Electrochemotherapy is a local treatment of cancer employing electric pulses to improve transmembrane transfer of cytotoxic drugs. In this paper we discuss electrochemotherapy from the perspective of ...biomedical engineering and review the steps needed to move such a treatment from initial prototypes into clinical practice. In the paper also basic theory of electrochemotherapy and preclinical studies in vitro and in vivo are briefly reviewed. Following this we present a short review of recent clinical publications and discuss implementation of electrochemotherapy into standard of care for treatment of skin tumors, and use of electrochemotherapy for other targets such as head and neck cancer, deep-seated tumors in the liver and intestinal tract, and brain metastases. Electrodes used in these specific cases are presented with their typical voltage amplitudes used in electrochemotherapy. Finally, key points on what should be investigated in the future are presented and discussed.
Electrochemotherapy is now in routine clinical use to treat cutaneous metastases of any histology, and is listed in national and international guidelines for cutaneous metastases and primary skin ...cancer. Electrochemotherapy is used by dermatologists, surgeons, and oncologists, and for different degrees and manifestations of metastases to skin and primary skin tumours not amenable to surgery. This treatment utilises electric pulses to permeabilize cell membranes in tumours, thus allowing a dramatic increase of the cytotoxicity of anti-cancer agents. Response rates, often after only one treatment, are very high across all tumour types. The most frequent indications are cutaneous metastases from malignant melanoma and breast cancer. In 2006, standard operating procedures (SOPs) were written for this novel technology, greatly facilitating introduction and dissemination of the therapy. Since then considerable experience has been obtained treating a wider range of tumour histologies and increasing size of tumours which was not originally thought possible. A pan-European expert panel drawn from a range of disciplines from dermatology, general surgery, head and neck surgery, plastic surgery, and oncology met to form a consensus opinion to update the SOPs based on the experience obtained. This paper contains these updated recommendations for indications for electrochemotherapy, pre-treatment information and evaluation, treatment choices, as well as follow-up.
Summary
Background
(ECT) is an effective local treatment for cutaneous metastasis. Treatment involves the administration of chemotherapeutic drugs followed by delivery of electrical pulses to the ...tumour.
Objectives
To investigate the effectiveness of ECT in cutaneous metastases of melanoma and to identify factors that affect (beneficially or adversely) the outcome.
Methods
Thirteen cancer centres in the International Network for Sharing Practices on Electrochemotherapy consecutively and prospectively uploaded data to a common database. ECT consisted of intratumoral or intravenous injection of bleomycin, followed by application of electric pulses under local or general anaesthesia.
Results
In total, 151 patients with metastatic melanoma were identified from the database, 114 of whom had follow‐up data of 60 days or more. Eighty‐four of these patients (74%) experienced an overall response (OR = complete response + partial response). Overall, 394 lesions were treated, of which 306 (78%) showed OR, with 229 showing complete response (58%). In multivariate analysis, factors positively associated with overall response were coverage of deep margins, absence of visceral metastases, presence of lymphoedema and treatment of nonirradiated areas. Factors significantly associated with complete response to ECT treatment were coverage of deep margins, previous irradiation of the treated area and tumour size (< 3 cm). One‐year overall survival in this cohort of patients was 67% (95% confidence interval 57–77%), while melanoma‐specific survival was 74% (95% confidence interval 64–84%). No serious adverse events were reported, and the treatment was in general very well tolerated.
Conclusions
ECT is a highly effective local treatment for melanoma metastases in the skin, with no severe adverse effects noted in this study. In the presence of certain clinical factors, ECT may be considered for local tumour control as an alternative to established local treatments, or as an adjunct to systemic treatments.
What's already known about this topic?
Electrochemotherapy (ECT) is an effective local treatment for cutaneous metastasis.
Treatment efficacy is correlated to tumour size.
What does this study add?
With multivariate analysis, several new factors associated with a favourable response to treatment have been identified: coverage of deep tumour margin, presence of lymphoedema, treatment of nonirradiated areas and absence of visceral metastases.
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Linked Comment: Cerio and Moir. Br J Dermatol 2017; 176:1427
Electroporation is a well-known phenomenon that occurs at the cell membrane when cells are exposed to high-intensity electric pulses. Depending on electric pulse amplitude and number of pulses, ...applied electroporation can be reversible with membrane permeability recovery or irreversible. Reversible electroporation is used to introduce drugs or genetic material into the cell without affecting cell viability. Electrochemotherapy refers to a combined treatment: electroporation and drug injection to enhance its cytotoxic effect up to 1000-fold for bleomycin. Since several years, electrochemotherapy is gaining popularity as minimally invasive oncologic treatment. The adoption of electrochemotherapy procedure in interventional oncology poses several unsolved questions, since suitable tumor histology and size as well as therapeutic efficacy still needs to be deepen. Electrochemotherapy is usually applied in palliative settings for the treatment of patients with unresectable tumors to relieve pain and ameliorate quality of life. In most cases, it is used in the treatment of advanced stages of neoplasia when radical surgical treatment is not possible (eg, due to lesion location, size, and/or number). Further, electrochemotherapy allows treating tumor nodules in the proximity of important structures like vessels and nerves as the treatment does not involve tissue heating. Overall, the safety profile of electrochemotherapy is favorable. Most of the observed adverse events are local and transient, moderate local pain, erythema, edema, and muscle contractions during electroporation. The aim of this article is to review the recent published clinical experiences of electrochemotherapy use in deep-seated tumors with particular focus on liver cases. The principle of electrochemotherapy as well as the application to cutaneous metastases is briefly described. A short insight in the treatment of bone metastases, unresectable pancreas cancer, and soft tissue sarcoma will be given. Preclinical and clinical studies on treatment efficacy with electrochemotherapy of hepatic lesions and safety of the procedure adopted are discussed.
We evaluated feasibility, safety and efficacy of Electrochemotherapy (ECT) in a prospective series of patients with unresectable Perihilar-Cholangiocarcinoma (PHCCA).
Five patients with PHCCA ...underwent ECT. Three patients underwent percutaneous ECT of a single PHCCA nodule. One patient underwent resection of a nodule in the IV segment and intraoperative ECT of a large PHCCA in the VIII segment. Another patient underwent percutaneous ECT of a large PHCCA recurrence after left lobectomy and RF ablation of a synchronous metastasis in the VI segment.
ECT was performed under US guidance. Efficacy was evaluated by contrast-enhanced multiple-detector-computed-tomography (MDCT) 4 weeks after treatment. Follow-up entailed MDCT every 6 months thereafter.
No major complication occurred. Follow-up ranges from 10 to 30 months. Four weeks post-treatment CT showed complete response in 3 cases. These patients are still alive, and follow-up CT controls demonstrated no local or distant intrahepatic recurrences and no biliary duct dilation in 2 cases and local recurrence at 18 months follow-up control in 1 patient. In the remaining 2 cases, 4-weeks-post-treatment CT showed incomplete response (>90%). In these patients follow-up CT demonstrated local progression of the disease at 6 months. One of them had bilateral external biliary drainages and died because of tumor progression at 16-months-follow-up. The other patient, died at 10 months follow-up for cardiovascular failure not related to the hepatobiliary disease.
ECT is feasible, safe and effective therapy to improve prognosis and quality of life of patients with unresectable PHCCA.
We consider electroconvective fluid flows initiated by ion concentration polarization (ICP) under pressure-driven shear flow, a scenario often found in many electrochemical devices and systems. ...Combining scaling analysis, experiment, and numerical modeling, we reveal unique behaviors of ICP under shear flow: a unidirectional vortex structure, its height selection, and vortex advection. Determined by both the external pressure gradient and the electric body force, the dimensionless height of the sheared electroconvective vortex is shown to scale as (ϕ(2)/U(HP))(1/3), which is a clear departure from the previous diffusion-drift model prediction. To the best of our knowledge, this is the first microscopic characterization of ion concentration polarization under shear flow, and it firmly establishes electroconvection as the mechanism for an overlimiting current in realistic, large-area ion exchange membrane systems such as electrodialysis. The new scaling law has significant implications on the optimization of electrodialysis and other electrochemical systems.
Electrochemotherapy combined with peritumoral interleukin‐12 (IL‐12) gene electrotransfer was used for treatment of mast cell tumours in 18 client‐owned dogs. Local tumour control, recurrence rate, ...as well as safety of combined therapy were evaluated. One month after the therapy, no side effects were recorded and good local tumour control was observed with high complete responses rate which even increased during the observation period to 72%. IL‐12 gene electrotransfer resulted in 78% of patients with detectable serum IFN‐γ and/or IL‐12 levels. In the treated tumours vascular changes as well as minimal T‐lymphocytes infiltration was observed. After 1 week, the plasmid DNA was not detected intra‐ or peritumorally and no horizontal gene transfer was observed. In summary, our study demonstrates high antitumour efficacy of electrochemotherapy combined with IL‐12 electrotransfer, which also prevented recurrences or distant metastases, as well as its safety and feasibility in treatment of canine mast cell tumours.
Electrochemotherapy, a combination of high voltage electric pulses and of an anticancer drug, has been demonstrated to be highly effective in treatment of cutaneous and subcutaneous tumors. Unique ...properties of electrochemotherapy (e.g., high specificity for targeting cancer cells, high degree of localization of treatment effect, capacity for preserving the innate immune response and the structure of the extracellular matrix) are facilitating its wide spread in the clinics. Due to high effectiveness of electrochemotherapy in treatment of cutaneous and subcutaneous tumors regardless of histological origin, there are now attempts to extend its use to treatment of internal tumors. To advance the applicability of electrochemotherapy to treatment of internal solid tumors, new technological developments are needed that will enable treatment of these tumors in daily clinical practice. New electrodes through which electric pulses are delivered to target tissue need to be designed with the aim to access target tissue anywhere in the body. To increase the probability of complete tumor eradication, the electrodes have to be accurately positioned, first to provide an adequate extent of electroporation of all tumor cells and second not to damage critical healthy tissue or organs in its vicinity. This can be achieved by image guided insertion of electrodes that will enable accurate positioning of the electrodes in combination with patient-specific numerical treatment planning or using a predefined geometry of electrodes. In order to be able to use electrochemotherapy safely for treatment of internal tumors located in relative proximity of the heart (e.g., in case of liver metastases), the treatment must be performed without interfering with the heart’s electrical activity. We describe recent technological advances, which allow treatment of liver and bone metastases, soft tissue sarcomas, brain tumors, and colorectal and esophageal tumors. The first clinical experiences in these novel application areas of electrochemotherapy are also described.
Significance: Irreversible electroporation (IRE) is gaining popularity as a focal ablation modality for the treatment of unresectable tumors. One clinical limitation of IRE is the absence of methods ...for real-time treatment evaluation, namely actively monitoring the dimensions of the induced lesion. This information is critical to ensure a complete treatment and minimize collateral damage to the surrounding healthy tissue. Goal: In this study, we are taking advantage of the biophysical properties of living tissues to address this critical demand. Methods: Using advanced microfabrication techniques, we have developed an electrical impedance microsensor to collect impedance data along the length of a bipolar IRE probe for treatment verification. For probe characterization and interpretation of the readings, we used potato tuber, which is a suitable platform for IRE experiments without having the complexities of in vivo or ex vivo models. We used the impedance spectra, along with an electrical model of the tissue, to obtain critical parameters such as the conductivity of the tissue before, during, and after completion of treatment. To validate our results, we used a finite element model to simulate the electric field distribution during treatments in each potato. Results: It is shown that electrical impedance spectroscopy could be used as a technique for treatment verification, and when combined with appropriate FEM modeling can determine the lesion dimensions. Conclusions: This technique has the potential to be readily translated for use with other ablation modalities already being used in clinical settings for the treatment of malignancies.
To provide an overview of current clinical results of irreversible electroporation (IRE), a novel, nonthermal tumor ablation technique that uses electric pulses to induce cell death, while preserving ...structural integrity of bile ducts and vessels.
All in-human literature on IRE reporting safety or efficacy or both was included. All adverse events were recorded. Tumor response on follow-up imaging from 3 months onward was evaluated.
In 16 studies, 221 patients had 325 tumors treated in liver (n = 129), pancreas (n = 69), kidney (n = 14), lung (n = 6), lesser pelvis (n = 1), and lymph node (n = 2). No major adverse events during IRE were reported. IRE caused only minor complications in the liver; however, three major complications were reported in the pancreas (bile leak n = 2, portal vein thrombosis n = 1). Complete response at 3 months was 67%-100% for hepatic tumors (93%-100% for tumors o 3 cm). Pancreatic IRE combined with surgery led to prolonged survival compared with control patients (20 mo vs 13 mo) and significant pain reduction.
In cases where other techniques are unsuitable, IRE is a promising modality for the ablation of tumors near bile ducts and blood vessels. This articles gives an extensive overview of the available evidence, which is limited in terms of quality and quantity. With the limitations of the evidence in mind, IRE of central liver tumors seems relatively safe without major complications, whereas complications after pancreatic IRE appear more severe. The available limited results for tumor control are generally good. Overall, the future of IRE for difficult-to-reach tumors appears promising.
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