Abstract Background This systematic review has two purposes: to consolidate the current knowledge about clinical effectiveness of electrochemotherapy, a highly effective local therapy for cutaneous ...and subcutaneous tumors; and to investigate the differences in effectiveness of electrochemotherapy with respect to tumor type, chemotherapeutic drug, and route of drug administration. Methods All necessary steps for a systematic review were applied: formulation of research question, systematic search of literature, study selection and data extraction using independent screening process, assessment of risk of bias, and statistical data analysis using two-sided common statistical methods and meta-analysis. Studies were eligible for the review if they provided data about effectiveness of single-session electrochemotherapy of cutaneous or subcutaneous tumors in various treatment conditions. Results In total, 44 studies involving 1894 tumors were included in the review. Data analysis confirmed that electrochemotherapy had significantly ( p < .001) higher effectiveness (by more than 50%) than bleomycin or cisplatin alone. The effectiveness was significantly higher for intratumoral than for intravenous administration of bleomycin ( p < .001 for CR%, p = .028 for OR%). Bleomycin and cisplatin administered intratumorally resulted in equal effectiveness of electrochemotherapy. Electrochemotherapy was more effective in sarcoma than in melanoma or carcinoma tumors. Conclusions The results of this review shed new light on effectiveness of electrochemotherapy and can be used for prediction of tumor response to electrochemotherapy with respect to various treatment conditions and should be taken into account for further refinement of electrochemotherapy protocols.
Abstract Aim Electrochemotherapy is a local drug delivery approach aimed at treatment with palliative intent of cutaneous and subcutaneous tumour nodules of different histologies. ...Electrochemotherapy, via cell membrane permeabilising electric pulses, potentiates the cytotoxicity of non-permeant or poorly permeant anticancer drugs with high intrinsic cytotoxicity, such as bleomycin or cisplatin, at the site of electric pulse application. Methods An overview of preclinical and clinical studies is presented, and the treatment procedure is further critically evaluated. Results In clinical studies electrochemotherapy has proved to be a highly efficient and safe approach for treating cutaneous and subcutaneous tumour nodules. The treatment response for various tumours (predominantly melanoma) was ∼75% complete and 10% partial response of the treated nodules. Conclusions Electrochemotherapy is a new, clinically acknowledged method for the treatment of cutaneous and subcutaneous tumours. Its advantages are high effectiveness on tumours with different histologies, simple application, minimal side effects and the possibility of effective repetitive treatment.
Electrochemotherapy (ECT) is a treatment for both primary and secondary cutaneous tumours. The international Network for sharing practices on ECT group investigates treatment outcomes after ECT using ...a common database with defined parameters.
Twenty-eight centres across Europe prospectively uploaded data over an 11-year period. Response rates were investigated in relation to primary diagnosis, tumour size, choice of electrode type, route of bleomycin administration, electrical parameters recorded and previous irradiation in the treated field.
Nine hundred eighty-seven patients, with 2482 tumour lesions were included in analysis. The overall response (OR) rate was 85% (complete response CR: 70%, partial response rate: 15%, stable disease: 11%, and progressive disease: 2%). For different histologies, OR and CR rates for metastases of malignant melanoma were 82% and 64%, basal cell carcinoma were 96% and 85%, breast cancer metastases were 77% and 62%, squamous cell carcinoma were 80% and 63% as well as Kaposi's sarcoma were 98% and 91%, respectively. Variance was demonstrated across histotypes (p < 0.0001) and in accordance with size of lesion treated (dichotomised at diameter of 3 cm (p < 0.0001). Hexagonal electrodes were generally used for larger tumours, but for tumours up to 3 cm, linear array electrodes provided better tumour control than hexagonal electrodes (80%:74%, p < 0.003). For tumours more than 2 cm, intravenous administration was superior to intratumoural (IT) administration (p < 0.05). Current recorded varied across tumour histologies and size but did not influence response rate. In previously irradiated areas, responses were selectively lower for IT administration.
These cumulative data endorse efficiency of ECT across a broad range of histotypes. Analysis of 2482 lesions details subgroup analysis on treatment response informing future treatment choices.
•Electrochemotherapy (ECT) is highly efficient in the treatment of cutaneous metastases.•ECT is efficient across tumour histologies.•ECT response is higher for smaller tumours.•Intravenous bleomycin was more efficient than intratumoural, in tumours more than 2 cm size.•Linear array electrodes were more efficient in tumours less than 3 cm size.
•In vitro, lipofection of CCL5/CCL17 modifies the expression of cytokines.•The main driver of these changes was the entry of foreign DNA into the cytosol.•In vivo, ECT pulses lead to high expression ...of Ccl5 and Ccl17 after GET.•GET of CCL5 or CCL17 results in increased expression of Cxcl9 and Ifnγ.•Cxcl9 and Ifnγ are potent activators of the immune system in the CT26 tumor model.
The effectiveness of immunotherapy highly correlates with the degree and the type of infiltrated immune cells in the tumor tissue. Treatments based on modifying the immune cell infiltrate of the tumor microenvironment are thus gaining momentum. Therefore, the aim of our study was to investigate the effects of gene therapy with two proinflammatory chemokines CCL5 and CCL17 on inflammatory cytokine expression profile and immune cell infiltrate in two murine breast tumor models, 4T1 and E0771, and two murine colon tumor models, CT26 and MC38. In vitro, lipofection of plasmid DNA encoding CCL5 or CCL17 resulted in changes in the cytokine expression profile similar to control plasmid DNA, implying that the main driver of these changes was the entry of foreign DNA into the cell’s cytosol. In vivo, gene electrotransfer resulted in high expression levels of both Ccl5 and Ccl17 transgenes in the 4T1 and CT26 tumor models. Besides a minor increase in the survival of the treated mice, the therapy also resulted in increased expression of Cxcl9 and Ifnγ, potent activators of the immune system, in CT26 tumors. However, this was not recapitulated in changes of TME, implying that a further refinement of the dosing schedule is needed.
The aim of our study was to evaluate the efficacy of electrochemotherapy (ECT) with cisplatin as a single or adjuvant treatment for sarcoids in equids. Different treatment options with different ...success rates were proposed. Thirty-one horses and one donkey with different clinical type, size and location of tumours were treated with ECT as a single treatment (18 animals with 52 tumour nodules) or as adjuvant treatment with marginal surgical excision (14 animals with 18 tumour nodules). In animals treated only with ECT with cisplatin, complete response was obtained in 48/52 (92.3 per cent) nodules and partial response in the other 4 nodules (7.7 per cent). In most cases, one to three sessions, only in two cases four and in one case five sessions, every 4 weeks were needed to obtain the measurable response. During the observation time, only in one case was the recurrence noted 60 months after treatment. Complete response in all 18 tumour nodules treated with surgery and adjuvant ECT was obtained and only one recurrence was noted after 14 months during the observation time. The results of this study show that ECT with cisplatin is an effective, safe, and simple local treatment of sarcoids in equids. According to the tumour size and location, single or combined treatment should be performed.
Electrochemotherapy is now in development for treatment of deep-seated tumors, like in bones and internal organs, such as liver. The technology is available with a newly developed electric pulse ...generator and long needle electrodes; however the procedures for the treatment are not standardized yet. In order to describe the treatment procedure, including treatment planning, within the ongoing clinical study, a case of successful treatment of a solitary metastasis in the liver of colorectal cancer is presented. The procedure was performed intraoperatively by inserting long needle electrodes, two in the center of the tumor and four around the tumor into the normal tissue. The insertion of electrodes proved to be feasible and was done according to the treatment plan, prepared by numerical modeling. After intravenous bolus injection of bleomycin the tumor was exposed to electric pulses. The delivery of the electric pulses did not interfere with functioning of the heart, since the pulses were synchronized with electrocardiogram in order to be delivered outside the vulnerable period of the ventricles. Also the post treatment period was uneventful without side effects. Re-operation of the treated metastasis demonstrated feasibility of the reoperation, without secondary effects of electrochemotherapy on normal tissue. Good antitumor effectiveness with complete tumor destruction was confirmed with histological analysis. The patient is disease-free 16 months after the procedure. In conclusion, treatment procedure for electrochemotherapy proved to be a feasible technological approach for treatment of liver metastasis. Due to the absence of the side effects and the first complete destruction of the treated tumor, treatment procedure for electrochemotherapy seems to be a safe method for treatment of liver metastases with good treatment effectiveness even in difficult-to-reach locations.
Electrochemotherapy in Veterinary Oncology Cemazar, M; Tamzali, Y; Sersa, G ...
Journal of veterinary internal medicine,
July–August 2008, Volume:
22, Issue:
4
Journal Article
Peer reviewed
Open access
Electropermeabilization is a method that uses electric field pulses to induce an electrically mediated reorganization of the plasma membrane of cells. Electrochemotherapy combines local or systemic ...administration of chemotherapeutic drugs such as bleomycin or cisplatin that have poor membrane permeability with electropermeabilization by direct application of electric pulses to the tumors. Preclinical studies have demonstrated excellent antitumor effectiveness of electrochemotherapy on different animal models and various tumor types, minimal toxicity, and safety of the procedure. Based on results of preclinical studies, clinical studies were conducted in human patients, which demonstrated pronounced antitumor effectiveness of electrochemotherapy with 80–85% objective responses of the treated cutaneous and SC tumors. Clinical studies in veterinary oncology have demonstrated that electrochemotherapy is very effective in the treatment of cutaneous and SC tumors of different histologic types in cats, dogs, and horses. The results of these studies have also demonstrated approximately 80% long‐lasting objective responses of tumors treated by electrochemotherapy. Primary tumors of different histologic types were treated. Electrochemotherapy in veterinary oncology has future promise to be highly effective, and could be used to treat primary or recurrent solitary or multiple cutaneous and SC tumors of different histology or as an adjuvant treatment to surgery.
Electrochemotherapy has a direct cytotoxic effect on tumour cells, and presumably, a vascular disrupting effect. In this study, on the basis of the prediction of the mathematical model, histological ...evaluation and physiological measurements of the tumours were carried out to confirm that electroporation and electrochemotherapy of tumours have a vascular disrupting action. In the study, SA-1 solid subcutaneous sarcoma tumours in A/J mice were treated by bleomycin (BLM) given intravenously (1 mg kg(-1)), application of electric pulses (8 pulses, 1040 V, 100 micros, 1 Hz) or a combination of both - electrochemotherapy. The vascular effect was determined by laser Doppler flowmetry, power Doppler ultrasonographic imaging and Patent blue staining. The extent of tumour hypoxia was determined immunohistochemically by hypoxia marker pimonidazole and partial pressure of oxygen (pO(2)) in tumours by electron paramagnetic resonance oximetry. Electrochemotherapy with BLM induced good antitumour effect with 22 days, tumour growth delay and 38% tumour cures. The application of electric pulses to the tumours induced instant but transient tumour blood flow reduction (for 70%) that was recovered in 24 h. During this tumour blood flow reduction, we determined an increase in hypoxic tumour area for up to 30%, which was also reflected in reduced tumour oxygenation (for 70%). According to the described mathematical model, endothelial cells lining in tumour blood vessels are exposed to a approximately 40% higher electric field than the surrounding tumour cells, and therefore easily electroporated, allowing access of high BLM concentration to the cytosol. Consequently, electrochemotherapy has, besides the immediate vascular disrupting action, also a delayed one (after 24 h), as a consequence of endothelial cell swelling and apoptosis demonstrated by extensive tumour necrosis, tumour hypoxia, prolonged reduction of tumour blood flow and significant tumour growth delay, and tumour cures. Our results demonstrate that in addition to the well-established direct cytotoxic effect on tumour cells, electrochemotherapy also has an indirect vascular disrupting action resulting altogether in extensive tumour cell necrosis leading to complete regression of tumours.
•Gene electrotransfer of IL-2 and IL-12 is an effective treatment for B16.F10 model.•Complete responses were obtained in 71% of mice treated with IL-2 and IL-12.•Immune memory observed in mice ...treated with gene electrotransfer of IL-2 and IL-12.•Strong vitiligo was observed in cured mice after the combination therapy.
Gene therapy has become an important approach for treating cancer, and electroporation represents a technology for introducing therapeutic genes into a cell. An example of cancer gene therapy relying on gene electrotransfer is the use of immunomodulatory cytokines, such as interleukin 2 (IL-2) and 12 (IL-12), which directly stimulate immune cells at the tumour site. The aim of our study was to determine the effects of gene electrotransfer with two plasmids encoding IL-2 and IL-12 in vitro and in vivo. Two different pulse protocols, known as EP1 (600 V/cm, 5 ms, 1 Hz, 8 pulses) and EP2 (1300 V/cm, 100 µs, 1 Hz, 8 pulses), were assessed in vitro for application in subsequent in vivo experiments. In the in vivo experiment, gene electrotransfer of pIL-2 and pIL-12 using the EP1 protocol was performed in B16.F10 murine melanoma. Combined treatment of tumours using pIL2 and pIL12 induced significant tumour growth delay and 71% complete tumour regression. Furthermore, in tumours coexpressing IL-2 and IL-12, increased accumulation of dendritic cells and M1 macrophages was obtained along with the activation of proinflammatory signals, resulting in CD4 + and CD8 + T-lymphocyte recruitment and immune memory development in the mice. In conclusion, we demonstrated high antitumour efficacy of combined IL-2 and IL-12 gene electrotransfer protocols in low-immunogenicity murine B16.F10 melanoma.
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