Hester J. Scheffer

Irreversible Electroporation for Nonthermal Tumor Ablation in the Clinical Setting: A Systematic Review of Safety and Efficacy

PURPOSE To provide an overview of current clinical results of irreversible electroporation (IRE), a novel, nonthermal tumor ablation technique that uses electric pulses to induce cell death, while preserving structural integrity of bile ducts and vessels. METHODS All in-human literature on IRE reporting safety or efficacy or both was included. All adverse events were recorded. Tumor response on follow-up imaging from 3 months onward was evaluated. RESULTS In 16 studies, 221 patients had 325 tumors treated in liver (n = 129), pancreas (n = 69), kidney (n = 14), lung (n = 6), lesser pelvis (n = 1), and lymph node (n = 2). No major adverse events during IRE were reported. IRE caused only minor complications in the liver; however, three major complications were reported in the pancreas (bile leak [n = 2], portal vein thrombosis [n = 1]). Complete response at 3 months was 67%-100% for hepatic tumors (93%-100% for tumors o 3 cm). Pancreatic IRE combined with surgery led to prolonged survival compared with control patients (20 mo vs 13 mo) and significant pain reduction. CONCLUSIONS In cases where other techniques are unsuitable, IRE is a promising modality for the ablation of tumors near bile ducts and blood vessels. This articles gives an extensive overview of the available evidence, which is limited in terms of quality and quantity. With the limitations of the evidence in mind, IRE of central liver tumors seems relatively safe without major complications, whereas complications after pancreatic IRE appear more severe. The available limited results for tumor control are generally good. Overall, the future of IRE for difficult-to-reach tumors appears promising.

Anaesthetic management during open and percutaneous irreversible electroporation

BACKGROUND Irreversible electroporation (IRE) is a novel tumour ablation technique involving repetitive application of electrical energy around a tumour. The use of pulsed electrical gradients carries a risk of cardiac arrhythmias, severe muscle contractions, and seizures. We aimed to identify IRE-related risks and the appropriate precautions for anaesthetic management. METHODS All patients who were treated with IRE were prospectively included. Exclusion criteria were arrhythmias, congestive heart failure, active coronary artery disease, and epilepsy. All procedures were performed under general anaesthesia with complete muscle relaxation during ECG-synchronized pulsing. Adverse events, cardiovascular effects, blood samples, cerebral activity, and post-procedural pain were analysed. RESULTS Twenty-eight patients underwent 30 IRE sessions for tumours in the liver, pancreas, kidney, and lesser pelvis. No major adverse events occurred during IRE. Median systolic and diastolic blood pressure increased by 44 mm Hg (range -7 to 108 mm Hg) and 19 mm Hg (range 1-50 mm Hg), respectively. Two transient minor cardiac arrhythmias without haemodynamic consequences were observed. Muscle contractions were mild and IRE caused no reactive brain activity on a simplified EEG. Pain in the first 24 h after percutaneous IRE was generally mild, but higher pain scores were reported after pancreatic treatment (mean VAS score 3; range 0-9). CONCLUSIONS Side-effects during IRE on tumours in the liver, pancreas, kidney, and lesser pelvis seem mild and manageable when current recommendations for anaesthesia management, including deep muscle relaxation and ECG synchronized pulsing, are followed. Electrical pulses do not seem to cause reactive cerebral activity and evidence for pre-existing atrial fibrillation as an absolute contra-indication for IRE is questionable.

Thermal Energy during Irreversible Electroporation and the Influence of Different Ablation Parameters

PURPOSE Irreversible electroporation (IRE) uses high-voltage electric fields to achieve cell death. Although the mechanism of IRE is mainly designated as nonthermal, development of secondary Joule heating is inevitable. The study purpose was to gain understanding of temperature development and distribution during IRE. MATERIALS AND METHODS IRE was performed in a transparent polyacrylamide gel resembling soft tissue. Mechanical effects, changes in temperature gradient, and absolute temperature changes were measured with three different optical techniques (high-speed, color Schlieren, and infrared imaging) to investigate the effect on temperature of variations in voltage, pulse length, active tip length (ATL), interelectrode distance, electrode configuration (parallel, convergent, and divergent), and sequential pulsing (pulse delivery interrupted by breaks). The total delivered energy was calculated. RESULTS A temperature gradient, starting at the tips of both electrodes and expanding toward each other, developed immediately with pulse delivery. Temperatures increased with increasing voltage (by 2.5°C-40.4°C), pulse length (by 5.3°C-9.8°C), ATL (by 5.9°C-17.6°C), and interelectrode distance (by 7.6°C-21.5°C), in accordance with higher energy delivery. Nonparallel electrode placement resulted in heterogeneous temperature distribution with the peak temperature focused in the area with the shortest interelectrode distance. Sequential pulse delivery significantly reduced the temperature increase compared with continuous pulsing (4.3°C vs 11.7°C). CONCLUSIONS Voltage, pulse length, interelectrode distance, ATL, and electrode configuration each have a strong effect on temperature development and distribution during IRE. Sequential pulsing reduces the extent and volume of thermal distribution and may prove beneficial with respect to procedural safety.

Bipolar radiofrequency ablation for symptomatic giant (>10 cm) hepatic cavernous haemangiomas: Initial clinical experience

AIM To describe initial clinical experience with bipolar radiofrequency ablation (RFA) for symptomatic giant hepatic haemangiomas. MATERIALS AND METHODS Four consecutive patients with a large-volume, symptomatic hepatic cavernous haemangioma of >10 cm were treated with bipolar RFA during laparotomy with ultrasound guidance. Complications were carefully noted. Clinical and radiological effectiveness were evaluated comparing baseline with 3 and 6 months follow-up of symptom assessments and upper abdominal magnetic resonance imaging (MRI) or computed tomography (CT). RESULTS RFA was successfully performed for all four giant haemangiomas. No major complications were observed. Peri-procedural shrinking was remarkable and intermediate-term volume reduction ranged from 58-92% after 6 months. Symptom relief after 6 months was complete in two patients and considerable in the other two. CONCLUSION Preliminary results suggest intra-operative bipolar RFA to be a safe, feasible, and effective technique for treatment of giant symptomatic hepatic cavernous haemangiomas.

Percutaneous Image-Guided Irreversible Electroporation for the Treatment of Unresectable, Locally Advanced Pancreatic Adenocarcinoma

PURPOSE To describe safety and effectiveness of percutaneous irreversible electroporation (IRE) for treatment of unresectable, locally advanced pancreatic adenocarcinoma (LAPC). MATERIALS AND METHODS This retrospective study included 50 patients (23 women, 27 men; age range, 46-91 y; median age, 62.5 y) with biopsy-proven, unresectable LAPC who received percutaneous computed tomography (CT)-guided IRE. The primary objective was to assess the safety profile of the procedure; the secondary objective was to determine overall survival (OS). All patients had prior chemotherapy (1-5 lines, median 2), and 30 (60%) of 50 patients had prior radiation therapy. Follow-up included CT at 1 month and at 3-month intervals thereafter. RESULTS There were no treatment-related deaths and no 30-day mortality. Serious adverse events occurred in 10 (20%) of 50 patients (abdominal pain [n = 7], pancreatitis [n = 1], sepsis [n = 1], gastric leak [n = 1]). Median OS was 27.0 months (95% confidence interval [CI], 22.7-32.5 months) from time of diagnosis and 14.2 months (95% CI, 9.7-16.2 months) from time of IRE. Patients with tumors ≤ 3 cm (n = 24) had significantly longer median OS than patients with tumors > 3 cm (n = 26): 33.8 vs 22.7 months from time of diagnosis (P = .002) and 16.2 vs 9.9 months from time of IRE (P = .031). Tumor size was confirmed as the only independent predictor of OS at multivariate analysis. CONCLUSIONS Percutaneous image-guided IRE of unresectable LAPC is associated with an acceptable safety profile.

The influence of a metal stent on the distribution of thermal energy during irreversible electroporation

Purpose Irreversible electroporation (IRE) uses short duration, high-voltage electrical pulses to induce cell death via nanoscale defects resulting from altered transmembrane potential. The technique is gaining interest for ablations in unresectable pancreatic and hepatobiliary cancer. Metal stents are often used for palliative biliary drainage in these patients, but are currently seen as an absolute contraindication for IRE due to the perceived risk of direct heating of the metal and its surroundings. This study investigates the thermal and tissue viability changes due to a metal stent during IRE. Methods IRE was performed in a homogeneous tissue model (polyacrylamide gel), without and with a metal stent placed perpendicular and parallel to the electrodes, delivering 90 and 270 pulses (15–35 A, 90 μsec, 1.5 cm active tip exposure, 1.5 cm interelectrode distance, 1000–1500 V/cm, 90 pulses/min), and in-vivo in a porcine liver (4 ablations). Temperature changes were measured with an infrared thermal camera and with fiber-optic probes. Tissue viability after in-vivo IRE was investigated macroscopically using 5-triphenyltetrazolium chloride (TTC) vitality staining. Results In the gel, direct stent-heating was not observed. Contrarily, the presence of a stent between the electrodes caused a higher increase in median temperature near the electrodes (23.2 vs 13.3°C [90 pulses]; p = 0.021, and 33.1 vs 24.8°C [270 pulses]; p = 0.242). In-vivo, no temperature difference was observed for ablations with and without a stent. Tissue examination showed white coagulation 1mm around the electrodes only. A rim of vital tissue remained around the stent, whereas ablation without stent resulted in complete tissue avitality. Conclusion IRE in the vicinity of a metal stent does not cause notable direct heating of the metal, but results in higher temperatures around the electrodes and remnant viable tissue. Future studies should determine for which clinical indications IRE in the presence of metal stents is safe and effective.

Transcatheter CT Arterial Portography and CT Hepatic Arteriography for Liver Tumor Visualization during Percutaneous Ablation

PURPOSE To evaluate the feasibility of combining transcatheter computed tomography (CT) arterial portography or transcatheter CT hepatic arteriography with percutaneous liver ablation for optimized and repeated tumor exposure. MATERIALS AND METHODS Study participants were 20 patients (13 men and 7 women; mean age, 59.4 y; range, 40-76 y) with unresectable liver-only malignancies--14 with colorectal liver metastases (29 lesions), 5 with hepatocellular carcinoma (7 lesions), and 1 with intrahepatic cholangiocarcinoma (2 lesions)--that were obscure on nonenhanced CT. A catheter was placed within the superior mesenteric artery (CT arterial portography) or in the hepatic artery (CT hepatic arteriography). CT arterial portography or CT hepatic arteriography was repeatedly performed after injecting 30-60 mL 1:2 diluted contrast material to plan, guide, and evaluate ablation. The operator confidence levels and the liver-to-lesion attenuation differences were assessed as well as needle-to-target mismatch distance, technical success, and technique effectiveness after 3 months. RESULTS Technical success rate was 100%; there were no major complications. Compared with conventional unenhanced CT, operator confidence increased significantly for CT arterial portography or CT hepatic arteriography cases (P < .001). The liver-to-lesion attenuation differences between unenhanced CT, contrast-enhanced CT, and CT arterial portography or CT hepatic arteriography were statistically significant (mean attenuation difference, 5 HU vs 28 HU vs 70 HU; P < .001). Mean needle-to-target mismatch distance was 2.4 mm ± 1.2 (range, 0-12.0 mm). Primary technique effectiveness at 3 months was 87% (33 of 38 lesions). CONCLUSIONS In patients with technically unresectable liver-only malignancies, single-session CT arterial portography-guided or CT hepatic arteriography-guided percutaneous tumor ablation enables repeated contrast-enhanced imaging and real-time contrast-enhanced CT fluoroscopy and improves lesion conspicuity.

Percutaneous Liver Tumour Ablation: Image Guidance, Endpoint Assessment, and Quality Control

Liver tumour ablation nowadays represents a routine treatment option for patients with primary and secondary liver tumours. Radiofrequency ablation and microwave ablation are the most widely adopted methods, although novel techniques, such as irreversible electroporation, are quickly working their way up. The percutaneous approach is rapidly gaining popularity because of its minimally invasive character, low complication rate, good efficacy rate, and repeatability. However, matched to partial hepatectomy and open ablations, the issue of ablation site recurrences remains unresolved and necessitates further improvement. For percutaneous liver tumour ablation, several real-time imaging modalities are available to improve tumour visibility, detect surrounding critical structures, guide applicators, monitor treatment effect, and, if necessary, adapt or repeat energy delivery. Known predictors for success are tumour size, location, lesion conspicuity, tumour-free margin, and operator experience. The implementation of reliable endpoints to assess treatment efficacy allows for completion-procedures, either within the same session or within a couple of weeks after the procedure. Although the effect on overall survival may be trivial, (local) progression-free survival will indisputably improve with the implementation of reliable endpoints. This article reviews the available needle navigation techniques, evaluates potential treatment endpoints, and proposes an algorithm for quality control after the procedure.

Percutaneous Irreversible Electroporation for Recurrent Thyroid Cancer—A Case Report

A 74-year-old man presented with a small locoregional, histopathologically proven, fluorodeoxyglucose positron emission tomography/computed tomography-avid recurrence of follicular thyroid carcinoma in the left subglottic space after extensive surgical resection, adjuvant radioactive iodine therapy, and external beam radiation therapy. Because all established focal therapies were contraindicated, percutaneous irreversible electroporation was performed without complications. Follow-up imaging at 7 months showed a small ablation scar without signs for residual vital tumor tissue. Irreversible electroporation may be a viable treatment option for selected cases of recurring head and neck tumors that are unsuitable for other local treatments.

Irreversible Electroporation of Liver Tumors

The liver is a well-known site for tumors of benign as well as malignant origin. In the Western world, the most frequent hepatic malignancies encountered are liver metastases, especially but not solely from colorectal origin. Primary liver tumors, or the hepatocellular carcinoma (HCC), more frequently develop in people from Asian and Mediterranean countries. Although treatment of various tumors can be very different, they all have one thing in common. The only treatment option with curative intent is local treatment. Because nowadays several treatment modalities are available, diagnosis and treatment evaluation should be done by a specialized multidisciplinary (oncologic) liver team including a dedicated surgeon, an interventional and a diagnostic radiologist, a medical oncologist, a hepatologist, a radiation oncologist, a pathologist, and a nuclear medicine physician.