Barbara Mali

Antitumor effectiveness of electrochemotherapy: A systematic review and meta-analysis

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.

Electrochemotherapy: from the drawing board into medical practice

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: A New Technological Approach in Treatment of Metastases in the Liver

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.

Tumor size and effectiveness of electrochemotherapy

Abstract Background. Electrochemotherapy (ECT) is an effective and safe method for local treatment of tumors. However, relatively large variability in effectiveness of ECT has been observed, which likely results from different treatment conditions and tumor characteristics. The aim of this study was to investigate the relationship between tumor size and effectiveness of a single-session ECT. Materials and methods. A systematic search of various bibliographic databases was performed and nine studies eligible for this study were extracted. Different statistical methods including meta-analysis were applied to analyze the data. Results. The results of analysis based on data from 1466 tumors of any histotype show significantly lower effectiveness of ECT on tumors with maximal diameter equal to or larger than 3 cm (complete response (CR) of 33.3%, objective response (OR) of 68.2%) in comparison to smaller tumors (CR% of 59.5%, OR% of 85.7%). The results of meta-analysis indicated that ECT performed on tumors smaller than 3 cm statistically significantly increases the probability of CR by 31.0% and OR by 24.9% on average in comparison to larger tumors. The analysis of raw data about the size and response of tumors showed statistically significant decrease in effectiveness of ECT progressively with increasing tumor diameter. The biggest drop in CR% was detected at tumor diameters as small as 2 cm. Conclusions. The standard operating procedures for ECT should be reexamined and refined for the treatment of large tumors. We propose that future clinical trials should include accurate ECT treatment planning and/or multiple ECT cycles, besides a prolonged observation for tumor response evaluation.

Intraoperative Electrochemotherapy of Colorectal Liver Metastases

Electrochemotherapy is effective in treatment of various cutaneous tumors and could be translated into treatment of deep‐seated tumors. With this aim a prospective pilot study was conducted to evaluate feasibility, safety, and efficacy of intraoperative electrochemotherapy in the treatment of colorectal liver metastases.

Effects of high voltage nanosecond electric pulses on eukaryotic cells (in vitro): A systematic review

For this systematic review, 203 published reports on effects of electroporation using nanosecond high-voltage electric pulses (nsEP) on eukaryotic cells (human, animal, plant) in vitro were analyzed. A field synopsis summarizes current published data in the field with respect to publication year, cell types, exposure configuration, and pulse duration. Published data were analyzed for effects observed in eight main target areas (plasma membrane, intracellular, apoptosis, calcium level and distribution, survival, nucleus, mitochondria, stress) and an additional 107 detailed outcomes. We statistically analyzed effects of nsEP with respect to three pulse duration groups: A: 1-10ns, B: 11-100ns and C: 101-999ns. The analysis confirmed that the plasma membrane is more affected with longer pulses than with short pulses, seen best in uptake of dye molecules after applying single pulses. Additionally, we have reviewed measurements of nsEP and evaluations of the electric fields to which cells were exposed in these reports, and we provide recommendations for assessing nanosecond pulsed electric field effects in electroporation studies.

The effect of electroporation pulses on functioning of the heart

Electrochemotherapy is an effective antitumor treatment currently applied to cutaneous and subcutaneous tumors. Electrochemotherapy of tumors located close to the heart could lead to adverse effects, especially if electroporation pulses were delivered within the vulnerable period of the heart or if they coincided with arrhythmias of some types. We examined the influence of electroporation pulses on functioning of the heart of human patients by analyzing the electrocardiogram. We found no pathological morphological changes in the electrocardiogram; however, we demonstrated a transient RR interval decrease after application of electroporation pulses. Although no adverse effects due to electroporation have been reported so far, the probability for complications could increase in treatment of internal tumors, in tumor ablation by irreversible electroporation, and when using pulses of longer durations. We evaluated the performance of our algorithm for synchronization of electroporation pulse delivery with electrocardiogram. The application of this algorithm in clinical electroporation would increase the level of safety for the patient and suitability of electroporation for use in anatomical locations presently not accessible to existing electroporation devices and electrodes.

Electrochemotherapy in non-melanoma head and neck cancers: a retrospective analysis of the treated cases.

Electrochemotherapy increases the permeability of tumours to drugs by electric voltages applied locally. Its value in tumours of the head and neck is unknown. We retrospectively reviewed a 2-centre database, and found 39 patients with squamous cell carcinoma (SCC) of the oral cavity or oropharynx (n=12) or non-melanoma skin tumours (n=27) who had been treated with bleomycin electrochemotherapy with needle electrodes. A further 3 patients were given cisplatin electrochemotherapy (n=2), or bleomycin electrochemotherapy by plate electrodes (n=1). Local toxicity was mild. The complete response rate was 38% and was associated with whether the tumour was primary or recurrent (p<0.001), its size (p=0.02), and the route by which the drug was given (p=0.02). We did not study enough patients with basal cell carcinomas to say whether the response was significantly better or not (p=0.07). Skin tumours and SCC of the oral cavity or oropharynx showed comparable complete responses (41% and 33%, p=0.73) and local control (1-year local progression-free survival, 51% compared with 59%, p=0.89), particularly if they were small (p=0.001), primary (p=0.002), chemonaive (p=0.03). Patients treated with cisplatin were unresponsive. Electrochemotherapy with bleomycin is an effective option for skin tumours of the head and neck and is a feasible alternative in highly selected (small, primary, and not previously treated by chemotherapy) SCC of the oral cavity and oropharynx.

Electrochemotherapy of colorectal liver metastases--an observational study of its effects on the electrocardiogram.

BackgroundElectrochemotherapy (ECT) is a combined treatment in which high voltage electroporation (EP) pulses are used to facilitate the uptake of a chemotherapeutic drug into tumor cells, thus increasing antitumor effectiveness of the drug. The effect of ECT of deep-seated tumors located close to the heart on functioning of the heart has not been previously investigated. In this study, we investigate the effects of intra-abdominal ECT of colorectal liver metastases on functioning of the heart during the early post-operative care period.MethodsFor ECT high voltage EP pulses with amplitudes of up to 3000 V and 30 A were delivered in synchronization with electrical activity of the heart. Holter electrocardiographic (ECG) signals were obtained from 10 patients with colorectal liver metastases treated with ECT. ECG was recorded during the periods of 24 hours before and after the surgical procedure involving ECT. Four-hour long night-time ECG segments from both periods exhibiting the highest level of signal stationarity were analyzed and compared. Changes in several ECG and heart rate variability (HRV) parameters were evaluated.ResultsNo major heart rhythm changes (i.e., induction of extrasystoles, ventricular tachycardia or fibrillation) or pathological morphological changes (i.e., ST segment changes) indicating myocardial ischemia were found. However, we found several minor statistically significant but clinically irrelevant changes in HRV parameters after ECT procedures: a decrease in median values of the mean NN interval, a decrease in the low-frequency and in the normalized low-frequency component, and an increase in the normalized high-frequency component.ConclusionsOnly minor effects of intra-abdominal ECT treatment on functioning of the heart were found. They were expressed as statistically significant but clinically irrelevant changes in heart rate and long-term HRV parameters and were as such not life-threatening to the patients. The nature of these changes is such that they can be attributed to the known effects of the drugs given to the patients in the post-operative care. Further investigation is still warranted to unambiguously resolve whether ECT with high voltage EP pulses applied in immediate vicinity of the heart is responsible for the observed effects.

An algorithm for synchronization of in vivo electroporation with ECG

The combined treatment of tumours in which delivery of a chemotherapeutic agent is followed by high voltage electroporation pulses has been termed electrochemotherapy. The electrochemotherapy of tumours located relatively close to the heart muscle can lead to fibrillation of the heart, especially if electroporation pulses are delivered in the vulnerable period of the heart or in coincidence with heart arrhythmias. We built an electroporation pulse delivery algorithm that enables safer use of electrochemotherapy. The algorithm is designed to deliver pulses outside the vulnerable period and to prevent pulses from being generated in the presence of heart arrhythmias. We evaluated the algorithms performance using records of the Long-Term ST Database, thus simulating real-world conditions. The results of the evaluation, a sensitivity of 91.751%, a positive predictivity of 100.000% and a delivery error rate of 8.268% for electroporation pulse delivery (medians), suggest that the algorithm is accurate and appropriate for application in electrochemotherapy of tumours regardless of tumour location.