Anti-tumor electrochemotherapy, which consists in increasing anti-cancer drug uptake by means of electroporation, is now implanted in about 140 cancer treatment centers in Europe. Its use is ...supported by the English National Institute for Health and Care Excellence for the palliative treatment of skin metastases, and about 13,000 cancer patients were treated by this technology by the end of 2015. Efforts are now focused on turning this local anti-tumor treatment into a systemic one. Electrogenetherapy, that is the electroporation-mediated transfer of therapeutic genes, is currently under clinical evaluation and has brought excitement to enlarge the anti-cancer armamentarium. Among the promising electrogenetherapy strategies, DNA vaccination and cytokine-based immunotherapy aim at stimulating anti-tumor immunity. We review here the interests and state of development of both electrochemotherapy and electrogenetherapy. We then emphasize the potent beneficial outcome of the combination of electrochemotherapy with immunotherapy, such as immune checkpoint inhibitors or strategies based on electrogenetherapy, to simultaneously achieve excellent local debulking anti-tumor responses and systemic anti-metastatic effects.
Summary
Reasons for performing study: Sarcoids are the commonest form of equine skin tumour. Several therapeutic measures have been described but none is considered to be universally effective. ...Electrochemotherapy (ECT) is a new anticancer therapy that utilises electrical field pulses to induce increased cell membrane permeability to antitumour hydrophilic drugs, such as cisplatin. The increased intracellular concentration of the drugs has a significant therapeutic benefit. The procedure has not been previously reported in a large number of horses.
Objective: To validate ECT as a novel alternative treatment for equine sarcoids.
Methods: A retrospective study evaluating the efficacy of cisplatin ECT in the treatment of equine sarcoids was performed. Electrochemotherapy treatments were applied under general anaesthesia at 2 week intervals with or without prior excision or debulking. Electric pulses were directly applied to the lesions following intra‐tumoural injections of an aqueous solution of cisplatin.
Results: One‐hundred‐and‐ninety‐four sarcoids on 34 horses, 2 ponies, 11 donkeys and one mule were treated with ECT. The 4 year nonrecurrence rate was 97.9% for animals (47/48) and 99.5% (193/194) for tumours. When ECT was used as a single treatment, a significant influence of tumour size (ρ= 0.55) on the number of treatments required for cure was shown. When prior surgery was performed, there was a significant influence (P<0.001) of the excision quality (complete or incomplete) and the healing mode (closed or open wound) on the number of treatments. The most common adverse effect was a slight oedematous reaction for lesions located on thin skin regions.
Conclusion and clinical relevance: Results demonstrate that ECT, with or without concurrent tumour debulking, is an effective alternative for treatment of equine sarcoids.
Background
Following induction chemotherapy, both resection or irreversible electroporation (IRE) may further improve survival in patients with locally advanced pancreatic cancer (LAPC). However, ...prospective studies combining these strategies are currently lacking, and available studies only report on subgroups that completed treatment. This study aimed to determine the applicability and outcomes of resection and IRE in patients with nonprogressive LAPC after induction chemotherapy.
Methods
This was a prospective, single-center cohort study in consecutive patients with LAPC (September 2013 to March 2015). All patients were offered 3 months of induction chemotherapy (FOLFIRINOX or gemcitabine depending on performance status), followed by exploratory laparotomy for resection or IRE in patients with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 nonprogressive, IRE-eligible tumors.
Results
Of 132 patients with LAPC, 70% (
n
= 93) started with chemotherapy (46%
n
= 61 FOLFIRINOX). After 3 months, 59 patients (64%) had nonprogressive disease, of whom 36 (27% of the entire cohort) underwent explorative laparotomy, resulting in 14 resections (11% of the entire cohort, 39% of the explored patients) and 15 IREs (11% of the entire cohort, 42% of the explored patients). After laparotomy, 44% (
n
= 16) of patients had Clavien–Dindo grade 3 or higher complications, and 90-day all-cause mortality was 11% (
n
= 4). With a median follow-up of 24 months, median overall survival after resection, IRE, and for all patients with nonprogressive disease without resection/IRE (
n
= 30) was 34, 16, and 15 months, respectively. The resection rate in 61 patients receiving FOLFIRINOX treatment was 20%.
Conclusion
Induction chemotherapy followed by IRE or resection in nonprogressive LAPC led to resection or IRE in 22% of all-comers, with promising survival rates after resection but no apparent benefit of IRE, despite considerable morbidity. Registered at Netherlands Trial Register (NTR4230).
Electrochemotherapy is a novel, locoregional therapy that is used to treat cutaneous and deep-seated tumors. The electric pulses used in electrochemotherapy increase the permeability of the cell ...membranes of the target lesion and thus enhance the delivery of low-permeant cytotoxic drugs to the cells, leading to their death. It has also been postulated that electrochemotherapy acts as an
vaccination by inducing immunogenic cell death. This in turn leads to an enhanced systemic antitumor response, which could be further exploited by immunotherapy. However, only a few clinical studies have investigated the role of combined treatment in patients with melanoma, breast cancer, hepatocellular carcinoma, and cutaneous squamous cell carcinoma. In this review, we therefore aim to review the published preclinical evidence on combined treatment and to review clinical studies that have investigated the combined role of electrochemotherapy and immunotherapy.
Hundreds of high frequency bipolar pulse bursts with ∼1 μs have been suggested to alleviate muscle contractions and pain during the irreversible electroporation (IRE) tumor treatment. This study is ...performed to verify whether eight bursts of high frequency reversible electroporation pulses (HFREs) with bleomycin could be used for electrochemotherapy (ECT) tumor treatment. Firstly, in vitro experiments on B16 cells are performed to determine the cytotoxicity of the HFREs with bleomycin. The result indicates that the protocol of HFREs with bleomycin has a significant killing effect compared with only bleomycin, in which the used HFRE pulses are set to induce high membrane permeabilization while maintaining high cell viability. The immunogenic cell death (ICD) that generates danger associated molecular patterns (DAMPs) could trigger an adaptive immune response against tumors. We demonstrated that HFREs with bleomycin could trigger the hallmarks of ICD with obvious up-regulation of DAMPs, including ATP, HMGB1, and CRT. The ICD process may begin at 3 h but perform at 6 h after HFREs with bleomycin stimulation. The in vivo experiment on mice tumor treatment also showed that the protocol of HFREs with bleomycin could inhibit tumor growth with more cytotoxic CD8+ T cells infiltration. The results obtained from in vitro and in vitro experiments preliminary confirmed that the HFREs with bleomycin could be used for ECT tumor treatment associated with the hallmarks of ICD and preliminary trigger the adaptive immune response.
Basal cell carcinoma (BCC) are the commonest cutaneous malignancy and incidence continues to increase. There is a need to expand the therapeutic toolbox to increase options for patients that are ...unsuitable for or unwilling to undergo the current therapies.
Electrochemotherapy (ECT) is a technique where cells are temporarily permeabilized after exposure to a brief pulsed electrical field and combined with low dose chemotherapeutics to ablate malignancies. It is a simple technique causing minimal damage to the surrounding healthy tissue and has the potential to avoid the need for complex reconstruction. ECT is an established treatment for skin metastases but its role as a primary treatment modality is not demonstrated.
A prospective randomised control trial evaluating ECT against the gold standard of treatment, Surgery, was performed for patients with primary BCC and patients followed for 5 years. All lesions treated with ECT (n = 69) responded although 8/69 (12%) needed a second treatment to ensure a complete response. All surgical lesions (n = 48) showed histological evidence of complete excision with 2/48 (4%) undergoing a second excision. At 5 years, in the surgical arm there was no evidence of recurrence in 39/40 (97.5%) lesions with 1/40 (2.5%) confirmed recurrence. In the ECT arm there was no evidence of recurrence in 42/48 lesions (87.5%). There was 5 confirmed recurrences. These groups show statistical equivalence in this non inferiority study design (p = 0.33).
ECT is an effective and durable treatment option for primary BCC and should be considered as part of the armamentarium of options available.
The role of electrochemotherapy (ECT) using intratumoral bleomycin and electroporation as a first line treatment for oral tongue carcinoma has not been defined.
To evaluate the method of ECT in oral ...tongue carcinoma.
Twenty-one successive patients with primary T1-T2 oral cancer predominantly of the oral tongue underwent either ECT (test; n = 9), or standard surgical resection and reconstruction (control; n = 12). Outcome variables were: local recurrence rates, 10-year-survival, adverse events, treatment cost, and quality of life.
The 10-year local recurrence rate (44.4%) was higher and the tumour-specific survival rate (55.6%) was lower in the ECT group compared to the control group (17% and 91.6%, respectively). Postoperative haemorrhage, dysphagia, and pain were more frequent in ECT patients, treatment time was shorter, but treatment cost was higher. Quality of life was not improved by ECT.
Our results indicate that ECT seems not as suitable for the treatment of early tongue cancer as it is for neoplastic and metastatic skin lesions and less favourable than standard surgical therapy.
Abstract Background Cutaneous 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. Methods This 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). Results We 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 1,304 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). Conclusions ECT 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.
The effectiveness of electrochemotherapy of tumors (ECT) and of irreversible electroporation ablation (IRE) depends on different mechanisms and delivery protocols. Both therapies exploit the ...phenomenon of electroporation of the cell membrane achieved by the exposure of the cells to a series of high-voltage electric pulses. Electroporation can be fine-tuned to be either reversible or irreversible, causing the cells to either survive the exposure (in ECT) or not (in IRE), respectively. For treatment of tissues located close to the heart (e.g., in the liver), the safety of electroporation-based therapies is ensured by synchronizing the electric pulses with the electrocardiogram. However, the use of ECT and IRE remains contraindicated for patients with implanted cardiac pacemakers if the treated tissues are located close to the heart or the pacemaker. In this study, two questions are addressed: can the electroporation pulses interfere with the pacemaker; and, can the metallic housing of the pacemaker modify the distribution of electric field in the tissue sufficiently to affect the effectiveness and safety of the therapy?
The electroporation pulses induced significant changes in the pacemaker ventricular pacing pulse only for the electroporation pulses delivered during the pacing pulse itself. No residual effects were observed on the pacing pulses following the electroporation pulses for all tested experimental conditions. The results of numerical modeling indicate that the presence of metal-encased pacemaker in immediate vicinity of the treatment zone should not impair the intended effectiveness of ECT or IRE even when the casing is in direct contact with one of the active electrodes. Nevertheless, the contact between the casing and the active electrode should be avoided due to significant tissue heating at the site of the other active electrode for the IRE protocol and may cause the pulse generator to fail to deliver the pulses due to excessive current draw.
The observed effects of electroporation pulses delivered in close vicinity of the pacemaker or its electrodes do not indicate adverse consequences for either the function of the pacemaker or the treatment outcome. These findings should contribute to making electroporation-based treatments accessible also to patients with implanted cardiac pacemakers.
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