Medical Policy

 

Subject: Irreversible Electroporation (IRE)
Document #: SURG.00126 Publish Date:    09/27/2017
Status: Reviewed Last Review Date:    08/03/2017

Description/Scope

This document addresses use of the NanoKnife® Oncobionic System (AngioDynamics® Inc., Fremont, CA) which is classified by the U.S. Food and Drug Administration (FDA) as a Class II electrosurgical cutting and coagulation device.  This document exclusively addresses all uses of irreversible electroporation (IRE), as a specific form of tissue ablation.

Note: For information related to other ablative techniques for cancer treatment, please see:

Position Statement

Investigational and Not Medically Necessary:

Irreversible electroporation (IRE) is considered investigational and not medically necessary for all indications, including, but not limited to, ablation of soft tissue or of solid organs, such as the liver and pancreas.

Rationale

The NanoKnife Oncobionic System is a low energy, direct current, nonthermal ablative device system for use in performing a minimally invasive procedure referred to as "irreversible electroporation (IRE)."  The NanoKnife received FDA clearance, as substantially equivalent to prior Oncobionic Systems, also manufactured by AngioDynamics, Inc., as a Class II device for, "The surgical ablation of soft tissue" (FDA, 2011). 

Use of the NanoKnife Oncobionic System involves the process of using brief and controlled electric pulses to open microscopic pores in a targeted area.  By increasing the number, strength, and duration of electric pulses, electroporation can be made permanent or irreversible.  It is purported by the manufacturer, AngioDynamics, Inc., that IRE technology allows for extreme precision in targeting soft-tissue cells of interest while blood vessels and other sensitive structures in the area remain functional.  However, to date, there is very limited scientific evidence to demonstrate the safety or efficacy of this technology.  The first such procedure was performed at Stony Brook University Medical Center (New York) in December 2009 to treat pancreatic cancer.

The published evidence to date has consisted of limited studies using theoretical calculations, in vitro experiments, and statistical models to examine potential uses of this technology (Goldberg, 2010; Miller, 2005; Neal, 2009; Shafiee, 2009).  One single-center, prospective, nonrandomized cohort study was performed to investigate the safety of IRE for tumor ablation in 38 humans with advanced malignancy of the liver, kidney, or lung.  Transient ventricular arrhythmia occurred in 4 subjects, and electrocardiographically (ECG) synchronized delivery was used subsequently in the remaining 30 participants with occurrence of two further arrhythmias (supraventricular tachycardia and atrial fibrillation).  One subject developed obstruction of the upper ureter after IRE.  One adrenal gland was unintentionally directly electroporated, which produced transient severe hypertension.  There was no other evidence of adjacent organ damage related to the electroporation.  Only 30-day outcomes were reported.  Although not a primary aim of this preliminary study, complete target tumor ablation verified by computed tomography (CT) was achieved in 46 of the 69 tumors treated with IRE (66%).  Most treatment failures occurred in renal and lung tumors.  Biopsy in 3 subjects showed coagulative necrosis in the regions treated by IRE.  The authors concluded, "IRE appears to be safe for human clinical use provided ECG-synchronized delivery is used. Comparative evaluation with alternative ablative technologies is warranted" (Thomson, 2011). 

There have been clinical trials of IRE; one is the Pilot Study of Irreversible Electroporation (IRE) to Treat Early-Stage Primary Liver Cancer (HCC), which was sponsored by the manufacturer, AngioDynamics, Inc., and is currently listed as, "Completed" as of November 7, 2016.  However, to date, no articles have been published about this study (NCT01078415).  Another study listed on 'Clinical trials.gov" indicates this manufacturer-sponsored study is also "Completed," but nothing has been published regarding trial results (NCT01369420).  There is currently inadequate evidence in the published literature to support the safety and efficacy of this technology or to demonstrate how treatment with this surgical device will impact clinical outcomes for any condition or indication.  Recent publications of small retrospective chart reviews and prospective pilot studies of IRE in the treatment of advanced malignancies of the pancreas and liver have reported limited short-term improvements with high rates of adverse events and trends toward recurrence in larger tumors (over 4 cm) also noted (Cannon, 2013; Kingham, 2012; Martin, 2012; Moir, 2014).  A small prospective, single-arm, phase II clinical trial was conducted at two centers to evaluate the safety and effectiveness of IRE as a treatment for lung cancers which failed to meet primary and secondary endpoints.  The expected effectiveness was not met at interim analysis, and the trial was stopped prematurely after inclusion of 23 subjects (Ricke, 2015).

Background/Overview

The NanoKnife Oncobionic System received initial clearance from the U.S. Food and Drug Administration (FDA) on November 21, 2006 as a tissue ablation system indicated for surgical ablation of soft tissue, including cardiac and smooth muscle (FDA, 2006).  Subsequent FDA clearance clarified the indications, "For the surgical ablation of soft tissue" (FDA, 2008).  According to the FDA information available online, "It has not received clearance for the therapy or treatment of any specific disease or condition" (510[k] Number: K080376, 2008).  The NanoKnife System is classified by the FDA as an electrosurgical cutting and coagulation device (FDA, 2011).  

On January 21, 2011 the FDA Center for Devices and Radiological Health (CDRH) issued a warning letter to the manufacturer, AngioDynamics, Inc. regarding the NanoKnife Oncobionic System branding and labeling indications listed on the manufacturer's website.  The FDA requested that the words, "treat," "treatment," and "therapy" be removed and replaced with the word "ablation" throughout the labeling for the device, since the FDA clearance is not for any specific disease or condition.  The FDA also requested that a precise definition of "Irreversible Electroporation or IRE" be provided, since this term was not part of the initial FDA application (FDA, 2011).  The information currently available on the FDA web site for the NanoKnife no longer refers to the terms, "Irreversible Electroporation or IRE" and identifies the device as, "A low energy, direct current, non-thermal ablation device" (FDA, 2011).

Definitions

Electroporation: The process of using brief and controlled electric pulses to open microscopic pores in a targeted area. By increasing the number, strength, and duration of electric pulses, electroporation can be made permanent or irreversible (IRE). After IRE, the pores in the cells remain open permanently with resultant microscopic damage to cells.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary: 

CPT  
  For the following unlisted codes, when specified as ablation by irreversible electroporation:
32999 Unlisted procedure, lungs and pleura
47399 Unlisted procedure, liver
48999 Unlisted procedure, pancreas
53899 Unlisted procedure, urinary system
   
ICD-10 Diagnosis  
  All diagnoses
   
References

Peer Reviewed Publications:

  1. Ball C, Thomson KR, Kavnoudias H. Irreversible electroporation: a new challenge in "out of operating theater" anesthesia. Anesth Analg. 2010; 110(5):1305-1309.
  2. 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. 2013; 107(5):544-549.
  3. Golberg A, Rubinsky B. A statistical model for multidimensional irreversible electroporation cell death in tissue.  Biomed Eng Online. 2010; 9-13.
  4. Gomez FM, Patel PA, Stuart S, Roebuck DJ. Systematic review of ablation techniques for the treatment of malignant or aggressive benign lesions in children. Pediatr Radiol. 2014; 44(10):1281-1289.
  5. Kim HB1, Sung CK, Baik KY, Moon KW, et al. Changes of apoptosis in tumor tissues with time after irreversible electroporation.  Biochem Biophys Res Commun. 2013; 435(4):651-656.
  6. Kingham TP, Karkar AM, D'Angelica MI, et al. Ablation of perivascular hepatic malignant tumors with irreversible electroporation. J Am Coll Surg. 2012; 215(3):379-387.
  7. Mandel Y, Laufer S, Belkin M, et al. Irreversible electroporation of human primary uveal melanoma in enucleated eyes. PLoS One. 2013; 8(9):e71789.
  8. 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. 2015; 262(3):486-494.
  9. Martin RC 2nd, McFarland K, Ellis S, Velanovich V. Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma. J Am Coll Surg. 2012; 215(3):361-369.
  10. Miller L, Leor J, Rubinsky B. Cancer cells ablation with irreversible electroporation. Technol Cancer Res Treat. 2005; 4(6):699-705.
  11. Moir J, White SA, French JJ, et al. Systematic review of irreversible electroporation in the treatment of advanced pancreatic cancer. Eur J Surg Oncol. 2014; 40(12):1598-1604.
  12. Neal RE 2nd, Davalos RV. The feasibility of irreversible electroporation for the treatment of breast cancer and other heterogeneous systems. Ann Biomed Eng. 2009; 37(12):2615-2625.
  13. Pech M, Janitzky A, Wendler JJ, et al. Irreversible electroporation of renal cell carcinoma: a first-in-man phase I clinical study. Cardiovasc Interven Radiol. 2011; 34(1):132-138.
  14. 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. 2015; 38(2):401-408.
  15. Scheffer HJ, Nielsen K, de Jong MC, et al. Irreversible electroporation for nonthermal tumor ablation in the clinical setting: A systematic review of safety and efficacy. J Vasc Interv Radiol. 2014a; 25(7):997-1011.
  16. 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. 2014b; 24(10):2467-2475.
  17. Shafiee H, Garcia PA, Davalos RV. A preliminary study to delineate irreversible electroporation from thermal damage using the arrhenius equation. J Biomech Eng. 2009; 131(7):074509.
  18. Silk MT, Wimmer T, Lee KS, et al. Percutaneous ablation of peribiliary tumors with irreversible electroporation. J Vasc Interv Radiol. 2014; 25(1):112-118.
  19. Thomson KR, Cheung W, Ellis SJ, et al. Investigation of the safety of irreversible electroporation in humans. J Vasc Interv Radiol. 2011; 22(5):611-621.
  20. Yeung ES, Chung MW, Wong K, et al. An update on irreversible electroporation of liver tumours. Hong Kong Med J. 2014; 20(4):313-316.

 Government Agency, Medical Society, and Other Authoritative Publications:

  1. AngioDynamics, Inc. A Prospective, Multi-Center, Clinical Trial Using Irreversible Electroporation (IRE) for the Treatment of Early-Stage Hepatocellular Carcinoma (HCC). NLM Identifier: NCT01078415. Last updated on November 7, 2016. Available at: http://clinicaltrials.gov/ct2/show/NCT01078415. Accessed on June 27, 2017.
  2. AngioDynamics, Inc. NanoKnife Low Energy Direct Current (LEDC) System in Subjects with Locally Advanced Unresectable Pancreatic Cancer. NLM Identifier: NCT01369420. Last updated on November 7, 2016. Available at:  http://clinicaltrials.gov/ct2/show/NCT01369420?term=NanoKnife+Low+Energy+Direct+Current+%28LEDC%29+System+in+Subjects+With+Locally+Advanced+Unresectable+Pancreatic+Cancer&rank=1. Accessed on June 27, 2017.
  3. Azienda Ospedaliera di Padova. Pilot Study of Irreversible Electroporation (IRE) to Treat Metastatic Liver Cancer & Cholangiocarcinoma. NLM Identifier: NCT 01442324. Last updated on July 17, 2012. Available at: http://clinicaltrials.gov/ct2/show/NCT01442324?term=NCT01442324&rank=1. Accessed on June 27, 2017.
  4. U.S. Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH). Oncobionic System with six probe output (Oncobionic, Inc., Rancho Santa Margarita, CA). Summary of Safety and Effectiveness. No. K080376. April 2, 2008. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf8/K080376.pdf. Accessed on June 27, 2017.
  5. U.S. Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH). The NanoKnife® System (AngioDynamics, Inc. Fremont, CA). Summary of Safety and Effectiveness. No. K102329. October 24, 2011. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf10/K102329.pdf. Accessed on June 27, 2017.
Websites for Additional Information
  1. Information available at the manufacturer's web site, AngioDynamics, Inc. Available at: http://www.angiodynamics.com/products/nanoknife. Accessed on June 27, 2017.
Index

Ablation, Soft Tissue
Electroporation, Irreversible
IRE
NanoKnife
Oncobionic System
Soft Tissue Ablation

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. The Rationale and References sections were updated.
Reviewed 08/04/2016 MPTAC review. The Rationale and References were updated. Removed ICD-9 codes from Coding section.
Reviewed 08/06/2015 MPTAC review. The Rationale and References were updated.
Reviewed 08/14/2014 MPTAC review. The Rationale and References sections were updated.
Reviewed 08/08/2013 MPTAC review. The Rationale, Background and References were updated.
Revised 08/09/2012 MPTAC review. The document was revised to make clear that all uses of IRE are addressed and considered investigational and not medically necessary. Document was retitled:  Irreversible Electroporation (IRE). The Scope, Rationale and References were updated.  
New 08/18/2011 MPTAC. Initial policy development.