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Clinical Policy Bulletin:
Irreversible Electroporation (NanoKnife)
Number: 0828


Policy

Aetna considers the use of irreversible electroporation (IRE) including use of the NanoKnife for tissue ablation experimental and investigational due to insufficient evidence in the peer-reviewed literature.



Background

The field of irreversible electroporation (IRE) in medicine has been growing in recent years as a tool in tissue ablation (Rubinsky, 2007).  The process of IRE occurs as a consequence of  certain electrical fields being applied across a cell permeabilizing the cell membrane and leading to cell death, primarily when the electrical fields cause permanent permeabilization and consequent loss of cell homeostasis.  In comparison with current physical ablation technologies, IRE does not result in any thermal effect (Breton and Mir, 2011).

The Nanoknife is a low-energy direct current (LEDC) thermal ablation system, which received Food and Drug Administration (FDA) 510K clearance on October 24, 2011 (FDA, 2011).  The NanoKnife System has received FDA clearance for the surgical ablation of soft tissue.  It has not received clearance for the therapy or treatment of any specific disease or condition (AngioDynamics, 2011).  The NanoKnife System transmits LEDC energy from the generator to electrode probes placed in a target area for the surgical ablation of soft tissue.

Ball et al (2010) conducted a clinical trial of IRE for tumor ablation therapy.  A pulsating direct current of 20 to 50 A and 500 to 3000 V was delivered into metastatic or primary tumors of the liver, kidney, or lung via needle electrodes inserted under computed tomography (CT) or ultrasound guidance with use of a relaxant general anesthetic.  Twenty-one patients were included.  The results showed that electrical discharge produced generalized upper body muscular contractions requiring neuromuscular blockade.  Two patients developed positional neuropraxia because of the extended arm position requested for CT scanning.  Some patients developed self-limiting ventricular tachycardias that are now minimized by using an electrocardiogram (ECG) synchronizer.  Three patients developed pneumothoraces as a result of the needle electrode insertion.  The authors concluded that relaxant general anesthesia is required for IRE of the liver, lung, and kidney and that an ECG synchronizer should be used to minimize the risk of arrhythmias.  The authors further  noted that attention to the position of the arms is required to maximize CT scan quality but minimize brachial plexus strain and that simple post-operative analgesia is all that is required in most patients.

Pech et al (2011) studied 6 patients scheduled for curative resection of renal cell carcinoma (RCC) to assess the feasibility and safety of ablating RCC tissue by IRE.  Irreversible electroporation was performed during anesthesia immediately before the resection with ECG synchronization.  Analysis of hematological, serum biochemical, and ECG variables, including ST waveforms and axis deviations, showed no relevant changes during the study period.  No changes in cardiac function after IRE therapy were found, but 1 case of supraventricular extrasystole was encountered.  Initial histopathologic examination did not identify any immediate adverse effects of IRE.  The authors concluded that “IRE seems to offer a feasible and safe technique by which to treat patients with kidney tumours and could offer some potential advantages over current thermal ablative techniques.”

Thomson et al (2011) conducted a single-center prospective non-randomized cohort study to investigate the safety of IRE for tumor ablation in humans.  Thirty-eight study subjects received IRE treatment under general anesthesia.  The study population included patients with advanced malignancy of the liver, kidney, or lung (69 separate tumors) which were unresponsive to alternative treatment.  Clinical examination, biochemistry, and CT scans of the treated organ were performed before, immediately after, and at 1 month and 3 post-procedure.  The authors reported no mortalities occurring by 30 days post-procedure and that transient ventricular arrhythmia occurred in 4 patients and that ECG synchronized delivery was used subsequently in the remaining 30 patients, with 2 further arrhythmias (supraventricular tachycardia and atrial fibrillation).  One patient 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.  Two patients developed temporary neurapraxia as a result of arm extension during a prolonged period of anesthesia and biopsy in 3 patients showed coagulative necrosis in the regions treated by IRE.  The authors further noted that complete target tumor ablation verified by CT was achieved in 46 of the 69 tumors treated with IRE (66 %), while most treatment failures occurred in renal and lung tumors.   The authors concluded that IRE appears safe for human clinical use if ECG-synchronized delivery is utilized.  They recommended comparative  evaluation with alternative ablative technologies.

Charpentier (2012) explored IRE as a novel, non-thermal form of tissue ablation using high-voltage electrical current to induce pores in the lipid bilayer of cells, resulting in cell death.  PubMed searches were performed using the keywords electroporation, IRE, and ablation.  The abstracts for the 2012 meetings of both the American Hepato-Pancreato-Biliary Association and the Society for Interventional Radiology were also searched.  All articles and abstracts with any reference to electroporation were identified and reviewed.  All studies and abstracts pertaining to electroporation were reviewed.  All data pertaining to the safety and effectiveness of IRE were extracted from pre-clinical and clinical studies.  Pre-clinical data detailing the theory and design of IRE systems were also extracted.  Pre-clinical studies have suggested that IRE may have advantages over conventional forms of thermal tumor ablation including no heat sink effect and preservation of the acellular elements of tissue, resulting in less unwanted collateral damage.  The early clinical experience with IRE demonstrated safety for the ablation of human liver tumors.  Short-term data regarding oncologic outcome is now emerging and appears encouraging.  The author concluded that IRE is likely to fill a niche void for the ablation of small liver tumors abutting a major vascular structure and for ablation of tumors abutting a major portal pedicle where heat sink and collateral damage must be avoided for maximum efficacy and safety.  Moreover, they stated that studies are still needed to define the short-term and long-term oncologic effectiveness of IRE.

Olweny and Cadeddu (2012) provided an overview of the current research on renal tissue ablation, high-lighting novel ablation techniques and technologies.  Although nephron-sparing surgery is the gold standard treatment for small renal masses confirmed malignant, ablative therapies are an option in elderly patients, who may be poor surgical candidates.  Radio-frequency ablation (RFA) and cryoablation have each been used for renal tissue ablation for over a decade, but their effectiveness in ablation of central lesions or lesions more than 3 cm in size is limited.  Increasing ablation size and improving effectiveness of thermal energy delivery are the goals of research in RFA and cryoablation.  The authors stated that novel ablation technologies including IRE, microwave ablation, and high-intensity focused ultrasound among others have undergone preliminary pre-clinical and clinical evaluation in select series, but require further development and assessment of outcomes prior to routine clinical use for renal tumor ablation.

Kingham et al (2012) evaluated the safety and short-term outcomes of IRE to ablate peri-vascular malignant liver tumors.  A retrospective review of patients treated with IRE between January 1, 2011 and November 2, 2011 was performed.  Patients were selected for IRE when resection or thermal ablation was not indicated due to tumor location.  Treatment outcomes were classified by local, regional, and systemic recurrence and complications.  Local failure was defined as abnormal enhancement at the periphery of an ablation defect on post-procedure contrast imaging.  A total of 28 patients had 65 tumors treated; 22 patients (79 %) were treated via an open approach and 6 (21 %) were treated percutaneously.  Median tumor size was 1 cm (range of 0.5 to 5 cm).  Twenty-five tumors were less than 1 cm from a major hepatic vein; 16 were less than 1 cm from a major portal pedicle.  Complications included 1 intra-operative arrhythmia and 1 post-operative portal vein thrombosis.  Overall morbidity was 3 %.  There were no treatment-associated mortalities.  At median follow-up of 6 months, there was 1 tumor with persistent disease (1.9 %) and 3 tumors recurred locally (5.7 %).  The authors concluded that this early analysis of IRE treatment of peri-vascular malignant hepatic tumors demonstrated safety for treating liver malignancies. They stated that larger studies and longer follow-up are needed to determine long-term effectiveness.

Narayanan et al (2012) evaluated the safety of percutaneous IRE in patients with pancreatic adenocarcinoma.  Irreversible electroporation was performed in patients with pancreatic cancer whose tumors remained unresectable after, or who were intolerant of, standard therapy.  The procedures were all performed percutaneously under general anesthesia.  Patients were then followed for adverse events, tumor response, and survival.  A total of 15IRE procedures were performed in 14 patients (1 was treated twice).  Three patients had metastatic disease and 11 had locally advanced pancreatic cancer (LAPC).  All patients had received chemotherapy previously, and 11 had received radiation.  The median tumor size was 3.3 cm (range of 2.5 to 7 cm).  Immediate and 24-hour post-procedural scans demonstrated patent vasculature in the treatment zone in all patients.  Two patients underwent surgery 4 and 5 months after IRE, respectively.  Both had margin-negative resections, and 1 had a pathologic complete response; both remain disease-free after 11 and 14 months, respectively.  Complications included spontaneous pneumothorax during anesthesia (n = 1) and pancreatitis (n = 1), and both patients recovered completely.  There were no deaths directly related to the procedure.  All 3 patients with metastatic disease at IRE died from progression of their disease.  The authors concluded that percutaneous IRE for pancreatic adenocarcinoma is feasible and safe; and they stated that a prospective trial is being planned.

Martin et al (2012) evaluated the overall survival (OS) in patients with LAPC treated with IRE.  A prospective, multi-institutional evaluation of 54 patients who underwent IRE for unresectable pancreatic cancer from December 2009 to October 2010 was evaluated for OS and propensity matched to 85 matched stage III patients treated with standard therapy defined as chemotherapy and radiation therapy alone.  A total of 54 LAPC patients have undergone IRE successfully, with 21 women, 23 men (median age of 61 (range of 45 to 80) years).  Thirty-five patients had pancreatic head primary and 19 had body tumors; 19 patients underwent margin accentuation with IRE and 35 underwent in situ IRE.  Forty-nine (90 %) patients had pre-IRE chemotherapy alone or chemo-radiation therapy for a median duration 5 months.  Forty (73 %) patients underwent post-IRE chemotherapy or chemo-radiation.  The 90-day mortality in the IRE patients was 1 (2 %).  In a comparison of IRE patients to standard therapy, these researchers have seen an improvement in local progression-free survival ([PFS]; 14 versus 6 months, p = 0.01), distant PFS (15 versus 9 months, p = 0.02), and OS (20 versus 13 months, p = 0.03).  The authors concluded that IRE ablation of locally advanced pancreatic tumors remains safe and in the appropriate patient who has undergone standard induction therapy for a minimum of 4 months can achieve greater local palliation and potential improved OS compared with standard chemo-radiation-chemotherapy treatments.  Moreover, they stated that validation of these early results will need to be validated in the current multi-institutional phase 2 IDE study.

Cannon et al (2013) evaluated the safety and effectiveness of IRE for hepatic tumors in the clinical setting.  An IRB approved prospective registry of patients undergoing IRE for hepatic tumors over a 2-year period.  Factors analyzed included patient and tumor characteristics, treatment related complications, and local recurrence free survival (LRFS) for ablated lesions -- LRFS was calculated according to Kaplan-Meier, with secondary analyses stratified by procedural approach (laparotomy, laparoscopy, and percutaneous) and tumor histology.  There were 44 patients undergoing 48 total IRE procedures, 20 colorectal metastases, 14 hepatocellular, and 10 other metastases.  Initial success was achieved in 46 (100 %) treatments.  Five patients had 9 adverse events, with all complications resolving within 30 days.  Local recurrence free survival at 3, 6, and 12 months was 97.4 %, 94.6 %, and 59.5 %, respectively.  There was a trend toward higher recurrence rates for tumors over 4 cm (HR 3.236, 95 % confidence interval [CI]: 0.585 to 17.891; p = 0.178).  The authors concluded that IRE appears to be a safe treatment for hepatic tumors in proximity to vital structures.  Moreover, they stated that further prospective evaluation is needed to determine the optimal effectiveness of IRE in relation to size and technique for IRE of the liver.

Mandel et al (2013) noted that uveal melanoma (UM) is the most common primary intra-ocular tumor in adults and is characterized by high rates of metastatic disease.  Although brachytherapy is the most common globe-sparing treatment option for small- and medium-sized tumors, the treatment is associated with severe adverse reactions and does not lead to increased survival rates as compared to enucleation.  The use of IRE for tumor ablation has potential advantages in the treatment of tumors in complex organs such as the eye.  Following previous theoretical work, these researchers evaluated the use of IRE for uveal tumor ablation in human ex-vivo eye model.  Enucleated eyes of patients with UM were treated with short electric pulses (50 to 100 µs, 1,000 to 2,000 V/cm) using a customized electrode design.  Tumor bio-impedance was measured before and after treatment and was followed by histopathological evaluation.  These investigators found that IRE caused tumor ablation characterized by cell membrane disruption while sparing the non-cellular sclera.  Membrane disruption and loss of cellular capacitance were also associated with significant reduction in total tumor impedance and loss of impedance frequency dependence.  The effect was more pronounced near the pulsing electrodes and was dependent on time from treatment to fixation.  The authors concluded that future studies should further evaluate the potential of IRE as an alternative method of UM treatment.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
Irreversible Electroporation (NanoKnife) :
No specific code


The above policy is based on the following references:
  1. Rubinsky B. Irreversible electroporation in medicine. Technol Cancer Res Treat. 2007;6(4):255-260.
  2. Ball C, Thomson KR, Kavnoudias H. Irreversible electroporation: A new challenge in 'out of operating theater' anesthesia. Anesth Analg. 2010;110(5):1305-1309.
  3. AngioDynamics. NanoKnife System [website]. Latham, NY: AngioDynamics; 2011. Available at: http://www.angiodynamics.com/products/nanoknife. Accessed December 22, 2011.
  4. Breton M, Mir LM. Microsecond and nanosecond electric pulses in cancer treatments. Bioelectromagnetics. 2012;33(2):106-123.
  5. 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. 2011;34(1):132-138.
  6. 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.
  7. U.S. Food and Drug Administration (FDA). Nanoknife System. Low Energy Direct Current Thermal Ablation System. 510(k) No. K102329. Silver Spring, MD: FDA; October 24, 2011.
  8. Charpentier KP. Irreversible electroporation for the ablation of liver tumors: Are we there yet? Arch Surg. 2012;147(11):1053-1061.
  9. Olweny EO, Cadeddu JA. Novel methods for renal tissue ablation. Curr Opin Urol. 2012;22(5):379-384.
  10. 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.
  11. Narayanan G, Hosein PJ, Arora G, et al.  Percutaneous irreversible electroporation for downstaging and control of unresectable pancreatic adenocarcinoma. J Vasc Interv Radiol. 2012;23(12):1613-1621.
  12. Martin RC 2nd, McFarland K, Ellis S, Velanovich V. Irreversible electroporation in locally advanced pancreatic cancer: Potential improved overall survival. Ann Surg Oncol. 2012 Nov 6. [Epub ahead of print]
  13. 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.
  14. Mandel Y, Laufer S, Belkin M, et al. Irreversible electroporation of human primary uveal melanoma in enucleated eyes. PLoS One. 2013;8(9):e71789.


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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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