Application of irreversible electroporation in the ablation treatment of Hver cancer was published on J Intervent Radiol 2022，V01．31，No．5  Here is a partial quote from the article, hoping to provide reference for the clinical application and promotion of this new technology.

【Citation of literature】XU Min，XU Danxia，JIANG Tian’ J Intervent Radiol 2022，V01．31，No．5 

XU Min，XU Danxia，JIANG Tian’

[Department of Ultrasound Medicine,First Affiliated Hospital,School of Medicine,Zhejiang University]

Abstract

Irreversible electroporation (IRE) is a new non-thermal ablation method that uses high-voltage pulsed electric fields to create irreversible nanoscale pores on the cell membrane, without damaging surrounding important blood vessels or bile duct structures. It has the advantages of fewer complications, high safety, and fast recovery, and has shown broad application prospects in the treatment of liver cancer. This article introduces the mechanism, advantages, effectiveness, safety, and development direction of IRE technology in the ablation treatment of liver cancer, in order to provide reference for the clinical application and promotion of this technology.

Liver cancer is currently the fifth most common malignant tumor and the second leading cause of cancer-related deaths in China, posing a serious threat to people's lives and health. Although surgical resection is the preferred method for the treatment of liver cancer, only 20%-30% of patients can have the opportunity for surgical resection due to the fact that most patients have cirrhosis or have reached the middle and late stages at the time of diagnosis. In recent years, local ablation therapy has been widely used, which has the advantages of minimally invasive, precise local efficacy, and few contraindications, making it an effective treatment for many patients who cannot undergo surgery or are intolerant to surgery. The currently commonly used local ablation methods are thermal ablation, including RFA and MWA. Although the above methods have their own advantages, it is difficult to avoid the high temperature generated during the ablation process, which not only damages important tissues such as blood vessels, bile ducts, pancreatic ducts, or nerves in the ablation area while killing the tumor, but also limits the application of thermal ablation in tumors adjacent to important structures due to the thermal sink effect caused by blood circulation.

Irreversible electroporation (IRE) is an emerging non-thermal ablation treatment method that has gradually been applied in clinical practice. Current research shows that IRE is safe and effective, and can overcome the shortcomings of thermal ablation techniques. It has demonstrated unique advantages in the treatment of liver cancer, especially in liver cancer located in special areas such as adjacent blood vessels or bile ducts.

IRE mechanism of action and advantages

n the 1950s, scholars discovered that under the action of pulsed electric fields, the lipid bilayer of the cell membrane was rearranged to form nanoscale hydrophilic pores, which were called electroporation. According to whether the cell membrane can return to its normal physiological state after the external electric field is removed, electroporation is divided into reversible electroporation (RE) and irreversible electroporation (IRE). RE is applied to assist chemotherapy drugs or gene drugs to enter cells and is the theoretical basis of electrochemical therapy and gene electrotransfection technology. IRE is developed based on RE, which forms irreversible micropores on the cell membrane by increasing the electrical energy, increasing the permeability of ions and macromolecules, changing the cell osmotic pressure, and disrupting the balance between the inside and outside of the cell, leading to cell swelling or apoptosis.

In 2005, Davalos et al. first validated the effectiveness of IRE as a ablation method and proposed that it could become a powerful weapon for tumor treatment. Subsequently, more and more basic experiments and clinical trials have confirmed this view. Existing research results show that IRE, as a new non-thermal ablation technology, has the following advantages: 1) IRE acts on the lipid bilayer of the cell membrane, while the skeleton components that make up blood vessels, pancreatic ducts, and nerves can be preserved, ensuring rapid recovery of normal tissues after treatment; 2) IRE does not rely on temperature to kill tumor cells, so its therapeutic effect is not affected by thermal sink effects, which improves the complete ablation rate of tumors around blood vessels and bile ducts; 3) The working principle of IRE is to induce cell apoptosis rather than protein denaturation and necrosis, which can better preserve tumor antigens, activate host anti-tumor immunity, and combined with immunotherapy, IRE is expected to improve the long-term efficacy of patients.

Efficacy and safety of IRE in the treatment of liver cancer

Since IRE was proposed as a novel local treatment modality for tumors, a series of experimental studies have explored the areas of IRE ablation parameters in the liver, whether it damages blood vessels and bile ducts, imaging performance before and after ablation, and immune response. 2005, Miller et al. used pulsed electric field to ablate HepG2 human hepatocellular carcinoma cell line and showed that in vitro ablation parameters of 1500 V/cm electric field intensity, 300 μs pulse width, and 10 pulses could completely inactivate hepatocellular carcinoma cells, Lee et al. found by scanning electron microscopy that nanoscale micropores (80-490 nm) were produced in the hepatocyte membrane after IRE ablation, and the size of the micropores remained unchanged 24 h after surgery, confirming that IRE can induce irreversible perforation of hepatocytes. The effectiveness of IRE treatment was confirmed at the pathological level. Lee et al. performed ultrasound-guided IRE treatment on 16 pigs and found that the ablated area of IRE was clearly demarcated from normal liver tissue, with bile ducts and blood vessels intact. The ablated area was clearly demarcated from the normal liver tissue, and the bile ducts and blood vessels were intact. The ablated area showed positive staining for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and BCL-2 oncoprotein, indicating that the apoptotic process was involved in cell death caused by IRE.

Based on a large number of experimental verifications that indicate the effectiveness of IRE in the treatment of liver cancer, scientists have begun to explore the method of combining IRE with other treatments to further improve its efficacy. Isfort et al. found that immediate drug-eluting bead transarterial chemoembolization (DEB-TACE) after IRE treatment can produce a larger ablation volume and improve local efficacy compared to IRE alone. Tam et al. found that IRE can cause the deposition of nano-gold particles in tumor cells and the surrounding area, achieving coverage of the treatment area and its edges, and the combination of these two methods can effectively reduce the risk of residual after IRE treatment. Fang et al. used a 3D liver tumor model to explore the enhancing effect of RFA preheating on IRE ablation, and the results showed that compared to IRE alone, using RFA preheating can increase the ablation volume of IRE and reduce the electric field threshold intensity for tumor cell killing. This combined method is expected to be used for large tumors adjacent to important organs.

In 2009, Angio Dynamics developed the first IRE ablation device, Nanoknife, and in April 2012, the FDA formally approved Nanoknife for clinical use. in June 2015, China's Food In June 2015, China's Food and Drug Administration approved the application of Nanoknife for the ablation treatment of liver and pancreatic tumors. In recent years, as IRE technology has been gradually applied widely, many medical institutions at home and abroad have conducted in-depth studies on the effectiveness and safety of IRE for the treatment of liver cancer, and have achieved better observation and evaluation results. 

Selecting the right patient is the key to achieving safe and effective treatment.IRE is recommended for the treatment of single lesions ≤5 cm in diameter: the number of multiple lesions ≤3 and the maximum diameter ≤3 cm. IRE can be used for the treatment of hepatocellular carcinoma, hepatic metastases and cholangiocellular carcinoma and other pathological types of liver tumors. It is especially suitable for liver tumors that are not suitable for surgery or thermal ablation. According to the modified Delphi Expert Consensus on IRE for liver tumors issued in 2020, contraindications to IRE include: tumors >5 cm in maximum diameter, ventricular arrhythmias, installation of implantable cardioverter-defibrillators, congestive heart failure (NYHA class III and IV), platelets<50x10³ l="" or="" inr="">1.7.

In 2012, Kingham et al. reported IRE ablation of a total of 65 hepatocellular carcinoma lesions (within 1 cm of the hepatic vein or portal vein trunk) in 28 patients. The median follow-up time was 6 months, and the results showed a 98.1% complete tumor ablation rate and a 5.7% local recurrence rate, with only one case of intraoperative arrhythmia and one case of portal vein thrombosis, with no serious complications. 2013, Cannon et al conducted a prospective multicenter study on the efficacy and safety of IRE ablation of hepatocellular carcinoma adjacent to vital structures. The results showed that 44 patients had local recurrence-free survival rates of 97.4%, 94.6%, and 59.5% at 3, 6, and 12 months postoperatively, respectively, and 5 patients had mild adverse effects postoperatively, all of which resolved spontaneously within 30 d. The complete ablation rate and local recurrence rate of IRE for hilar hepatocellular carcinoma were found to be similar to that of surgical resection in Kevin Huang's study. Clinical studies of IRE for hepatocellular carcinoma treatment have been widely conducted. Its main subjects are patients with hepatocellular carcinoma adjacent to important structures such as blood vessels, bile ducts, diaphragm, gastrointestinal tract or liver hilum. It has demonstrated good efficacy in hepatocellular carcinoma in these difficult sites for surgical and conventional thermal ablation treatment.

The current findings show that IRE is a minimally invasive and effective treatment option not only for liver cancer in specific sites but also for those patients with impaired liver reserve function. Bhutiani et al. treated 55 patients with hepatocellular carcinoma in the setting of Child_Pugh grade B cirrhosis with either MWA or IRE ablation and showed no significant difference in the rate of complete ablation between the two, but patients treated with IRE tolerated the procedure better and had a shorter hospital stay than those treated with MWA. Martin et al. performed IRE ablation after percutaneous hepatic biliary drainage in 26 patients with progressive cholangiocarcinoma, and the success rate of the procedure was 96%, and all patients in the IRE group did not require biliary drainage during the follow-up time, avoiding complications such as infection or occlusion caused by biliary drainage, suggesting that IRE can effectively improve the outcome of progressive Cannon et al. treated five patients with intermediate to advanced hepatocellular carcinoma with IRE, and patients underwent liver transplantation from 47 to 264 d after IRE with a median follow-up time of 403 d. Four patients survived without recurrence, and one patient died after 297 d after IRE due to transplantation-related complications, indicating that IRE has the potential to buy more time for liver transplantation in patients with high-risk liver cancer.

Niessen et al. found that lesion size was independently associated with pathological staging and local recurrence rate. Patients with lesions >5 cm in diameter and cholangiocarcinoma or metastatic carcinoma had a higher recurrence rate, while the distance of lesions from the hepatic artery, hepatic vein, portal vein and bile duct was not significantly associated with local recurrence rate. Patients with Child-Pugh class A had significantly longer survival than patients with Child-Pugh class B/C cirrhosis.

Complications of IRE ablation include arrhythmias, abdominal pain, bleeding, bile duct injury, infection and thrombosis. Cardiac arrhythmias often occur close to the heart, and to avoid them, the entire IRE ablation procedure should be performed under synchronized cardiac monitoring, with controlled electrical impulses applied during the overdrive phase of the cardiac cycle. 3.4% to 46% of patients experience postoperative pain after IRE ablation, but only a few patients require high-dose intravenous morphine, while the rest require only observation or simple pain medication. Although IRE is a non-thermal ablation, when the electrode needles are not placed parallel to each other, the temperature between the electrode needles will be concentrated in the area of small electrode spacing, and the heat generated may damage the bile ducts or blood vessels, leading to bile duct stenosis or vascular thrombosis. ALT, AST and total bilirubin levels are elevated after IRE, and generally return to preoperative baseline levels 2 weeks after the IRE procedure.

Summary and Outlook

IRE is a safe and effective ablation technique for the treatment of liver cancer, but there are still a series of problems to be solved: ① The direct current stimulation generated by IRE ablation can cause strong involuntary muscle contraction, resulting in patient pain and electrode needle displacement, so adequate general anesthesia and the use of muscle relaxants are required to ensure intraoperative safety, which increases the risk and complexity of the procedure. In recent years, it has been found that high-frequency irreversible electroporation (H-FIRE) raises the cell-induced transmembrane potential more uniformly by generating alternating polarity pulses with frequencies up to 500 KHz or more to H-FIRE) has shown promising applications in reducing muscle contraction and efficient tumor inactivation by generating alternating polar pulses at frequencies up to 500 KHz or more, more uniformly raising the cell-induced transmembrane potential to simulate the electroporation threshold. ②IRE multi-needle treatment requires parallel needle placement and electrode distance to maintain stability, which is technically difficult to operate and requires high level of the puncturer, therefore, more convenient electrode needles and fixation devices need to be developed so as to guarantee the precision and minimally invasive treatment process. (③) IRE treatment parameters are numerous and poor synergy can easily lead to poor efficacy and side effects such as heat production. Therefore, the quantitative-effect relationship between different treatment parameters and ablation efficacy needs to be studied in depth, and intelligent modeling algorithms and navigation systems need to be developed to escort IRE ablation treatment.

In summary, IRE has become an important treatment method for difficult liver cancer cases and patients with poor liver reserve function who cannot be treated with traditional thermal ablation or surgery, thanks to its unique advantages. It is believed that with the development of new treatment equipment, optimization of treatment parameters, and the demonstration of long-term clinical trials, IRE will play an increasingly important role in the local treatment of liver cancer.

Currently, a multi-center clinical registration trial of the Steep Pulse Therapeutic Apparatus (Nanoknife) for the ablation treatment of pancreatic malignant tumors is underway in several hospitals across the country. For more information, please leave a message in the background or contact the following person by phone.

Contact person:Manage Zuo from Alpmed

Tel:022-23788188 Ext 7206