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| Irreversible Electroporation, Nanoknife | |
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| 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.
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 or 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 (Scheltema, 2016, Rubinsky, 2007; Davalos, 2005).
Regulatory Status
The NanoKnife System (Angiodynamics) was originally cleared through the 510(k) process (K102329) in 2011 for the surgical ablation of soft tissue. NanoKnife has not received clearance for the treatment of any specific disease. FDA product code: OAB.
At this time, there is no specific CPT code for this procedure. We would expect this service to be billed with an unlisted code.
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Policy/ Coverage: |
Effective January 2025
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
Irreversible Electroporation using the NanoKnife does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication, including but not limited to irreversible electroporation for the treatment of primary or metastatic solid tumors (e.g., tumors to the liver, pancreas, kidney, or lungs).
For members with contracts without Primary Coverage Criteria, Irreversible Electroporation using the NanoKnife is considered Not Medically Necessary or is investigational and is not covered for any indication, including but not limited to irreversible electroporation for the treatment of primary or metastatic solid tumors (e.g., tumors to the liver, pancreas, kidney, or lungs). Not Medically Necessary or investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective June 2021 – December 2024
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Irreversible Electroporation using the NanoKnife™ for any indication does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For member with contracts without primary coverage criteria, Irreversible Electroporation using the NanoKnife™ for any indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
EFFECTIVE PRIOR TO June 2021
Irreversible Electroporation using the NanoKnife™ for any indication does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This technology is the subject of ongoing clinical trials.
For contracts without primary coverage criteria, Irreversible Electroporation using the NanoKnife™ for any indication is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.
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| Rationale: |
A search of the MEDLINE database did not identify any randomized controlled trials on the use of the Nanoknife™ IRE System. Studies for potential uses in the prostate, liver, lung, kidney and lymph nodes are being planned or conducted in the United States and Europe. A search of the ClinicalTrials.gov website revealed a pilot study which is ongoing in Europe for the treatment of primary liver cancer (NCT01078415).
An in vitro study was conducted on mammary gland epithelial adenocarcinoma cells to determine a baseline electrical field required to induce IRE (Neal, 2009). However, no in vivo studies have been reported using IRE to treat breast cancer lesions.
There is an absence of data concerning the effectiveness of this procedure.
2012 Update
A literature search was conducted using the MEDLINE database through May 2012. There were no randomized controlled trials identified using irreversible electroporation or NanoKnife. One small single site study was identified. Pech and colleagues reported on a small phase I clinical trial assessing the feasibility and safety of irreversible electroporation in the treatment of renal cell carcinoma (Pech, 2011). In this study, six patients selected for resection of renal cell carcinoma received irreversible electroporation during anesthesia prior to the resection. ECG monitoring and blood sampling were performed as safety assessments. The authors report no clinically significant changes in the ECG and laboratory assessments. Results of this small, first-in-man, study does not prompt a change in the coverage statement.
The NanoKnife technology is currently being studied outside the United States in the following clinical trials:
2013 Update
The policy is updated with a search of the Medline database and the clinicaltrials.gov website. There was no new information identified that would prompt a change in the coverage statement.
Two trials assessing the use of irreversible electroporation in the treatment of pancreatic carcinoma were published in 2012 (Martin, 2012; Narayanan, 2012). In both trials, the procedure was concluded to be both safe and feasible. The authors indicate that further studies are indicated and planned. One ongoing clinical trial in patients with pancreatic cancer was identified (NCT01369420) and is discussed below.
Clinical Trials
A search of the clinicaltrials.gov website identified the following clinical trials assessing the safety and efficacy of irreversible electroporation in the treatment of various malignancies.
NCT01835977- This is a phase 2, multi-center, randomized, single blind trial assessing the safety and efficacy of irreversible electroporation for the ablation of localized prostate cancer. The trial is sponsored by the Clinical Research Office of the Endourological Society. This study is planned to begin enrollment in January 2014.
NCT01726894-This open-label, prospective study assessing the use of irreversible electroporation in the treatment of localized prostate cancer is sponsored by the University College London Hospitals. The study was scheduled to begin recruitment in January 2013.
NCT01799044-Pilot study assessing the safety and efficacy of irreversible electroporation in the treatment of colorectal liver metastases. This trial is sponsored by Dr. M.R. Meijerink in collaboration with VU University Medical Center. This study is currently recruiting participants. The estimated completion date is listed as July 2013.
NCT01790451-This is a phase 1, open label trial assessing the use of irreversible electroporation in the treatment of prostate cancer. Procedural related side affects and post prostatectomy histology will be assessed. The study is sponsored by the Clinical Research Office of the Endourological Society. The study has an estimated start date of March 2013 but is listed as not yet open for recruitment.
NCT01369420-NanoKnife Low Energy Direct Current (LEDC) System in Subjects With Locally Advanced Unresectable Pancreatic Cancer. This is a Phase II safety study assessing the use of the device in the treatment of locally advanced unresectable pancreatic cancer. The study is sponsored by Angiodynamics, Inc. and is ongoing but not recruiting patients (clinicaltrials.gov).
NCT01078415-This study is a pilot study to assess irreversible electroporation to treat early-stage primary liver cancer. The study is sponsored by Angiodynamics and is currently ongoing but not recruiting patients (clinicaltrials.gov).
NCT01442324- This single arm pilot study to assess the safety of irreversible electroporation to treat metastatic liver cancer and cholangiocarcinoma is currently recruiting patients (clinicaltrials.gov).
There is currently a lack of scientific evidence that the use of irreversible electroporation improves health outcomes.
2014 Update
A literature search conducted using the Medline database through May 2014 did not reveal any new literature that would prompt a change in the coverage statement. One small Phase 1 open-label trial assessing the use of irreversible electroporation for the treatment of localized pancreatic cancer was published in 2014 (Ṁansson, 2014). In this study, 5 patients with localized pancreatic cancer were treated with irreversible electroporation. There were no serious treatment related adverse events reported. At 6 months following treatment, two patients had no signs of recurrence on CT or contrast-enhanced ultrasound.
A search of the clinicaltrials.gov website identified two ongoing clinical trials of IRE in the treatment of pancreatic cancer. The PANFIRE study (NCT01939665) is a Phase 1 trial assessing the safety and efficacy of IRE in the treatment of locally advanced pancreatic cancer. The estimated enrollment is 10 subjects with an estimated study completion date of September 2015. Additionally, the NanoKnife IRE system is being studied in unresectable pancreatic cancer (NCT02041936). This study is estimated to complete in February 2018 with an estimated enrollment of 12 subjects.
Other ongoing clinical trials include:
Irreversible Electroporation of Kidney Tumors Before Partial Nephrectomy (IRENE). NCT01967407 is a Phase I/II open label prospective study assessing the effectiveness of IRE in the treatment of locally confined renal cell carcinomas. The study is estimated to enroll about 20 subjects with an estimated completion date of December 2015.
NCT01972867 is an open-label pilot study of the use of NanoKnife for the treatment of prostate cancer in low-risk patients. The trial is sponsored by Angiodynamics, Inc. Six patients are estimated to enroll with a completion date of August 2014.
NCT01726894-This open-label, prospective study assessing the use of irreversible electroporation in the treatment of localized prostate cancer is sponsored by the University College London Hospitals. The study was scheduled to begin recruitment in January 2013.
NCT01442324- This single arm pilot study to assess the safety of irreversible electroporation to treat metastatic liver cancer and cholangiocarcinoma is currently recruiting patients (clinicaltrials.gov).
NCT01835977- This is a phase 2, multi-center, randomized, single blind trial assessing the safety and efficacy of irreversible electroporation for the ablation of localized prostate cancer. The trial is sponsored by the Clinical Research Office of the Endourological Society. This study is planned to begin enrollment in June 2014 but is still listed as not yet recruiting.
The following studies are listed as completed with no study results posted:
NCT01799044-Pilot study assessing the safety and efficacy of irreversible electroporation in the treatment of colorectal liver metastases. This trial is sponsored by Dr. M.R. Meijerink in collaboration with VU University Medical Center. This study is currently recruiting participants. This study has completed but no study results are posted on clinicaltrials.gov.
NCT01790451-This is a phase 1, open label trial assessing the use of irreversible electroporation in the treatment of prostate cancer. Procedural related side affects and post prostatectomy histology will be assessed. The study is sponsored by the Clinical Research Office of the Endourological Society. This study has completed but no study results are posted on clinicaltrials.gov.
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2014 Morling and colleagues performed the Edinburgh type 2 diabetes study: using non-invasive biomarkers to identify hepatic fibrosis in people with type 2 diabetes mellitus (Morling, 2014). In the Edinburgh Type 2 Diabetes Study, a population-based cohort aged 60-74 years with type 2 diabetes, 831 participants underwent ultrasound assessment for fatty liver and had serum aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), aspartate to platelet ratio index (APRI), European Liver Fibrosis panel (ELF), Fibrosis-4 Score (FIB4) and liver stiffness measurement (LSM) measured. Literature based cut-offs yielded marked differences in the proportions of the cohort with probable liver fibrosis in the full cohort. Agreement between the top 5% of the distribution for each biomarker pair was poor. APRI and FIB4 had the best positive agreement at 76.4%, but agreement for all of the other serum biomarker pairs was between 18% and 34%. Agreement with LSM was poor (9-16%). Poor correlation was found between the five biomarkers of liver fibrosis studied. Using the top 5% of each biomarker resulted in good agreement on the absence of advanced liver disease but poor agreement on the presence of advanced disease. Further work is required to validate these markers against liver biopsy and to determine their predictive value for clinical liver-related endpoints, in a range of different low and high risk population groups.
Pérez and colleagues did a Validation study of systems for noninvasive diagnosis of fibrosis in nonalcoholic fatty liver disease in Latin population (Pérez, 2013). The incidence of liver cirrhosis is significantly high in Latin population. The high prevalence of nonalcoholic fatty liver disease NAFLD is likely partially responsible for these figures. Liver biopsy is not a practical diagnostic option in this scenario. The validation of noninvasive markers of fibrosis is important in populations with a high prevalence of NAFLD. Aim was to compare the diagnostic value of noninvasive assessment systems to detect fibrosis in a cohort of Latin patients with biopsy-proven NAFLD. Material and methods. Patients with biopsy-proven NAFLD were included. Noninvasive evaluations included calculations of NAFLD fibrosis, FIB-4, BARD scores, APRI, and AST/ALT ratio. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver-operating characteristic curve (AUROC) were calculated. Results were a total of 228 patients (mean age, 48.6 ± 12.7 years) were included. Fifty-one percent were women; 48% were overweight and 23% were obese. The severity of fibrosis was classified as G0, 56.6%; G1, 25%; G2, 6.6%; G3, 7%; and G4, 4.8%. The AUROC values for advanced fibrosis were 0.72 for the NAFLD fibrosis score, 0.74 for FIB-4 score, 0.67 for AST/ALT ratio, 0.66 for APRI score, and 0.65 for BARD score. In 54% of patients with undetermined FIB-4 score and in 60% of patients with undetermined NAFLD fibrosis score, fibrosis was observed in the liver biopsy. The conclusion was the NAFLD fibrosis, FIB-4, and APRI scores can be used for the noninvasive diagnosis of fibrosis. However, 25% of patients evaluated by these methods have an indeterminate degree of fibrosis.
2016 Update
A literature search conducted through May 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Wichtowski and colleagues published a study on irreversible electroporation,a new, non-thermal ablation technique in the treatment of parenchymal organ tumors which uses short high voltage pulses of electricity in order to induce apoptosis of targeted cells (Wichtowski, 2016). Locally advanced pancreatic cancer (LAPC) and liver cancer is analyzed with this method of treatment.
Between 04.2014 and 09.2014 two patients with LAPC and one with colorectal liver metastasis (CRLM) were qualified for treatment with irreversible electroporation. Both patients remained under constant observation and control. PubMed/Medline, Embase and Google Scholar databases were searched and eight original reports on irreversible electroporation of pancreatic and liver tumors based on the biggest groups of patients were found. Two patients with LAPC and one with CRLM were qualified for ablation with irreversible electroporation. In all three patients a successful irreversible electroporation (IRE) procedure of the whole tumor was conducted. In the minimum seven-month follow-up 100% local control was achieved - without progression. In the literature review the local response to treatment ranged from 41% to 100%. The event-free survival rate in six-month observation was 94%.
To evaluate the safety of the NanoKnife Low Energy Direct Current (LEDC) System (Irreversible Electroporation, IRE) to treat patients with unresectable pancreatic adenocarcinoma Pajella and colleagues published a prospective, nonrandomized, single-center clinical evaluation of ten patients with a cytohystological diagnosis of unresectable locally advanced pancreatic cancer (LAPC) that was no further responsive to standard treatments (Pajella, 2015).. The primary outcome was the rate of procedure-related abdominal complications. The secondary endpoints included the evaluation of the short-term efficacy of IRE through the evaluation of tumor reduction at imaging and biological tumor response as shown by CA 19-9, clinical assessments and patient quality of life. Ten patients (5 males, 5 females) were enrolled, with a median age of 66 and median tumor size of 30 mm. All patients were treated successfully with a median procedure time of 79.5 min. Two procedure-related complications were described in one patient (10%): a pancreatic abscess with a pancreoduodenal fistula. Three patients had early progression of disease: one patient developed pulmonary metastases 30 days post-IRE and two patients had liver metastases 60 days after the procedure. We registered an overall survival of 7.5 months (range: 2.9-15.9).
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement.
2018 Update
A literature search conducted through May 2018 did not reveal any new information that would prompt a change in the coverage statement.
2019 Update
A literature search was conducted through May 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
A literature search was conducted through May 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2023. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2024. No new literature was identified that would prompt a change in the coverage statement.
Additional 2024 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Liver Tumors
The American Cancer Society estimates that there will be over 41,000 new cases of liver and intrahepatic bile duct cancer in 2024. Liver and intrahepatic-bile duct cancer death is the 5th most common cancer related death in males and the 7th most common in females (Siegel, 2024). 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 (McGlynn, 2021). The prognosis following diagnosis depends on several factors including tumor mass and hepatic reserve.
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. 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 or smaller). 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 (NCCN, 2024).
Systematic Reviews
Wade et al 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 (Wade, 2023). The objective was to review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small HCC (3 cm or smaller). The authors included 37 RCTs (n greater than 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.
Nonrandomized Studies
The majority of studies of IRE for liver cancer have not included a comparator and have included samples sizes smaller than 50 (Cheung, 2013; Cannon, 2013, Fruhling, 2017; Granata, 2015; Padia, 2016; Niessen, 2016; Scheffer, 2014; Narayanan, 2024; Belfiore, 2020).
Cannon et al reported results of the largest single-arm study (n=44) which was from a prospective registry of patients undergoing IRE for hepatic tumors (Cannon, 2013). The patients had colorectal metastasis (n=20), HCC (n=14), and other metastasis (n=10). 5 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 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 (Sugimoto, 2019).
Blaise et al reported results of a retrospective comparative study including patients with HCC and tumor portal invasion treated by percutaneous ablation (n = 44) from one center compared to a control group drawn from an external RCT including patients treated with sorafenib or trans-arterial radioembolization (Blaise, 2021). 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. 41 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% 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 (Blaise, 2021).
Pancreatic Tumors
Pancreatic ductal adenocarcinoma has a poor prognosis. The American Cancer Society estimates that in 2024, there will be over 66,000 new cases of pancreatic cancer in the US and over 51,000 pancreatic cancer deaths. Pancreatic cancer is the third-leading cause of cancer death in men and women (Siegel, 2024).
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 less than 5% for locally advanced, unresectable disease (Balaban, 2016).
The NCCN recommended treatment for patients with locally advanced pancreatic adenocarcinoma includes systemic therapy with FOLFIRINOX-based or gemcitabine-based therapy, potentially with radiation therapy, with the goal of shrinking the tumor enough for surgical resection. People who are unable to undergo surgery may continue systemic therapy. Depending on the kind of cancer and the genetic makeup some people may be candidates for immunotherapy or poly adenosine diphosphate-ribose polymerase (PARP) inhibitors (NCCN, 2024). Thermal (radiofrequency and microwave) ablation therapies are not commonly used due to the increased risk of trauma to the adjacent major anatomical structures. Irreversible electroporation (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.
Local ablation treatment is not currently recommended in NCCN guidelines and not commonly used due to concerns regarding the increased risk of thermal injury to the adjacent structures. The role of ablation treatments in addition to systemic therapy is unclear. However, local ablation with radiofrequency ablation (RFA) and microwave ablation (MWA) has been considered for some patients with persistent locally advanced disease after systemic therapy as a strategy to downstage.
Systematic Reviews
Charallambous et al reported results of a systematic review of 9 studies of IRE in 460 patients with locally advanced pancreatic cancer published between 2000 and 2019 (Charalambous, 2020). 4 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 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 (Charalambous, 2020).
Randomized Controlled Trials
No published RCTs were identified. The DIRECT RCT (NCT03899636; n=528) is registered on clinicaltrials.gov with a completion date of December 2023 but results have not been published. 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 scheduled to be completed in November 2025.
Nonrandomized Studies
The published studies for IRE in pancreatic cancer are single-arm (Martin, 2012; Martin, 2015; Mansson, 2014; Scheffer, 2017; Ruarus, 2020; Narayanan, 2012; Narayanan, 2017; Martin, 2013; Kluger, 2016; Leen, 2018; Liu, 2019).
Holland et al 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 (Holland, 2019). 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%. 19 (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.
Raurus et al 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) (Ruarus, 2020). 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 (IQR, 3.7 to 4.6 cm). 14 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%). 2 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) (Ruarus, 2020).
Kidney Tumors
The American Cancer Society estimates that there will be over 81,000 new cases of kidney cancer and over 14,000 kidney cancer related deaths in 2024 (Siegel, 2024). At diagnosis, approximately 65% of disease is localized disease (SEER, 2024). 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 or smaller 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 (NCCN, 2024).
Systematic Reviews
Hilton et al reported results of a systematic review of safety and early oncological outcomes of 10 studies (n=83) of IRE for small renal masses (Hilton, 2022). The review included studies published through 2020. One cohort study included 41 participants with renal cell carcinoma (Canvasser, 2017). 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 (Hilton, 2022).
Nonrandomized Studies
The studies of IRE for renal cell cancer are single-arm and the majority have included 10 or fewer participants (Buijs, 2019; Canvasser, 2017; Xing, 2018; Thomson, 2011; Pech, 2011; Diehl, 2016; Vroomen, 2017; Liu, 2019; Wendler, 2018; Wendler, 2018).
Canvasser et al 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 (Canvasser, 2017). 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%.
Lung Tumors
The American Cancer Society estimates that there will be over 234,000 new cases of lung cancer and over 125,000 lung cancer deaths in 2024. Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer death in both men and women (Siegel, 2024).
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 considered for those patients who are deemed “high risk” (medically inoperable due to comorbidities) and is an option for the management of NSCLC lesions less than 3 cm. The guidelines also state that in the setting of progression at a limited number of site (oligoprogression), local ablative therapy may extend the duration of benefit of the current line of systemic therapy (NCCN, 2024).
Nonrandomized Studies
Two nonrandomized, prospective, single-arm studies have been published (Thomson, 2011; Ricke, 2015). Thomson et al includes a mix of tumor types in 38 participants including lung.
Ricke et al reported results of the ALICE single-arm, multicenter (2) trial (Ricke, 2015). 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. 61% (14/23) of participants developed progressive disease. 4% (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 (Ricke, 2015).
Supplemental Information
The National Comprehensive Cancer Network (NCCN) guidelines for Hepatocellular Carcinoma (v2.2024) 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, 2024).
The National Comprehensive Cancer Network (NCCN) guidelines for Biliary Tract Cancers (v3.2024) states that ablation is a reasonable alternative to surgical resection for intrahepatic CCA, particularly in patients with high-risk disease and 'Options for ablation include cryoablation, radiofrequency ablation, microwave ablation, and irreversible electroporation' for treatment of small, single intrahepatic cholangiocarcinoma tumors (less than 3cm) amenable to complete ablation, whether recurrent or primary (NCCN, 2024).
The National Comprehensive Cancer Network (NCCN) guidelines for Pancreatic Adenocarcinoma (v3.2024) states that 'Irreversible electroporation (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, 2024).
The National Comprehensive Cancer Network (NCCN) guidelines for Kidney Cancer (v1.2025) do not refer to irreversible electroporation. The guidelines state that 'Thermal ablation (e.g., cryosurgery, radiofrequency ablation, microwave ablation) is an option for the management of clinical stage T1 renal lesions (NCCN, 2024). Thermal ablation is suitable for renal masses 3 cm or smaller. Thermal ablation is an option for clinical T1b masses in select patients not eligible for surgery.'
The National Comprehensive Cancer Network (NCCN) guidelines for Non-Small Cell Lung Cancer (v8.2024) do not refer to irreversible electroporation (NCCN, 2024). With respect to ablation therapies, the guidelines state that:
The National Institute for Health and Care Excellence (NICE) published an interventional procedures guidance in 2017 on irreversible electroporation for treating pancreatic cancer (NICE, 2024). 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.'
Some currently unpublished trials that might influence this review are listed below.
Summary of Key Trials
Ongoing
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2025. No new literature was identified that would prompt a change in the coverage statement.
2026 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2025. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
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 (Martin, 2024). 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 plus leucovorin plus irinotecan plus oxaliplatin (FOLFIRINOX)-based regimens. Initial results demonstrated equivalent morbidity and mortality rates with IRE plus 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.
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 (FDA, 2025).
The IRE procedure is performed under computed tomography guidance and electrocardiography synchronization due to the possibility of muscular spasms caused by high-voltage pulses (Geboers, 2020). 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 (AngioDynamics, 2025).
Zhang et al and Prabhakar et al 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 (Zhang, 2025; Prabhakar, 2024). The heterogeneity across studies did not allow for meta-analyses or pooled results in either review.
Zhang et al reported that the in-field clinically significant prostate cancer rate was reported between 0% to 15.6% in the repeat biopsy after IRE (Zhang, 2025). The retreatment rate was reported from 8% to 36.6%. The 3 years failure-free survival was presented between 90% to 96.8%. The post-operative pad-free rate (an assessment of urinary function) ranged between 96.7% to 100%. The most common reported complications were urinary tract infection and hematuria, and major complications were rare.
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 (Prabhakar, 2024). 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.
George et al 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 (George, 2025). 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 less than or equal to T2c prostate cancer, with prostate-specific antigen (PSA) less than or equal to 15 ng/mL or a PSA density of less than 0.15 ng/mL2 if PSA greater than 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 greater than or equal to 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 greater than or equal to 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.
Yilmaz et al published a systematic review investigating the use of IRE as salvage therapy in men with recurrent prostate cancer after radiation therapy (Yilmaz, 2025). 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. The study by 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.
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, reirradiation (i.e., brachytherapy, stereotactic body radiotherapy), and prostatectomy plus pelvic lymph node dissection (NCCN, 2025).
NICE published an interventional procedure guidance in 2023 on IRE for treating prostate cancer (NICE, 2023). 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."
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AngioDynamics.(2025) NanoKnife Patient Guide. https://nanoknife.com/resources/. Accessed October 6, 2025.
Food and Drug Administration (FDA).(2025) NanoKnife System 510(k) Summary: K183385. https://www.accessdata.fda.gov/cdrh_docs/pdf18/K183385.pdf. Accessed October 6, 2025. Geboers B, Scheffer HJ, Graybill PM, et al.(2020) High-Voltage Electrical Pulses in Oncology: Irreversible Electroporation, Electrochemotherapy, Gene Electrotransfer, Electrofusion, and Electroimmunotherapy. Radiology. May 2020; 295(2): 254-272. PMID 32208094 George AK, Miocinovic R, Patel AR, et al.(2025) 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 International Society for Clinical Densitometry (ISCD).(2025) 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. Martin RCG, White RR, Bilimoria MM, et al.(2024) 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 Morling JR, Fallowfield JA, Guha IN, et al.(2014) Using non-invasive biomarkers to identify hepatic fibrosis in people with type 2 diabetes mellitus: the Edinburgh type 2 diabetes study. J Hepatol. 2014 Feb;60(2):384-91. Epub 2013 Oct 26 National Institute for Health and Care Excellence (NICE).(2023) Irreversible electroporation for treating prostate cancer: Interventional procedures guidance [IPG768]. 2023. https://www.nice.org.uk/guidance/ipg768. Accessed October 23, 2025. Neal RE, Davalos RV.(2009) The feasibility of irreversible electroporation for the treatment of breast cancer and other heterogeneous systems. Ann Biomed Eng. 2009 Dec; 37(12):2615-2625. Paiella S, Butturini G, Frigerio I, et al.(2015) Safety and feasibility of Irreversible Electroporation (IRE) in patients with locally advanced pancreatic cancer: results of a prospective study Dig Surg. 2015;32(2):90-7. Pech M., Janitzky A., Wendler JJ, et al.(2011) Irreversible electroporation of renal cell carcinoma: a first-in-man phase I clinical study. Cardiovasc Intervent Radiol (2011) 34:132-138. Pérez-Gutiérrez OZ, Hernández-Rocha C, Candia-Balboa RA, et al.(2013) Validation study of systems for noninvasive diagnosis of fibrosis in nonalcoholic fatty liver disease in Latin population. Ann Hepatol. 2013 May-Jun;12(3):416-24. Pilot Study of Irreversible Electroporation (IRE) to Treat Early-Stage Primary Liver Cancer (HCC). NCT01078415. www.clinicaltrials.gov. Accessed 4/26/10. Prabhakar P, Avudaiappan AP, Sandman M, et al.(2024) Irreversible electroporation as a focal therapy for localized prostate cancer: A systematic review. Indian J Urol. 2024; 40(1): 6-16. PMID 38314081 Rubinsky B.(2007) Irreversible electroporation in medicine. Technol Cancer Res Treat. 2007 Aug;6(4):255-60. Wichtowski M, Nowaczyk P, Kocur J, et al.(2016) Irreversible electroporation in the treatment of locally advanced pancreas and liver metastases of colorectal carcinoma Contemp Oncol (Pozn). 2016;20(1):39-44. Yilmaz M, Karaaslan M, Sirin ME, et al.(2025) 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 Zhang K, Teoh J, Zhu G, et al.(2025) Irreversible Electroporation for the Focal Treatment of Prostate Cancer: A Systematic Review. World J Mens Health. Apr 2025; 43(2): 321-332. PMID 39028129 |
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