent. All disposable materials utilized during the procedure should be discarded in an appropriate chemotherapy waste or sharps container. Tools utilized such as the electroporator, anesthetic machine, and monitoring equipment should be thoroughly wiped down with Lysol wipes or with paper towels that have been sprayed with a Lysol or bleach solution. Tools or contaminated surfaces should not be sprayed directly as this could potentially cause aerosolization of chemotherapeutic agents. The area treated on the patient should be cleaned thoroughly post-electrochemotherapy to ensure no residual contamination is present.

Should a person be exposed to a chemotherapeutic agent the area should be flushed copiously with water. Should a contaminated needle stick occur, flush the area copiously with water as previously advised and seek medical attention as needed. Bleomycin and cisplatin rarely cause acute effects with skin surface contamination, although irritation may occur.² Every safety measure should be utilized to prevent any exposure to these agents as long-term exposure has been linked to a variety of significant medical issues.

Conclusion

Electrochemotherapy is a promising treatment for a variety of superficial malignancies. The procedure is affordable, fast, and less invasive when compared to surgery and/or radiation. Appropriate care must be taken to perform the procedure properly and to protect all those involved from exposure to chemotherapeutic agents. Further research and studies will likely lead to further applications of electrochemotherapy for cancer treatment.

References

1.  Miklavcic D, et al. Biomed Eng Online. 2014;13:29.

2.  Tozon N, et al. J Vis Exp. 2016;116.

3.  Sersa G, et al. Radiol Oncol 2006;40(3):163.

4.  Spugnini EP, et al. J Transl Med 2011;9:152.