Outcomes of Irreversible Electroporation for Treatment of Refractory Locally Advanced Pancreatic Cancer

Abstract

Purpose:

To evaluate the safety and effectiveness of irreversible electroporation (IRE) as salvage therapy for locally advanced pancreatic cancer (LAPC).

Materials and Methods:

A retrospective cohort study was conducted of IRE performed by interventional radiologists or hepatopancreaticobiliary surgeons at a tertiary care institution for salvage treatment of LAPC. Procedures were performed between 2010 and 2024; 30 subjects (men, 18; women, 12; median age, 63.5 years) with biopsy-proven adenocarcinoma, evidence of vascular encasement, and progression on chemotherapy were included. Data were collected for patient demographics, prior treatments, tumor size, carbohydrate antigen (CA)19-9 levels, length of treatment stay, IRE treatment parameters, adverse events, posttreatment therapies, overall survival (OS), and progression-free survival (PFS).

Results:

Of 30 patients, 14 received percutaneous IRE and 16 received surgical IRE. Nine subjects received palliative surgery with IRE. OS was 11.4 months (IQR, 6–28 months). PFS was 7.6 months (IQR, 4–21 months). The overall adverse event rate was 33.3%. The serious adverse event rate was 12.1%. There was no association between survival or adverse event rate and age, tumor size, tumor location, or CA19–9 level. Moreover, 50% of subjects received additional treatment following IRE. OS for IRE with chemotherapy was 20.4 months. Outcome and adverse event rate were similar regardless of prior radiation treatment.

Conclusions:

This study demonstrates that IRE may be a safe and effective option for salvage treatment of LAPC following chemotherapy and radiation.

Pancreatic adenocarcinoma is the third leading cause of cancer-related death in the United States, with a dismal 5-year survival rate of 8% (1,2). Meanwhile, incidence has increased by 0.2%–0.3% annually (1,2). Approximately 30% of cases present as locally advanced pancreatic cancer (LAPC), defined by invasion of critical abdominal vasculature. The current standard of care for LAPC involves systemic chemotherapy with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) or GEM-NabP (gemcitabine and nab-paclitaxel) with or without neoadjuvant radiotherapy (3,4). This recommendation is largely based on extrapolation of studies on metastatic disease (3-7). Evidence for FOLFIRINOX and GEM-NabP in LAPC is limited, and both are Category 2A recommendations by the National Comprehensive Cancer Network (4). A meta-analysis of 355 subjects with LAPC across 13 retrospective studies demonstrated a pooled median OS of 24.2 months (95% confidence interval, 21.7–26.8) with FOLFIRINOX.

Data are more limited in the salvage setting after first-line treatment failure for LAPC. Two retrospective studies described OS between 6.5 and 19 months among patients with LAPC or borderline resectable pancreatic cancer who switch chemotherapy agents (8-10). Of the chemotherapeutic options, a fluorouracil-based triplet regimen is preferred in fit patients (7,11). However, FOLFIRINOX toxicity leads to discontinuation in 23%–25% of patients (7,9). Data in the salvage setting of LAPC and in patients who do not tolerate chemotherapy are lacking.

Studies have shown that irreversible electroporation (IRE), a percutaneous nonthermal ablative technique, with or without chemotherapy can improve survival in LAPC (12-23). IRE uses high-voltage, low-energy, electrical pulses to create pores in the cell membrane that lead to cell death (24). In contrast to microwave ablation or cryoablation, IRE is minimally disruptive to vasculature (25). The Percutaneous Irreversible Electroporation in Locally Advanced and Recurrent Pancreatic Cancer (PANFIRE-2) prospective phase II trial demonstrated that IRE improves median survival of patients with LAPC or locally recurrent pancreatic cancer to 15 and 16 months, respectively (17). The MRI-guided stereotactic ablative body radiotherapy versus CT-guided percutaneous irreversible electroporation for locally advanced pancreatic cancer (CROSSFIRE) open-label Phase II trial demonstrated that IRE is as efficacious as stereotactic ablative body radiotherapy for LAPC and locally recurrent pancreatic cancer. This study hypothesizes that IRE also provides a survival benefit as salvage treatment for LAPC.

MATERIALS AND METHODS

Study Design

A retrospective study was performed on all patients that underwent IRE of LAPC at a single tertiary care institution. The study was approved by the institutional review board at the University of California, Irvine Medical Center (Irvine, California). Data were manually collected from electronic medical records, entered into a spreadsheet, and validated by a second observer. All subjects had biopsy-proven adenocarcinoma, radiologic evidence of vascular encasement, and progression on chemotherapy. All subjects had baseline characteristics collected including gender, age, body mass index, American Society of Anesthesiologists Physical Status, Eastern Cooperative Oncology Group Performance Status, carbohydrate antigen (CA)19-9 levels, primary tumor diameter, and prior treatments for pancreatic cancer. The decision to offer IRE was made by a multidisciplinary tumor board. Subjects underwent IRE between August 2010 and December 2024. The primary objective of the study was to determine the effect of IRE on survival outcomes.

Subjects

Thirty-one subjects were identified as treated with IRE for pancreatic adenocarcinoma (Fig 1). One subject who received IRE as first-line neoadjuvant therapy was excluded from this study. The subject was found to have unresectable disease during resection, and the operation was converted to IRE (Fig 1). Therefore, 30 subjects (men, 18; women, 12) were included in this study. Twenty-seven (90%) subjects had LAPC, and 3 (10%) had metastatic disease. Most subjects (53%) had encasement of the superior mesenteric artery (SMA) (Table E1, available online on the article’s Supplemental Material page at www.jvir.org). The median age was 63.5 years (interquartile range [IQR], 56–73 years) at the time of IRE treatment. The median tumor size was 3.4 cm (IQR, 2.7–4.2 cm), and most tumors (53%) were located at the pancreatic head (Tables 1, E2, available online at www.jvir.org). Median CA19-9 level was 65 U/mL (IQR, 24–200 U/mL). Prior to IRE, all subjects progressed on at least 1 line of chemotherapy, 20 subjects (67%) received radiation therapy, 11 subjects (38%) received surgical treatment, and 1 subject (3%) received cryoablation (Table 1).

Figure 1.

Schematic of the study design. IRE = irreversible electroporation.

Table 1.

Baseline Subject Characteristics

Characteristic	Value (N = 30)
Gender
Female	12 (40.0)
Male	18 (60.0)
Age (y)	63.5 (56.0–73.5)
Body mass index (kg/m2)	21.9 (19.5–26.9)
American Society of Anesthesiologists score
0	0 (0.0)
1	0 (0.0)
2	3 (10.0)
3	27 (90.0)
Eastern Cooperative Oncology Group score
0	11 (39.3)
2	9 (32.1)
1	8 (28.6)
Carbohydrate antigen 19-9 (U/mL)	65.0 (24.0–200.0)
Tumor size (cm)	3.4 (2.7–4.2)
Received radiation therapy	20 (66.7)
Received surgical treatment	11 (36.7)
Received cryoablation	1 (3.3)
Prior chemotherapy lines
0	0 (0.0)
1	17 (58.6)
2	11 (37.9)
3	0 (0.0)
4	1 (3.4)

Note–Characteristics are reported as n (%) for categorical data and median (interquartile range) for continuous data.

IRE Procedure

IRE procedures were performed percutaneously by an interventional radiologist or during open abdominal surgery under ultrasound (US) guidance by a surgeon (Fig 2). All procedures were done under general anesthesia in the supine position. Fourteen subjects (47%) underwent percutaneous IRE. Sixteen subjects (53%) underwent surgical IRE. Of surgically performed IRE procedures, 8 (27%) included additional palliative tumor decompression. The additional surgeries performed are reported in Table E3 (available online at www.jvir.org). Prophylactic ceftriaxone was administered intravenously 1 hour before the procedure. Subjects with a documented ceftriaxone allergy were given an alternative antibiotic with similar coverage that did not overlap with their documented allergies.

Figure 2.

Example percutaneous irreversible electroporation (IRE) procedure. Pretreatment axial computed tomography (CT) with fluorodeoxyglucose (FDG)-positron emission tomography (PET) overlay (left) to highlight tumor (white arrows). During treatment (middle), electrodes were advanced under cone-beam CT guidance. Standard CT may also be used. Electrodes were visible as hyperdense lines on axial CT (middle, top) or circles on coronal CT reconstruction (middle, bottom). Here, 3 electrodes were placed 1.5–2 cm apart to encompass the tumor and provide a 5-mm margin. Posttreatment axial CT with FDG-PET overlay (right) demonstrated good response. Ant, anterior; Inf, inferior; Post, posterior; Sup, superior.

All procedures were done using the Nanoknife system (AngioDynamics, Latham, New York) with electrocardiography synchronization. Percutaneous procedures were performed on a Philips image guided-therapy system using Xperguide for needle positioning (Philips, Amsterdam, Netherlands). Surgical procedures were done under US guidance using a laparoscopic US scan-head (LAP L9-5; Phillips, Amsterdam, Netherlands). Electrode positioning was done to ensure a 5-mm tumor margin around the tumor while maintaining a 1.5- to 2.4-cm electrode spacing. Ablation was performed at several depths, and electrode exposure was 1.0–2.0 cm as needed to obtain adequate margins. Electrical parameters were consistent with standard practice guidelines and are reported (Table E4, available online at www.jvir.org) (24,26). Procedures were performed by 3 senior faculty with a combined 64 years of experience. Technical success was defined as delivery of all planned pulses to the tumor while providing an adequate margin and proper electrode spacing. Postprocedural care was done under the guidance of the treating physician. Subjects were observed for a minimum of 1 night and discharged once their pain was controlled, they were voiding, they were tolerating a diet, and they were hemodynamically stable.

Follow-up

One month after the IRE procedure, all subjects underwent a CT abdomen and pelvis with and without contrast to verify ablation with adequate margins. Subject were also seen in clinic at 1 month. Subjects were subsequently followed every 3 months with imaging, laboratories, and clinical visits until their date of death. Subjects also followed up every 3 months with a medical oncologist. Four subjects declined postprocedural chemotherapy. The date of death was collected for all deceased patients. All subjects were retroactively evaluated for progression using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria to determine progression-free survival (PFS). All adverse events related to IRE were graded using the Common Terminology Criteria for Adverse Events v6.0 (CTCAE).

Statistical Methods

Analysis and visualization were done in Python 3.10 (Python Software Foundation, Wilmington, Delaware). There were no missing values across the dataset. Continuous data are expressed as median (IQR), and statistical comparisons were done using the Student t test. Categorical data are expressed as frequency (percentage), and statistical comparisons were performed using the Pearson χ² test. Estimated survival statistics were derived using the Kaplan–Meier estimator within the lifelines 0.30.0 python library. Correlation testing between continuous variables was done using the Pearson product-moment correlation coefficient. OS and PFS are calculated from the date of first IRE procedure.

RESULTS

IRE Treatment

Among the 30 subjects who received IRE, percutaneously treated subjects were significantly older than surgically treated subjects (median, 69.5 vs 58.0; P = .04) and more likely to have had prior surgical treatment (P = .01) (Table E5, available online at www.jvir.org). The median time from diagnosis to IRE was 17.9 months (IQR, 9.7–34.2 months). Technical success was 100% for all procedures. Following treatment, the median length of stay was 1 day (IQR, 1.0–2.0 days) for percutaneous IRE, 5 days for surgical IRE alone (IQR, 5.0–5.5 days), and 11 days (IQR, 9.5–14.0 days) for surgical IRE with additional surgery. Fifteen subjects (50%) received additional therapy after IRE consisting of subsequent IRE procedures, radiation therapy, palliative surgery, or chemotherapy. Three subjects (10%) received subsequent IRE treatment following local recurrence (Table 2).

Table 2.

Therapy Received After Initial IRE.

Thearpy	Value (N =30)
Received therapy after initial IRE	15 (50.0)
IRE	3 (10.0)
Radiation therapy	4 (13.3)
Surgical treatment	1 (3.3)
Chemotherapy	13 (43.3)

Note–Value are given as n (%).

IRE = irreversible electroporation.

The adverse event rate was 33% for all IRE procedures, including repeat IRE. The minor adverse event rate was 24.2%, and the serious adverse event rate was 12.1% (CTCAE Grade III+) (Table 3). Serious adverse events included gastrointestinal bleeding, pancreatitis, SMA pseudoaneurysm, SMA thrombosis without urgent intervention, and sepsis secondary to an abscess. Minor adverse events (CTCAE Grade I/II) included delayed gastric emptying, delayed wound healing, pleural effusion, superior mesenteric vein thrombosis, wound infection, and bile leak (Table 3). The adverse events varied by treatment type (Table E6, available online at www.jvir.org).

Table 3.

Adverse Event Rates and Number of Individual Adverse Events Across All IRE Procedures Performed

Adverse event	Value (N = 33)
Overall adverse event rate	11 (33.3)
Adverse event rate grade I/II	8 (24.2)
Adverse event rate grade III+	4 (12.1)
Adverse events grade I/II
Delayed gastric emptying	3
SMA thrombosis	1
Delayed wound healing	1
Pleural effusion	1
SMV thrombosis	1
Wound infection	1
Bile leak	1
Adverse events grade III+
Gastrointestinal bleed	1
Pancreatitis	1
SMA pseudoaneurysm	1
Septic abscess	1

Note–Values are n (%) or n.

IRE = irreversible electroporation; SMA = superior mesenteric artery; SMV = superior mesenteric vein.

Survival

Of 30 subjects included in this study, 22 (73%) were deceased and 8 (27%) were alive at the time of data collection. The OS rate after IRE was 11.4 months (IQR, 6–28 months) (Fig 3a). The estimated survival rates at 3, 6, and 12 months were 80%, 77%, and 50% respectively. The OS rates for subjects who received percutaneous IRE and surgical IRE are also reported in Table 4. Per RECIST 1.1, 25 subjects (83%) had progression following IRE, and 5 subjects (17%) had stable disease. Of subjects with progression, 8 had new distant lesions, 4 had increased tumor size, and 13 died. Median PFS was 7.6 months (IQR, 4–21 months) (Fig 3b, Table 5). The estimated PFS rates at 3, 6, and 12 months are 80%, 63%, and 39%, respectively (Table 5). There was no significant association between OS or PFS and age, tumor size, tumor location, or pretreatment CA19-9 level (P > .05). Subjects who received additional therapies after IRE including chemotherapy, radiation therapy, surgical treatment, or a second IRE procedure, did not have significantly longer OS or PFS than those who received no additional therapy (P > .05). However, OS among the 13 subjects (43.3%) who received chemotherapy following IRE was 20.4 months.

Figure 3.

Kaplan–Meier survival curves for overall survival (a) and progression-free survival (b) across all subjects following first irreversible electroporation (IRE) procedure. The vertical axis represents the predicted survival (% of all subjects), and the horizontal axis denotes time from first IRE procedure (months). Shaded regions denote the 95% confidence interval for the survival function. “X” marks represent censored subjects. The number at risk and number censored at 0, 10, 20, 30, 40, and 50 months are reported below each graph.

Table 4.

Overall Survival

Survival	All procedures	Percutaneous IRE	Surgical IRE
Subjects	30	14	16
Deceased	23 (76.7)	12 (85.7)	11 (68.8)
Censored	7 (23.3)	2 (14.3)	5 (31.2)
OS (mo)	11.4 (6.3–32.2)	7.1 (1.5–18.1)	18.6 (8.2–39.2)
Estimated OS (mo)
3	80.0	64.0	94.0
6	77.0	57.0	94.0
12	50.0	43.0	56.0

Note–Values are n (%), median (IQR), or n.

IQR = interquartile range; IRE = irreversible electroporation; OS = overall survival.

Table 5.

Progression-Free Survival

Survival	All procedures	Percutaneous IRE	Surgical IRE
Subjects	30	14	16
Deceased	23 (76.7)	12 (85.7)	11 (68.8)
Censored	7 (23.3)	2 (14.3)	5 (31.2)
PFS	7.6 (4.4–24.8)	4.6 (1.5–7.7)	14.9 (6.7–37.4)
Estimated PFS (mo)
3	80.0	64.0	94.0
6	63.0	43.0	81.0
12	39.0	27.0	50.0

Note–Values are n (%), median (IQR), or n.

IQR = interquartile range; IRE = irreversible electroporation; PS = performance-free survival.

DISCUSSION

Few studies have characterized the effectiveness of second line and salvage treatments for LAPC. This retrospective study reports a PFS of 7.6 months and OS of 11.4 months among subjects who receive IRE in the salvage setting. The OS reported in this study is similar to that reported for salvage chemotherapy after failure of first-line chemotherapy (8,9). Despite this, chemotherapy with or without radiation is most often recommended. However, many patients do not tolerate FOLFIRINOX regimens and opt for palliative care (7). Moreover, radiation dose limits prevent treatment of recurrence after stereotactic ablative body radiotherapy (27). The OS for IRE with posttreatment chemotherapy was 20.4 months. IRE appears to be an effective local salvage therapy for LAPC. Its integration within the multimodal treatment paradigm of LAPC might improve local control and improve outcomes in patients with nonmetastatic disease.

The goal of this study was not to compare surgical vs percutaneous IRE. Subjects treated with percutaneous IRE were significantly older and more likely to have had surgery. Given these demographic differences, statistical comparison of survival between surgical and percutaneous IRE was avoided. Further studies should be conducted to determine whether either method confers a survival benefit. The present study suggests that surgical IRE is associated with a longer length of stay and different set of adverse events, likely owing to the more invasive nature of surgical IRE. Despite these differences, both percutaneous and surgical IRE appear to be reasonable options in the salvage setting.

This study had an overall treatment-related adverse event rate of 33.3% and severe (CTCAE Grade III+) adverse event rate of 12.1%. There was no difference in the adverse event rate among the 67% of subjects who received radiation treatment prior to IRE, suggesting that prior radiation treatment should not exclude patients from receiving IRE on the basis of safety. A meta-analysis demonstrated a mean overall adverse event rate of 45% and a serious adverse event rate of 15.2% following percutaneous IRE for pancreatic adenocarcinoma (28). The overall adverse event rate in the present study compares favorably with that in literature. This may be due to a combination of factors including a low number of subjects, differences in reporting criteria, and variation in patient selection.

This study had several limitations. First, as a retrospective study, there is a propensity for selection bias. Second, the number of subjects is low, limiting analysis of survival predictors and treatment subgroups. Third, follow-up intervals were determined by the treating physician, which may affect the reporting of adverse events. Fourth, subjects may have opted for palliative care after IRE, which may have led to underreporting of adverse events. Finally, the timing of chemotherapy after IRE was not controlled.

In conclusion, this retrospective study found that IRE for treatment-refractory oligometastatic and locally advanced pancreatic cancer is associated with an OS of 11.4 months. This result is promising given that 50% did not receive additional treatment. Interpretation of these results is limited by lack of survival outcomes for LAPC salvage therapy in the literature. Nonetheless, this study provides evidence that IRE should be considered in patients with poor chemotherapy tolerance or treatment-refractory LAPC.

RESEARCH HIGHLIGHTS.

• Irreversible electroporation following failure of first-line treatment due to progression or intolerance is associated with an overall survival (OS) of 11.4 months (interquartile range [IQR], 6–28 months) and progression-free survival of 7.6 months (IQR, 4–21 months).

• Irreversible electroporation with chemotherapy following failure of first-line treatment is associated with an OS of 20.4 months.

• The overall adverse event rate was 33.3%. There was no difference in adverse event rate among subjects that received prior radiation treatment.

ABBREVIATIONS

CA

carbohydrate antigen

CT

computed tomography

CTCAE

Common Terminology Criteria for Adverse Events

FOLFIRINOX

5-fluorouracil, leucovorin, irinotecan, and oxaliplatin

IQR

interquartile range

IRB

institutional review board

IRE

irreversible electroporation

LAPC

locally advanced pancreatic cancer

OS

overall survival

PFS

progression-free survival

RECIST

Response Evaluation Criteria in Solid Tumors

SMA

superior mesenteric artery

US

ultrasound