Abstract
Background
Locally advanced pancreatic cancer (LAPC) is one of the most aggressive malignancies. Irreversible electroporation (IRE) is a novel technique that uses a non-thermal ablation to avoid vessel or duct injury.
Purpose
To investigate the safety and efficacy of IRE for the management of LAPC in a Korean population.
Material and Methods
Twelve patients (median age 64 years; age range 46–73 years) treated between December 2015 and March 2017 underwent intraoperative IRE for LAPC. Technical success and clinical outcomes, including complications, serum pancreatic enzyme levels, overall survival (OS), and progression-free survival (PFS), were evaluated.
Results
Tumors were located in the pancreas head in 7 (58.3%) patients and in the body/tail in 5 (41.7%) patients. The median tumor diameter in the longest axis was 3.1 cm. Vascular invasion was observed in all patients and bowel abutment in 3 (25%) patients. Technical success was achieved in all patients. The median serum levels of amylase and lipase were 55 U/L and 31 U/L, respectively, at baseline, increased to 141.5 U/L (P = 0.008) and 53 U/L (P = 0.505), respectively, one day after IRE, and normalized after one week. The rate of 30-day mortality of unknown relation was 8.3% (one individual experienced massive hematemesis 12 days after IRE). The median OS from diagnosis and IRE was 24.5 months and 13.5 months, respectively. The median PFS from diagnosis and IRE was 19.2 months and 8.6 months, respectively.
Conclusion
For patients with LAPC, IRE appears to be a promising treatment modality with an acceptable safety profile.
Keywords
Introduction
Pancreatic adenocarcinoma is one of the most aggressive malignancies, with a one-year survival rate < 20% (1,2). Approximately 30%–40% of patients are diagnosed as locally advanced pancreatic cancer (LAPC) and the overall five-year survival rate of these patients is < 5% (3). The standard therapy for these patients is systemic chemotherapy, with or without radiation (4). Recently, novel chemotherapy regimens, such as FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) or nab-paclitaxel with gemcitabine, have demonstrated improved overall survival, although the prognosis for LAPC remains poor (5,6).
Ablation techniques, including radiofrequency ablation (RFA) and microwave ablation (MWA), have been used to provide symptom relief, improve survival time, and decrease tumor size (2,7,8). However, these techniques can cause inadvertent thermal injury to adjacent major vessels and bile ducts, resulting in high morbidity (28%–40%) and mortality (7.5%) through significant bleeding or bile leakage (7,8).
Irreversible electroporation (IRE) is a novel technique that uses a non-thermal ablation to avoid vessel or duct injury (9). This technique applies pulsatile high-voltage current through electrodes placed into or around the tumor. The current creates nanoscale pores in the lipid bilayer of the cell membrane, disrupting cellular homeostasis and leading to apoptosis (10,11). Several studies investigating the safety and efficacy of IRE for LAPC have reported improved progression-free survival (PFS) and overall survival (OS) compared with conventional chemotherapy or chemoradiation therapy, as well as acceptable overall complication rate (3,12–16). However, studies in the Korean population have not been reported.
The purpose of the present study was to investigate the safety and efficacy of IRE for the management of LAPC in the Korean population.
Material and Methods
Patients
Our Institutional Review Board approved this single-center prospective study. Participants provided written informed consent for study participation, the ablation procedure, and use of their data. The cohort included 12 patients (median age = 64 years; age range = 46–73 years) treated between December 2015 and March 2017. All patients underwent IRE for LAPC as they were not suitable for curative resection due to major vessel invasion > 180° after chemotherapy or chemoradiation therapy. All patient records were reviewed by a multidisciplinary tumor conference before the patient underwent IRE to ensure that all treating physicians agreed with treatment plan. Patient records included information on patient characteristics, previous treatment histories, laboratory findings, and tumor characteristics.
Definitions
LAPC was defined as stage III pancreatic cancer with encasement of the major arterial structures (superior mesenteric artery and/or celiac axis) in > 180° and no evidence of any type of metastatic disease to a distant organ or distant lymph nodes (16). Technical success was defined as the successful delivery of the planned therapy in the operation room. A procedure-related adverse event (AE) was defined as a complication occurring within one month of treatment. The severity of procedure-related AEs was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. A major complication was defined as a grade 3 or higher AE. Disease progression was defined as a focal or diffuse growing mass (i.e. > 20% increase in the longest diameter of the solid lesion in the axial plane compared with the second baseline scan four weeks after IRE) located within 1 cm of the ablated region (17).
IRE procedure
Before and after IRE, all patients received intravenously 7500 U/day of low-molecular-weight heparin to prevent coagulation. Before IRE, a contrast-enhanced computed tomography (CT) scan was collected to determine the size and shape of the tumor and its proximity to surrounding structures (Fig. 1a). The required number of electrodes and their insertion position were planned based on this scan. All patients underwent intraoperative IRE under general anesthesia with standard endotracheal intubation and complete muscular relaxation. For most patients (10/12 patients), a superior midline incision was placed, and the pancreas was exposed. In some patients (2/12 patients), a transgastric approach was used because adhesion around the tumor prevented exposure of the pancreas.
A 63-year-old woman with locally advanced pancreatic cancer. (a) Contrast-enhanced CT scan reveals a 3.3-cm-sized low attenuating mass at the pancreas body (arrow) with celiac trunk and splenic vein invasion (open arrow). (b) Intraoperative US shows a hypoechoic mass. She underwent IRE with three electrodes under US guidance. (c) Contrast-enhanced CT obtained one day after IRE shows complete ablation of the mass (arrow) with preservation of the celiac trunk and splenic veins (open arrow). (d) Contrast-enhanced CT obtained 17 months after IRE indicates stable status of the pancreatic cancer (arrow) with preservation of the celiac trunk and splenic veins (open arrow). CT, computed tomography; IRE, irreversible electroporation; US, ultrasound.
Depending on the tumor size and shape, 19-gauge unipolar IRE electrodes (Nanoknife; AngioDynamics, Amsterdam, the Netherlands) with active tip lengths in the range of 1–1.5 cm and distances in the range of 1.0–2.0 cm were used. The electrodes were placed in the tumor perpendicular to the major axis of the pancreas (ventral to dorsal) under ultrasound (US) guidance (Fig. 1b). After placing the electrodes, ten 1500-V/cm test pulses were delivered to evaluate the current. Electrode voltage setting, pulse length, and exposed-tip length were manually adjusted if the current was excessive or insufficient. Once calibrated, two cycles of 70–90 pulses (pulse length = 70–90 μs; maximum voltage = 3000 V) were administered sequentially by each electrode pair using electrocardiographic triggering. After the initial pulse sequence, additional pulses were applied if the current increase was < 15 A. If the size of the tumor was > 3 cm based on the preoperative CT scan, the electrodes were pulled back and another pulse sequence was performed to ablate the remainder of the tumor.
Follow-up
While in the hospital, patients’ clinical signs and symptoms were closely monitored, and laboratory tests, including those for amylase and lipase level, were performed. To evaluate potential acute procedure-related complications, such as major vessel or bowel injury, contrast-enhanced CT scans were performed one and seven days after IRE (Fig. 1c). After discharge from the hospital, contrast-enhanced CT scans and laboratory tests for amylase and lipase levels were performed one and three months after IRE and every three months thereafter (Fig. 1d). Given the patient’s general condition, additional chemotherapy was performed after IRE.
Statistical analysis
Differences in pancreatic enzymes before and after treatment were assessed using the Wilcoxon signed-rank test. A two-sided P value < 0.05 was considered statistically significant. PFS and OS were calculated using the Kaplan–Meier method. SPSS v23.0 software (SPSS, Chicago, IL, USA) was used to manage and analyze data.
Results
Patient characteristics
Baseline patient and tumor characteristics are provided in Table 1. In total, 12 patients (5 men, 7 women) underwent IRE for LAPC. The median time between diagnosis and IRE was 11.8 months (range = 4.6–44.7 months). All patients had previously undergone multiple rounds of chemotherapy (n = 11, 91.7%) and/or chemoradiation therapy (n = 5, 41.7%). At the time of IRE, 9 (75%) patients had stable disease status and 3 (25%) patients had partial response. In 7 (58.3%) patients, the tumor was located in the pancreas head; in 5 (41.7%) patients, it was located in the pancreas body or tail. The median baseline tumor diameter of the longest axis was 3.1 cm (range = 2.4–4.6 cm). Invasion of the celiac trunk was observed in 7 (58.3%) patients, the superior mesenteric artery in 6 (50%) patients, and the superior mesenteric vein, portal vein, or splenic vein in 9 (75%) patients. Further, 3 (25%) patients had abutment of the bowel, including the stomach (n = 1, 8.3%) and duodenum (n = 3, 16.7%).
Baseline patient and tumor characteristics.
Values are given as n (%) or median (range).
*Oxaliplatin, irinotecan, fluorouracil, and leucovorin.
ECOG-PS, Eastern Cooperative Oncology Group performance status; 5-FU, Fluorouracil; PV, portal vein; SMA, superior mesenteric artery; SMV, superior mesenteric vein; SV, splenic vein.
Technical outcomes
Details of the procedures are summarized in Table 2. Technical success was achieved in all patients (100%). The median number of electrodes used was 4 (range = 3–6). The number of pulses per electrode was in the range of 90–270; electrode intervals were in the range of 1.5–2.0 cm; voltage was in the range of 2250–3000 V; and the tip exposure length was in the range of 1–1.5 cm. Most patients (n = 10, 83.3%) required 1–2 electrode pull-back techniques to treat target lesions > 30 mm. Two (16.7%) patients required placement of additional electrodes to obtain sufficient tumor coverage. The mean current before IRE was 19.8 A (range = 7–33 A) and that after IRE was 35.2 A (range = 15–49 A).
IRE procedure details.
Values are given as n (%) or median (range).
IRE, irreversible electroporation.
Follow-up
The median in-hospital stay after IRE was nine days (range = 7–17 days). Table 3 lists procedure-related complications. Eighteen minor complications (less than grade 2) occurred in 8 (75%) patients after IRE. Abdominal pain was the most common complication (n = 7, 58.3%). All patients with minor complications recovered completely following conservative management. One (8.3%) patients had acute pancreatitis (grade 2). The pre-procedural serum levels of amylase and lipase in this patient were 192 U/L and 44 U/L, and increased to 1244 U/L and 174 U/L, respectively. However, these values normalized to 89 U/L and 61 U/L one week after IRE. In all 12 patients, before IRE, the median serum levels of amylase and lipase were 55 U/L and 31 U/L, respectively. These values increased to 141.5 U/L (P = 0.008) and 53 U/L (P = 0.505), respectively, at one day after IRE. However, these values normalized within one week after IRE (Fig. 2). There was one mortality of unknown relation to IRE (8.3%), who presented with massive hematemesis 12 days after IRE.
Complications and mortality.
Values are given as n (%).
The median values of pancreatic enzymes collected one day before and one day, one week, and one month after IRE. The median serum values of amylase and lipase increased one day after IRE and normalized within one week after IRE. IRE, irreversible electroporation.
Among the 12 patients, 10 (83.3%) patients underwent additional chemotherapy after IRE. However, 2 (16.7%) patients could not undergo chemotherapy due to poor general condition and death, respectively. After a median follow-up period of 19.7 months (range = 12.0–27.3 months), the median OS from diagnosis was 24.5 months (range = 15.9–51.0 months) and the median OS from IRE was 13.5 months (range = 0.4–19.4 months) (Fig. 3a and b). The median PFS from diagnosis was 19.2 months (range = 9.5–47.4 months) and from IRE was 8.6 months (range = 0.4–17 months) (Fig. 3c and d).
Kaplan–Meier curves depict the OS and PFS of 12 patients with LAPC treated with IRE. (a) The median OS from diagnosis was 24.5 months; (b) the median OS from IRE was 13.5 months. (c) The median PFS from diagnosis was 19.2 months; (d) the median PFS from IRE was 8.6 months. IRE, irreversible electroporation; LAPC, locally advanced pancreatic cancer; OS, overall survival; PFS, progression-free survival.
Discussion
The present study reports our initial experiences with using the IRE procedure for LAPC in a Korean population. In this single-center study, the rate of 30-day mortality of unknown relation was 8.3% (1/12 patients). The median OS and PFS from IRE were 13.5 months and 8.6 months, respectively.
Pancreatic cancer is the second most common gastrointestinal malignancy; patients with this disease have a grave prognosis (18). The overall one- and five-year survival rates of pancreatic cancer are < 20% and 5%, respectively (2,18). Only 15%–20% of patients are anatomically resectable at diagnosis and large proportions of patients present with LAPC (30%–40%) and metastatic pancreatic cancer (40%) (3,18,19). Unfortunately, the overall five-year survival rate of these patients is < 5% despite advances in chemotherapy and chemoradiation therapy (3). Recently, newly developed chemotherapy regimens, such as FOLFIRINOX, have provided increases in OS and PFS compared with conventional chemotherapy or chemoradiation therapy in patients with LAPC (a median OS of 24.2 months and a median PFS of 15 months). Nevertheless, the prognosis for LAPC remains poor (20). In addition, thermal ablation technique have high morbidity and mortality rates (7,8).
IRE is based on a non-thermal mechanism; therefore, in theory, the supporting extracellular matrix structures are preserved. Therefore, vulnerable adjacent tissues, such as vessels and pancreatic and bile ducts, should remain intact (21). However, several studies have reported fatal complications, including hemorrhage from gastrointestinal (GI) ulceration, major vessel stenosis, or thrombotic occlusion as well as bile duct injury (12,16,22,23). Previous studies reported major complication rates in the range of 19%–59% (3,12,16,18,22–24). In the present study, there was one mortality with unknown relation mortality (8.3%, grade V) within the 30-day follow-up period.
While GI hemorrhage due to ulceration or inflammatory vessel wall erosion is uncommon, it is one of the most life-threatening complications associated with IRE. Scheffer et al. (12) reported a massive hematemesis resulting from duodenal ulcer following IRE in their study. In this study, one patient died 12 days after IRE (the day after their discharge) due to massive hematemesis. In this case, the possible cause of death can be assumed as follows: Portal vein thrombosis might have been caused by an injury to the upper mesenteric vein after IRE, which can lead to esophageal variceal hemorrhage due to portal hypertension. However, we observed no portal vein thrombosis that may cause esophageal variceal hemorrhage on abdominal CT performed two days after IRE in this patient. Another possible reason for death may have been that perforation occurred in the adjacent duodenum after IRE because the tumor was adjacent to the duodenum. Still, nevertheless, there were no abnormal findings suggesting duodenal perforation or hemorrhage on the abdominal CT performed two days after the procedure. In addition, there was no decrease in hemoglobin level during the patient’s 11-day stay in the hospital after the procedure. Based on these CT scans and blood tests, there was little evidence to support the possibility of hemorrhage due to duodenal injury caused by IRE. Considering the fact that the patient was treated at another hospital at the time of the occurrence of the hematemesis, we were not able to accurately grasp the patient’s condition and it was impossible to judge the causal relationship between the IRE and the adverse reaction (death). Accordingly, we deemed the event to be a mortality of unknown relation. Notwithstanding, as delayed bleeding after IRE can be fatal, patients need to be observed closely for at least one week, and post-procedure CT scans should be checked in all patients undergoing IRE.
Previous studies have reported a 4%–7% incidence of portal or superior mesenteric vein thrombosis after IRE; this complication is thought to contribute to the mortality and morbidity of IRE (3,16,18,24). Kluger et al. (22) hypothesized that the combination of hypercoagulability associated with pancreatic cancer, a low-flow rate due to prior stenosis, and theoretical damage to the venous endothelium after IRE could be causes of venous thrombosis. In the present study, all patients received intravenous heparin before and after IRE to prevent coagulation, and no thrombotic complications were observed. These results suggest that prophylactic anticoagulation treatment could help prevent venous thrombosis.
In this study, 8 (75%) patients reported 18 minor complications primarily associated with GI dysfunction (e.g. abdominal pain, anorexia, dyspepsia, constipation, nausea/vomiting), all of which were controlled with conservative management. These complications could be caused by transient edema and inflammation of the bowel wall after IRE. Further, Scheffer et al. (12) hypothesized that damage of the sympathetic celiac ganglia, splanchnic nerves, and gastric branches of the vagal nerve adjacent the pancreas could cause gastric emptying or secretion dysfunction. In the present study, transient elevation of serum amylase (141.5 U/L, P = 0.008) and lipase levels (53 U/L, P = 0.505) was observed one day after IRE, although these values normalized by one week after IRE. This result could be due to transient inflammation of the pancreas after inserting the electrode during the procedure (25).
Regarding the surgical approach, Martin et al. (26) reported that using a caudad-cephalad approach through the transverse mesentery could prevent vascular needle trauma. By contrast, other studies reported no major complications when patients were treated using a percutaneous anteroposterior approach and there were no statistical association between major complication rates and the type of approach used (15,22,27). In addition, it is difficult to displace the transverse mesocolon in patients who have undergone prior surgery or radiation therapy due to adhesion. All patients in this study underwent IRE successfully using an anteroposterior approach and acceptable outcomes were observed.
Several studies have investigated the outcomes of percutaneous IRE using ultrasound or CT guidance in the patients with LAPC (12,15,19,27,28). Narayanan et al. (27) reported a median OS of 14.5 months from the date of IRE with no procedure-related deaths for percutaneous IRE, which is similar to those reported for intraoperative IRE (12,16). The potential benefits of percutaneous IRE include a relatively short recovery time and fewer potential surgery-related complications. Additionally, the operator can determine the position and distance of needles while performing the procedure under CT guidance. In our institution, two patients have successfully undergone percutaneous IRE without major complications. However, they were not included in the present study because of their short follow-up period.
In the present study, the median OS from diagnosis was 24.5 months and median OS from IRE was 13.5 months, which are comparable to those reported in previous studies (17–23.2 months from diagnosis, 7.5–18 months from IRE) (12,15,16,22,27,28). In terms of PFS, the median PFS from diagnosis was 19.2 months and median PFS from IRE was 8.6 months; these are similar to those reported in previous studies (15 months from diagnosis, 6.1–12.4 months from IRE) (12,15,16,22). These results are comparable to or higher than those of conventional chemotherapy or chemoradiation therapy for LAPC (OS, 9.2–11.4 months; PFS, 5.5–6.3 months) (4,6,20,29,30).
The present study has some limitations. First, this study included a small number of patients. Second, the follow-up time after IRE was relatively short. Further studies with long-term follow-up are needed to determine the OS and its associated factors. Third, there was no control group, such as patients undergoing conventional chemotherapy, to compare OS and PFS. Also, in our study populations, patients with poor performance status due to poor response during anti-cancer treatment (chemotherapy or chemoradiation therapy) before IRE were excluded because the first aim of our study was to assess safety. Therefore, there is a possibility of selection bias. Further randomized controlled studies are needed to overcome these limitations.
In conclusion, for patients with LAPC, IRE appears to be a promising treatment modality with an acceptable safety profile. However, prospective studies with a control group are necessary to determine the efficacy of IRE.
Footnotes
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JHK, MJC, JYP, HSL, HKH, CMK, WJL, MSP, NK, SB, and MDK report grants from the Ministry of Health and Welfare, during the conduct of the study; Initial Experience of Irreversible Electroporation for Locally Advanced Pancreatic Cancer in Korean Population.
Funding
The author(s) received the following financial support for the research, authorship, and/or publication of this article: This research was supported by the “Conditional Approval System of Health Technology” funded by the Ministry of Health and Welfare (Grant No. CAS-2015-01-02). The funder has no role in the present study.
