Laurien G. P. H. Vroomen

Time-Dependent Impact of Irreversible Electroporation on Pancreas, Liver, Blood Vessels and Nerves: A Systematic Review of Experimental Studies.

Introduction Irreversible electroporation (IRE) is a novel ablation technique in the treatment of unresectable cancer. The non-thermal mechanism is thought to cause mostly apoptosis compared to necrosis in thermal techniques. Both in experimental and clinical studies, a waiting time between ablation and tissue or imaging analysis to allow for cell death through apoptosis, is often reported. However, the dynamics of the IRE effect over time remain unknown. Therefore, this study aims to summarize these effects in relation to the time between treatment and evaluation. Methods A systematic search was performed in Pubmed, Embase and the Cochrane Library for original articles using IRE on pancreas, liver or surrounding structures in animal or human studies. Data on pathology and time between IRE and evaluation were extracted. Results Of 2602 screened studies, 36 could be included, regarding IRE in liver (n = 24), pancreas (n = 4), blood vessels (n = 4) and nerves (n = 4) in over 440 animals (pig, rat, goat and rabbit). No eligible human studies were found. In liver and pancreas, the first signs of apoptosis and haemorrhage were observed 1–2 hours after treatment, and remained visible until 24 hours in liver and 7 days in pancreas after which the damaged tissue was replaced by fibrosis. In solitary blood vessels, the tunica media, intima and lumen remained unchanged for 24 hours. After 7 days, inflammation, fibrosis and loss of smooth muscle cells were demonstrated, which persisted until 35 days. In nerves, the median time until demonstrable histological changes was 7 days. Conclusions Tissue damage after IRE is a dynamic process with remarkable time differences between tissues in animals. Whereas pancreas and liver showed the first damages after 1–2 hours, this took 24 hours in blood vessels and 7 days in nerves.

Locally Advanced Pancreatic Cancer: A Review of Local Ablative Therapies

Pancreatic cancer is typically characterized by its aggressive tumor growth and dismal prognosis. Approximately 30% of patients with pancreatic cancer present with locally advanced disease, broadly defined as having a tumor-to-artery interface >180°, having an unreconstructable portal vein or superior mesenteric vein and no signs of metastatic disease. These patients are currently designated to palliative systemic chemotherapy, though median overall survival remains poor (approximately 11 months). Therefore, several innovative local therapies have been investigated as new treatment options for locally advanced pancreatic cancer (LAPC). This article provides an overview of available data with regard to morbidity and oncological outcome of novel local therapies for LAPC.

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.

Irreversible Electroporation in Hepatopancreaticobiliary Tumours

Hepatopancreaticobiliary tumours are often diagnosed at an advanced disease stage, in which encasement or invasion of local biliary or vascular structures has already occurred. Irreversible electroporation (IRE) is an image-guided tumour ablation technique that induces cell death by exposing the tumour to high-voltage electrical pulses. The cellular membrane is disrupted, while sparing the extracellular matrix of critical tubular structures. The preservation of tissue integrity makes IRE an attractive treatment option for tumours in the vicinity of vital structures such as splanchnic blood vessels and major bile ducts. This article reviews current data and discusses future trends of IRE for hepatopancreaticobiliary tumours.

Ablation with irreversible electroporation in patients with advanced perihilar cholangiocarcinoma (ALPACA): a multicentre phase I/II feasibility study protocol

Introduction The majority of patients with perihilar cholangiocarcinoma (PHC) has locally advanced disease or distant lymph node metastases on presentation or exploratory laparotomy, which makes them not eligible for resection. As the prognosis of patients with locally advanced PHC or lymph node metastases in the palliative setting is significantly better compared with patients with organ metastases, ablative therapies may be beneficial. Unfortunately, current ablative options are limited. Photodynamic therapy causes skin phototoxicity and thermal ablative methods, such as stereotactic body radiation therapy and radiofrequency ablation, which are affected by a heat/cold-sink effect when tumours are located close to vascular structures, such as the liver hilum. These limitations may be overcome by irreversible electroporation (IRE), a relatively new ablative method that is currently being studied in several other soft tissue tumours, such as hepatic and pancreatic tumours. Methods and analysis In this multicentre phase I/II safety and feasibility study, 20 patients with unresectable PHC due to vascular or distant lymph node involvement will undergo IRE. Ten patients who present with unresectable PHC will undergo CT-guided percutaneous IRE, whereas ultrasound-guided IRE will be performed in 10 patients with unresectable tumours detected at exploratory laparotomy. The primary outcome is the total number of clinically relevant complications (Common Terminology Criteria for Adverse Events, score of≥3) within 90 days. Secondary outcomes include quality of life, tumour response, metal stent patency and survival. Follow-up will be 2 years. Ethics and dissemination The protocol has been approved by the local ethics committees. Data and results will be submitted to a peer-reviewed journal. Conclusion The Ablation with irreversible eLectroportation in Patients with Advanced perihilar CholangiocarcinomA (ALPACA) study is designed to assess the feasibility of IRE for advanced PHC. The main purpose is to inform whether a follow-up trial to evaluate safety and effectiveness in a larger cohort would be feasible.

The Effect of Irreversible Electroporation on Blood Vessels, Bile Ducts, Urinary Tract, Intestines, and Nerves

Surgical resection is the definitive treatment option for patients with primary or metastatic cancers, resulting in the best possible patient outcomes when resection is achieved with negative margins. However, involvement of vital structures such as blood vessels and genitourinary or gastrointestinal tract often poses a contraindication to safe and successful surgical resection.

Irreversible Electroporation of Tumors Within the Pelvic Cavity

Malignancies that are notorious for their recurrence within the lesser pelvis following radiotherapy and/or surgery are female and male urogenital tract tumors and locoregional recurrences from gastrointestinal origin such as anorectal carcinomas [1, 2]. Due to ingrowth in or compression on peripheral nerves, these relapsing malignancies can cause aggravating pain and neural function loss. The presence of extensive adhesions induced by previous surgical procedures and the risk of radiation-induced toxicity in a previously irradiated area precludes radical local treatment options such as repeat surgery [3] and stereotactic ablative body radiation therapy (SABR) [4–6]. The risk of severe treatment-induced morbidity does not seem to outweigh clinical benefit [2, 7, 8]. In general, therapy for this specific patient population primarily aims at prolonging the – preferably quality-preserved – life span, and most patients will be referred to medical oncologists for either palliative chemotherapy or best supportive care. Selected patients can be offered other local treatment modalities such as radiofrequency ablation (RFA) or cryotherapy [9–11]. One important drawback of these thermal treatment modalities is the high risk of inducing thermal damage to important neural structures like the sciatic nerve or presacral plexus, as well as to the intestines, ureters, and large vessels [12, 13].

Complications and Procedures to Enhance Safety

Like any interventional procedure, IRE is associated with its own distinctive complications and contraindications. Complications of IRE can be divided into three categories: risks related to (I) the general procedure, (II) needle placement, and (III) the applied electrical field. In general, patient selection is crucial in minimizing the risk of complications. Tumor characteristics and patients’ performance status should be taken into account. The open and percutaneous techniques both have their advantages and disadvantages. In this chapter, frequently encountered complications as well as different treatment strategies to prevent their occurrence are discussed. These should aid the clinician during the procedure as well as during post-IRE patient management.