Irreversible Electroporation Ablation Therapy for Pancreatic Adenocarcinoma：Observation of Its Safety and Short-term Effect  was published on J Intervent Radiol 2016，V01．25，No．3.This article quotes part of the content to provide a new treatment idea for patients with locally advanced pancreatic cancer that cannot be surgically removed.

【Citation of literature】NIU Li—zhi，ZENG Jian-ying，ZHANG Yi-shi，LIANG Bing，ZHOU Liang，FANG Gang，LI Shu-Ying，LI Zhong-hai，LI Rong-rong，CHEN Ji-bing，LI Chao—long，WANG Jian-nan，LI Hai-bo，MU Feng，XU Ke-cheng.

J Intervent Radiol 2016，V01．25，No．3

NIU Li—zhi，ZENG Jian-ying，ZHANG Yi-shi，LIANG Bing，ZHOU Liang，FANG Gang，

LI Shu-Ying，LI Zhong-hai，LI Rong-rong，CHEN Ji-bing，LI Chao—long，

WANG Jian-nan，LI Hai-bo，MU Feng，XU Ke-cheng

[Fuda Cancer Hospital，School of Medicine，Ji’nan  University]

Abstract

0bjective：To treat unresectable locally—advanced pancreatic cancer with irreversible

Methods：The adverse reactions，which occurred within 30 days after IRE，were recorded，and the postoperative objective curative effect(30±7 days after IRE)was evaluated with modified RECIST criteria

Results：A total of 12 patients received IRE therapy，and the procedure was successfully accomplished in all patients．The adverse reactions occurring within 30 days after IRE included pain at puncturing site(n=5，41．7％)，nausea and vomiting(n=3，25％)，cough(n=2，16．7％)，postoperative hypoglycemia(n=2，16．7％)，hypokalemia(n=2，16．7％)，edema of gastric and duodenal wall(n=2，16．7％)，gastric retention(n=l，8．3％)，fever(n=l，8．3％)，chest tightness and shortness of breath(n=l，8．3％)．After symptomatic treatment these symptoms were improved，and no severe IRE—related complications，such as massive hemorrhage，bile leakage or pancreatic leakage，occurred．The serum amylase levels measured at 24 hours and 7 days after IRE were not significantly different with preoperative levels(Dn05)．Evaluation of curative effects made at(30±7)days after IRE showed that complete response(CR)was achieved in one patient，partial response(PR)in 9 patients and stable disease(SD)in 2 patients，with the tumor remission rate(CR+PR)being 83．3％．

Conclusion：For the treatment of inoperable pancreatic cancer，irreversible eleetroporation ablation is highly safe with mild adverse reaction and obvious short-term efficacy．although its long—term effect needs to be further clarified．

Pancreatic cancer is one of the tumors with a severe prognosis, with a 5-year survival rate of 7%. Only 10%-20% of pancreatic cancer cases are eligible for curative surgical resection. For locally advanced pancreatic cancer patients who have lost the opportunity for surgery, radiotherapy and chemotherapy are commonly used in clinical practice to reduce the tumor size and even make it operable. However, the overall efficacy is unsatisfactory. Other local therapies such as traditional thermal ablation methods like radiofrequency, microwave, and cryotherapy can cause significant damage to the surrounding pancreatic tissue structure and lead to complications such as pancreatic leakage and bile leakage. Irreversible electroporation (IRE) is a new emerging tumor ablation technology that does not rely on heat. It uses minimally invasive electrodes to deliver millisecond-level electric pulses, which create an external electric field that changes the transmembrane potential of the cell membrane phospholipid bilayer, causing the cell membrane to rearrange and many nanoscale pores to appear on the cell surface. This leads to an increase in cell membrane osmotic pressure. When the pulse energy exceeds a certain electric field threshold, it causes irreversible cell damage, induces cell apoptosis, and has the characteristics of limiting extracellular matrix damage and protecting large blood vessels and bile duct structures. Therefore, IRE technology may be an important choice for treating unresectable pancreatic cancer that surrounds or encloses important lumens such as the celiac trunk, portal vein, and common bile duct. Since July 2, 2015, we have conducted a prospective study on 12 patients with unresectable locally advanced pancreatic cancer who received IRE treatment, focusing on the safety and short-term efficacy of IRE treatment.

Research Results

Postoperative CT examination：Immediate and 24-hour follow-up CT after IRE showed multiple dark areas with bubbles of 1-3 mm in diameter in the ablation zone. Enhanced scanning at 7 days postoperatively showed disappearance of the CT bubble shadows, enhancement of the lesion edge, and clearer boundaries compared to before. The lesion range slightly increased in two patients. Enhanced CT re-examination at 30 days postoperatively showed a reduction in the enhanced area of the lesion compared to before. Among the 12 patients, one achieved complete response (CR), nine achieved partial response (PR), and two had stable disease (SD) at 30±7 days postoperatively, with a tumor response rate (CR+PR) of 83.3%.

（Image changes before and after IRE ablation of pancreatic head tumors）

Note: ① Preoperative MRI showed that the tumor was adjacent to the duodenum and compressed it. The tumor wrapped around the adjacent common bile duct and pancreatic duct, with a size of 2.8cm × 2.3cm; ② Intraoperative CT showed that the main electrode and standard electrode were inserted into the center of the tumor, with an electrode distance of 2.0cm; ③ Postoperative CT enhanced scan after 30 days showed no enhancement in the center of the lesion, and the range was slightly reduced compared to before.

(Figure 2: Radiological changes before and after IRE ablation of pancreatic body tumor)

Note: ① Preoperative CT enhanced scan showed that the tumor wrapped around the celiac trunk, splenic artery and vein, mesenteric artery and vein, with a size of 5.6cm × 4.6cm; ② Intraoperative ultrasound showed the appearance of bubbles with high echogenicity in the needle tract area during the ablation of the tumor with two electrodes; ③ Postoperative 24-hour enhanced CT showed small bubbles in the center of the tumor and enhancement at the edge of the tumor; ④ Postoperative CT enhanced scan after 30 days showed that the size of the tumor was 4.8cm × 4.0cm.

Discussion

Pancreatic cancer is one of the most common malignant tumors in the digestive system. Early diagnosis is difficult, and patients often present with advanced stage when seeking medical attention, resulting in low surgical resection rates. For pancreatic cancer patients who have lost the opportunity for surgery, radiation and chemotherapy are standard treatment methods, but the median survival period is only 6-11 months. Local minimally invasive ablation therapy for these patients can reduce tumor burden and provide some patients with a second chance for surgery, which is currently an available treatment strategy. However, local ablation methods such as radiofrequency ablation, microwave ablation, and cryoablation are prone to incomplete ablation of lesions adjacent to large blood vessels due to the difficulty in achieving thermal or cold suction effects, and may damage blood vessels, pancreatic ducts, bile ducts, and nerves in the ablation area.

IRE is a new technology for soft tissue tumor ablation. This technology uses high-voltage direct current to produce multiple nanoscale micropores on the cell membrane, irreversibly disrupting the balance inside and outside the cell and inducing cell apoptosis. In April 2012, the US FDA approved IRE ablation for clinical treatment of soft tissue tumors. On June 18, 2015, the China Food and Drug Administration officially approved the application of the US NanoKnife TM System for clinical treatment of pancreatic tumors. IRE technology has the following characteristics: 1) Unlike thermal ablation techniques such as radiofrequency, microwave, and cryoablation, IRE does not require heat and is not affected by thermal suction effects; 2) While inducing cell apoptosis, IRE does not damage important tissue structures such as collagen fibers and other connective tissue components; 3) IRE ablation is thorough, with clear ablation boundaries, allowing for accurate assessment of treatment efficacy; 4) Treatment time is short, and multiple and/or partitioned ablation of the target area can be performed in a relatively short time; 5) Since IRE can induce cell apoptosis, apoptotic cells can be recognized by the mononuclear macrophage system and cleared in a non-inflammatory manner through phagocytosis, resulting in minimal postoperative local inflammatory reactions.

IRE ablation technology has been applied in the treatment of liver cancer, lung cancer, kidney cancer, and has shown promising results in the treatment of pancreatic cancer. Bagla et al. first reported the use of percutaneous IRE ablation technology to treat an inoperable pancreatic tumor, and after 6 months of follow-up, MRI examination showed no residual local lesions and a decrease in CA19-9 levels. In recent years, Dunki-Jacobs et al. prospectively evaluated the local recurrence rate and disease-free survival of 65 patients with advanced pancreatic cancer who underwent IRE treatment, and found that 48 patients had no local recurrence after IRE treatment. The disease-free survival of patients without local recurrence was significantly higher than that of patients with local recurrence (12.6 months vs. 5.5 months, P=0.03). Martin et al. conducted a multicenter prospective evaluation of 200 patients with stage III advanced pancreatic cancer who underwent IRE treatment, including 50 patients who underwent combined resection. All patients received preoperative induction chemotherapy, and 52% of patients received concurrent radiotherapy and chemotherapy before surgery (average 6 months). At 29 months of follow-up, 6 cases of local recurrence occurred, and the average overall survival was 24.9 months.

We formally launched a prospective study of IRE for the treatment of inoperable resectable locally progressive pancreatic cancer. The main study objective focused on the clinical observation of the exploration of the safety and efficacy of using IRE for the treatment of pancreatic cancer. Observations on safety outcomes revealed that all 12 pancreatic cancer patients tolerated IRE treatment well, with a low incidence and mild degree of postoperative adverse effects. They could improve after supportive treatment and simple symptomatic treatment. There was no significant increase in serum amylase at 24 h postoperatively, and none of them developed pancreatitis, which was consistent with the experimental and clinical results reported by Martin. 3 patients developed occasional ventricular prematureness during IRE probably related to current stimulation and stress response. However, no serious complications such as bile leak, large vessel bleeding, deep vein thrombosis or pancreatic leak associated with IRE for pancreatic cancer were seen within 30 d after surgery. This shows that the IRE technique is indeed effective in preserving the peritumoral vessels and pancreatic ducts of the pancreas and other tissue structures with better intraoperative and postoperative safety.

The enhanced CT scan taken one month after surgery for the enrolled patients showed a response rate (CR PR) of 83.3%. Most patients had a PR response. Compared with Martin's report of a 3% local recurrence rate (out of 200 cases) after a 29-month follow-up of IRE surgery, it is considered that the inflammatory reaction around the ablation zone may be a contributing factor, and long-term follow-up is needed to obtain local recurrence rates and survival results. At the same time, there was no statistically significant difference in CA19-9 levels between 7 days and 1 month after surgery compared to before surgery. Considering that the enrolled patients had advanced pancreatic tumors, IRE ablation can effectively control local lesions but is not a curative method. Therefore, a multidisciplinary treatment approach, including preoperative induction chemotherapy and postoperative adjuvant chemotherapy, is needed to further prolong patient survival.

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