Coverage Policy Manual
Policy #: 2010025
Category: Surgery
Initiated: May 2010
Last Review: June 2018
  Irreversible Electroporation, Nanoknife

Description:
The NanoKnife™ is a surgical ablation tool using the novel technique of Irreversible Electroporation to treat soft tissue lesions.  
 
Tissue electroporation uses electrodes to deliver short-length electric pulses to create tiny nano-scale pores in the cell membrane.  If the energy is delivered at a low voltage, the pores will eventually close as the electrical potential of the cell stabilizes.  This phenomenon, known as reversible electroporation, was discovered in the 1970’s and has been used in electrochemotherapy and electrogenetransfer.
 
In irreversible electroporation (IRE), a higher voltage is used to create permanent nano-sized defects in the cell membrane and thus causes cell death.  Unlike cryoablation and radiofrequency ablation, IRE treats without utilizing extreme cold or heat, possibly decreasing the damage to normal tissue.
 
Treatment with the NanoKnife system is done under general anesthesia using either ultrasound or CT guidance.  A series of micro-pulses is delivered through an electrode probe which induces cell death in seconds.  
 
IRE technology which is now being used in the Nanoknife™ was developed by a research team based at the University of California, Berkeley.  The technology was licensed to a company called Oncobionic which was later acquired by AngioDynamics.  NanoKnife™ received FDA 510K marketing clearance for surgical ablation of soft tissue in February 2008.  
 
At this time, there is no specific CPT code for this procedure.  We would expect this service to be billed with an unlisted code.
 

Policy/
Coverage:
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.
 

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:
 
    • 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).
 
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.

References: 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

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.

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.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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