Electrochemotherapy has received considerable attention in the last few years as an emerging therapeutic. Until recently its availability has been confined to outside the United States, but this is now changing and a brief review of the technology is both necessary and timely as more oncologists in North America take advantage of this new technology. Electrochemotherapy involves combining a normally poorly absorbed chemotherapy agent and the delivery of an electrical field directly to the tumor. The tumor is exposed to an electric field for a few milliseconds, which causes the tumor cells to become porous for up to an hour after the procedure and allows for an increase of up to a thousandfold in the local absorption of the chemotherapy. Electrochemotherapy has been successfully used to treat cancer forms that ordinarily cannot be treated with chemotherapy or in situations where chemotherapy no longer has any effect. Electrochemotherapy also can treat patients who have previously been treated with radiation. To date, the primary experience clinically has been with cutaneous disease such as malignant melanoma, recurrent breast cancer, squamous cell carcinoma and Kaposi sarcoma. The published literature indicates that solid tumors of all histological types are sensitive to treatment with electrochemotherapy. Evidence also is growing for its utilization in the treatment of intraluminal disease, with specialized systems now developed for the treatment of gastrointestinal, lung and liver tumor masses. Endoscopic Applications Clinical studies are underway in Europe to evaluate the safety and efficacy of electrochemotherapy to gastrointestinal cancers via an endoscopic procedure. To date, evidence from preclinical work in canine colorectal cancers has demonstrated excellent responses in the treatment of obstructive disease and similar observations have been made in the ongoing phase I/II clinical study at the Cork Cancer Research Centre in Ireland. A keyhole surgical system to allow for the electroporation treatment of lung and laparoscopically accessible tumors has been developed and is under phase I clinical evaluation. A bronchoscopic approach is under development for nasal tumors. How It Is Done The treatment is performed as a day case, with the actual procedure conducted normally in less than 30 minutes. In the veterinary setting a short general anesthetic is required. The chemotherapeutic drug may be administrated as a direct injection (intratumoral) or provided intravenously via a drip. The actual concentration of drug used is significantly reduced compared to standard chemotherapy protocols due to the greater cancer cell absorption achieved. Consequently, its toxicity is focused on the cancer itself, largely eliminating side effects normally associated with chemotherapy. The cancer cells are made porous by applying a very brief electrical pulse directly to the cancer. This involves the placement of an electrode array around the tumor location. The electrical pulses are delivered as 0.1msec bursts with a single application taking less than 1msec in total. The pulses cause only the cells directly around the electrode to become permeabilized, and only these cells absorb any significant quantity of anticancer drug. The process is repeated several times until the clinician is happy that the full surface area of the tumor and its margins have been treated. The generator equipment used provides the operator with real-time feedback in terms of the current, voltage delivered into the tissue and any changes to the tissue impedance, which assists in ensuring the procedure has been completed successfully. A checkup will be conducted usually three to four weeks after the treatment. Treatment can be repeated over the course of weeks or months to achieve regression of large lesions. Dr. Declan Soden, Cork Cancer Center, Cork, Ireland Canine colorectal tumor: pre- and post-endoVe treatment. Clinical Relevance In a number of clinical studies (phase II and phase III) investigators have concluded that electrochemotherapy with bleomycin and cisplatin of cutaneous or subcutaneous metastasis or tumors has an objective response rate of more than 80 percent. 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, Kaposi sarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma or breast cancer have been successfully treated. First clinical results of electrochemotherapy of internal tumors (e.g. liver metastases) are also promising and encouraging. Safety Electrochemotherapy employs lower dosages of chemotherapeutic drugs than standard chemotherapy protocols. In the clinical use of electrochemotherapy, limited side effects related to bleomycin or cisplatin use are recorded. Provided that appropriate anesthesia is used for alleviation of the symptoms associated with application of electric pulses, the control of the pain level during the electrochemotherapy is good and acceptable for the patients. Besides pain, which is limited to the treated tumor and surrounding tissue, muscle contraction during electric pulse delivery is the only discomfort for human patients associated with electrochemotherapy. 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. In tumors, however, vascular lock is of a longer duration and can contribute to the effectiveness of the electrochemotherapy. A good indicator that electrochemotherapy is not a stressful or painful procedure is that the majority of the people interviewed during a clinical study aimed at defining the European Standard Operating Procedure of Electrochemotherapy (ESOPE) would be willing to accept the treatment another time if necessary. Veterinary Use Electrochemotherapy has been published for use in veterinary oncology in dogs, cats, exotics and horses. There are centers in Brazil, France, Italy, Ireland, Slovenia and the United Kingdom where the treatment is available. It is used for a wide variety of tumors: Fibrosarcoma in the mouth, eyelid, foot pad, skin or distal limb, feline vaccine-associated fibrosarcoma before and after surgery. Melanoma in the mouth, eyelid or foot pad. Squamous cell carcinoma in mouth, eyelid, ear, nasal planum or foot pad. n Incompletely resected soft tissue sarcomas where aggressive surgical treatment would necessitate amputation. Feline vaccine-associated fibrosarcoma before and after surgery. Localized cutaneous lymphoma in dogs or cats. Local control of mast cell tumors. Perianal and rectal tumors. Prostate. Pancreas. Hepatocellular carcinomas and adenomas after resection. Operation site margins where there is significant risk of remaining tumor tissue. Sarcoids and squamous cell carcinomas in horses. Superficial tumors on exotics (small mammals, birds and zoo animals). DR. DECLAN SODEN, CORK CANCER CENTER, CORK, IRELAND Electroporation process: 1. Cell pre-electroporation (drug, in blue, is poorly absorbed); 2. Cell is electroporated in less than 1msec; 3. Pores are formed temporarily on the membrane, allowing (4) the cell to absorb up to 1,000 times more drug. Advantages Electrochemotherapy is a locally very effective treatment for the ablation of solid tumors. The process overall is very well tolerated with no side effects largely observed due to the significant reduction in chemotherapeutic doses. The targeted nature of the treatment along with the minimal damage caused to surrounding healthy tissue structures makes electrochemotherapy an exciting new utility for clinicians to have in their armory. Some larger tumors may require repeat treatments to obtain a full remission but overall this technology is easy to perform on an outpatient basis, low cost and has a minimal impact on the patient’s quality of life. The Future The use of electrical pulses for cancer therapy has exciting potential applications beyond permeabilizing the tumor cell membrane. The cell death mechanism induced by electrochemotherapy has been previously published to induce a type of immunogenic cell death, which helps in priming a strong local anticancer immune response. Clinical studies are about to commence in Europe, looking to combine the immune priming effect of electrochemotherapy with newly available immunotherapeutic antibodies. Early indications have shown that this combination can be effective in generating a systemic tumor antigen specific cytotoxic T-cell response.
