Medical Policy


Subject:Electric Tumor Treatment Field (TTF)
Policy #:  DME.00035Current Effective Date:  01/01/2014
Status:ReviewedLast Review Date:  11/14/2013

Description/Scope

Electrical fields known as "tumor treatment fields (TTF)" are created by low-intensity, intermediate frequency (100 – 200 kilohertz [kHz]) electric currents delivered to the malignant tumor site by insulated electrodes placed on the skin surface.  TTF is felt to cause tumor cell death (apoptosis) by disrupting the assembly of microtubules during later stages of cell division.

Position Statement

Investigational and Not Medically Necessary:

The use of devices to generate electric tumor treating fields (TTF) as a treatment for malignant tumors is considered investigational and not medically necessary.

Rationale

The use of electric fields and the corresponding effects upon living tissue has been studied in the laboratory and clinical settings.  Alternating electric fields at very low frequencies (below 1 kHz) stimulate excitable tissue resulting from membrane depolarization (Kirson 2004, 2007, 2009; Salzberg, 2008).  Electric fields in the tens of kHz to megahertz (intermediate-frequency) alternate too fast to stimulate tissue and results in minute heating.  Kirson and colleagues (2004) demonstrated targeted inhibitory effects on dividing cells with the application of alternating electric fields of very low-intensity (less than 2 V/centimeter [cm]) and intermediate-frequency, called TTF.  Utilizing time-lapse microphotography of mouse melanoma cell cultures, unique cellular processes as a result of TTF exposure were identified.  Prolongation of mitosis in TTF-treated cells was statistically significant, and one quarter of the treated cells was destroyed.  Cellular destruction was observed only in mitotic cells, and cells at rest (quiescent) remained intact, both functionally and morphologically.  Nuclear rotation was also observed in TTF treated cell cultures.  Microtubules, in the form of spatially organized mitotic spindles in dividing cells, have very large electric dipole moments that may be disoriented by TTF forces.  In the control cell cultures, 95% of the mitotic spindles were intact and exhibited normal features in cells undergoing mitosis compared to 50% of abnormal cell activity in TTF-treated cultures.  The use of TTF was then applied in vivo, to two animal tumor models (adenocarcinoma and malignant melanoma cells).  TTF-treated tumors were significantly smaller compared to the control tumor size, and the surrounding normal tissue was spared from injury.  The encouraging preclinical data led to studies of electric TTF treatment in humans based on the principle that TTF results in disruption of the cell membrane and programmed cell death of cancer cells.

Glioblastoma Multiforme (GBM)

In an industry-sponsored study, Kirson and colleagues (2007) reported results of TTF treatment on various tumor cell lines and animal tumor models and noted "Optimal frequencies differed between cancer cell types."  Additionally, the effects of a total of 280 weeks of TTF treatment on 10 individuals with recurrent GBM were reported in the pilot study.  TTF treatment resulted in a median time to progression (TTP) of 26.1 weeks (range 3 – 124 weeks) and the progression free survival at 6 months (PFS6) of 50% (23 -77% confidence interval [CI]).  The median overall survival (OS) was 62.2 weeks (range 20.3 - 124.0 weeks).  One individual achieved a complete response (CR) and is free from tumor ten months after stopping treatment, and one participant achieved and continues to maintain a partial response (PR) seven months after stopping treatment.  The authors concluded TTF treatment is encouraging when compared to historical average PFS6 of 15.3 ± 3.8% and average historical TTP of 9.5 ± 1.6 weeks and an average OS 29.3 ± 6 weeks.  Mild to moderate contact dermatitis was reported in nine out of ten participants.

The U.S. Food and Drug Administration (FDA) approved the premarket approval application (PMA) for NovoTTF™-100A System (NovoCure™ Ltd., Portsmouth, NH; Haifa, Israel) in 2011.  The approved indication for NovoTTF is as a treatment for adults with histologically-confirmed, recurrent GBM in the supratentorial region of the brain after receiving chemotherapy.  The label (2011) states "The device is intended to be used as monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted."  

The PMA was based on data presented to the committee from a phase III, multinational, randomized, controlled pivotal clinical trial.  Between September 2006 and May 2009, 28 clinical centers enrolled 237 adult participants with relapsed or progressive GBM despite conventional therapy (e.g., surgery and chemo-radiotherapy followed by chemotherapy) (Stupp, 2012).  One hundred twenty participants were randomized in a 1:1 ratio to receive monotherapy with NovoTTF treatment and 117 participants were randomized to the group treated with available best standard care (BSC) chemotherapies as practiced at each of the participating clinical centers.  Chemotherapy agents considered as BSC during the trial included platinum-based chemotherapy (i.e., carboplatin); nitrosureas (BCNU); procarbazine; combination of procarbazine, lomustine and vincristine (PCV); temozolomide; and bevacizumab.  A period of twenty-eight-days of treatment with NovoTTF was considered one full treatment course.  Participants treated with NovoTTF were allowed to take breaks from treatment up to an hour, twice per day for personal needs such as showers.  The primary endpoint of the study was OS.  Secondary endpoints included PFS6, TTP, 1-year survival rate, quality of life (QOL), and radiological response.  Participants were seen in clinic monthly, and magnetic resonance imaging (MRI) was performed after 2, 4 and 6 months from initiation of treatment and subsequent MRIs were done according to local practice until disease progression.  Medical follow-up continued for 2 months after disease progression.  Monthly telephone interviews with the participants' caregivers were used to assess participant mortality rates.

Of the 237 enrollees, 8 participants (4 in each group) did not receive the assigned therapy.  Ninety-seven percent (116) of 120 enrollees in the NovoTTF group started treatment and 93 participants (78%) completed one cycle (4 weeks) of therapy.  Discontinuation of TTF occurred in 27 participants due to noncompliance or the inability to handle the device.  For each TTF treatment month, the median compliance was 86% (range 41-98%), which equaled a mean use of 20.6 hours per day.  In the BSC (active control) group, 113 (97%) of the 117 assigned participants received chemotherapy and all completed one full treatment course with the exception of one individual.  In the BSC cohort, 21 participants did not return to the site and details on disease progression and toxicity were not available.  Stupp and colleagues (2012) noted the median survival of 6.6 months in the TTF group was marginally higher than 6 months in the BSC group (hazard ratio 0.86 [95% CI 0.66 – 1.12]; p=0.27).  For both groups, one-year survival was 20%.  The survival rates for 2- and 3-years were 8% (95% CI 4, 13) and 4% (95% CI 1, 8) versus 5% (95% CI 3, 10) and 1% (95% CI 0, 3) for the TTF cohort compared to the BSC cohort, respectively.  With a median follow-up of 39 months, 93% (220 participants) had died.  Objective radiological responses (partial and complete response) were noted in 14 participants in the TTF group and 7 in the BSC group, with a calculated response rate of 14.0% (95% CI 7.9- 22.4%) compared to 9.6% (95% CI 3.9 – 18.8%), respectively.  Sixteen percent of the TTF participants had grade 1 and 2 contact dermatitis on the scalp, which resolved with topical steroids.  BSC participants experienced grade 2-4 events by organ system related to the pharmacologic activity of chemotherapy agents utilized.  Quality of life data were available in 63 participants (27%).  Based on the QLQ C-30 and BN-20 questionnaires, 5 out of 6 general scales and 7 of 9 symptom scales including nausea, vomiting, diarrhea, constipation and pain, quality of life was consistently higher in NovoTTF than in the control group.  There were no meaningful differences observed between the domains of global health and social functioning.  The BSC cohort had a larger decrease in the negative effects of seizures than the TTF cohort.  The self-reporting of QOL indicators may be influenced by bias for the treatment group (FDA Label, 2011; Stupp, 2012).

Results from an industry sponsored pilot study of TTF alone and TTF in combination with chemotherapy for individuals with diagnosed GBM were reported (Kirson, 2009b).  In this single arm study, the first group included 10 individuals with recurrent GBM after failure of maintenance temozolomide and 10 individuals with newly diagnosed GBM treated with TTF combined with temozolomide were in the second cohort.  All 20 individuals were treated for an average of 1 year (range 2.5 – 24 months) continuously.  The first group was compared to a matched group of 18 concurrent controls who received salvage chemotherapy for relapsed/recurrent GBM.  The TTF-chemotherapy group was compared to a matched group of 32 concurrent controls who received temozolomide alone.  In addition, OS for both cohorts was compared to matched historical control data.  Data for the first group were reported in 2007 (Kirson).  For the group of 10 individuals with newly diagnosed GBM, PFS was significantly different (P=0.0002, HR 3.32 [95% CI 1.9 – 5.9]) between the TTF-chemotherapy group compared to the matched concurrent and historical controls.  The difference in OS was also significant (P=0.0018).  The authors concluded TTF may also be an effective sensitizer when used concurrently with chemotherapeutic agents.  However, the results were compared to historical data and need to be confirmed in prospective trials.

Although the NovoTTF-100A device has received FDA approval, the pivotal trial did not achieve the primary endpoint of the study, which was improved survival with NovoTTF treatment in comparison to chemotherapy.  In addition, the long-term safety and efficacy as a treatment for recurrent GBM has not been demonstrated.  The expedited premarket approval (PMA) included a requirement for a post-market non-randomized, unblinded, concurrent control study of NovoTTF-100A in individuals with recurrent GBM.  The primary question to be addressed by the study (FDA Label, 2011): "Is the overall survival of patients treated with NovoTTF-100A non-inferior to the survival of patients treated with the best standard of care (chemotherapy)."  There are currently ongoing clinical trials investigating the safety and effectiveness of the novel TTF device.  In addition, there are ongoing investigations to determine the optimal TTF dosing for specific tumor types; the use of TTF alone and in combination with chemotherapy agents; and its place in therapy.  Currently, most of the published articles include animal studies, in vitro studies and small case series.

Treatment recommendations published by the National Comprehensive Cancer Network® (NCCN, 2013) and the National Cancer Institute (NCI, 2013) include surgical resection, radiation therapy and/or chemotherapy as treatment options.  In January 2013, the NCCN clinical practice guideline for CNS Tumors was updated to include a consideration for alternating electric field therapy for individuals with recurrent, diffuse or multiple GBM as a category 2B level of evidence.  The NCI Adult Brain Tumors Treatment (PDQ®) (2013) does not include TTF treatment for recurrent GBM.

Currently, there are phase II and III trials recruiting participants with GBM to treatment with NovoTTF-100A and other agents to evaluate the effect on progression-free survival, objective response rate and overall survival.  Similarly, a phase II trial is studying the effect of NovoTTF-100A after stereotactic radio-surgery (SRS) to treat individuals with brain metastases from non-small cell lung cancer.  The studies are expected to be completed in 2015. 

Other Solid Tumors

In addition to TTF treatment for brain tumors, this novel therapy has been studied in other types of malignancies.  A pilot study (Salzberg, 2008) included six participants with locally advanced or metastatic malignant tumors (3 cases - skin metastasis from primary breast cancer; 1 case each: GBM, malignant melanoma, mesothelioma).  Participants had no concomitant anti-tumor therapy and had no additional standard therapy available.  All six participants had a total of 128 full days of TTF treatment with individual exposure of 13 – 46 days.  Compliance was greater than 80%.  Three out of six participants had grade 1 skin irritation which was reversible with electrode repositioning and application of topical steroid ointments.  A partial response in skin metastasis from primary breast cancer was observed in one participant.  Tumor growth was arrested in three participants and one participant had progressive disease.  The participant with mesothelioma had stabilization of a portion of the tumor while another part of the tumor had progressive disease.  The individual with GBM did not respond to 4 weeks of treatment.  The mixed results and minimal toxicities from TTF warranted "further investigation in larger clinical trials." 

A phase I/II trial investigating the use of NovoTTF-100L device in combination with pemetrexed as a treatment for individuals with advanced non-small cell lung cancer (NSCLC) has been completed.  However, a future phase III trial has been planned to confirm the results of the initial studies and to further investigate the application of electric TTF as a treatment for progressive NSCLC.

The NCCN clinical practice guideline for NSCLC (2013) and the 2013 NCI NSCLC Treatment PDQ do not include the use of electric TTF treatment.

Background/Overview

The NovoTTF-100A System was approved by the U.S. Food and Drug Administration in April 2011, as a novel device to treat adults with glioblastoma multiforme (GBM) that recurs or progresses after receiving chemotherapy and radiation therapy.  TTF technology is also being studied as a treatment for other solid tumors such as non-small cell lung cancer and melanoma.  There are published data from TTF use to treat tumors in pre-clinical trials and from small case series.  However, there is a paucity of published evidence from randomized controlled trials comparing the long term safety and efficacy of TTF as a treatment of tumors.

According to the National Cancer Institute (2013), glioblastoma (World Health Organization grade IV) is also known as glioblastoma multiforme (GBM).  The peak incidence for GBM occurs between the ages of 45 and 70 years.  Glioblastoma is highly invasive and is the most frequently occurring brain tumor accounting for approximately 12% to 15% of all brain tumors and 50% to 60% of all astrocytic tumors.  Giant cell glioblastoma and gliosarcoma are two histologic variants of glioblastoma multiforme.  According to the NCCN (2013) GBM is the "deadliest brain tumor with only a third of patients surviving for one year and less than 5% living beyond 5 years."  Anaplastic astrocytomas have a 5-year survival rate of 27%.

Definitions

Cytokinesis: The cytoplasmic changes accompanying mitosis.  The cleavage of the cytoplasm into daughter cells following nuclear division.

Glioblastoma multiforme: Stage IV glioblastoma, which includes World Health Organization [WHO] recognized variants, giant cell glioblastoma and gliosarcoma.

Mitosis: The process by which a single parent cell divides to make two new daughter cells.  Each daughter cell receives a complete set of chromosomes from the parent cell, allowing the body to grow and replace cells.

Progressive disease: Disease that is growing, spreading or getting worse.

Recurrent disease: Disease that has recurred (come back), usually after a period of time during which the disease could not be detected.  In the case of cancer, the disease may come back to the same place as the original (primary) tumor or to another place in the body.  Also called recurrence.

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:

When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

HCPCS 
A4555Electrode/transducer for use with electrical stimulation device used for cancer treatment, replacement only
E0766Electrical stimulation device used for cancer treatment, includes all accessories, any type
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2014]
 All diagnoses
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2014]
 All diagnoses
  
References

Peer Reviewed Publications: 

  1. Kirson ED, Dbaly V, Tovarys F, et al. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007; 104(24):10152-10157.
  2. Kirson ED, Giladi M, Gurvich Z, et al. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis. 2009a; 26(7):633-640.
  3. Kirson ED, Gurvich Z, Schneiderman R, et al. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004; 64(9):3288-3295.
  4. Kirson ED, Schneiderman RS, Dbalý V, et al. Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys. 2009b; 9:1.
  5. Pless M, Droege C, von Moos R, et al. A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer. Lung Cancer. 2013; 81(3):445-450.
  6. Rulseh AM, Keller J, Klener J, et al. Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields. World J Surg Oncol. 2012; 10:220.
  7. Salzberg M, Kirson E, Palti Y, Rochlitz C. A pilot study with very low-intensity, intermediate-frequency electric fields in patients with locally advanced and/or metastatic solid tumors. Onkologie. 2008; 31(7):362-365.
  8. Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012; 48(14):2192-2202.

Government Agency, Medical Society, and Other Authoritative Publications: 

  1. National Cancer Institute (NCI) - Adult Brain Tumors Treatment (PDQ®). Last modified May 14, 2013. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/adultbrain/HealthProfessional. Accessed on August 12, 2013.
  2. NCCN Clinical Practice Guidelines in Oncology™. © 2013 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on August 12, 2013.
    • Breast Cancer (V.3.2013). May 3, 2013.
    • Central Nervous System Cancers (V.2.2013). April 25, 2013.
    • Melanoma (V.1.2014). August 2, 2013.
    • NonSmall Cell Lung Cancer (V.2.2013). January 17, 2013.
    • Pancreatic Adenocarcinoma (V.1.2013). April 9, 2013.
  3. U.S. Food and Drug Administration (FDA). Neurological Devices Panel. March 17, 2011a. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/UCM247168.pdf. Accessed on September 26, 2013.
  4. U.S. Food and Drug Administration (FDA) Premarket Notification Database. Tumor Treatment Fields. NovoTTF-10A System. Summary of Safety and Effectiveness Data (SSED). No. P100034. Rockville, MD: FDA. April 8, 2011b. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100034b.pdf. Accessed on August 12, 2013.
Web Sites for Additional Information
  1. American Cancer Society (ACS). What's new in adult brain and spinal cord tumor research and treatment? February 6, 2013. Available at: http://www.cancer.org.  Accessed August 12, 2013.
  2. National Cancer Institute (NCI). Available at: http://www.cancer.gov/. Accessed on August 12, 2013.
  3. National Institutes of Health. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/. Accessed on August 12, 2013.
Index
NovoTTF-100A System
NovoTTF-100L System
TTF
Tumor Treatment Field

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

Reviewed11/14/2013Medical Policy & Technology Assessment Committee (MPTAC) review.
Reviewed11/13/2013Hematology/Oncology Subcommittee review. Updated Rationale, References and Websites.  Updated Coding section with 01/01/2014 HCPCS changes.
Reviewed11/08/2012MPTAC review.
Reviewed11/07/2012Hematology/Oncology Subcommittee review. Updated Rationale, References and Websites.
Reviewed11/17/2011MPTAC review.
Reviewed11/16/2011Hematology/Oncology Subcommittee review. Updated References and Websites.
New08/18/2011MPTAC review. Initial document development.