The beneficial effects of electrochemotherapy (ECT) for superficial tumours and, more recently, deep-seated malignancies in terms of local control and quality of life are widely accepted. However, ...the variability in responses across histotypes needs to be explored. Currently, patient selection for ECT is based on clinical factors (tumour size, histotype, and exposure to previous oncological treatments), whereas there are no biomarkers to predict the response to treatment. In this field, two major areas of investigation can be identified, i.e., tumour cell characteristics and the tumour microenvironment (vasculature, extracellular matrix, and immune infiltrate). For each of these areas, we describe the current knowledge and discuss how to foster further investigation. This review aims to provide a summary of the currently used guiding clinical factors and delineates a research roadmap for future studies to identify putative biomarkers of response to ECT. These biomarkers may allow researchers to improve ECT practice by customising treatment parameters, manipulating the tumour and its microenvironment, and exploring novel therapeutic combinations.
•Electrochemotherapy is widely accepted therapeutic approach in terms of local tumor control and quality of life.•Currently the patient selecton is based on clinical factors, tumor size, histotype and exposure to previous treatments.•Biomarkers to predict tumor response to electrochemotherapy are needed.•For identification of potential biomarkers research on tumor cell characteristics and tumor stroma is needed.•Knowledge of putative biomarkers could improve electrochemotherapy practice, customize the treatment parameters and explore novel therapeutic combinations.
The number of liver cancer patients is likely to continue to increase in the coming decades due to the aging of the population and changing risk factors. Traditional treatments cannot meet the needs ...of all patients. New treatment methods evolved from pulsed electric field ablation are expected to lead to breakthroughs in the treatment of liver cancer. This paper reviews the safety and efficacy of irreversible electroporation in clinical studies, the methods to detect and evaluate its ablation effect, the improvements in equipment and its antitumor effect, and animal and clinical trials on electrochemotherapy. We also summarize studies on the most novel nanosecond pulsed electric field ablation techniques
and
. These research results are certain to promote the progress of pulsed electric field in the treatment of liver cancer.
Objectives
We conducted an in vivo trial to investigate the safety and efficacy of a newly developed system for the application of a combined therapy consisting of irreversible electroporation (IRE) ...and electrochemotherapy (IRECT) in the liver. The system is conceived as a single-needle multitined applicator with expandable electrodes that allow interstitial injection of fluids, e.g., chemotherapy.
Methods
Experiments were conducted in ten domestic pigs. The applicator was placed in different liver lobes under CT guidance. In one lobe, the applicator was used for conventional IRE (1500 V, 120 pulses, pulse length 100 μs). In the other lobe, the same procedure was performed preceded by the injection of a doxorubicin mixture through the expandable electrodes (IRECT). Contrast-enhanced CT and MRI were performed on days 1, 3, and 7 after the procedure. Accordingly, three animals were sacrificed on days 1, 3, and 7 after the imaging and ablation volumes were evaluated histopathologically. Related
t
test was used to compare the groups.
Results
Technical success was achieved in 9/10 experiments. One animal deceased during the intervention because of ventricular fibrillation. Follow-up CT 1 and 3 days after intervention showed a significant (
p
< 0.05) difference in the ablation volumes of IRECT vs IRE, respectively, of 4.47 ± 1.78 ml vs 2.51 ± 0.93 ml and of 3.39 ± 1.05 vs 1.53 ± 0.78 ml.
Conclusions
IRECT using the newly developed system proved to be effective and provided significantly larger ablation volumes compared with IRE alone. However, ECG triggering is a necessary prerequisite to allow a safe application of the system.
Key Points
• Working on the geometry of the IRE applicator in terms of expandable electrodes may overcome the current limitations of IRE resulting from the placement of multiple electrodes.
• Efficacy of IRE ablations can be enhanced by the interstitial application of chemotherapy in the periphery of ablation areas.
Background
Electromotive drug administration (EMDA) is the use of electrical current to improve the delivery of intravesical agents to reduce the risk of recurrence in people with non‐muscle invasive ...bladder cancer (NMIBC). It is unclear how effective this is in comparison to other forms of intravesical therapy.
Objectives
To assess the effects of intravesical EMDA for the treatment of NMIBC.
Search methods
We performed a comprehensive search using multiple databases (CENTRAL, MEDLINE, EMBASE), two clinical trial registries and a grey literature repository. We searched reference lists of relevant publications and proceedings. We applied no language restrictions. The last search was February 2017.
Selection criteria
We searched for randomised studies comparing EMDA of any intravesical agent used to reduce bladder cancer recurrence in conjunction with transurethral resection of bladder tumour (TURBT).
Data collection and analysis
Two review authors independently screened the literature, extracted data, assessed risk of bias and rated quality of evidence (QoE) according to GRADE on a per outcome basis.
Main results
We included three trials with 672 participants that described five distinct comparisons. The same principal investigator conducted all three trials. All studies used mitomycin C (MMC) as the chemotherapeutic agent for EMDA.
1. Postoperative MMC‐EMDA induction versus postoperative Bacillus Calmette‐Guérin (BCG) induction: based on one study with 72 participants with carcinoma in situ (CIS) and concurrent pT1 urothelial carcinoma, we are uncertain (very low QoE) about the effect of MMC‐EMDA on time to recurrence (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.64 to 1.76; corresponding to 30 more per 1000 participants, 95% CI 180 fewer to 380 more). There was no disease progression in either treatment arm at three months' follow‐up. We are uncertain (very low QoE) about serious adverse events (RR 0.75, 95% CI 0.18 to 3.11).
2. Postoperative MMC‐EMDA induction versus MMC‐passive diffusion (PD) induction: based on one study with 72 participants with CIS and concurrent pT1 urothelial carcinoma, postoperative MMC‐EMDA may (low QoE) reduce disease recurrence (RR 0.65, 95% CI 0.44 to 0.98; corresponding to 147 fewer per 1000 participants, 95% CI 235 fewer to 8 fewer). There was no disease progression in either treatment arm at three months' follow‐up. We are uncertain (very low QoE) about the effect of MMC‐EMDA on serious adverse events (RR 1.50, 95% CI 0.27 to 8.45).
3. Postoperative MMC‐EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance: based on one study with 212 participants with pT1 urothelial carcinoma of the bladder with or without CIS, postoperative MMC‐EMDA with sequential BCG may result (low QoE) in a longer time to recurrence (hazard ratio (HR) 0.51, 95% CI 0.34 to 0.77; corresponding to 181 fewer per 1000 participants, 95% CI 256 fewer to 79 fewer) and time to progression (HR 0.36, 95% CI 0.17 to 0.75; corresponding to 63 fewer per 1000 participants, 95% CI 82 fewer to 24 fewer). We are uncertain (very low QoE) about the effect of MMC‐EMDA on serious adverse events (RR 1.02, 95% CI 0.21 to 4.94).
4. Single‐dose, preoperative MMC‐EMDA versus single‐dose, postoperative MMC‐PD: based on one study with 236 participants with primary pTa and pT1 urothelial carcinoma, preoperative MMC‐EMDA likely (moderate QoE) results in a longer time to recurrence (HR 0.47, 95% CI 0.32 to 0.69; corresponding to 247 fewer per 1000 participants, 95% CI 341 fewer to 130 fewer) for a median follow‐up of 86 months. We are uncertain (very low QoE) about the effect of MMC‐EMDA on time to progression (HR 0.81, 95% CI 0.00 to 259.93; corresponding to 34 fewer per 1000 participants, 95% CI 193 fewer to 807 more) and serious adverse events (RR 0.79, 95% CI 0.30 to 2.05).
5. Single‐dose, preoperative MMC‐EMDA versus TURBT alone: based on one study with 233 participants with primary pTa and pT1 urothelial carcinoma, preoperative MMC‐EMDA likely (moderate QoE) results in a longer time to recurrence (HR 0.40, 95% CI 0.28 to 0.57; corresponding to 304 fewer per 1000 participants, 95% CI 390 fewer to 198 fewer) for a median follow‐up of 86 months. We are uncertain (very low QoE) about the effect of MMC‐EMDA on time to progression (HR 0.74, 95% CI 0.00 to 247.93; corresponding to 49 fewer per 1000 participants, 95% CI 207 fewer to 793 more) or serious adverse events (HR 1.74, 95% CI 0.52 to 5.77).
Authors' conclusions
While the use of EMDA to administer intravesical MMC may result in a delay in time to recurrence in select patient populations, we are uncertain about its impact on serious adverse events in all settings. Common reasons for downgrading the QoE were study limitations and imprecision. A potential role for EMDA‐based administration of MMC may lie in settings where more established agents (such as BCG) are not available. In the setting of low or very low QoE for most comparisons, our confidence in the effect estimates is limited and the true effect sizes may be substantially different from those reported here.
A previous pilot study proved the feasibility, safety and efficacy of electrochemotherapy in the treatment of colorectal liver metastases. The aim of this study was to evaluate long-term ...effectiveness and safety of electrochemotherapy in the treatment of unresectable colorectal liver metastases.
In this prospective phase II study, patients with metachronous colorectal liver metastases were included. In all patients, at least one metastasis was unresectable due to its central location or a too-small future remnant liver volume. Patients were treated by electrochemotherapy using intravenously administered bleomycin during open surgery. Treated were 84 metastases in 39 patients. Local tumor control, progression-free survival and overall survival were evaluated.
The objective response was 75% (63% CR, 12% PR). The median duration of the response was 20.8 months for metastases in CR and 9.8 months for metastases in PR. The therapy was significantly more effective for metastases smaller than 3 cm in diameter than for larger ones. There was no difference in response according to the metastatic location, i.e., metastases in central vs. peripheral locations. Progression-free survival was better in patients who responded well to electrochemotherapy compared to those metastases that had a partial response or progressive disease. However, there was no difference in overall survival, with a median of 29.0 months.
Electrochemotherapy has proven to be safe and effective in the treatment of colorectal liver metastases, with a durable response. It provides local tumor control that enables patients with unresectable metastases to receive further treatments.
•The objective response of electrochemotherapy-treated colorectal liver metastases is 75%.•Electrochemotherapy is equally effective on metastases located either in the vicinity of or away from major liver blood vessels.•Metastases smaller than 3 cm respond better than larger ones.•The overall survival of the patients with unresectable colorectal liver metastases resistant to standard chemotherapy after electrochemotherapy was 29 months.
Irreversible electroporation (IRE) is a novel nonthermal ablation technique that has been used for the treatment of solid cancers. However, it has not been evaluated for use in brain tumors. Here, ...the authors report on the safety and feasibility of using the NanoKnife IRE system for the treatment of spontaneous intracranial gliomas in dogs.
Client-owned dogs with a telencephalic glioma shown on MRI were eligible. Dog-specific treatment plans were generated by using MRI-based tissue segmentation, volumetric meshing, and finite element modeling. After biopsy confirmation of glioma, IRE treatment was delivered stereotactically with the NanoKnife system using pulse parameters and electrode configurations derived from therapeutic plans. The primary end point was an evaluation of safety over the 14 days immediately after treatment. Follow-up was continued for 12 months or until death with serial physical, neurological, laboratory, and MRI examinations.
Seven dogs with glioma were treated. The mean age of the dogs was 9.3 ± 1.6 years, and the mean pretreatment tumor volume was 1.9 ± 1.4 cm(3). The median preoperative Karnofsky Performance Scale score was 70 (range 30-75). Severe posttreatment toxicity was observed in 2 of the 7 dogs; one developed fatal (Grade 5) aspiration pneumonia, and the other developed treatment-associated cerebral edema, which resulted in transient neurological deterioration. Results of posttreatment diagnostic imaging, tumor biopsies, and neurological examinations indicated that tumor ablation was achieved without significant direct neurotoxicity in 6 of the 7 dogs. The median 14-day post-IRE Karnofsky Performance Scale score of the 6 dogs that survived to discharge was 80 (range 60-90), and this score was improved over the pretreatment value in every case. Objective tumor responses were seen in 4 (80%) of 5 dogs with quantifiable target lesions. The median survival was 119 days (range 1 to > 940 days).
With the incorporation of additional therapeutic planning procedures, the NanoKnife system is a novel technology capable of controlled IRE ablation of telencephalic gliomas.
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.
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.
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).
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