Year : 2021 | Volume
: 17 | Issue : 3 | Page : 613--618
Chinese expert consensus of image-guided irreversible electroporation for pancreatic cancer
Yingtian Wei1, Yueyong Xiao1, Zhongmin Wang2, Xiaokun Hu3, Guang Chen4, Xiaoyi Ding5, Yong Fan6, Yue Han7, Kaiwen Huang8, Xuequan Huang9, Ming Kuang10, Xu Lang11, Hailiang Li12, Chengli Li13, Jiakai Li14, Jiaping Li15, Maoquan Li16, Yinying Lu17, Caifang Ni18, Lizhi Niu19, Junhui Sun20, Jinlin Tian21, Hao Wang4, Liwei Wang22, Peihong Wu23, Xiaoyan Xie24, Wenge Xing25, Linfeng Xu26, Po Yang27, Haipeng Yu25, Chunwang Yuan28, Bo Zhai29, Yanfang Zhang30, Jiasheng Zheng28, Zhigang Zhou31, Xiaoli Zhu32, Tianan Jiang33, Yingxun Zhang34,
1 Department of Radiology, First Medical Center, Chinese PLA General Hospital, Beijing, China
2 Department of Radiology, Ruijin Hospital/Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3 Interventional Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, China
4 Department of Interventional Radiology, Tianjin Medical University General Hospital, Tianjin First Central Hospital, Tianjin, China
5 Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Qingdao, China
6 Department of Radiology, Tianjin Medical University General Hospital, Tianjin First Central Hospital, Tianjin, China
7 Department of Interventional Radiology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
8 Department of Surgery, National Taiwan University, Taipei, Taiwan, China
9 Department of Radiology, First Hospital Affiliated to Army Medical University, Chongqing, China
10 Department of Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
11 Department of Radiology, Tianjin Medical University General Hospital, Tianjin, China
12 Department of Radiology, Henan Cancer Hospital, Zhengzhou, China
13 Department of Radiology, Shandong Medical Imaging Research Institute, Jinan, Shandong, China
14 Department of Interventional Radiology, Hainan Hospital, Chinese PLA General Hospital, Beijing, China
15 Interventional Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
16 Department of Interventional and Vascular Surgery, Affiliated Tenth People's Hospital of Tongji University, Interventional Vascular Institute of Tongji University, Shanghai, China
17 Comprehensive Liver Cancer Center, The 5th Medical Center of the PLA General Hospital, Beijing, China
18 Department of Interventional Radiology, First Affiliated Hospital of Soochow University, Suzhou, China
19 Department of Surgical Oncology, Fuda Cancer Hospital, Guang Zhou, Fuda Cancer Hospital, Guangzhou, China
20 Interventional Diagnosis and Treatment Center of Hepatobiliary and Pancreatic Diseases, Affiliated First Hospital, Medical College of Zhejiang University, Zhejiang, China
21 Department of Interventional Vascular Surgery, PLA 252 Hospital, Baoding, China
22 Department of Oncology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
23 Department of Minimally Invasive Intervention, Sun Yat-sen University Cancer Center, Guangzhou, China
24 Ultrasound Medicine, The First Affiliated Hospital of Sun Yat-sen University, Zhengzhou, China
25 Department of Interventional Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
26 Department of Interventional Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
27 Department of Interventional and Vascular Therapy, The 4th Hospital of Harbin Medical University, Harbin, China
28 Center of Interventional Oncology and Liver Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
29 Department of Tumor Intervention, Affiliated Renji Hospital, Medical College of Shanghai Jiaotong University, Shanghai, China
30 Department of Interventional Radiology, Second Clinical Medical College, Shenzhen People's Hospital, Jinan University, Guangzhou, China
31 Department of Radiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
32 IR Department of the First Affiliated Hospital of Soochow University, Suzhou, China
33 Department of Ultrasonic Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Harbin, China
34 Department of Nuclear Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, China
Interventional Medical Center, The Affiliated Hospital of Qingdao University, Qingdao
Department of Radiology, First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853
Department of Radiology, Ruijin Hospital/Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, No. 149, South Chongqing Road, Huangpu District, Shanghai 200020
Pancreatic cancer (PC) is a lethal disease with extremely high mortality. Although surgical resection is the optimal therapeutic approach for PC, about 30%–40% of those patients are not candidates for surgical resection when diagnosed. Chemotherapy and radiotherapy also could not claim a desirable effect on PC. The application of interventional radiology approaches is limited by unavoidable damage to the surrounding vessels or organs. By the superiority of mechanism and technology, IRE could ablate the tumor by creating irreversible pores on the membrane of PC cells with other tissues like vessels and pancreatic ducts untouched. This consensus gathers the theoretical basis and clinical experience from multiple Chinese medical centers, to provide the application principles and experience from Chinese experts in the IRE field.
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Wei Y, Xiao Y, Wang Z, Hu X, Chen G, Ding X, Fan Y, Han Y, Huang K, Huang X, Kuang M, Lang X, Li H, Li C, Li J, Li J, Li M, Lu Y, Ni C, Niu L, Sun J, Tian J, Wang H, Wang L, Wu P, Xie X, Xing W, Xu L, Yang P, Yu H, Yuan C, Zhai B, Zhang Y, Zheng J, Zhou Z, Zhu X, Jiang T, Zhang Y. Chinese expert consensus of image-guided irreversible electroporation for pancreatic cancer.J Can Res Ther 2021;17:613-618
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Wei Y, Xiao Y, Wang Z, Hu X, Chen G, Ding X, Fan Y, Han Y, Huang K, Huang X, Kuang M, Lang X, Li H, Li C, Li J, Li J, Li M, Lu Y, Ni C, Niu L, Sun J, Tian J, Wang H, Wang L, Wu P, Xie X, Xing W, Xu L, Yang P, Yu H, Yuan C, Zhai B, Zhang Y, Zheng J, Zhou Z, Zhu X, Jiang T, Zhang Y. Chinese expert consensus of image-guided irreversible electroporation for pancreatic cancer. J Can Res Ther [serial online] 2021 [cited 2021 Oct 27 ];17:613-618
Available from: https://www.cancerjournal.net/text.asp?2021/17/3/613/321015
Pancreatic cancer (PC) is the third reason of cancer-related death in the US and the mortality rate in Asian countries is rising incessantly. The following reasons hindered therapeutics, either surgical or radiochemical, from being effective: (1) pancreatic cancer is more aggressive than most other tumors and often progresses rapidly with undetectable concomitant symptoms. (2) At the initial stage of germination, PC volume can revolve around or abut to some vital structures like the superior mesenteric artery/vein (SMA/SMV) or celiac trunk, make it hard to be excised radically, and about 30%–40% of those patients are not candidates for surgical resection when diagnosed.,, (3) Only a few patients are suitable for surgery, and for the sake of surgical injury and complications, most patients prefer not to undergo surgical resection. Even more, because the invasiveness, unresectability, and high recurrent rate of PC, overall survival is not prolonged as expected. (4) Chemotherapy regimens based on either gemcitabine or FOLFIRINOX do not claim a desirable effect on unresectable pancreatic cancer. (5) Although radiotherapy methods such as intensity-modulated radiotherapy and CyberKnife have an advantage over traditional radiation therapy, the control rate of PC is still poor. (6) Brachytherapy of 125I particles has an effort on the treatment of PC, but sometimes, the outcomes are coming synchronously with complications of pancreatic leakage, bleeding, and radiation enteritis, and there is no evidence which shows that 125I could prolong the OS. (7) Physical ablation techniques such as radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation, based on the extreme temperature, which destroys tumor structure nonspecifically. During the ablating procession, the damages from extreme temperature will destroy normal tissues like vasculature and bile duct concurrently with tumors.,, All of these have to limit the application of these techniques in PC. Irreversible electroporation (IRE) is an emerging local ablation technique which could only target cell membranes and spare the neighboring vessel and bile duct from compromise during the whole procession of ablation. And in this regard, IRE compares favorably to other local ablation techniques in the treatment of PC, in particular, those tumors positioned close to some vital structures or organs. IRE device delivers high-voltage and high-frequency pulses during ablation among the electrodes that create an appropriate ablation area covers over the tumor and forms nanopores on the cell membrane that opens a channel for uniformed ions exchange and then causes irreversible damage depends on the voltage rising incessantly. Those pulses delivered by IRE electrodes apply to the lipid bilayer of the cell membrane, and then break the internal environment of the tumor cell, causing apoptosis and death of cells., This advantage of IRE makes it an optimal method for tumors revolving around or invading SMA/SMV like locally advanced pancreatic cancer (LAPC). Moreover, other than RFA, MWA, and cryoablation, IRE is unimpeded by the heat-sink effect, which will take away the heat energy initiated by extreme temperatures, and could ensure a radical ablation. IRE can be performed under image (computed tomography [CT]/ultrasound) guidance or in open surgery. For the treatment of LAPC, to improve the curative effect, IRE is always conducted combined with chemotherapy. Published studies have demonstrated that IRE can prolong the OS of LAPC patients and when combining IRE with chemotherapy, the median OS of patients could attain to 30.7 months.,, IRE is a novel ablation technique, possesses different rational and applicable principles, necessitating more exquisite and strict operation techniques. After gathering the theoretical basis and clinical experience from multiple centers, to expedite the clinical application and maximize the therapeutic advantages of IRE in PC, a Chinese consensus was accomplished accordantly.
Indications and Contraindications
Patients with biopsy-proved primary and solitary pancreatic tumors and are suitable for general anesthesiaAccording to the American Joint Committee on Cancer stage criteria (8th ed.ition), LAPC of stage II or III (T4N1M0) with regional positive lymph nodes ≤3, not matter treatment-naïve or notTumor size (maximal axial diameter measured on preoperative contrast-enhanced CT/magnetic resonance imaging [MRI] within a week) ≤5 cmPatients are not candidates for radical resection or someone who refuses the surgical operationPatients with a predictable OS longer than 3 months, Karnofsky Performance Score >50.
Patients with serious arrhythmia, epilepsy, heart attacks, or had peacemakers implanted within 1 yearPatients with poor cardiac or pulmonary function are not candidates for general anesthesiaSomeone is allergic to the contrast medium or for other reasons cannot accomplish contrast-enhanced CT/MRIHb <70 g/L, platelet <80 × 109/L within a week before IREMetal implants exist in the 2.5 cm to ablation areaPatients with the preoperative invasion of the portal vein system and occluded portal vein accompanied by portal hypertension and ascitesPatients with bile duct obstruction and serum bilirubin ≥40 μmol/LPatients have taken anticoagulants within 7 days before IRE or have got coagulation disordersAcutely infected personThe pregnant woman or someone who has mental disease could not cooperate well.
Percutaneous IRE including two common image guidance approaches – CT and ultrasound. Preoperative preparation for these two approaches is indiscriminate.
Contrast-enhanced abdominal CT or MRI to identify the relationship of the tumor to surrounding tissue. Positron emission tomography (PET)-CT is ordered if necessary. Dynamic electrocardiogram, X-ray, and cardiac ultrasound are routine tests. For duodenal invasion, the gastroscopy is recommended.
Preoperative baseline workup including blood routine examination, coagulation test, biochemistry examination, and tumor marker examination.
If the tumor obstructs the bile duct, a nonmetallic stent is necessary to be positioned for maintaining lumen patent. If it is unavailable, percutaneous transhepatic cholangiodrainage is an alternative method. Anticoagulants are forbidden within 7 days before the procedure. Dynamic electrocardiogram, pulmonary function tests, and preanesthetic evaluation are routine work. Trypsin inhibitors are prescribed the day before the procedure. The patient is fasted 6 h before IRE and prophylactic antibiotics are recommended. Other preanesthetic preparations such as gastric and urethral intubation are conducted 2 h before the procedure. To get the consent from the patients before the procedure.
The Principles of Percutaneous Irreversible Electroporation
Anesthetic management of irreversible electroporation
To keep a stable breath and muscular relaxation during the procedure, IRE prefers general anesthesia. Propofol is used for anesthesia induction. Air/oxygen/sevoflurane inhalation is used for the maintenance of anesthesia. Fentanyl or remifentanil is used for analgesia. Pressure monitoring of the radial artery as well as electrocardiogram
(ECG) and oxygen saturation monitoring are routine operations. High-voltage pulses will induce muscular contraction, and moderate or severe muscular stimulation in the posterior peritoneum or diaphragm will cause displacement of target tumor, so during IRE procedure, to minimize muscular contraction, nondepolarizing neuromuscular blocking agents (vecuronium bromide and rocuronium bromide) are prerequisite. Furthermore, delivering pulses will cause tachycardia, hypertension, or even trigger arrhythmia.,
Planning and process of irreversible electroporation
Computed tomography-guided percutaneous irreversible electroporation
According to the size and location of the tumor outlined on the preoperative CT/MRI images to select a most suitable position for the patients. Put the marker on the skin over the ablation area or employ the robotic-assistance technique to mark the puncture sites. Set up the intravenous access and monitor the blood pressure of the radial artery. After the accomplishment of anesthesia, ordering an intraoperative contrast-enhanced CT scanning to project a puncture route and determine the number of electrodes used in the procedure. The principles of choosing a puncture route including the shortest path, avoidance of vital vessels, and bile duct. One can pass through the liver, stomach, and intestine if necessary.
Ultrasound-guided percutaneous irreversible electroporation
After fixing the body of the patient, contrast-enhanced ultrasound (CEUS) is used to determine the margin, microcirculation, and perfusion of the tumor as well the vascularity revolving around it. To measure the size of the tumor intraoperatively and insert the electrodes respectively under the guidance of ultrasound. The principles of the CT approach are equally applicable to the ultrasound approach.
Arrangement of irreversible electroporation electrodes
Two to six 19G monopolar IRE electrodes are parallelly positioned into the target area with an active tip length of 1.0–2.0 cm and the distance between the electrodes is 1.5–2.3 cm. Electrodes are commonly inserted along with the long axis of the tumor and create an ablation area cover over the tumor. Maximally avoid making the active tips of any of those electrodes positioned within 0.5 cm perpendicular to large vessels.
Parameters and operation
After all the electrodes are in place, ordering an abdominal CT scan (or under ultrasound guidance) to make sure the position of electrodes is appropriate. Making multiple planner reconstruction (under CT guidance) to measure the distance between tips of electrodes and the position-correlation of the active tips to surrounding tissues. Input the measured parameters into the IRE device and set ablation parameters as recommended – voltage of 1500 V/cm, pulses of 70–100, pulse length of 70–90 μs. Test the IRE device by outputting 20 pulses to see the wave pattern of both current and voltage. Initiating the first session of ablation if the current exceeds 25A and rises over time. If not, then adjust the parameters until it is up to grade. After one session of ablation, recheck the wave pattern, if the current increased by 12A to 15A, it is sound to initiate one more session in this modality. If not, then adjust the parameters until it is up to grade. For those tumors larger than 2 cm, after one session of ablation, withdraw the electrodes for 1 cm along with the needle-tract and repeat. When the procedure is accomplished, make sure the complete ablation is attained by immediate contrast-enhanced CT/CEUS or otherwise IRE-related complications.
Postoperative nursing of irreversible electroporation
After recovery from general anesthesia, the patient is sent back to the ward. ECG monitoring, supporting therapy, and intravenous antibiotics are carried out immediately. Low-molecular heparin is injected hypodermically 6 h after the procedure to prevent thrombosis. The patient is asked for fast for 24–72 h and the trypsin inhibitor is used for at least 24 h.
The complications of image-guided percutaneous IRE include arrhythmia, vomit, abdominal pain, thrombosis, hemorrhage, pancreatic leakage, and infection.
Electrical pulse will damage the vascular endothelial cell during ablation, although it would not rupture the vessels. The veins are more prone to forming thrombus after IRE, especially for the tumor has invaded the portal vein system preoperatively, and ensued a nonocclusive lumen of the portal vein. Hence, the anticoagulants are routinely used for at least within 24 h after the procedure.
IRE -related hemorrhage is commonly caused by, (1) the damage of electrode tip during the inserting process, which could be immediately found on intraoperative CT or ultrasound, (2) mutilation of the preoperatively invaded blood vessel wall, which is necrosed concomitantly with the tumor occurs in about 1–3 days after IRE, (3) slight damage of the integrity of tumor invaded vessel that forms pseudoaneurysm, which will rupture about 2–3 weeks after IRE.
A high-voltage electric field will change the transmembrane potential during the ablation and the open nanopores will alter the permeability of the cell membrane, which will disturb the balance of electrolyte. Furthermore, the stimulation from electric pulses will cause muscle contraction and epileptic seizures.,, All of these above are risk factors of arrhythmia, and necessitate general anesthesia and neuromuscular blocking agents for IRE. Published reports demonstrated that IRE for PC could cause self-limited premature ventricular contraction, which vanished after the termination of pulse delivery. Some patients have suffered self-limited hypertension and tachycardia during IRE which are most common in PC procedure. The hemodynamic changes may correlate with the distance between the electrode needle tip and adrenal gland. Hence, we recommend a defibrillator as a standby application for the IRE procedure.
Because the pancreas is a retroperitoneal organ, sometimes, the electrode will transverse consequentially to the anterior intestines, which increases the exposure of infection. If subsequently, the electrode passes through any vessel around the tumor, it will cause bacteremia. Anyway, this kind of complication correlates to the route selection, the experience of the operator, and the preoperative bowel preparation. During the piercing process, the operator must focus on the depth and direction of the electrodes and advance gently. To avoid repetitive adjustment of the electrodes. The breathing movement of the patient will make the electrode deviate from the predetermined route, therefore request the cooperation of a seasoned anesthetist.
Theoretically, IRE is almost a temperature-constant ablation technique that destroys the cells utilizes electric pulses, and will not be affected by the heat sink. But when the current created by the high-voltage field passes the tissues, the temperature of the tissues wrapped around the active tip of the electrode will go up and cause coagulative necrosis. This kind of thermal damage is localized and only occurs with about 5 mm around the active tip. The thermal damage of IRE correlates to the default voltage, length of active tip, ablation time, and overlaps of repeat ablation.,,,,, If there is a metallic stent in the ablation area, we recommend performing IRE after removing it, otherwise it will conduct heat or induce incomplete ablation. To avoid the damage of the pancreatic duct, intestines, and blood vessels, it is suggested to avert the active tip from fitting closely to those structures above.
If the tumor is close to the hollow viscera like intestines, preoperative assessment should emphasize the interaction of the tumor and intestinal wall. If the tumor has invaded the full-thickness of the intestinal wall, after IRE, the necrotic tissue will make the intestinal wall incomplete and subsequently intestinal leakage.
Taking the modified RSCIST criteria as reference, an IRE-specific criterion was accomplished. Complete response (CR) indicates vanishment of the outline of the tumor immediately after the procedure with low density on contrast-enhanced CT. Scattered gas pockets are presented on the treated volume. In the follow-up images, the tumor vanishes and the tumor marker reduces to the normal level. Partial response (PR) indicates equal or larger than 70% of the tumor are necrotic without enhancement. Stable disease (SD) means the necrotic area is smaller than 70%, and the residual tumor is no larger than the original tumor. Progressive disease (PD) means any new or recurrent lesion detected on contrast-enhancement CT/MRI.
The follow-up examination (enhanced CT/MRI and blood workups) is conducted in 1 week, and 1, 3, and 6 months, respectively, after IRE and then at intervals of about 1 year. On the 3-month interval, PET/CT is suggested to be a basis of reference. Blood workups include blood routine, amylopsin, lipase, and tumor marker.
INDIVIDUALIZED SCHEDULE OF IRREVERSIBLE ELECTROPORATION
The published study has illustrated the optimal tumor size for IRE is no larger than 5.0 cm, and those tumors smaller than 3.0 cm could attain the best ablative effectiveness., Larger tumor volume correlates to poorer prognosis. Hence, IRE requires the most strict control of preoperative indication, feasibility of individual treatment, and evaluation of the desired effect. Induced chemotherapy could improve the long-term effect of LAPC.,
An appropriate guidance approach is of equal importance in the treatment of PC. It is more minimally invasive for image-guided IRE compared to the open surgery. Ultrasound is a real-time monitoring approach, surveilling the vessel and pancreatic duct that hampered the advancing in the puncture route, make for an orientational and accuracy insertion and fewer complications. Under CT guidance, the interference of bowel gas is negligible, but lack of monitoring makes the normal tissues more susceptible to be damaged by the tip of the electrode. The preference for any kind of guidance approach is individualized and depends on the body position of the patient. Multiple imagine fusion is more preferable for deeply located tumors like pancreatic cancer.
When combined with chemotherapy and resection, IRE has shown significantly prolonged survival in patients with LAPC., The production of oncoantigens and the decrease of suppressive immune cell populations such as Treg cells in the ablated tissues can induce increased pro-inflammatory immune response after IRE. This can potentiate the damage of both primary and metastatic cancerous cells and prevent the likelihood of cancer relapse following IRE. Recently, Nielsen et al. have demonstrated that by inactivating systemic Treg cells and activating PD-1+ T cells, IRE could alleviate the immunosuppression of LAPC, indicating the capability of the favorable prognosis. And the combination of IRE with innate immune activators and PD-1 checkpoint blockade may have abscopal effects on distant or secondary tumors like work as the vaccine. But most studies of the immunotherapy and further clinical trials are still underway. The long-term outcome and therapeutic protocols deserve further studies.
Conflicts of interest
There are no conflicts of interest.
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