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Campana, L.G.; Daud, A.; Lancellotti, F.; Arroyo, J.P.; Davalos, R.V.; Di Prata, C.; Gehl, J. Irreversible Electroporation in Oncology. Encyclopedia. Available online: https://encyclopedia.pub/entry/46162 (accessed on 12 August 2024).
Campana LG, Daud A, Lancellotti F, Arroyo JP, Davalos RV, Di Prata C, et al. Irreversible Electroporation in Oncology. Encyclopedia. Available at: https://encyclopedia.pub/entry/46162. Accessed August 12, 2024.
Campana, Luca G., Adil Daud, Francesco Lancellotti, Julio P. Arroyo, Rafael V. Davalos, Claudia Di Prata, Julie Gehl. "Irreversible Electroporation in Oncology" Encyclopedia, https://encyclopedia.pub/entry/46162 (accessed August 12, 2024).
Campana, L.G., Daud, A., Lancellotti, F., Arroyo, J.P., Davalos, R.V., Di Prata, C., & Gehl, J. (2023, June 28). Irreversible Electroporation in Oncology. In Encyclopedia. https://encyclopedia.pub/entry/46162
Campana, Luca G., et al. "Irreversible Electroporation in Oncology." Encyclopedia. Web. 28 June, 2023.
Irreversible Electroporation in Oncology
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15133340

Locoregional therapies play an ever-increasing role in contemporary oncology. Researchers provide an up-to-date, informed analysis of locoregional therapies harnessing electric pulses. Irreversible electroporation (IRE), gene electrotransfer (GET), electrochemotherapy (ECT), calcium electroporation (Ca-EP), and tumour-treating fields (TTF) are integral to the therapeutic strategy in several solid tumours, ranging from skin cancers to visceral and bone metastases.

cancer electroporation irreversible electroporation gene electrotransfer electrochemotherapy

1. Principles of IRE

EP is a biophysical phenomenon in which nanoscale defects or “nanopores” are generated on the cell plasma membrane when exposed to an external electric field. By increasing cell transmembrane potential beyond a critical threshold of ~0.2–1 V, the lipid molecules along the phospholipid bilayer shift, creating temporary hydrophilic openings [1][2][3][4]. Transient membrane disruption (reversible EP) was initially designed for delivering chemotherapeutics [5] and gene therapies [1]; however, protracted or permanent nanopore formation leads to cell death. This phenomenon, called IRE, was previously an unwanted consequence of applying strong electric fields for biomedical applications. The cell death caused by IRE occurs without significant thermal heating or subsequent damage [6]. This initial theory was validated the following year through an in vivo rat study demonstrating IRE’s capability to produce a sizeable soft tissue ablation while effectively minimising thermal heating [7]. This ablation modality has been shown to spare surrounding nerve fibres [8] and extracellular matrices and minimise the heat sink effect [9], a phenomenon that hinders the effectiveness of other treatment modalities when the target lesion is in close proximity (<1 cm) to a large vessel (≥3 mm in diameter); the flowing blood, in fact, causes a cooling effect, which reduces the actual ablation volume.
Multiple in vivo studies have investigated the efficacy of IRE in the prostate [10], pancreas [11], liver [7][12][13], lung [14], kidney [15][16], breast [17], skin [18], heart [19], and brain [20]. Importantly, preclinical studies clarified important operational aspects, such as the need for neuromuscular blocking to reduce muscle contractions caused by electrical stimulation and ECG synchronisation to prevent the induction of cardiac arrhythmias. Clinically, IRE is delivered using needle electrodes inserted into the target lesion under ultrasound (US) or computed tomography (CT) guidance with the patient under general anaesthesia. Two to six monopolar needle electrodes are inserted depending on tumour size (generally between 1.0 and 5.0 cm) and anatomical location. Hence, the patient receives 60–100 high voltage (1.5–3 kV) bursts of 80–100 µs duration between the electrodes [21]. These pulses disrupt cell homeostasis, leading to necrosis, apoptosis, and autophagy within 8–24 h [22].
At the time of writing, there are more than sixty completed and ongoing clinical trials with IRE [23]. Researchers focused on studies conducted over the last five years and includes some of the most recent clinical experiences, whereas Aycock et al. reviewed earlier studies [21]. From a practical standpoint, since the IRE application has high requirements for needle electrode insertion and parameter settings, a suboptimal procedure (e.g., incomplete coverage of the target volume) can affect the treatment outcome (e.g., incomplete response or local recurrence). Therefore, it is imperative to standardise the operative procedures, concentrate treatments at referral centres, and establish shared treatment indications/contraindications and management schedules within a multidisciplinary team.

2. Prostate Cancer

Radical prostatectomy or external beam radiotherapy is the standard of care in prostate cancer. However, these modalities are associated with side effects such as incontinence, urgency, and erectile dysfunction [24]. IRE can potentially reduce this risk by selectively targeting the tumour while sparing the surrounding tissues. Interestingly, a recent randomised trial with 106 patients has shown that focal (i.e., on the area of the prostate with positive biopsy cores) IRE ablation has similar short-term oncological outcomes and superior QoL to extended (i.e., zonal ablation) IRE [25].
Encouraging results also come from a mono-institutional study in Sydney with 229 patients with a median follow-up of 60 months following IRE. Participants were assessed at six months with magnetic resonance imaging (MRI) and at 12 months with transperineal biopsies. The six-month MRI showed eradication in 82% of patients, whereas residual clinically significant disease was found in 24% of patients in the one-year follow-up biopsy. Overall, 38 patients (17%) progressed to radical treatment at a median of 35 months after IRE [26].
Various experiences support the notion that patients treated with IRE for prostate cancer witness decreased prostate-specific antigen (PSA) levels and experience a better QoL [27][28][29]. In addition, rare posttreatment complications include urinary strictures [30][31], dysuria, haematuria, urinary tract infections, urgency [28][29][31], and erectile dysfunction [28][29][30][31]. Notably, complications commonly occurring with traditional procedures, such as urinary incontinence and erectile dysfunction, are drastically reduced when utilising IRE with a rate of 100% patient continence and 97% patient potency [32].
In addition to its use in primary prostate cancer, IRE has been used as a salvage treatment for local recurrences after radiotherapy [30]. A recently published mono-institutional study with 74 patients provides convincing data towards IRE’s short- to mid-term safety, oncological, and QoL outcomes in this setting. After a median follow-up of 48 months, local control was achieved in 57 patients (77%). Among patients who returned QoL questionnaires, 93% had preserved urinary continence, and 23% had sustained erectile function. Complications included one rectal fistula, whereas urethral sloughing occurred in eight cases and required transurethral resection [33]. This complication is likely due to unintentional tissue heating when rapidly delivering an electric current to previously irradiated fibrotic tissue. Similar results have been shown in the two-centre prospective focal IRE (FIRE) trial [34].
Interestingly, various imaging modalities have been utilised to assess tumour response, such as multiparametric MRI (mpMRI) [35], contrast-enhanced ultrasound (CEUS) [36], and prostate-specific membrane antigen (PSMA) positron emission tomography—CT (PET-CT) [37]. Nevertheless, tissue biopsy remains the gold standard for accurately evaluating tumour response or recurrence. Finally, imaging modalities used in conjunction with IRE, such as the MRI-transrectal US fusion-guided IRE, provide novel opportunities to increase the accuracy of treatment delivery [38].

3. Pancreatic Cancer

IRE’s role in the treatment of pancreatic ductal adenocarcinoma (PDAC) is versatile [39]. Unfortunately, only a minority of these patients are candidates for surgical resection due to locally advanced disease (locally advanced pancreatic cancer [LAPC]). In this highly challenging scenario, IRE may be an option. Most published literature on IRE in PDAC is on stage III/IV LAPC, whereby the role is palliative, including local tumour control and pain management [40][41][42][43].
Additionally, and interestingly, IRE can be used as a consolidative treatment following chemotherapy or chemoradiotherapy; alternatively, it can be an adjunct to surgery in patients with borderline resectable disease [44]; finally, it can be used in the control of local recurrence after previous curative surgery or palliation in patients unfit for surgery or chemotherapy [45][46]. A recent clinical trial from Eastern Asia involving 74 patients treated with induction chemotherapy and IRE during open surgery at 11 centres reported a 5-year progression-free survival (PFS) rate and a 5-year overall survival (OS) rate of 28.8% and 31.2%, respectively. The authors observed 30 complications that occurred in 13 (17.6%) patients, which were primarily associated with the direction of electrode placement and gastrointestinal disease infiltration. In multivariate analysis, the type of chemotherapy regimen was the only significant factor associated with PFS and OS [47]. Other studies investigated the efficacy of IRE and chemotherapy versus standard-of-care treatments such as chemotherapy alone [48] or the combination of induction chemotherapy and radiation [44] in patients with LAPC. These trials indicated improved PFS and OS for the combination of IRE and chemotherapy. Interestingly, the PANFIRE phase II trial aimed to deliver IRE percutaneously, thus avoiding the necessity for laparotomic surgery. Median OS was 17 months, regardless of induction chemotherapy [49].
Concerning the modality of IRE application, it is worth noting that clinicians have utilised this technique to treat surgical resection margins to target residual microscopic disease [50]. Thus, IRE is an attractive tool for the so-called “margin accentuation” (MA) near the superior mesenteric artery, celiac trunk, superior mesenteric vein, and portal vein to achieve lower rates of positive margins. This approach is generally directed towards three critical anatomical areas, i.e., pancreas neck margin, superior mesenteric/portal vein margin, and superior mesenteric artery margin [51]. The initial use of IRE for MA (MA-IRE) was published by Kwon et al. using two IRE electrodes in bracketing and parallel to the vascular structure (artery or vein, or both) to enhance the resection margin [41]. There are few reports of intraoperative IRE and margin accentuation followed by pancreaticoduodenectomy in borderline resectable pancreatic cancer (BRPC), suggesting a significant role in reducing the risk of local recurrence and improving survival [40][52]. Martin et al. enrolled 200 patients with LAPC who underwent IRE alone (n = 150) or surgery plus IRE on resection margins (n = 50). All patients received induction chemotherapy, and 52% received chemoradiation therapy before IRE. Thirty-seven per cent of patients suffered from complications, with a median grade of 2 (range, 1–5). The median length of hospital stay was six days. With a median follow-up of 29 months, six patients (3%) experienced local recurrence; of note, the median OS was 28.3 months in the surgery-IRE group and 23.2 months in the IRE group. These results support that adding IRE to conventional chemotherapy and radiation therapy prolongs survival compared with historical controls [40]. Martin et al. investigated the rates of local recurrence and margin positivity in patients with BRPC who underwent pancreatectomy with (n = 75) or without (n = 71) IRE-MA using a prospective database. It is showed that IRE-MA can be performed safely and effectively. In particular, local recurrence rates and disease-free intervals were similar between groups. Finally, the IRE-MA group’s OS was significantly higher than the pancreatectomy-alone group [53]. Kundalia et al. evaluated the margins positivity rate of IRE-MA in pancreatic head tumours and compared disease-free survival (DFS) and OS with a retrospective control group. They reported a trend towards reduced margin positivity (from 51.6% in the control group to 35.0% in the IRE-MA cohort) and no significant differences in OS and DFS.
Notably, using IRE for MA is not associated with increased postoperative complications [51]. Numerous studies have reported on the safety and feasibility of IRE [47][49][54]. The main treatment-related adverse events include complications to the pancreas (pancreatitis, fistula, abscess), liver (bile leak, biliary peritonitis, cholangitis, abscess), bowel (ileus, perforation, bleeding, fistula), vessels (pseudo-aneurysm, hepatic arterial thrombosis, non-occlusive superior mesenteric vein/portal vein thrombosis), and spleen (infarction). Although rare, patients may suffer from multiple types of complications. In the largest series, all-grade morbidity is in the range of 36–40% [40][53]. Therefore, weighing trade-offs between benefits and harms is imperative. To date, the optimal timing and patient selection criteria for IRE remain debated. The recent analysis of a multicentre database with 187 LAPC patients treated with induction chemotherapy followed by open IRE has suggested patient age, serum CA 19-9, no previous irradiation, and induction chemotherapy with FOLFIRINOX-gemcitabine/abraxane as possible selection criteria [55].

4. Liver Malignancies

Managing hepatic malignancies, even when localised, is challenging due to the frequent association with parenchymal disease and complex anatomy [56]. By sparing the structural framework of adjacent vessels and tissues while inducing apoptosis in the targeted cells, IRE allows treating tumours adjacent to critical structures whose critical location represents an exclusion criterion from other ablative treatments [57]. IRE is a valuable option for tumours near the hepatic artery and hepatic hilum in this setting. A recent analysis by Gupta et al., including 25 studies in patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), or colorectal cancer liver metastasis (CRLM), indicates a collective 3-year PFS of 49% and 3-year OS of 41%, with better outcomes in the HCC subgroup [58].

4.1. Primary Liver Cancers

According to a single-centre retrospective analysis, IRE has efficacy in treating early-stage HCC not amenable to standard ablative techniques, with an excellent complete response (CR) rate and long-term local control, particularly in small lesions. 23 patients received IRE for 33 HCC with a median 2.0 cm tumour size. Twenty-nine (87.9%) tumours were ablated after one (n = 26) or two (n = 3) procedures. The median local-recurrence-free survival was 34.5 months [59].

4.2. Liver Metastases

IRE’s ability to specifically treat CRLM was demonstrated in COLDFIRE-1, an ablate-and-resect study [60], and COLDFIRE-2 [61], a phase II open-label clinical trial. As a result, the latest multidisciplinary consensus guidelines recommend IRE use for perihilar or perivascular CRLM [62]. In particular, IRE is recommended for 3–5 cm tumours when additional systemic therapy is not viable. The safety of IRE within 1.0 cm from critical structures is evident. Additionally, the procedure is efficacious even for tumours abutting or encasing large high-flow vascular structures such as the portal vein and hepatic arteries [63][64]. Other typical applications of IRE are tumour ablation near bile ducts, the gallbladder, or the bowel [65][66][67]. The evidence suggests superior results in lesions ≤3 cm in size [59][64]. Postoperative complication rates after IRE are comparable to that of radiofrequency ablation (RFA) and microwave ablation (MWA) [68]. The most common major complication is a liver abscess, whose incidence correlates with the presence of bilioenteric anastomosis [69]; subcapsular hematoma or need for laparotomy due to haemorrhage, arterioportal fistula, bile leak, post-procedure biliary strictures, and post-IRE liver failure occur rarely. As IRE is typically reserved for patients who are not RFA or MWA candidates, a direct, matched, and unbiased comparison between IRE and thermal ablation is not feasible. Additionally, a direct comparison between IRE, surgery, and stereotactic body radiation therapy is impossible.
Additionally, most participants in IRE clinical trials have been heavily pre-treated; therefore, comparing overall survival rates with other techniques carries an inherent bias. Finally, as patients underwent several other anti-cancer interventions before and after IRE, no PFS or OS outcomes can be attributed solely to this intervention. In the COLDFIRE-2 trial, 51 patients with CRLM up to 5 cm underwent IRE during either an open or percutaneous procedure. The per-patient 1-year local PFS was 68%. Following repeat procedures, local control was achieved in 74% of participants. A total of 23 patients experienced 34 adverse events (complication rate, 40%) [61]. A range of complications can occur when delivering IRE to the liver. These vary from minor side effects such as mild pain and fever [70] to major complications such as hydrothorax [70], pneumothorax, and brachial plexus injuries [71]. The overall complication rate is 23.7% from collective data, with severe adverse events arising in 6.9% of cases [58].

5. Localised Renal Cell Carcinoma

While the standard of care for localised renal cell carcinoma is partial nephrectomy, professional societies increasingly accept alternative strategies thanks to low complication rates and comparable oncologic outcomes [72]. Percutaneous ablation is particularly attractive in patients with significant comorbidities, renal impairment, old age, recurrent and multiple hereditary renal cell carcinomas or those unwilling to undergo surgery [73]. Although the experience with IRE is limited compared with traditional ablative modalities, this technique has the potential to overcome limitations of thermal ablation, enabling the ablation of small renal masses near vital structures. The procedure has proved feasible and safe [74], although short- and mid-term oncological outcomes appear inferior to other treatments due to residual microscopic disease leading to local recurrence [75]. In fact, according to a 2017 review of 41 patients, the 2-year local-recurrence-free survival was 83% [76], and another retrospective analysis of 47 patients published in 2019 reported a 5-year local-recurrence-free survival of 81.4% [77]. The early operator’s learning curve may partially explain suboptimal results, and more recent series indicate improved oncological durability [78].

6. Research Directions—IRE

6.1. Gastrointestinal Tract

Upper gastrointestinal tract malignancies have only recently been treated with IRE. In this setting, specifically designed catheter electrodes have been designed that are suitable for coupling with an endoscope to allow visualisation and avoid hollow viscus perforation. A recent study used a finite element analysis of the digestive tract to simulate the effects of electric fields and thermal dispersions emitted from different catheter configurations to assist with treatment planning [79]. Furthermore, Jeon et al. investigated catheter-based IRE within in vivo pig models to identify upper threshold voltage limits in the oesophagus, stomach, and duodenum [80]. It is revealed that potential complications from intense electrical fields in these tissues, such as perforation and bleeding, as the critical voltage required the production of an ablative effect. Despite the launch in 2015 of a clinical trial on IRE in patients with unresectable oesophageal cancer, no results have been reported so far [81].

6.2. Immune Effect and Combined Strategies

Beyond ablation, IRE induces an immune response. The initial cell death is followed by the release of damage-associated molecular patterns (DAMPS), which stimulate the antigen-presenting cells (APC). These, in turn, migrate to the regional lymph nodes, where they stimulate an antitumour response by priming T cells [82][83]. This effect of IRE—called immunogenic cell death (ICD), has the potential to elicit a systemic immune response and produce the abscopal effect, where off-target tumours are recognised and targeted by the adaptive immune response [84]. In this regard, IRE, similar to other local therapies [85], acts as an “in situ” vaccination to elicit a systemic immune response [86][87]. Several studies have investigated the immunomodulatory effect of IRE. Interestingly, IRE has been shown to eliminate PD-L1-positive tumour cells, which have an inhibitory effect on PD-1-positive lymphocytes [50]. Furthermore, a sharp decrease in regulatory T cells (Tregs), which inhibit cytotoxic T cells and dendritic cells, has been shown [88][89]. Taken together, these effects promote immune cell infiltration and the activation of the antitumour immune response.
Conversely, there is evidence that the increase in IFN-γ produced by the immune infiltrate may increase PD-L1 expression in the residual tumour cells [90]. This highlights the importance of achieving complete tumour ablation and associating other (immune)therapies to achieve an effective immune response. Tracking immune cell subpopulations in the tumour microenvironment following IRE has opened exciting opportunities for the association with immunotherapy. For example, two clinical studies using patients with LAPC investigated PD-1 immune checkpoint inhibition to prevent the remaining tumour cells from suppressing the antitumour response [90][91]. Of note, anti-PD-1 immunotherapy was associated with a significant increase in OS and PFS compared with IRE alone (44 vs. 23 months and 27 months vs. 10 months, respectively [91]. In another clinical study, researchers administered allogenic, cytotoxic immune cells (i.e., Vγ9Vδ2 T cells) [92] or allogenic natural killer (NK) cells [93] in combination with IRE. In murine models, stimulator of interferon genes (STING) agonists have shown efficacy as an adjuvant due to their ability to increase IFN-γ production from the tumour, which, together with DAMPs, stimulates APC maturation [94][95]. While, encouragingly, this effect may promote an abscopal effect, on the other side, it has been observed that post-IRE residual tumour cells may be more resistant due to the increased presence of IFN-γ. Finally, the use of multiple immunotherapies to assist in the various steps of the antitumour response has proven efficacious in the preclinical setting. For example, a study used a TLR7 agonist to stimulate the innate immune system in a murine model along with IRE and anti-PD-1 agents to generate a sustained immune response [86]. Similarly, Peng et al. demonstrated that combining IRE, anti-PD-1, and TGF-β inhibitors was more effective than any of them alone [96].

6.3. High-Frequency Irreversible Electroporation

Introduced in 2011 by Arena et al. [97], a second generation of IRE was developed to reduce electrochemical effects, enhance cell selectivity toward malignant cell types [98], mitigate nerve and muscle excitation, and negate the need for cardiac synchronisation [99] by delivering bursts of short, bipolar pulses (0.5–10 µs) into heterogeneous tissue. This new technology was coined ‘high-frequency irreversible electroporation’ (H-FIRE). Since its emergence, H-FIRE has been validated to treat malignancies in vivo within the breast [100], liver [101][102], and brain [103]. In rodent models, H-FIRE has been shown to cause significant blood–brain barrier disruption [104][105] and immune infiltration [100][103] when targeting various malignant, promising avenues for future combinatorial therapeutics with this ablation modality. H-FIRE has also shown efficacy in selectively treating myocardial tissue as a remedy for cardiac arrhythmias [106][107]. In 2018, an initial H-FIRE clinical study treated 40 prostate cancer patients without ECG synchronisation. Following six months post-treatment, all 40 patients sustained urinary function, and 14 of 14 patients maintained sexual potency [108]. A recent expansive clinical evaluation by Wang et al. [109] saw 109 prostate cancer patients pooled from four centres treated with H-FIRE and evaluated after six months. Of 100 patients who underwent a biopsy, 14 developed recurrences in the prostate, with six patients classified as having clinically significant prostate cancer (csPCa) (5 outside and one inside of the treatment zone). Compared with similar ablation modalities, the rate of residual csPCa was significantly lower, making H-FIRE a rising, competitive clinical therapeutic. Lastly, 98% of patients retained urinary function, with 9% of patients experiencing emergent sexual dysfunction at six months.

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Subjects: Oncology; Engineering, Electrical & Electronic
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Luca G. Campana
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Adil Daud
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Francesco Lancellotti
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Julio P. Arroyo
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Rafael V. Davalos
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Claudia Di Prata
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Julie Gehl
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