Medical Policy

Policy Num:      07.001.176
Policy Name:    Irreversible Electroporation of Tumors Located in the Liver, Pancreas, Kidney, or Lung
Policy ID:          [07.001.176] [Ac / B / M- / P-] [6.01.68]

Last Review:      January 14, 2026
Next Review:      January 20, 2027
 

Related Policies:

02.002.019 - Catheter Ablation as Treatment for Atrial Fibrillation
06.001.015 - Stereotactic Radiosurgery and Stereotactic Body Radiotherapy
07.001.090 - Microwave Tumor Ablation
07.001.100 - Cryosurgical Ablation of Primary or Metastatic Liver Tumors
07.001.060 - Radiofrequency Ablation of Primary or Metastatic Liver Tumors
07.001.066 - Cryoablation of Tumors Located in the Kidney, Lung, Breast, Pancreas, or Bone
07.001.071- Radiofrequency Ablation of Miscellaneous Solid Tumors Excluding Liver Tumors
02.003.008- Transcatheter Arterial Chemoembolization to Treat Primary or Metastatic Liver Malignancies
06.001.077- Radioembolization for Primary and Metastatic Tumors of the Liver
08.001.059 - Focal Treatments for Prostate Cancer

Irreversible Electroporation of Tumors Located in the Liver, Pancreas, Kidney, or Lung

Summary

Description

Irreversible electroporation produces high-frequency electric pulses to create an electric current that permanently damages cell membranes causing cell death due to the inability to maintain homeostasis. Irreversible electroporation produces no thermal effect and appears to preserve vessels, nerves and the extracellular matrix.

Summary of Evidence

For individuals being treated with locoregional therapy for tumors in the liver who receive irreversible electroporation (IRE), the evidence includes primarily single-arm studies. Relevant outcomes are overall survival, disease-specific survival, symptoms, morbid events, functional outcomes, and quality of life. Irreversible electroporation may be an option for locoregional therapy that is less damaging to nearby blood vessels, bile ducts, and nerves than thermal ablation therapies. Most studies of IRE for liver tumors lack a comparator arm. One comparative study was identified reporting health outcomes but the study is retrospective and included 18 patients treated with IRE. Therefore, there are insufficient data to determine how survival or adverse events compare to other methods for locoregional therapy. There is a lack of standardization on appropriate use. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with locally advanced pancreatic cancer who receive IRE , the evidence includes single-arm studies. Relevant outcomes are overall survival, disease-specific survival, symptoms, morbid events, functional outcomes, and quality of life. Thermal ablation therapies are not commonly used to treat pancreatic cancer due to the increased risk of trauma to the adjacent major anatomical structures. Irreversible electroporation may be an alternative that does not cause thermal injury to nearby sensitive structures. However, there is a lack of consensus on the optimal IRE treatment protocol. Studies of IRE for pancreatic tumors are single-arm. There are insufficient data to determine whether survival is improved with chemotherapy followed by IRE compared to chemotherapy alone. Two randomized controlled trials are underway. Prospective, single arm studies suggest a high complication rate. There are no studies reporting functional or quality of life outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals being treated with locoregional therapy for tumors in the kidneys who receive IRE , the evidence includes single-arm studies. Relevant outcomes are overall survival, disease-specific survival, symptoms, morbid events, functional outcomes, and quality of life. Studies of IRE for kidney tumors are single-arm. Only one study has included more than 10 participants. No comparative data are available. Therefore, there are no data to determine how survival or adverse events compare to other methods for locoregional therapy. There are no studies reporting functional or quality of life outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals being treated with locoregional therapy for tumors in the lungs who receive IRE , the evidence includes single-arm studies. Relevant outcomes are overall survival, disease-specific survival, symptoms, morbid events, functional outcomes, and quality of life. Irreversible electroporation may be an option for locoregional therapy that is less damaging to nearby bronchovascular structures. Studies of IRE for lung tumors are single-arm. The ALICE study was a prospective, single-arm study conducted at 2 centers that was stopped early (n=23) due to failing to meet expected efficacy at an interim analysis based on high recurrence rates of 61% at a median follow-up of 1 year. No comparative data are available. Therefore, there are no data to determine how survival or adverse events compare to other methods for locoregional therapy. There are no studies reporting functional or quality of life outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals being treated with locoregional therapy for tumors in the prostate who receive IRE, the evidence includes systematic reviews of observational studies and prospective nonrandomized trials. Relevant outcomes are overall survival, disease-specific survival, symptoms, morbid events, functional outcomes, and quality of life. Irreversible electroporation is suggested as an option in clinical guidelines for secondary treatment of biopsy-proven recurrence of prostate cancer after radiation. Studies included in systematic reviews for IRE as initial therapy were too heterogeneous to conduct any pooled analyses. Across those studies, reports of biopsy-proven recurrence post-IRE ranged from 0% to 38.9%. Similarly, studies included in the systematic review for IRE as salvage therapy were also too dissimilar to conduct meta-analyses. Rates of local oncological control post-IRE varied from 67% to 77%, although the definition of control also varied across studies. In the PRESERVE study, 71% of patients had negative in-field biopsies at 12 months, which aligned with results from observational studies across systematic review. The small sample sizes, heterogeneity across studies and study populations, and observational study designs all preclude conclusions of efficacy compared to other standard treatments. No subgroup analyses have been conducted across various severities of prostate cancer. Additionally, the short follow-up times are insufficient to establish long-term oncological effects. No comparative data with guideline-recommended standard of care are available. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether the use of irreversible electroporation improves the net health outcome in individuals with tumors located in the liver, pancreas, kidney, lung, or prostate.

Policy Statements

Irreversible electroporation is considered investigational for treatment of primary or metastatic solid tumors including, but not limited to, tumors of the liver, pancreas, kidney, lung, or prostate.

Policy Guidelines

Other uses of Irreversible Electroporation

Pulsed field ablation is a form of irreversible electroporation energy used to treat individuals with atrial fibrillation. Pulsed field ablation for atrial fibrillation is discussed in evidence review 2.02.19.

Focal therapy with irreversible electroporation as a treatment for prostate cancer is addressed separately in evidence review 8.01.61.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Irreversible Electroporation

Electroporation generates high-frequent electric pulses between two or more electrodes which produces an electric current that damages the cell membrane and allows molecules to pass into the cell passively. Electroporation can be temporary (reversible electroporation) or permanent (irreversible electroporation [IRE] ). In IRE the cell membrane is permanently damaged causing cell death due to the inability to maintain homeostasis. IRE achieves its action with no thermal effect. IRE appears to preserve vessels, nerves and the extracellular matrix.^1,2,3,

Liver Tumors

The National Cancer Institute estimates that there will be over 42,000 new cases of liver and intrahepatic bile duct cancer in 2025.^4, Liver and intrahepatic-bile duct cancer death is the fifth most common cancer related death in males and the seventh most common in females.^5, Approximately 75% of primary liver tumors are hepatocellular carcinoma (HCC) and the remaining cases are mostly cholangiocarcinoma (CCA). HCC is a primary liver malignant tumor that typically develops in the setting of chronic liver disease.^6, The prognosis following diagnosis depends on several factors including tumor mass and hepatic reserve.

The main risk factor for HCC in the U.S. is non-alcoholic fatty liver disease, followed by alcoholic liver disease, and hepatitis C virus and hepatitis B virus infections.^7, HCC is diagnosed more frequently in men than women. Asia-Pacific Islanders have higher rates of HCC compared with other racial and ethnic groups in the US.^8, Mortality rates are higher for Native American people.^5,

Treatment options for HCC are categorized as potentially curative surgical therapies (i.e., resection and liver transplantation) and nonsurgical therapies (liver-directed or systemic). The best long-term survival is observed after curative surgical therapies but many patients are not eligible because of tumor extent or underlying liver dysfunction. National Comprehensive Cancer Network (NCCN) guidelines for treatment of HCC state that all patients with HCC should be evaluated for potential curative therapies. For most patients with liver-isolated HCC who are not candidates for resection or transplant, liver-directed, locoregional therapies, such as ablation, are preferable to systemic therapy. Ablative strategies are potentially curative for small lesions (≤3 cm). IRE is thought to have some advantages over thermal methods of ablation, for example, the lack of “heat sink” effect from radiofrequency ablation (RFA) and the ability to treat tumors near vessels, bile ducts, and other critical structures.^9,

Similarly for treatment of intrahepatic CCA, NCCN guidelines state that patients with intrahepatic CCA should be evaluated for potentially curative therapies (i.e., resection, ablation for lesions <3 cm). The guidelines also state that locoregional treatment such as ablation may be considered in patients who are not candidates for resection or to downstage for other treatments.^10,

Pancreatic Cancer

Pancreatic ductal adenocarcinoma has a poor prognosis. The National Cancer Institute estimates that in 2025, there will be over 67,000 new cases of pancreatic cancer in the U.S. and over 51,000 pancreatic cancer deaths.^4, Pancreatic cancer is the third-leading cause of cancer death in men and women.^5,

Risk factors for developing pancreatic cancer include: cigarette smoking, obesity, alcohol use, diabetes, pancreatitis and hereditary factors.^11,

Surgical resection is considered the only curative therapy although the majority of cases of pancreatic cancer are unresectable. Locally advanced pancreatic cancer accounts for 30% of newly diagnosed cases of pancreatic cancer and is usually unresectable due to local involvement of adjacent vessels. The 5-year overall survival rate is < 5% for locally advanced, unresectable disease.^12,

The NCCN recommended treatment for patients with locally advanced pancreatic adenocarcinoma includes systemic therapy with fluorouracil + leucovorin + irinotecan + oxaliplatin (FOLFIRINOX)-based or gemcitabine-based therapy, potentially with radiation therapy, with the goal of shrinking the tumor enough for surgical resection. Individuals who are unable to undergo surgery may continue systemic therapy. Depending on the kind of cancer and the genetic makeup some individuals may be candidates for immunotherapy or poly adenosine diphosphate-ribose polymerase (PARP) inhibitors.^13, Thermal (radiofrequency and microwave) ablation therapies are not commonly used due to the increased risk of trauma to the adjacent major anatomical structures. IRE is being considered as an adjunct to systemic therapy because it may not cause thermal injury to nearby sensitive structures such as the superior mesenteric and portal veins, superior mesenteric and celiac arteries, bile duct adjacent nerves, or gastrointestinal structures.

Kidney Tumors

The National Cancer Institute estimates that there will be over 80,000 new cases of kidney cancer and over 14,000 kidney cancer related deaths in 2025.^4,5, At diagnosis, approximately 65% of disease is localized disease.^4,

Kidney cancer is approximately 2-fold more common in males compared to females. Mortality rates are 2-fold higher for kidney cancers in Native American people compared to White people.^5, There are many risk factors for kidney cancer such as smoking, hypertension, obesity, chronic kidney disease, exposure to analgesics, chemotherapy and certain toxic compounds, and kidney stones.^{14,15,16,17,18,19,20,}

Surgery is curative for most patients with localized kidney cancer and is therefore the preferred treatment. NCCN guidelines for kidney cancer recommend partial or radical nephrectomy for T1 kidney cancer, or ablation or active surveillance in select patients. The guidelines say that thermal ablation is an option for the management of clinical stage T1 renal lesion that are ≤3 cm and is an option for clinical T1b masses in select patients who not eligible for surgery. However, the guidelines caution that randomized phase III trials of ablative techniques with surgical resection have not been performed.^21,

Lung Tumors

The National Cancer Institute estimates that there will be over 226,000 new cases of lung cancer and over 124,000 lung cancer deaths in 2025.^4, Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer death in both men and women.^5,

Cigarette smoking is the leading risk factor for lung cancer, accounting for 80% to 90% of lung cancer deaths in the US. Other risk factors include radon exposure and radiation therapy to the chest.^22, Black men are approximately 12% more likely to develop lung cancer than White men and Black women are approximately 16% less likely to develop lung cancer than White women. Women have historically had a lower risk than men, but the gap is closing.^5,

The standard for treatment of stage I non–small cell lung cancer (NSCLC) in operable patients is surgical resection with lobectomy and systematic lymph node evaluation. However, a significant number of patients with stage I lung cancer are considered medically inoperable or high-risk surgical candidates. NCCN guidelines state that local ablative therapy with image-guided thermal ablation includes radiofrequency ablation, microwave ablation, and cryoablation, and may be be considered for those patients who are deemed “high risk” (medically inoperable due to comorbidities) and is an option for the management of NSCLC lesions <3 cm. The guidelines also state that in the setting of progression at a limited number of sites (oligoprogression), local ablative therapy may extend the duration of benefit of the current line of systemic therapy..^23,

Prostate Cancer

The National Cancer Institute estimates that there will be over 313,000 new cases of prostate cancer and over 35,000 prostate cancer deaths in 2025.^4, The 5-year relative survival rate for prostate cancer is 97.9%. The most common risk factor for developing prostate cancer is increasing age.^24, Black men are more likely to get prostate cancer compared to men of other races or ethnicities. Black men are also more than twice as likely to die from prostate cancer compared to men of other races. Genetic factors can also be a risk factor for prostate cancer, especially if a first-degree relative has had prostate cancer.

The standard for treatment of low-risk or favorable intermediate-risk prostate cancer includes active surveillance, radiation therapy, or radical prostatectomy. In patients with regional prostate cancer or higher risk groups, androgen deprivation therapy is recommended, generally in combination with radiation therapy or abiraterone. NCCN guidelines state that ablative therapy (either focal or whole gland ablative therapy) is an experimental and emerging technology for the initial treatment of localized prostate cancer that lacks randomized controlled trial evidence with long-term follow-up showing its superiority or noninferiority to current recommended management strategies. Focal therapy meets the criteria as an alternative therapy, or a non-standard treatment for initial treatment. External beam radiotherapy, brachytherapy, and cryotherapy ablation are currently US Food and Drug Administration (FDA) approved or cleared for initial treatment of prostate cancer, but randomized evidence to the superiority in long-term cancer control and/or quality of life are lacking when delivered as focal rather than whole gland therapy. Other device categories, including IRE, are noted as not currently FDA approved or cleared for the treatment of prostate cancer as focal or whole gland therapy and should only be used in the context of a clinical trial.^25,

NCCN guidelines recommend the use of local therapy as secondary treatment in the case of biopsy-proven recurrence in the prostate after radiation therapy without distant metastatic disease. Local therapy options for patients with recurrence in the prostate include cryotherapy, IRE, high-intensity focused ultrasound, reirradation (ie, brachytherapy, sterotactic body radiotherapy), and prostatectomy plus pelvic lymph node dissection.^25,

Regulatory Status

The NanoKnife System^TM (Angiodynamics) was originally cleared through the 510(k) process (K102329) in 2011 for the surgical ablation of soft tissue. In 2024, the indication for NanoKnife was expanded to surgical ablation of soft tissue, including prostate tissue. FDA product code: OAB.

Rationale

This evidence review was created in August 2024 with a search of the PubMed database. The most recent literature update was performed through October 6, 2025.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Population Reference No. 1

Liver Tumors

Clinical Context and Therapy Purpose

The purpose of irreversible electroporation (IRE) in individuals being treated with locoregional therapy for tumors in the liver is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest are individuals being treated with locoregional therapy for hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (CCA). These individuals are generally nonsurgical candidates with one or a few small localized HCC or intrahepatic CCA or those for whom local ablation is being used to downstage in preparation for other treatments. Ablative strategies may be used as a curative treatment for small lesions (≤3 cm).

IRE has also been used in patients with hepatic metastases.

Interventions

The therapy being considered is IRE. The NanoKnife System is an IRE system cleared in the US for the surgical ablation of soft tissue, including prostate tissue.

The NanoKnife System is a software-controlled low-energy direct-current generator that includes single electrode probes and an optional probe spacer. Voltage is applied between pairs of probes in a series of pulses with adjustable waveform.^26,

The IRE procedure is performed under computed tomography guidance and electrocardiography synchronization due to the possibility of muscular spasms caused by high-voltage pulses.^27, IRE is performed under general anesthesia, either percutaneously or open. The physician places 2 to 6 electrodes to bracket the targeted tissue and then applies the series of electrical pulses. ^28,

Comparators

The following therapies are currently being used to make decisions about locoregional therapy in HCC and intrahepatic CCA: radiofrequency ablation (RFA), microwave ablation (MWA), surgical ablation, percutaneous ethanol injection, cryoablation, arterially directed therapies (ie, arterial embolization), and radiation therapy (including stereotactic body radiation therapy [SBRT]).

Outcomes

Overall survival, disease-free survival and recurrence, quality of life, complications and adverse events are outcomes of interest. IRE can cause cardiac arrhythmias and uncontrolled muscle contractions.

Median survival for HCC depends on etiology but is generally less than 1 year.^29, Median survival for intrahepatic CCA is generally less than 2 years.^30, Therefore trials with outcomes of 1 to 2 years of follow-up are preferred.

There is no consensus as to the optimal approach for or length of post-treatment surveillance in patients undergoing locoregional therapy for HCC.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Wade et al (2023) reported results of a systematic review and meta-analysis of ablative and non-surgical therapies for early and very early HCC commissioned by the National Institute for Health Care Research in the UK.^31, The objective was to review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small HCC (≤ 3 cm). The authors included 37 RCTs (n>3700) comparing ablative and non-surgical therapies to any comparator in the network meta-analysis. The authors identified only 1 non-randomized, comparative study (Sugimoto et al) of IRE; the study compared IRE with RFA (n = 21 patients). The Sugimoto study was rated as having a high risk of bias using the Cochrane tool and is reviewed in the following section.

Randomized Controlled Trials

No RCTs were identified.

Nonrandomized Studies

The majority of studies of IRE for liver cancer have not included a comparator and have included samples sizes smaller than 50.^{32,33,34,35,36,37,38,39,40,}

Cannon et al (2013) reported results of the largest single-arm study (n=44) which was from a prospective registry of patients undergoing IRE for hepatic tumors.^33, The patients had colorectal metastasis (n=20), HCC (n=14), and other metastases (n=10). Five patients (11%) had 9 adverse events but all complications resolved within 30 days. Local recurrence free survival at 3, 6, and 12 months was 97%, 95%, and 60%, respectively.

Two comparative studies were identified. Sugimoto et al (2019) reported results of a prospective study in 21 patients with HCC comparing RFA (n=11) to IRE (n=10). However, they reported only physiological outcomes; no health outcomes were reported.^41,

Blaise et al (2021) reported results of a retrospective comparative study including patients with HCC and tumor portal invasion treated by percutaneous ablation (n=44) from 1 center compared to a control group drawn from an external RCT including patients treated with sorafenib or trans-arterial radioembolization (TARE).^42, The percutaneous ablation group included 26 patients treated by multi-bipolar radiofrequency ablation (MBP-RFA) alone, 15 by IRE alone, and 3 by both MBP-RFA and IRE. Forty-one patients treated by percutaneous ablation (MBP-RFA or IRE) were matched using propensity-score matching with 41 patients either from TARE or sorafenib groups from an external RCT. Median overall survival was 16 months (95% confidence interval [CI], 13 to 24) in the ablation group versus 14 months (95% CI, 9 to 24) in the control group. Median progression-free survival was 7 months (95% CI, 3 to 10) in the ablation group versus 4 months (95% CI, 3 to 6) in the control group.^42,

Section Summary: Liver Tumors

Studies of IRE for liver tumors are primarily single-arm. One comparative study was identified reporting health outcomes but the study is retrospective and included 18 patients treated with IRE. Therefore, there is insufficient data to determine how survival or adverse events compare to other methods for locoregional therapy. There are no studies reporting functional or quality of life outcomes. There is a lack of standardization on appropriate use. A protocol for patient selection, procedural parameters, perioperative care, and follow-up of IRE for the treatment of liver tumors has been proposed^43, but has not been tested.

For individuals being treated with locoregional therapy for tumors in the liver who receive irreversible electroporation (IRE), the evidence includes primarily single-arm studies. Relevant outcomes are overall survival, disease-specific survival, symptoms, morbid events, functional outcomes, and quality of life. Irreversible electroporation may be an option for locoregional therapy that is less damaging to nearby blood vessels, bile ducts, and nerves than thermal ablation therapies. Most studies of IRE for liver tumors lack a comparator arm. One comparative study was identified reporting health outcomes but the study is retrospective and included 18 patients treated with IRE. Therefore, there are insufficient data to determine how survival or adverse events compare to other methods for locoregional therapy. There is a lack of standardization on appropriate use. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2 

Pancreatic Cancer

Clinical Context and Therapy Purpose

The purpose of IRE in individuals with locally advanced pancreatic cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest are individuals with locally advanced pancreatic cancer.

Interventions

The therapy being considered is IRE in addition to systemic therapy. The NanoKnife System is an IRE system cleared in the US for the surgical ablation of soft tissue, including prostate tissue.

The NanoKnife System is a software-controlled low-energy direct-current generator that includes single electrode probes and an optional probe spacer. Voltage is applied between pairs of probes in a series of pulses with adjustable waveform.^26,

The IRE procedure is performed under computed tomography guidance and electrocardiography synchronization due to the possibility of muscular spasms caused by high-voltage pulses.^27, IRE is performed under general anesthesia, either percutaneously or open. The physician places 2 to 6 electrodes to bracket the targeted tissue and then applies the series of electrical pulses. ^28,

Comparators

The following therapies are currently being used to make decisions about locally advanced pancreatic cancer: systemic therapy alone, systemic therapy with RFA, and systemic therapy with MWA.

Outcomes

Overall survival, disease-free survival and recurrence, quality of life, complications and adverse events are outcomes of interest. IRE can cause cardiac arrhythmias and uncontrolled muscle contractions.

Locally advanced pancreatic Stage 3 cancer has a median survival of less 1 year.^44, Studies with at least 1 year follow-up are preferred.

American Society of Clinical Oncology published recommendations from a meeting of a working group on outcomes in clinical trials of treatments for pancreatic cancer. The group concluded that a 3- to 4-month improvement in overall survival in gemcitabine-eligible and gemcitabine/albumin-bound paclitaxel-eligible individuals and a 4- to 5-month improvement in overall survival for fluorouracil + leucovorin + irinotecan + oxaliplatin (FOLFIRINOX)-eligible individuals was clinically meaningful.^45,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Charallambous et al (2020) reported results of a systematic review of 9 studies of IRE in 460 patients with locally advanced pancreatic cancer published between 2000 and 2019.^46,Four of the studies were prospective and 5 were retrospective. None of the studies were comparative. Sample sizes ranged from 10 to 152. Follow-up duration ranged from 3 to 29 months. Adverse events were reported with varying methods across the studies. Intraoperative adverse events were described but rates were not given; hypertensive episodes, hypotensive episodes, and transient supraventricular tachycardia were noted in the studies. The rate of complications ranged from 14% to 53% across the studies but with varying definitions; IRE-related mortality was reported in 5 patients.^46,

Randomized Controlled Trials

No published RCTs were identified. The DIRECT RCT (NCT03899636; n=528) is registered on clinicaltrials.gov with a completion date of April 2025. The DIRECT trial is a multicenter trial in the US designed to compare chemotherapy alone to chemotherapy followed by IRE in patients with stage III pancreatic cancer. In the United Kingdom, the Treatment of unresectable Locally Advanced Pancreas cancer with Percutaneous Irreversible Electroporation following initial systemic chemotherapy (LAP-PIE; ISRCTN14986389) is also designed to compare chemotherapy alone to chemotherapy plus IRE and had a completion date of June 2025; results have not yet been published.

Nonrandomized Studies

The published studies for IRE in pancreatic cancer are single-arm.^{47,48,49,50,51,52,53,54,55,56,57,}

Holland et al (2019) reported results of the largest prospective, multicenter study including 152 patients with locally advanced pancreatic cancer treated with IRE from 2015 to 2017 from the American Hepato-Pancreato-Biliary Association (AHPBA) Pancreatic Registry.^58, The registry had a standardized protocol for settings and delivery of energy during the IRE procedure. The median follow-up was 19 months following diagnosis. The overall adverse event rate was 18% and mortality was 2%. Nineteen (13%) patients experienced severe adverse events. Nine (6%) patients experienced local recurrence. Median time to progression, progression free survival, and overall survival from diagnosis were 27 months, 23 months, and 31 months, respectively. ^58,

Raurus et al (2020) reported results of the phase 2, prospective, single-arm study conducted in the Netherlands between 2012 and 2017 called the Percutaneous Irreversible Electroporation in Locally Advanced and Recurrent Pancreatic Cancer (PANFIRE-2; NCT01939665).^51, PANFIRE-2 consecutively enrolled 50 study participants: 40 with locally advanced pancreatic cancer and 10 with isolated local recurrence after pancreatic tumor resection. Participants were adults with a maximum tumor diameter of 5 cm. Individuals with ventricular cardiac arrhythmias, an implanted stimulation device, or compromised liver function were excluded. The median hospital stay was 4 days (range, 2 to 21 days). The median largest tumor diameter was 4.0 cm (interquartile range [IQR], 3.7 to 4.6 cm). Fourteen minor and 21 major adverse events occurred in 29 participants (58% overall complication rate). Most minor adverse events involved gastrointestinal symptoms. Serious adverse events included biliary obstruction (n=4; 11%), cholangitis and/or pancreatitis (n=5; 14%) or pancreatic fistula (n=1; 3%), severe hematemesis due to bleeding from a duodenal ulcer (n=1; 3%), duodenal perforation (n=1; 3%), high-grade stenosis of the superior mesenteric artery (n=2; 6%), gastroparesis (n=3; 9%), and chyle leakage (n=1; 3%). Two participants died less than 90 days after IRE. The median overall survival for participants with locally advanced pancreatic cancer was 17 months from the time of diagnosis (95% CI, 15 to 19) and 10 months from IRE (95% CI, 8 to 11). Median local tumor progression-free survival was 10 months (95% CI, 8 to 11).^51,

The DIRECT registry study (NCT03899649) is a Food and Drug Administration-approved Investigational Device Exemption study that aims to prospectively investigate the safety and efficacy of IRE treatment combined with chemotherapy compared to chemotherapy alone in patients with pancreatic cancer. It is conducted by the same group as the ongoing DIRECT RCT. Initial results from the multicenter, observational, non-randomized study have been published by Martin et al (2024).^59, One hundred fourteen individuals were enrolled in the registry over 4 years (n=87 in IRE arm and n=27 in chemotherapy only arm). All patients received standard chemotherapy, with the majority of patients (76.3%) receiving fluorouracil + leucovorin + irinotecan + oxaliplatin (FOLFIRINOX)-based regimens. Initial results demonstrated equivalent morbidity and mortality rates with IRE + chemotherapy compared to chemotherapy alone. The 30-day all-cause mortality was similar in both groups (2 [2.3%] deaths with IRE vs 1 [3.7%] death in standard of care group). Ninety-day mortality was also similar (5 [6%] deaths and 2 [7.4%] deaths in the IRE and standard of care groups, respectively). Two patients in the IRE group died from treatment-related complications and 1 patient in the chemotherapy group died due to chemotherapy-related complications. Adverse event rates were similar between groups during the 90-day time period after enrollment.

Section Summary: Pancreatic Cancer

There is a lack of consensus on the optimal IRE treatment protocol.^60, Studies of IRE for pancreatic tumors are single-arm. There is insufficient data to determine whether survival is improved with chemotherapy followed by IRE compared to chemotherapy alone; RCTs are underway. Prospective, single arm studies suggest a high complication rate. There are no studies reporting functional or quality of life outcomes.

For individuals with locally advanced pancreatic cancer who receive irreversible electroporation, the evidence includes single-arm studies. Relevant outcomes are overall survival, disease-specific survival, symptoms, morbid events, functional outcomes, quality of life. Thermal ablation therapies are not commonly used to treat pancreatic cancer due to the increased risk of trauma to the adjacent major anatomical structures. IRE may be alternative that does not cause thermal injury to nearby sensitive structures. However, there is a lack of consensus on the optimal IRE treatment protocol. Studies of IRE for pancreatic tumors are single-arm. There is insufficient data to determine whether survival is improved with chemotherapy followed by IRE compared to chemotherapy alone. 2 RCTs are underway. Prospective, single arm studies suggest a high complication rate. There are no studies reporting functional or quality of life outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3

Kidney Tumors

Clinical Context and Therapy Purpose

The purpose of IRE in individuals being treated with locoregional therapy for tumors in the kidney is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest are individuals being treated with local ablation for renal cell carcinoma. These are generally individuals with T1a lesions that are ≤3 cm or T1b lesions that are not eligible for surgery.

Interventions

The therapy being considered is IRE. The NanoKnife System is an IRE system cleared in the US for the surgical ablation of soft tissue, including prostate tissue.

The NanoKnife System is a software-controlled low-energy direct-current generator that includes single electrode probes and an optional probe spacer. Voltage is applied between pairs of probes in a series of pulses with adjustable waveform.^26,

The IRE procedure is performed under computed tomography guidance and electrocardiography synchronization due to the possibility of muscular spasms caused by high-voltage pulses.^27, IRE is performed under general anesthesia, either percutaneously or open. The physician places 2 to 6 electrodes to bracket the targeted tissue and then applies the series of electrical pulses. ^28,

Comparators

The following therapies are currently being used to make decisions about locoregional therapy for tumors in the kidney: cryosurgery, RFA, MWA, SBRT, and active surveillance.

Outcomes

Overall survival, disease-free survival and recurrence, quality of life, complications and adverse events are outcomes of interest. IRE can cause cardiac arrhythmias and uncontrolled muscle contractions.

The incidence of renal cell carcinoma recurrence after nephrectomy has been reported to be about 7% with a median time to recurrence of 38 months for T1 tumors. The greatest risk of recurrence after nephrectomy is within the first 5 years.^61, Therefore studies should include follow-up of 3 to 5 years.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Hilton et al (2022) reported results of a systematic review of the safety and early oncological outcomes of 10 studies (n=83) of IRE for small renal masses.^62, The review included studies published through 2020. One cohort study (Canvasser 2017, described below) included 41 participants with renal cell carcinoma. The remaining studies were case series including 10 or fewer participants with renal masses. Follow-up was less than 12 months in 7 of the studies (range, 3 to 34 months). The most frequently reported adverse events were transient hematuria and asymptomatic perirenal hematomas.

Randomized Controlled Trials

No published RCTs were identified.

Nonrandomized Studies

The studies of IRE for renal cell cancer are single-arm and the majority have included 10 or fewer participants.^{63,64,65,66,67,68,69,70,71,72,}

Canvasser et al (2017) reported results of the largest study of IRE for renal masses, including 41 participants with cT1a renal masses treated with IRE in the US between 2013 and 2016.^64, The study was prospective and single center. Mean follow-up was 22 months. No grade II or higher intraoperative or post-operative complications were reported. 2-year local recurrence-free survival was 92%.

Section Summary: Kidney Tumors

Studies of IRE for kidney tumors are single-arm. Only one study has included more than 10 participants. No comparative data are available. Therefore, there is no data to determine how survival or adverse events compare to other methods for locoregional therapy. There are no studies reporting functional or quality of life outcomes.

For individuals being treated with locoregional therapy for tumors in the kidneys who receive irreversible electroporation, the evidence includes single-arm studies. Relevant outcomes are overall survival, disease-specific survival, symptoms, morbid events, functional outcomes, quality of life. Studies of IRE for kidney tumors are single-arm. Only one study has included more than 10 participants. No comparative data are available. Therefore, there is no data to determine how survival or adverse events compare to other methods for locoregional therapy. There are no studies reporting functional or quality of life outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Lung Tumors

Clinical Context and Therapy Purpose

The purpose of IRE in individuals being treated with locoregional therapy for tumors in the lung is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest are individuals being treated with local ablation for lung cancer. These individuals are generally nonsurgical candidates or those with lesions <3 cm.

Interventions

The therapy being considered is IRE. The NanoKnife System is an IRE system cleared in the US for the surgical ablation of soft tissue, including prostate tissue.

The NanoKnife System is a software-controlled low-energy direct-current generator that includes single electrode probes and an optional probe spacer. Voltage is applied between pairs of probes in a series of pulses with adjustable waveform.^26,

The IRE procedure is performed under computed tomography guidance and electrocardiography synchronization due to the possibility of muscular spasms caused by high-voltage pulses.^27, IRE is performed under general anesthesia, either percutaneously or open. The physician places 2 to 6 electrodes to bracket the targeted tissue and then applies the series of electrical pulses. ^28,

Comparators

The following therapies are currently being used to make decisions about locoregional therapy for tumors in the lung: RFA, MWA, and cryosurgery.

Outcomes

Overall survival, disease-free survival, and recurrence, quality of life, complications and adverse events are outcomes of interest. IRE can cause cardiac arrhythmias and uncontrolled muscle contractions.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

No published RCTs were identified.

Nonrandomized Studies

Two nonrandomized, prospective, single-arm studies have been published.^66,73, Thomson et al (2011) includes a mix of tumor types in 38 participants including lung.

Ricke et al (2015) reported results of the ALICE single-arm, multicenter (2 sites) trial.^73, The ALICE study was designed to enroll 36 participants with primary and secondary lung malignancies and preserved lung function. However, the study was stopped early (n=23) because the expected efficacy was not met at an interim analysis. Median follow-up was 12 months. Sixty-one percent (14/23) of participants developed progressive disease. Four percent (1/23) of participants had stable disease, 4% (1/23) had partial remission, and 30% (7/23) had complete remission. Pneumothoraces occurred in 48% (11/23) of participants with chest tubes required in 8 individuals.^73,

Section Summary: Lung Tumors

Studies of IRE for lung tumors are single-arm. The ALICE study was a prospective, single-arm study conducted at 2 centers that was stopped early (n=23) due to failing to meet expected efficacy at an interim analysis based on high recurrence rates of 61% at a median follow-up of 1 year. No comparative data are available. Therefore, there is no data to determine how survival or adverse events compare to other methods for locoregional therapy. There are no studies reporting functional or quality of life outcomes.

For individuals being treated with locoregional therapy for tumors in the lungs who receive irreversible electroporation, the evidence includes single-arm studies. Relevant outcomes are overall survival, disease-specific survival, symptoms, morbid events, functional outcomes, quality of life. Irreversible electroporation may be an option for locoregional therapy that is less damaging to nearby bronchovascular structures. Studies of IRE for lung tumors are single-arm. The ALICE study was a prospective, single-arm study conducted at two centers that was stopped early (n=23) due to failing to meet expected efficacy at an interim analysis based on high recurrence rates of 61% at a median follow-up of 1 year. No comparative data are available. Therefore, there is no data to determine how survival or adverse events compare to other methods for locoregional therapy. There are no studies reporting functional or quality of life outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5

Prostate Tumors

Clinical Context and Therapy Purpose

The purpose of IRE in individuals being treated with locoregional therapy for tumors in the prostate is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest are individuals being treated with local ablation for prostate cancer. These individuals generally have biopsy-proven recurrence in the prostate after radiation therapy without distant metastatic disease.

Interventions

The therapy being considered is IRE. The NanoKnife System is an IRE system cleared in the US for the surgical ablation of soft tissue, including prostate tissue.

The NanoKnife System is a software-controlled low-energy direct-current generator that includes single electrode probes and an optional probe spacer. Voltage is applied between pairs of probes in a series of pulses with adjustable waveform.^26,

The IRE procedure is performed under computed tomography guidance and electrocardiography synchronization due to the possibility of muscular spasms caused by high-voltage pulses.^27, IRE is performed under general anesthesia, either percutaneously or as an open procedure. The physician places 2 to 6 electrodes to bracket the targeted tissue and then applies the series of electrical pulses.^28,

Comparators

The following therapies are currently being used to make decisions about locoregional therapy for tumors in the prostate: prostatectomy, radiation therapy, systemic therapy, cryoablation, brachytherapy, high-intensity focused ultrasound (HIFU), and SBRT.

Outcomes

Overall survival, disease-free survival, and recurrence, quality of life, complications and adverse events are outcomes of interest. IRE can cause cardiac arrhythmias and uncontrolled muscle contractions.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Initial Treatment of Low- or Intermediate-Risk Prostate Cancer

Systematic Reviews

Zhang et al (2025)^74, and Prabhakar et al (2024)^75, published systematic reviews of IRE used for initial treatment of low- or intermediate-risk prostate cancer. Nineteen (N=1452) and 14 (N=899) observational studies were included in Zhang et al and Prabhakar et al, respectively. The heterogeneity across studies did not allow for meta-analyses or pooled results in either review.

Of the studies included in Prabhakar et al that reported on recurrence within the zone of ablation, recurrence ranged from 0% to 38.9% for in-field and 3.6% to 28% for out-of-field recurrence.^75, There was no standardized follow-up protocol that was followed across studies, but all the studies conducted serial prostate-specific antigen monitoring and a biopsy (6 to 12 months post-IRE). Across the studies, 58% reported that urinary continence returned to the pretreatment levels and 25% reported a minor decrease in the continence from the baseline at 12-months of follow-up. Erections sufficient for intercourse varied from 44% to 75% at the baseline to 55% to 100% at 12-months of follow-up across all the studies.

The limited sample sizes, heterogeneity across studies, and observational study designs all preclude conclusions of efficacy compared to other standard treatments. Tables 1 and 2 summarize the trials included and the characteristics of included studies.

Table 1. Comparison of Trials Included in Systematic Reviews of IRE for Initial Treatment of Low- or Intermediate-Risk Prostate Cancer

 IRE: irreversible electroporation.

Table 2. IRE as Initial Therapy Systematic Review Characteristics

 IRE: irreversible electroporation; NR: not reported. aSome patients in 2 included trials were treated with IRE as salvage therapy.

Randomized Controlled Trials

No randomized comparative trials were identified that assessed the use of IRE as initial therapy for low- or intermediate-risk prostate cancer.

Nonrandomized Trials

George et al (2025) published the PRESERVE study, a prospective, nonrandomized, multicenter trial evaluating the outcomes of IRE with the NanoKnife System as prostate tissue ablation in patients with intermediate-risk prostate cancer.^76, Individuals were eligible for inclusion if they were men older than 50 years of age, with magnetic resonance imaging-visible, biopsy-proven, organ confined clinical stage ≤T2c prostate cancer, with prostate-specific antigen (PSA) ≤15 ng/mL or a PSA density of <0.15 ng/mL² if PSA >15 ng/mL and Gleason grade group 2 or 3. All patients were treated under general anesthesia with IRE with the NanoKnife System, using a treatment margin of ≥10 mm. Duration of follow-up was 12 months post-IRE. The primary endpoint was the proportion of patients with an in-field biopsy negative for any amount of Gleason-gradable cancer at 12 months. Patients biopsied before 12 months with a positive in-field biopsy and those missing 12-month biopsy data were considered treatment failures. A total of 121 patients received IRE across 17 sites (median age, 67 years), with a median PSA at baseline of 5.8 ng/dL. The majority of patients included (83%) were White, 8.3% of patients were Black or African American, and 3.3% of patients were Hispanic or Latino. At 12 months, the primary efficacy endpoint showed that 71% of patients (86/121; 95% CI, 62% to 79%) had a negative in-field biopsy. At 12 months, the rate of any prostate cancer occurrence was 45% (49/110) and the rate of clinically significant prostate cancer anywhere was observed in 26% of patients (29/110). The secondary outcome of urinary function had a mean change from baseline to 12 months of 3 in the University of California Los Angeles Expanded Prostate Cancer Index Composite urinary domain total score and a mean change of -2 in the International Prostate Symptom Score total symptom score. Statistics were not reported on these secondary outcomes and no inferences can be made for statistical or clinical significance. At 12 months, 84% of patients with good baseline sexual function maintained erections sufficient for penetration. Fourteen (12%) patients experienced grade ≥3 adverse events and 3 patients experienced procedure-related grade 3 adverse events. The results of this trial led to the expanded indication for use of NanoKnife System in prostate tumor ablation.

Secondary Treatment for Biopsy-Proven Recurrence After Radiation

Systematic Reviews

Yilmaz et al (2025) published a systematic review investigating the use of IRE as salvage therapy in men with recurrent prostate cancer after radiation therapy.^77, Five studies were included and all studies were observational. The heterogeneity across studies did not allow for meta-analyses or pooled results. Following IRE, oncological outcomes varied across studies. Geboers et al (N=74) noted that only 56% of patients underwent biopsy after IRE. Of these patients, 77% of them achieved local oncological control, with a 5-year progression-free survival rate of 60% and overall metastasis-free survival rate of 91%. The lowest rate of local oncological control after IRE across other included studies was 67% No other studies reported 5-year progression-free survival rates or metastasis-free survival rates. Other functional outcomes included continence status post-IRE, which ranged from 73% to 100% across studies, and erection, with 2 studies reporting a decline in the proportion of patients maintaining erections and 2 studies reporting 50% preservation of erection. The small sample sizes, heterogeneity across studies, and observational study designs all preclude conclusions of efficacy compared to other standard treatments. Tables 3 and 4 summarize the trials included and the characteristics of included studies.

Table 3. Comparison of Trials Included in IRE as Salvage Therapy Systematic Review

 IRE: irreversible electroporation.

Table 4. IRE as Salvage Therapy Systematic Review Characteristics

 IRE: irreversible electroporation; RT: radiation therapy.

Randomized Controlled Trials

No RCTs were identified that assessed the use of IRE as salvage therapy for prostate cancer with recurrence after first-line therapy.

Section Summary: Prostate Tumors

Studies of IRE for prostate tumors include systematic reviews of observational studies investigating IRE as initial treatment or as salvage therapy post-recurrence and prospective nonrandomized trials. Studies included in systematic reviews for IRE as initial therapy were too heterogeneous to conduct any pooled analyses. Across those studies, reports of biopsy-proven recurrence post-IRE ranged from 0% to 38.9%. Similarly, studies included in the systematic review for IRE as salvage therapy were also too dissimilar to conduct meta-analyses. Rates of local oncological control post-IRE varied from 67% to 77%, although the definition of control also varied across studies. In the PRESERVE study, 71% of patients had negative in-field biopsies at 12 months, which aligned with results from observational studies across systematic review. The sample sizes, heterogeneity across studies and study populations, and observational study designs all preclude conclusions of efficacy compared to other standard treatments. No subgroup analyses have been conducted across various severities of prostate cancer. Additionally, the short follow-up times are insufficient to establish long-term oncological effects. No comparative data with guideline-recommended standard of care are available that would inform how survival or adverse events compare to other methods for locoregional therapy.

For individuals being treated with locoregional therapy for tumors in the prostate who receive IRE, the evidence includes systematic reviews of observational studies and prospective nonrandomized trials. Relevant outcomes are overall survival, disease-specific survival, symptoms, morbid events, functional outcomes, and quality of life. Irreversible electroporation is suggested as an option in clinical guidelines for secondary treatment of biopsy-proven recurrence of prostate cancer after radiation. Studies included in systematic reviews for IRE as initial therapy were too heterogeneous to conduct any pooled analyses. Across those studies, reports of biopsy-proven recurrence post-IRE ranged from 0% to 38.9%. Similarly, studies included in the systematic review for IRE as salvage therapy were also too dissimilar to conduct meta-analyses. Rates of local oncological control post-IRE varied from 67% to 77%, although the definition of control also varied across studies. In the PRESERVE study, 71% of patients had negative in-field biopsies at 12 months, which aligned with results from observational studies across systematic review. The small sample sizes, heterogeneity across studies and study populations, and observational study designs all preclude conclusions of efficacy compared to other standard treatments. No subgroup analyses have been conducted across various severities of prostate cancer. Additionally, the short follow-up times are insufficient to establish long-term oncological effects. No comparative data with guideline-recommended standard of care are available. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guidelines for hepatocellular carcinoma (HCC) (v1.2025 )^9, states that 'Irreversible electroporation (IRE) is an emerging modality for tumor ablation' and that 'Larger studies are needed to determine the effectiveness of IRE for local HCC treatment.'

NCCN guidelines for biliary tract cancers (v2.2025 )^10, states that ablation is a reasonable alternative to surgical resection for intrahepatic cholangiocarcinoma (CCA), particularly in patients with high-risk disease and 'Options for ablation include radiofrequency ablation, microwave ablation, and irreversible electroporation' for treatment of small, single intrahepatic CCA tumors (<3cm) amenable to complete ablation, whether recurrent or primary.

NCCN guidelines for pancreatic adenocarcinoma (v2.2025 )^13, states that 'IRE is an ablative technique in which electric pulses are used to create nanopores to induce cell death. This technique has been used in patients with locally advanced pancreatic cancer and may be safe and feasible and improve survival. However, due to concerns about complications and technical expertise, the Panel does not currently recommend IRE for treatment of locally advanced pancreatic cancer.'

NCCN guidelines for kidney cancer (v1.2026 )^21, do not refer to irreversible electroporation. The guidelines state that 'Percutaneous ablation (eg, cryosurgery, radiofrequency ablation, microwave ablation) is an option for the management of clinical stage T1 renal lesions. Percutaneous ablation is suitable for renal masses ≤3 cm. Percutaneous ablation is an option for clinical T1b masses in select patients not eligible for surgery.'

NCCN guidelines for non-small cell lung cancer (NSCLC) (v8.2025 )^23, do not refer to irreversible electroporation. With respect to ablation therapies, the guidelines state that:

• 'Image-guided thermal ablation (IGTA) therapy (eg, cryotherapy, microwave, radiofrequency) may be an option for select patients' for initial treatment for stage 1A disease.

• 'IGTA may be considered for those patients who are deemed “high risk”—those with tumors that are for the most part surgically resectable but rendered medically inoperable due to comorbidities. In cases where IGTA is considered for high-risk or borderline operable patients, a multidisciplinary evaluation is recommended.'

• 'IGTA is an option for the management of NSCLC lesions <3 cm. Ablation for NSCLC lesions >3 cm may be associated with higher rates of local recurrence and complications.'

• 'There is evidence on the use of IGTA for selected patients with stage 1A NSCLC, those who present with multiple lung cancers, or those who present with locoregional recurrence of symptomatic local thoracic disease.'

• 'In the setting of progression at a limited number of sites on a given line of systemic therapy (oligoprogression), local ablative therapy to the

  oligoprogressive sites may extend the duration of benefit of the current line of systemic therapy.'

NCCN guidelines for prostate cancer (v.2.2026) recommend the use of local therapy as secondary treatment in the case of biopsy-proven recurrence in the prostate after radiation therapy without distant metastatic disease. Local therapy options for patients with recurrence in the prostate include cryotherapy, IRE, high-intensity focused ultrasound, reirradation (ie, brachytherapy, sterotactic body radiotherapy), and prostatectomy plus pelvic lymph node dissection.^25,

National Institute for Health and Care Excellence

The NICE published an interventional procedures guidance in 2017 on IRE for treating pancreatic cancer.^78, The guidance stated that 'Current evidence on the safety and efficacy of irreversible electroporation for treating pancreatic cancer is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research.'

The NICE published an interventional procedure guidance in 2023 on IRE for treating prostate cancer.^79, The guidance states that "Irreversible electroporation for treating prostate cancer should only be used with special arrangements for clinical governance, consent, and audit or research...Further research should ideally be randomised controlled trials with an appropriate comparator. Further research could also include analysis of registry data or research databases. It should include details of patient selection, details of the procedure (including imaging) and short- and long-term outcomes."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 5.

Table 5. Summary of Key Trials

 NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial. b ISRCTN registry

References

1. Scheltema MJ, van den Bos W, de Bruin DM, et al. Focal vs extended ablation in localized prostate cancer with irreversible electroporation; a multi-center randomized controlled trial. BMC Cancer. May 05 2016; 16: 299. PMID 27150293
2. Rubinsky B, Onik G, Mikus P. Irreversible electroporation: a new ablation modality--clinical implications. Technol Cancer Res Treat. Feb 2007; 6(1): 37-48. PMID 17241099
3. Davalos RV, Mir IL, Rubinsky B. Tissue ablation with irreversible electroporation. Ann Biomed Eng. Feb 2005; 33(2): 223-31. PMID 15771276
4. Surveillance, Epidemiology, and End Results Program (SEER). Cancer Stat Facts. https://seer.cancer.gov/statfacts/. Accessed October 6, 2025.
5. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024; 74(1): 12-49. PMID 38230766
6. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology. Jan 2021; 73 Suppl 1(Suppl 1): 4-13. PMID 32319693
7. Kim HS, El-Serag HB. The Epidemiology of Hepatocellular Carcinoma in the USA. Curr Gastroenterol Rep. Apr 11 2019; 21(4): 17. PMID 30976932
8. Centers for Disease Control and Prevention (CDC). Hepatocellular carcinoma - United States, 2001-2006. MMWR Morb Mortal Wkly Rep. May 07 2010; 59(17): 517-20. PMID 20448528
9. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Hepatocellular Carcinoma. Version 1.2025. https://www.nccn.org/professionals/physician_gls/pdf/hcc.pdf. Accessed October 5, 2025.
10. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Biliary Tract Cancers. Version 2.2025. https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf. Accessed October 6, 2025.
11. Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. Jul 2021; 18(7): 493-502. PMID 34002083
12. Balaban EP, Mangu PB, Khorana AA, et al. Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. Aug 01 2016; 34(22): 2654-68. PMID 27247216
13. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 2.2025. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed October 2, 2025.
14. Cheungpasitporn W, Thongprayoon C, O'Corragain OA, et al. The risk of kidney cancer in patients with kidney stones: a systematic review and meta-analysis. QJM. Mar 2015; 108(3): 205-12. PMID 25208892
15. Argani P, Laé M, Ballard ET, et al. Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol. Apr 01 2006; 24(10): 1529-34. PMID 16575003
16. Cho E, Curhan G, Hankinson SE, et al. Prospective evaluation of analgesic use and risk of renal cell cancer. Arch Intern Med. Sep 12 2011; 171(16): 1487-93. PMID 21911634
17. Mandel JS, McLaughlin JK, Schlehofer B, et al. International renal-cell cancer study. IV. Occupation. Int J Cancer. May 29 1995; 61(5): 601-5. PMID 7768630
18. Lowrance WT, Ordoñez J, Udaltsova N, et al. CKD and the risk of incident cancer. J Am Soc Nephrol. Oct 2014; 25(10): 2327-34. PMID 24876115
19. Adams KF, Leitzmann MF, Albanes D, et al. Body size and renal cell cancer incidence in a large US cohort study. Am J Epidemiol. Aug 01 2008; 168(3): 268-77. PMID 18544571
20. Hidayat K, Du X, Zou SY, et al. Blood pressure and kidney cancer risk: meta-analysis of prospective studies. J Hypertens. Jul 2017; 35(7): 1333-1344. PMID 28157813
21. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. Version 1.2026. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed October 4, 2025.
22. Centers for Disease Control and Prevention. Lung Cancer Risk Factors. Updated February 13, 2025. https://www.cdc.gov/lung-cancer/risk-factors/index.html. Accessed October 6, 2025.
23. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 8.2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed October 3, 2025.
24. Prostate cancer risk factors. Centers for Disease Control and Prevention. February 11, 2025. https://www.cdc.gov/prostate-cancer/risk-factors/index.html. Accessed October 23, 2025.
25. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 2.2026. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed October 23, 2025.
26. Food and Drug Administration. NanoKnife System 510(k) Summary: K183385. https://www.accessdata.fda.gov/cdrh_docs/pdf18/K183385.pdf. Accessed October 6, 2025.
27. Geboers B, Scheffer HJ, Graybill PM, et al. High-Voltage Electrical Pulses in Oncology: Irreversible Electroporation, Electrochemotherapy, Gene Electrotransfer, Electrofusion, and Electroimmunotherapy. Radiology. May 2020; 295(2): 254-272. PMID 32208094
28. AngioDynamics. NanoKnife Patient Guide. https://nanoknife.com/resources/. Accessed October 6, 2025.
29. Brar G, Greten TF, Graubard BI, et al. Hepatocellular Carcinoma Survival by Etiology: A SEER-Medicare Database Analysis. Hepatol Commun. Oct 2020; 4(10): 1541-1551. PMID 33024922
30. Dhanasekaran R, Hemming AW, Zendejas I, et al. Treatment outcomes and prognostic factors of intrahepatic cholangiocarcinoma. Oncol Rep. Apr 2013; 29(4): 1259-67. PMID 23426976
31. Wade R, South E, Anwer S, et al. Ablative and non-surgical therapies for early and very early hepatocellular carcinoma: a systematic review and network meta-analysis. Health Technol Assess. Dec 2023; 27(29): 1-172. PMID 38149643
32. Cheung W, Kavnoudias H, Roberts S, et al. Irreversible electroporation for unresectable hepatocellular carcinoma: initial experience and review of safety and outcomes. Technol Cancer Res Treat. Jun 2013; 12(3): 233-41. PMID 23369152
33. Cannon R, Ellis S, Hayes D, et al. Safety and early efficacy of irreversible electroporation for hepatic tumors in proximity to vital structures. J Surg Oncol. Apr 2013; 107(5): 544-9. PMID 23090720
34. Frühling P, Nilsson A, Duraj F, et al. Single-center nonrandomized clinical trial to assess the safety and efficacy of irreversible electroporation (IRE) ablation of liver tumors in humans: Short to mid-term results. Eur J Surg Oncol. Apr 2017; 43(4): 751-757. PMID 28109674
35. Granata V, Fusco R, Catalano O, et al. Percutaneous ablation therapy of hepatocellular carcinoma with irreversible electroporation: MRI findings. AJR Am J Roentgenol. May 2015; 204(5): 1000-7. PMID 25905934
36. Padia SA, Johnson GE, Yeung RS, et al. Irreversible Electroporation in Patients with Hepatocellular Carcinoma: Immediate versus Delayed Findings at MR Imaging. Radiology. Jan 2016; 278(1): 285-94. PMID 26523493
37. Niessen C, Beyer LP, Pregler B, et al. Percutaneous Ablation of Hepatic Tumors Using Irreversible Electroporation: A Prospective Safety and Midterm Efficacy Study in 34 Patients. J Vasc Interv Radiol. Apr 2016; 27(4): 480-6. PMID 26922979
38. Scheffer HJ, Nielsen K, van Tilborg AA, et al. Ablation of colorectal liver metastases by irreversible electroporation: results of the COLDFIRE-I ablate-and-resect study. Eur Radiol. Oct 2014; 24(10): 2467-75. PMID 24939670
39. Narayanan G, Gentile NT, Eyshi J, et al. Irreversible Electroporation in Treating Colorectal Liver Metastases in Proximity to Critical Structures. J Vasc Interv Radiol. Dec 2024; 35(12): 1806-1813. PMID 39218213
40. Belfiore MP, Reginelli A, Maggialetti N, et al. Preliminary results in unresectable cholangiocarcinoma treated by CT percutaneous irreversible electroporation: feasibility, safety and efficacy. Med Oncol. Apr 09 2020; 37(5): 45. PMID 32270353
41. Sugimoto K, Kakimi K, Takeuchi H, et al. Irreversible Electroporation versus Radiofrequency Ablation: Comparison of Systemic Immune Responses in Patients with Hepatocellular Carcinoma. J Vasc Interv Radiol. Jun 2019; 30(6): 845-853.e6. PMID 31126596
42. Blaise L, Pereira H, Vilgrain V, et al. Percutaneous ablation for locally advanced hepatocellular carcinoma with tumor portal invasion. Clin Res Hepatol Gastroenterol. Nov 2021; 45(6): 101731. PMID 34139320
43. Ruarus AH, Barabasch A, Catalano O, et al. Irreversible Electroporation for Hepatic Tumors: Protocol Standardization Using the Modified Delphi Technique. J Vasc Interv Radiol. Nov 2020; 31(11): 1765-1771.e15. PMID 32978054
44. van Roessel S, Kasumova GG, Verheij J, et al. International Validation of the Eighth Edition of the American Joint Committee on Cancer (AJCC) TNM Staging System in Patients With Resected Pancreatic Cancer. JAMA Surg. Dec 01 2018; 153(12): e183617. PMID 30285076
45. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: Raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. Apr 20 2014; 32(12): 1277-80. PMID 24638016
46. Charalambous P, Moris D, Karachaliou GS, et al. The efficacy and safety of the open approach irreversible electroporation in the treatment of pancreatic cancer: A systematic review. Eur J Surg Oncol. Sep 2020; 46(9): 1565-1572. PMID 32536525
47. Martin RC, McFarland K, Ellis S, et al. Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma. J Am Coll Surg. Sep 2012; 215(3): 361-9. PMID 22726894
48. Martin RC, Kwon D, Chalikonda S, et al. Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy. Ann Surg. Sep 2015; 262(3): 486-94; discussion 492-4. PMID 26258317
49. Månsson C, Bergenfeldt M, Brahmstaedt R, et al. Safety and preliminary efficacy of ultrasound-guided percutaneous irreversible electroporation for treatment of localized pancreatic cancer. Anticancer Res. Jan 2014; 34(1): 289-93. PMID 24403476
50. Scheffer HJ, Vroomen LG, de Jong MC, et al. Ablation of Locally Advanced Pancreatic Cancer with Percutaneous Irreversible Electroporation: Results of the Phase I/II PANFIRE Study. Radiology. Feb 2017; 282(2): 585-597. PMID 27604035
51. Ruarus AH, Vroomen LGPH, Geboers B, et al. Percutaneous Irreversible Electroporation in Locally Advanced and Recurrent Pancreatic Cancer (PANFIRE-2): A Multicenter, Prospective, Single-Arm, Phase II Study. Radiology. Jan 2020; 294(1): 212-220. PMID 31687922
52. Narayanan G, Hosein PJ, Arora G, et al. Percutaneous irreversible electroporation for downstaging and control of unresectable pancreatic adenocarcinoma. J Vasc Interv Radiol. Dec 2012; 23(12): 1613-21. PMID 23177107
53. Narayanan G, Hosein PJ, Beulaygue IC, et al. Percutaneous Image-Guided Irreversible Electroporation for the Treatment of Unresectable, Locally Advanced Pancreatic Adenocarcinoma. J Vasc Interv Radiol. Mar 2017; 28(3): 342-348. PMID 27993507
54. Martin RC, McFarland K, Ellis S, et al. Irreversible electroporation in locally advanced pancreatic cancer: potential improved overall survival. Ann Surg Oncol. Dec 2013; 20 Suppl 3: S443-9. PMID 23128941
55. Kluger MD, Epelboym I, Schrope BA, et al. Single-Institution Experience with Irreversible Electroporation for T4 Pancreatic Cancer: First 50 Patients. Ann Surg Oncol. May 2016; 23(5): 1736-43. PMID 26714959
56. Leen E, Picard J, Stebbing J, et al. Percutaneous irreversible electroporation with systemic treatment for locally advanced pancreatic adenocarcinoma. J Gastrointest Oncol. Apr 2018; 9(2): 275-281. PMID 29755766
57. Liu S, Qin Z, Xu J, et al. Irreversible electroporation combined with chemotherapy for unresectable pancreatic carcinoma: a prospective cohort study. Onco Targets Ther. 2019; 12: 1341-1350. PMID 30863100
58. Holland MM, Bhutiani N, Kruse EJ, et al. A prospective, multi-institution assessment of irreversible electroporation for treatment of locally advanced pancreatic adenocarcinoma: initial outcomes from the AHPBA pancreatic registry. HPB (Oxford). Aug 2019; 21(8): 1024-1031. PMID 30737097
59. Martin RCG, White RR, Bilimoria MM, et al. Effectiveness and Safety of Irreversible Electroporation When Used for the Ablation of Stage 3 Pancreatic Adenocarcinoma: Initial Results from the DIRECT Registry Study. Cancers (Basel). Nov 21 2024; 16(23). PMID 39682087
60. Martin RC, Durham AN, Besselink MG, et al. Irreversible electroporation in locally advanced pancreatic cancer: A call for standardization of energy delivery. J Surg Oncol. Dec 2016; 114(7): 865-871. PMID 27546233
61. Chin AI, Lam JS, Figlin RA, et al. Surveillance strategies for renal cell carcinoma patients following nephrectomy. Rev Urol. 2006; 8(1): 1-7. PMID 16985554
62. Hilton A, Kourounis G, Georgiades F. Irreversible electroporation in renal tumours: A systematic review of safety and early oncological outcomes. Urologia. Aug 2022; 89(3): 329-337. PMID 35139717
63. Buijs M, Zondervan PJ, de Bruin DM, et al. Feasibility and safety of irreversible electroporation (IRE) in patients with small renal masses: Results of a prospective study. Urol Oncol. Mar 2019; 37(3): 183.e1-183.e8. PMID 30509869
64. Canvasser NE, Sorokin I, Lay AH, et al. Irreversible electroporation of small renal masses: suboptimal oncologic efficacy in an early series. World J Urol. Oct 2017; 35(10): 1549-1555. PMID 28255621
65. Xing M, Kokabi N, Zhang D, et al. Comparative Effectiveness of Thermal Ablation, Surgical Resection, and Active Surveillance for T1a Renal Cell Carcinoma: A Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked Population Study. Radiology. Jul 2018; 288(1): 81-90. PMID 29737950
66. Thomson KR, Cheung W, Ellis SJ, et al. Investigation of the safety of irreversible electroporation in humans. J Vasc Interv Radiol. May 2011; 22(5): 611-21. PMID 21439847
67. Pech M, Janitzky A, Wendler JJ, et al. Irreversible electroporation of renal cell carcinoma: a first-in-man phase I clinical study. Cardiovasc Intervent Radiol. Feb 2011; 34(1): 132-8. PMID 20711837
68. Diehl SJ, Rathmann N, Kostrzewa M, et al. Irreversible Electroporation for Surgical Renal Masses in Solitary Kidneys: Short-Term Interventional and Functional Outcome. J Vasc Interv Radiol. Sep 2016; 27(9): 1407-1413. PMID 27292599
69. Vroomen LGPH, Scheffer HJ, Melenhorst MCAM, et al. Irreversible Electroporation to Treat Malignant Tumor Recurrences Within the Pelvic Cavity: A Case Series. Cardiovasc Intervent Radiol. Oct 2017; 40(10): 1631-1640. PMID 28470395
70. Liu B, Clark J, Domes T, et al. Percutaneous irreversible electroporation for the treatment of small renal masses: The first Canadian case series. Can Urol Assoc J. Sep 2019; 13(9): E263-E267. PMID 30763229
71. Wendler JJ, Pech M, Fischbach F, et al. Initial Assessment of the Efficacy of Irreversible Electroporation in the Focal Treatment of Localized Renal Cell Carcinoma With Delayed-interval Kidney Tumor Resection (Irreversible Electroporation of Kidney Tumors Before Partial Nephrectomy [IRENE] Trial-An Ablate-and-Resect Pilot Study). Urology. Apr 2018; 114: 224-232. PMID 29305201
72. Wendler JJ, Pech M, Köllermann J, et al. Upper-Urinary-Tract Effects After Irreversible Electroporation (IRE) of Human Localised Renal-Cell Carcinoma (RCC) in the IRENE Pilot Phase 2a Ablate-and-Resect Study. Cardiovasc Intervent Radiol. Mar 2018; 41(3): 466-476. PMID 28929209
73. Ricke J, Jürgens JH, Deschamps F, et al. Irreversible electroporation (IRE) fails to demonstrate efficacy in a prospective multicenter phase II trial on lung malignancies: the ALICE trial. Cardiovasc Intervent Radiol. Apr 2015; 38(2): 401-8. PMID 25609208
74. Zhang K, Teoh J, Zhu G, et al. Irreversible Electroporation for the Focal Treatment of Prostate Cancer: A Systematic Review. World J Mens Health. Apr 2025; 43(2): 321-332. PMID 39028129
75. Prabhakar P, Avudaiappan AP, Sandman M, et al. Irreversible electroporation as a focal therapy for localized prostate cancer: A systematic review. Indian J Urol. 2024; 40(1): 6-16. PMID 38314081
76. George AK, Miocinovic R, Patel AR, et al. Irreversible Electroporation for Prostate Tissue Ablation in Patients with Intermediate-risk Prostate Cancer: Results from the PRESERVE Trial. Eur Urol. Jul 19 2025. PMID 40685282
77. Yilmaz M, Karaaslan M, Şirin ME, et al. Salvage irreversible electroporation for locally recurrent prostate cancer after definitive radiotherapy: a systematic review. Prostate Cancer Prostatic Dis. Sep 2025; 28(3): 707-717. PMID 39623055
78. National Institute for Health and Care Excellence (NICE). Irreversible electroporation for treating pancreatic cancer: Interventional procedures guidance [IPG579]. 2017. https://www.nice.org.uk/guidance/ipg579. Accessed October 6, 2025.
79. National Institute for Health and Care Excellence (NICE). Irreversible electroporation for treating prostate cancer: Interventional procedures guidance [IPG768]. 2023. https://www.nice.org.uk/guidance/ipg768. Accessed October 23, 2025.

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