European Standard Operating Procedures Of Electrochemotherapy Research Articles

Electrochemotherapy with intravenous bleomycin for heavily pre-treated vulvar cancer patients

ObjectiveThe management of vulvar cancer recurrences is complicated by patients’ advanced age and comorbidities. Bleomycin-based electrochemotherapy is a potential treatment option in this setting. However, no data on long-term outcomes...

Micro- and Nanosecond Pulses Used in Doxorubicin Electrochemotherapy in Human Breast and Colon Cancer Cells with Drug Resistance.

(1) Background: Pulsed electric field (PEF) techniques are commonly used to support the delivery of various molecules. A PEF seems a promising method for low permeability drugs or when cells demonstrate therapy resistance and the cell membrane becomes an impermeable barrier. (2) Methods: In this study, we have used doxorubicin-resistant and sensitive models of human breast cancer (MCF-7/DX, MCF-7/WT) and colon cancer cells (LoVo, LoVoDX). The study aimed to investigate the susceptibility of the cells to doxorubicin (DOX) and electric fields in the 20–900 ns pulse duration range. The viability assay was utilized to evaluate the PEF protocols’ efficacy. Cell confluency and reduced glutathione were measured after PEF protocols. (3) Results: The obtained results showed that PEFs significantly supported doxorubicin delivery and cytotoxicity after 48 and 72 h. The 60 kV/cm ultrashort pulses × 20 ns × 400 had the most significant cytotoxic anticancer effect. The increase in DOX concentration provokes a decrease in cell viability, affected cell confluency, and reduced GSSH when combined with the ESOPE (European Standard Operating Procedures of Electrochemotherapy) protocol. Additionally, reactive oxygen species after PEF and PEF-DOX were detected. (4) Conclusions: Ultrashort electric pulses with low DOX content or ESOPE with higher DOX content seem the most promising in colon and breast cancer treatment.

Electrochemotherapy for advanced cutaneous angiosarcoma: A European register-based cohort study from the International Network for Sharing Practices of electrochemotherapy (InspECT).

Cutaneous angiosarcoma (cAS) is a highly aggressive malignancy that challenges the radicality of surgical treatment. Electrochemotherapy (ECT), a skin-directed treatment based on cytotoxic chemotherapy combined with local electric pulses, may be an intraoperative adjunct and a new opportunity in the therapeutic strategy. This cohort study reports the experience with ECT as an option. Data on patients with locally-advanced/metastatic cAS who underwent ECT between October 2013 and October 2018 at eight European centres were prospectively submitted to the InspECT (International network for sharing practices of ECT) register. Patients received therapy according to the European Standard Operating Procedures of ECT (ESOPE). Treatment feasibility was assessed based on tumour coverage with electrodes and recorded tissue current; treatment toxicity and tumour response were graded according to CTCAE v5.0 and RECIST v1.1 criteria, respectively; patient-reported outcomes (PRO) were evaluated using a visual analogue score (VAS) for pain, acceptance of retreatment and the EQ-5D questionnaire. We enrolled 20 patients with advanced cAS in the scalp/face (n = 7), breast/trunk (n = 10) or limbs (n = 3). Target tumours (n = 51) had a median size of 2.3 cm (range, 1-20). We administered 24 ECT courses using 1-4 cm treatment safety margin around tumours. In five patients, ECT was combined/sequenced with surgery. Median tissue current was 3 A (range, 1.5-10), tumour margins coverage rate was 75% (15/20 patients). The objective response rate (ORR) was 80% (complete, 40%). Grade-3 toxicity included skin ulceration (15%) and pain (10%), with no significant change of PRO scores. Bleeding control was achieved in 13/14 patients with ulcerated tumours. With a median overall survival of 12.5 months, the local progression-free survival (LPFS) was 10.9 months. ECT produces sustained response rate with minimal side effects and should be considered an option for advanced cAS. Palliative benefits include patient tolerability, local haemostasis and durable local control. Definition of optimal timing, treatment safety margins and combination with surgery need further investigation.

Electrochemotherapy: new treatment approach for Hepatocellular Carcinoma: Results of phase I study

Background: Incidence of Hepatocellular Carcinoma(HCC) is rising across the world and it is one of the commonest causes of cancer-related deaths in the world but only 20 % of patients are candidates for curative treatment. When radical treatment is not indicated, transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and other methods are being used for disease control [1,2]. The data on effectiveness of electrochemotherapy (ECT) in cutaneous and some other tumors are numerous but there are limited data on feasibility and efficacy of ECT for liver tumor.[3, 4, 5]. Methods: For the treatment of patients with HCC with ECT, a phase I study was designed and concluded in 10 patients who fulfilled inclusion criteria. The primary goal of study was to assess the feasibility and effectiveness of ECT in HCC. Effectiveness was evaluated by mRECIST criteria using CT and/or MRI as a diagnostic tool. After multidisciplinary meeting included patients into study, a pretreatment plan was made.The treatment was performed during open surgery using electrodes with variable or fixed geometry guided by ultra sound.After their insertion, BLM was injected and the electric pulses was applied after 8 minutes. A CT scan or MRI was done according to the study protocol. Results: Our study shows high rate of complete responds lesions that were treated by mRECIST criteria without higher morbidity or mortality rate. Conclusion: Study proved that ECT is in some patients with HCC safe and effective treatment option. References. [1] Former A:, (2014), Treatment of intermediate-stage hepatocellular carcinoma, Nat Rev Clin Oncol, Nat Rev Clin Oncol, 525–535, 11. [2] Hong SN, (2005), Comparing the outcomes of radiofrequency ablation and surgery in patients with a single small hepatocellular carcinoma and well-preserved hepatic function. , J Clin Gastroenterol, 247–252 , 39. [3] Đokić M, (2016), Treatment of primary liver tumors with electrochemotherapy. [4] Edhemovic I., (2014), Edhemovic I Intraoperative electrochemotherapy of colorectal liver metastases , Journa of Surgical Oncology, 320–327 , 110. [5] Marty M Electrochemotherapy – an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study. , (2006), Electrochemotherapy – an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study, EJC Suppl , 3–13, 4.

Electrochemotherapy of unresectable cutaneous tumours with reduced dosages of intravenous bleomycin: analysis of 57 patients from the International Network for Sharing Practices of Electrochemotherapy registry.

Electrochemotherapy (ECT) is currently used to treat unresectable superficial tumours of different histotypes through the combination of cytotoxic chemotherapy and local application of electric pulses. In 2006, a collaborative project defined the ESOPE (European Standard Operating Procedures of Electrochemotherapy) guidelines to standardize the procedure. The International Network for Sharing Practices of Electrochemotherapy (InspECT) aims to refine the ESOPE and improve clinical practice. Limiting patient exposure to systemic chemotherapy would be advisable to ameliorate ECT safety profile. The aim of this study was to evaluate the efficacy and toxicity of ECT with reduced chemotherapy dosages. In a retrospective analysis of a prospectively maintained database (InspECT registry), we evaluated the outcome of patients who received ECT with reduced dosages of bleomycin (7500, 10 000 or 13 500 IU/m2 , instead of the standard dose of 15 000 IU/m2 ). Tumour response in melanoma patients was compared with melanoma patients of the InspECT registry who received the standard dose of bleomycin. We identified 57 patients with 147 tumours (melanoma, 38.6%; squamous cell carcinoma, 22.8%; basal cell carcinoma, 17.5%; breast cancer 7%; Kaposi sarcoma 7%; other histotypes, 7.1%). Per-tumour complete response (CR) rate at 60 days was 70.1% (partial, 16.3%); per-patient CR was 57.9% (partial, 21.1%). Local pain was the most frequently reported side-effect (n = 22 patients [39%]), mostly mild; two patients experienced flu-like symptoms, one patient nausea. We observed the same CR rate (55%) in patients with melanoma treated by reduced or conventional bleomycin dosages (P = 1.00). Electrochemotherapy performed with reduced bleomycin dosages could be as effective as with currently recommended dose. Patients with impaired renal function or candidate to multiple ECT cycles could benefit from a reduced dose protocol. Our findings need prospective confirmation before being adopted in clinical practice.

Treatment efficacy with electrochemotherapy: A multi-institutional prospective observational study on 376 patients with superficial tumors

BackgroundCutaneous metastases represent a therapeutic challenge. An increasing body of experience suggests that electrochemotherapy (ECT) provides effective tumor control, although its evidence basis should be strengthened. MethodsThis prospective, multicenter, observational study enrolled patients with superficial metastases, who underwent ECT at 10 centers between 2008 and 2013. Outcomes included adherence to European Standard Operating Procedures of ECT (ESOPE), tumor response, local progression-free survival (LPFS), toxicity and patient-reported outcomes (PROs, EORTC QLQ-C30 plus an 8-item questionnaire). ResultsWe enrolled 376 eligible patients. Tumor histotype distribution was as follows: melanoma, 56%; squamous cell carcinoma, 11%; Kaposi sarcoma, 11%; breast carcinoma, 8%; basal cell carcinoma, 6%; soft tissue sarcomas, 3%; others, 5%. We registered 1304 target tumors (median size 1 cm). Treatment adhered to ESOPE in 88% of patients as to the route of drug administration, and in 70% as to electrode application. The procedure was mainly performed under sedation (64.6%) and by using intravenous chemotherapy (93.4%). Tumor response rate at 60 days was 88% (complete, 50%). Small tumor size predicted complete response achievement (OR 2.24, p = 0.003), higher LPFS (HR 0.68, p = 0.004) and improved PROs (Global Health Status, p < 0.001; wound bleeding, p < 0.001; healing, p = 0.002; and aesthetics, p < 0.001). Skin toxicity (grade ≥3, 7.8%) was lower in patients with tumors <2 cm (p≤0.001). One-year LPFS was 73.7% (95%CI 68.4–78.3). ConclusionsECT represents a valuable skin-directed therapy across a range of malignancies. The most frequently applied treatment modality is intravenous chemotherapy under sedation. Small tumor size predicts durable tumor control, fewer side-effects and better PROs.

Electrochemotherapy in the Treatment of Melanoma Skin Metastases: A Report on 31 Cases

Introduction and objectivesElectrochemotherapy is indicated for the treatment of unresectable cutaneous and subcutaneous tumors. The technique involves the synergistic use of electroporation of cell membranes to increase the cytotoxicity of anticancer drugs delivered to the tumor cells. The aim of this study was to analyze the clinical effectiveness and safety of electrochemotherapy in the treatment of unresectable locoregional recurrent or metastatic melanomas. Material and methodsWe studied 31 patients treated between January 2007 and December 2012. The European Standard Operating Procedures of Electrochemotherapy (ESOPE) were applied in all cases. Treatment response was analyzed as overall patient response (mean response based on results for all lesions treated in a given patient). ResultsResponse was classified as partial in 49% of patients and complete in 23%. At 1 year, the level of response achieved had been maintained in 17 patients. Disease progression was observed in 28% of the series. Immediate local complications (pain, swelling, erythema) were mild and resolved within 48hours in most cases. Eight patients developed subsequent local complications, such as ulcers and secondary infections associated with necrosis of the lesions. These complications were brought under control with topical treatments. ConclusionsElectrochemotherapy is a very effective, safe, and efficient treatment for advanced locoregional disease in patients with unresectable melanoma lesions.

Electroquimioterapia en metástasis cutáneas de melanoma: Experiencia en 31 casos

Introduction and objectivesElectrochemotherapy is indicated for the treatment of unresectable cutaneous and subcutaneous tumors. The technique involves the synergistic use of electroporation of cell membranes to increase the cytotoxicity of anticancer drugs delivered to the tumor cells. The aim of this study was to analyze the clinical effectiveness and safety of electrochemotherapy in the treatment of unresectable locoregional recurrent or metastatic melanomas. Material and methodsWe studied 31 patients treated between January 2007 and December 2012. The European Standard Operating Procedures of Electrochemotherapy (ESOPE) were applied in all cases. Treatment response was analyzed as overall patient response (mean response based on results for all lesions treated in a given patient). ResultsResponse was classified as partial in 49% of patients and complete in 23%. At 1 year, the level of response achieved had been maintained in 17 patients. Disease progression was observed in 28% of the series. Immediate local complications (pain, swelling, erythema) were mild and resolved within 48hours in most cases. Eight patients developed subsequent local complications, such as ulcers and secondary infections associated with necrosis of the lesions. These complications were brought under control with topical treatments. ConclusionsElectrochemotherapy is a very effective, safe, and efficient treatment for advanced locoregional disease in patients with unresectable melanoma lesions.

In Vitro and In Vivo Experiments on Electrochemotherapy for Bladder Cancer

Electrochemotherapy is widely performed to treat solid tumors but experience with bladder cancer is limited. We investigated mitomycin C and cisplatin administered with electrochemotherapy for bladder cancer in vitro and in vivo. The human bladder cancer cell line SW780 was used. Cells were treated with electroporation, drug alone or electroporation plus increasing concentrations of drug (mitomycin C 0.001 to 2,000 μM or cisplatin 1.56 to 300 μM). Electrochemotherapy parameters were 8 pulses of 1.2 kV/cm for 99 microseconds at 1 Hz. We investigated survival and apoptosis, the latter evaluated by caspase activity. NMRI-Fox1nu nude mice were inoculated subcutaneously and randomized to 1) electrochemotherapy plus NaCl, 2) NaCl alone, 3) electrochemotherapy plus drug or 4) drug alone (mitomycin C 5 mM or cisplatin 250 μM). Tumors were measured 3 times per week. A similar experiment was done to assess necrosis by histology at days 2 and 6. In vitro mitomycin C cytotoxicity and caspase activity was unaffected by electrochemotherapy (p = 0.9057 and 0.53, respectively). However, electrochemotherapy with cisplatin caused 6.6-fold increased cytotoxicity and higher caspase activity (p <0.0001 and <0.001, respectively). In vivo electrochemotherapy plus mitomycin C resulted in tumor volume reduction (p <0.0005). The survival rate in mice that received electrochemotherapy plus mitomycin C and mitomycin C alone was greater than in controls (p = 0.0004). The tumor response rate was 100% for electrochemotherapy plus mitomycin C, 53% for mitomycin C alone, 14% for electrochemotherapy plus NaCl and 0% for NaCl alone. In vivo electrochemotherapy plus cisplatin was associated with slower tumor growth over other combinations as well as significantly higher survival (p = 0.0005 and 0.0003, respectively). The tumor response rate was 47% for electrochemotherapy plus cisplatin, 0% for cisplatin alone, 0% for electrochemotherapy plus NaCl and 8% for NaCl alone In vivo electrochemotherapy with mitomycin C or cisplatin was more effective than chemotherapy alone in a bladder cancer tumor model, opening new perspectives in bladder cancer therapy.

Electrochemotherapy as “new standard of care” treatment for cutaneous Kaposi's sarcoma

Electrochemotherapy (ECT) is a novel modality for the treatment of skin nodules and cutaneous or subcutaneous tumors that allows delivery of low and non-permeant drug into cells. The aim of this prospective single-center study was to evaluate ECT efficacy in the local treatment of Classic Kaposi's sarcoma (CKS) skin localization stage I-II sec. Brambilla et al. Nineteen consecutive patients affected by classic KS were included in this study. All patients underwent blood sampling and concurrent incisional biopsy for histological diagnosis and Kaposi's sarcoma related herpes virus 8 (HHV-8) molecular analysis. ECT treatment of KS cutaneous lesions were performed according to the European Standard Operating Procedures of Electrochemotherapy (ESOPE). The primary endpoint of the study was the evaluation of ECT efficacy in the treatment of KS skin nodules and the assessment of HHV-8 viral load in the peripheral blood following the ECT therapy. Complete response (CR) was observed in 14 (73.6%) patients after first ECT session, while 3 (15.7%) and 2 (10.5%) out of 19 patients received a second and a third ECT treatment, respectively. Clinical response dragged out the whole follow-up period that ranged between 6 and 31 months with a median of 16 months. Clinical management of CKS skin localizations still represents a challenging task for surgeons and oncologists. Therefore, according to this and other author's recent experiences, ECT is claimed to become the "new standard of care" as first line treatment strategy for stage I-II CKS patients.

Electrochemotherapy for Non-Melanoma Head and Neck Cancers

To evaluate and confirm the efficacy and safety of electrochemotherapy (ECT) using bleomicyn in a large series of non-melanoma head and neck cancers. ECT combines chemotherapy and electroporation to increase drug uptake into cancer cells. ECT has proven to be effective in the treatment of tumor nodules of cutaneous and subcutaneous localization. Up to now, this therapy has been mainly used as a local control of melanoma skin metastasis. Few studies have focused on its role in the treatment of head and neck cutaneous and subcutaneous cancers. Twenty-five patients underwent ECT for the treatment of non-melanoma head and neck cancers. All tumors were classified by histological type (confirmed by biopsy), size, and TNM Classification of Malignant Tumors (TNM). Treatments were performed using a bolus of bleomicyn and a pulse generator under local or general anesthesia after the ESOPE (European Standard Operating Procedures of Electrochemotherapy) standard operating procedures. An objective response was achieved in 100% of treated patients (n = 25) at 6 weeks after the initial treatment. The complete response rate according to the WHO criteria was 72% (n = 18); the partial response rate was 28% (n = 7). None of the lesions that achieved a complete response relapsed after a median follow-up period of 18 months. Partial responders showed stable disease for the duration of the follow-up. In accordance with the clinical results shown, we encourage further investigation to establish ECT's use as first line treatment especially in basocellular carcinomas of the head and neck area and for squamocellular carcinomas of the lip with no detectable cervical lymphoadenopathy.

Electrochemotherapy in the Treatment of Kaposi Sarcoma Cutaneous Lesions: A Two-Center Prospective Phase II Trial

Electrochemotherapy (ECT) is an emerging treatment for cutaneous lesions of different tumor types. The combination of chemotherapy and electroporation enhances drug uptake into tumoral cells. However, its role in the treatment of Kaposi sarcoma (KS) has not yet been well defined, and to date, literature reports are scarce. We prospectively evaluated clinical activity and safety of ECT in KS patients. Twenty-three patients with histologically confirmed unresectable KS, not treatable by radiotherapy or intralesional vincristine therapy, were enrolled onto the study according to the European Standard Operating Procedures of Electrochemotherapy (ESOPE) guidelines and treated with a pulse generator. A response to the first ECT session was obtained in all patients, with a complete response (CR) in 14 (60.9%) of 23 patients. A second ECT was performed in 5 (21.7%) and a third in 2, with a median interval between two sessions of 5.1 (range 2.5-25.5) months. Overall, a total of 15 patients (65%) experienced a CR. After a median follow-up of 1.5years (range 2months to 4.2years), 16 patients maintained the response, 4 after repeated courses. Sustained local control of treated lesions was present in 20 of 23 patients. The overall survival rate was 74.4% at 2years. ECT represents an additional therapeutic tool for the management of KS cutaneous lesions, characterized by a definite clinical activity and long-lasting remissions. The absence of systemic side effects and the low impact on the immune system also make this treatment suitable for elderly people, even with repeated courses.

Electrochemotherapy with Intravenous Bleomycin in the Local Treatment of Skin Melanoma Metastases

Electrochemotherapy (ECT) combines chemotherapy and electroporation to increase drug uptake. Its role in cutaneous melanoma metastasis treatment is not well defined; indeed, few studies have been reported, without complete follow-up data. To prospectively evaluate clinical activity and tolerability of ECT with i.v. bleomycin, and to analyze the response increase associated to repeated sessions, in the largest series of cutaneous melanoma metastases reported to date (n = 233). 14 stage III relapsed/refractory patients were enrolled according to European Standard Operating Procedures of Electrochemotherapy (ESOPE) guidelines and treated under general sedation using the Cliniporator(TM) pulse generator. A response was obtained in 13/14 patients (93%) after the first ECT, with a complete regression (CR) in 7 (50%). Seven patients underwent a second and three a third ECT on newly appearing and residual lesions, all achieving a response. Overall, a response was obtained in 93% metastases, with lower response rates in >1 cm(2) lesions. The CR rate was 58%; none of the CR nodules relapsed. The repeated ECT sessions gave rise to a new response in 21/29 (72%) re-treated lesions. The local tumor control rate was 74.5% at 2 years. ECT is a safe procedure, easily performed in terms of toxicities and cost-effectiveness ratios, and constitutes a therapeutic tool for relapsed/refractory cutaneous melanoma patients. The repeated ECT sessions are associated with a response increase in re-treated lesions which could allow to overcome the reduced activity in >1 cm(2) sized metastases.

Electrochemotherapy – An easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study

To evaluate and confirm efficacy and safety of electrochemotherapy with bleomycin or cisplatin on cutaneous and subcutaneous tumour nodules of patients with malignant melanoma and other malignancies in a multicenter study. This was a two year long prospective non-randomised study on 41 patients evaluable for response to treatment and 61 evaluable for toxicity. Four cancer centers enrolled patients with progressive cutaneous and subcutaneous metastases of any histologically proven cancer. The skin lesions were treated by electrochemotherapy, using application of electric pulses to the tumours for increased bleomycin or cisplatin delivery into tumour cells. The treatment was performed using intravenous or intratumoural drug injection, followed by application of electric pulses generated by a Cliniporator™ using plate or needle electrodes . Tumour response to electrochemotherapy as well as possible side-effects with respect to the treatment approach, tumour histology and location of the tumour nodules and electrode type were evaluated. An objective response rate of 85% (73.7% complete response rate) was achieved on the electrochemotherapy treated tumour nodules, regardless of tumour histology, and drug used or route of its administration. At 150 days after the treatment (median follow up was 133 days and range 60–380 days) local tumour control rate for electrochemotherapy was 88% with bleomycin given intravenously, 73% with bleomycin given intratumourally and 75% with cisplatin given intratumourally, demonstrating that all three approaches were similarly effective in local tumour treatment. Furthermore, electrochemotherapy was equally effective regardless of the tumour type and size of the nodules treated. Side-effects of electrochemotherapy were minor and acceptable, as reported by the patients. We demonstrated that electrochemotherapy is an easy, highly effective, safe and cost-effective approach for the treatment of cutaneous and subcutaneous tumour nodules of different malignancies. Electrochemotherapy can provide immediate clinical benefit in patients with advanced cutaneous and subcutaneous metastases.