Medical Policy: 06.01.34 

Original Effective Date: November 2014 

Reviewed: October 2018 

Revised: October 2018 

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Glioblastoma is the most aggressive cancer that begins within the brain. Due to its multiple forms, it is also termed Glioblastoma multiforme (GBM). According to its location in the brain it may also give rise to hemi paresis, seizures, memory or speech impairment and visual changes. It is found to be more common in males than females. Currently there is no known cure but treatments are available. Tumor treatment fields (TTF) (e.g. Optune® device) is one such treatment that aims to prolong progression-free survival (PFS) and overall survival (OS).

 

Optune® (formerly NovoTTF-100A System) is the only legally marketed TTF delivery system available in the United States. The system used for the therapy consists of the Optune® Treatment Kit (Novocure, Ltd.) and INE Transducer Arrays. The kit includes the Electric Field Generator (NovoTTF-100A/Optune® device), power supply, portable battery, battery rack, battery charger, connection cable, and carrying case. The arrays are packaged with a gel layer, padding, medical tape, and overlapping liner. The portable, battery-powered device is carried in a backpack or shoulder pack while carrying out activities of daily living. For the treatment of glioblastoma, 4 disposable transducer arrays with insulated electrodes are applied to the patient’s shaved head. The transducer array layout is typically determined using specialized software. The patient’s scalp is re-shaved and the transducer arrays replaced twice a week by the patient, caregiver, or device technician. The device is worn for up to 24 hours a day for the duration of treatment, except for brief periods for personal hygiene and 2 to 3 days at the end of each month. The minimum daily treatment is 18 hours. The minimum duration of treatment is 1 month, with the continuation of treatment available until recurrence.

 

In April 2011, the NovoTTF-100A™ System (Novocure; assigned the generic name of TTF) was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process. The FDA-approved label reads as follows: “The NovoTTF-100A System is intended as a treatment for adult patients (22 years of age or older) with confirmed glioblastoma multiforme (GBM), following confirmed recurrence in an upper region of the brain (supratentorial) after receiving chemotherapy. The device is intended to be used as a stand-alone treatment and is intended as an alternative to standard medical therapy for recurrent GBM after surgical and radiation options have been exhausted.”

 

In September 2014, FDA approved Novocure’s request for a product name change from NovoTTF-110A System to Optune®.

 

In October 2015, FDA expanded the indication for Optune® in combination with temozolomide to include newly diagnosed GBM. The device was granted priority review status in May 2015 because there was no legally marketed alternative device available for the treatment of newly diagnosed GBM, a life-threatening condition. In July 2016, a smaller, lighter version of the Optune® device, called the Optune® System (NovoTTF-200A System), received FDA approval.

 

The FDA-approved label for newly diagnosed GBM reads as follows: “This device is indicated as treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM). Optune® with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery and completion of radiation therapy together with concomitant standard of care chemotherapy.”

 

The mechanism of action as described by the manufacturer: Tumor treating fields (TTF)/Electric tumor treatment fields is a locally or regionally delivered treatment that produces electric fields within the human body to disrupt the rapid cell division exhibited by cancer cells. TTF therapy works by creating alternating, “wave-like” electric fields that travel across their region of usage in different directions. Because structures within dividing cells have an electric charge, they interact with these electric fields.

 

Mapping software to optimize TTF therapy (e.g. NovoTAL™ Simulation System)

The NovoTAL™ (Transducer Array Layout) System (Novocure Inc.) is a proprietary software tool that produces a custom transducer array layout to optimize Optune therapy for each patient. According to the manufacturer of Optune® (TTF) that also developed the NovoTAL™ Simulation System: To ensure patients receive the maximal therapeutic level of TTFields at the site of their tumor, tumor burden is mapped and an optimal array layout is personalized using the NovoTAL software. The NovoTAL software utilizes magnetic resonance imaging (MRI) measurements for head size and tumor location obtained from axial and coronal T1 post contrast sequences to determine the optimal paired transducer array configuration that will deliver the maximal field intensity at the site of the tumor.

 

Newly Diagnosed GBM

The primary treatment for glioblastoma multiforme (GBM) is debulking surgery to remove as much of the tumor as possible. At that time, some patients may undergo implantation of the tumor cavity with a carmustine (bis chloroethylnitrosourea [BCNU]) - impregnated wafer. Depending on the patient’s physical condition, adjuvant radiation therapy, chemotherapy (typically temozolomide), or a combination of the 2 are given. After adjuvant therapy, some patients may undergo maintenance therapy with temozolomide.

 

In the adjuvant setting, Optune® demonstrated an improvement in overall survival (OS) when combined with temozolomide, when compared with the chemotherapy agent alone. In an analysis of 695 patients enrolled in the phase III EF-14 study, the median OS was 19.4 months with Optune® compared with 16.6 months with temozolomide alone. Additionally, progression-free survival (PFS) was improved by approximately 3 months, according to the FDA.

 

Recurrent GBM

Treatment of GBM is rarely curative, and tumors will recur in mostly all patients.

 

No standard treatment exists for recurrent GBM. In patients with disease that recurs after initial treatment, additional debulking surgery may be used if recurrence is localized. Other treatment options for recurrent disease include various forms of systemic medications such as bevacizumab, bevacizumab plus chemotherapy (e.g., irinotecan, bis-chloroethylnitrosourea/chloroethylnitrosourea, temozolomide), temozolomide, nitrosourea, procarbazine plus chloroethylnitrosourea and vincristine), cyclophosphamide, and platinum-based agents.

 

Clinical studies are ongoing to determine the safety and efficacy of TTF therapy as part of combination therapy for treating recurrent GBM. TTF therapy is under investigation as a combination therapy with chemotherapy plus bevacizumab and as a combination therapy with chemotherapy after irradiation therapy for treating recurrent GBM.

 

Treatment Outside of Glioblastoma

Tumor treating fields technology (TTF) is also being studied as a treatment for other solid tumors (e.g., melanoma, pancreatic adenocarcinoma and non-small cell lung cancer). However, there is a lack of published evidence from randomized controlled trials examining the long-term safety and effectiveness of TTF as a treatment of these cancers at this time.

 

Guidelines and Position Statements

The National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines on Central Nervous Systems Tumors (v.1.2018) recommend TTF therapy in conjunction with standard brain radiation therapy and current/adjuvant temozolomide for patients with supratentorial disease with good performance status. The panel conceded that data regarding TTF therapy is limited to evidence from the RCT which demonstrated similar survival in between groups. In addition, in the background section, the panel indicated that TTF therapy may be considered as a treatment option for recurrent GBM but not all panelists recommend treatment for these patients due to a lack of efficacy. The NCCN guideline does not advocate for the use of TTF therapy in the recommendation section for patients with recurrent disease.

 

Karnofsky Performance Status Score

A 10 point scale used by healthcare providers to quickly evaluate how an individual is feeling. This scale is used within the clinical guidelines algorithm.

  • 100 Able to work. Normal; No complaints; No evidence of disease.
  • 90 Able to work. Able to carry on normal activity; Minor symptoms.
  • 80 Able to work. Normal activity with effort; some symptoms.
  • 70 Independent; not able to work. Cares for self; Unable to carry on normal activity.
  • 60 Disabled; dependent. Requires occasional assistance; cares for most needs.
  • 50 Moderately disabled; dependent. Requires considerable assistance and frequent care.
  • 40 Severely disabled; dependent. Requires special care and assistance.
  • 30 Severely disabled. Hospitalized, death not imminent.
  • 20 Very sick. Active supportive treatment needed.
  • 10 Moribund. Fatal processes are rapidly progressing

 

European Association of Neuro-Oncology (EANO)

EANO Guideline on the Diagnosis and Treatment of Anaplastic Gliomas and Glioblastoma. 2014. This guideline states: “new approaches of glioma therapy… device based therapies such as tumor-treating fields should only be administered in the context of clinical trials.”

 

European Society of Medical Oncology (ESMO)

High-grade Glioma: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up. 2014. This guideline states: “Applying alternating electric fields—tumor-treating fields—using a battery powered device connected to electrodes placed on the patient’s scalp—was compared with physicians’ choice of chemotherapy in a randomized trial in recurrent disease. TTF failed to prolong survival compared with second-line chemotherapy [I, A].” This guideline defines Level of Evidence I as “evidence from at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomized trials without heterogeneity.” This guideline defines Grade of Recommendation A as “strong evidence for efficacy with a substantial clinical benefit, strongly recommended.

 

Some clinical researchers assert that TTF "could be further evaluated in combination with chemotherapy, as a maintenance treatment, or as a salvage therapy if radiotherapy or surgery is not possible." Clinical studies are ongoing to determine the safety and efficacy of TTF therapy as part of combination therapy for treating recurrent GBM. TTF therapy is under investigation as a combination therapy with chemotherapy plus bevacizumab and as a combination therapy with chemotherapy after irradiation therapy for treating recurrent GBM.

 

National Institute for Health and Care Excellence (NICE)

Guideline Brain Tumours (primary) and Brain Metastases in Adults (2018) This guideline manages suspected and confirmed glioma, suspected and confirmed meningioma, and suspected and confirmed brain metastases. It does not mention the use of tumor treatment fields.

 

National Cancer Institute (NIH)

Adult Central Nervous System Tumors Treatment (PDQ®)–Health Professional Version-Glioblastoma treatment

For patients with glioblastoma (WHO grade IV), the cure rate is very low with standard local treatment.

Standard treatment options for patients with newly diagnosed glioblastoma include the following:

  1. Surgery plus radiation therapy and chemotherapy.
  2. Surgery plus radiation therapy.
  3. Carmustine-impregnated polymer implanted during initial surgery.
  4. Radiation therapy and concurrent chemotherapy.

 

The standard treatment for patients with newly diagnosed glioblastoma is surgery followed by concurrent radiation therapy and daily temozolomide, and then followed by six cycles of temozolomide. The addition of bevacizumab to radiation therapy and temozolomide did not improve overall survival (OS).

 

The use of TTF is not mentioned within the information provided in the treatment section for Glioblastoma.

 

Definitions

Supratentorial - the supratentorial region of the brain is the area located above the tentorium cerebelli. The area of the brain below the tentorium cerebelli is the infratentorial region. The supratentorial region contains the cerebrum, while the infratentorial region contains the cerebellum.

 

Prior Approval:

Not applicable.

 

Policy:

Tumor treating fields (TTF) therapy (e.g. Optune®) to treat glioblastoma multiforme is considered medically necessary as an adjunct to standard maintenance therapy with temozolomide in patients with newly diagnosed glioblastoma multiforme following initial treatment with surgery, radiotherapy, and chemotherapy when ALL of the following conditions are met:

  • Adult patients ≥22 years of age AND
  • Histologically-confirmed glioblastoma multiforme supratentorial tumor AND
  • Karnofsky Performance Status score ≥60% AND
  • Patient understands device use, including the requirement for a shaved head, and is willing to comply with use criteria according to the Food and Drug Administration label (at least 18 hours of use per day) AND
  • Lack of implanted medical devices, including but not limited to: spinal cord stimulators, pacemakers, defibrillators, and programmable shunts.

 

Tumor treatment fields (TTF) therapy to treat glioblastoma is considered investigational, including but not limited to the following:

  • As an adjunct to standard medical therapy (eg, bevacizumab, chemotherapy) for patients with progressive or recurrent glioblastoma multiforme OR
  • As an alternative to standard medical therapy for patients with progressive or recurrent glioblastoma multiforme OR
  • For brain metastases OR
  • For cancer in other areas of the brain.

 

The use of tumor treatment fields (TTF) therapy to treat all other types of cancer is considered investigational.

 

For individuals who have progressive or recurrent GBM who receive TTF therapy as an adjunct or alternative to standard medical therapy, the evidence includes an RCT and nonrandomized comparative studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related morbidity. The single RCT evaluating TTF therapy for recurrent GBM did not show superiority of TTF therapy for the primary outcome (overall survival) compared with physicians’ choice chemotherapy.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

  • E0766 Electrical stimulation device, used for cancer treatment, includes all accessories, any type
  • A4555 Electrode/transducer for use with electrical stimulation device, used for cancer treatment, replacement only

 

Selected References:

  • National Cancer Institute (NCI). Adult Brain Tumors Treatment 2013 
  • National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers V1.2018.1 
  • 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. Sep 2012;48(14):2192- 2202. PMID 22608262
  • U.S. Food and Drug Administration (FDA) Tumor treatment fields. NovoTTF-10A System. Summary of safety and effectiveness data (SSED). Premarket Approval Application (PMA) No. P100034 2011; Accessed June, 2014.
  • Wong ET, Lok E, Swanson KD, et al. Response assessment of NovoTTF-100A versus best physician's choice chemotherapy in recurrent glioblastoma. Cancer Med. Jun 2014;3(3):592-602. PMID 24574359
  • Ram Z, Gutin PH. Subgroup and quality of life analyses of the phase III clinical trial of NovoTTF-100A versus best standard chemotherapy for recurrent glioblastoma. Neuro-Oncology. 2010;12:iv48-iv49. PMID
  • Ram Z, Wong ET, Gutin PH. Comparing the effect of novottf to bevacizumab in recurrent GBM: A post-HOC sub-analysis of the phase III trial data. Neuro-Oncology. 2011;13
  • Salzberg M, Kirson E, Palti Y, et al. A pilot study with very low-intensity, intermediate-frequency electric fields in patients with locally advanced and/or metastatic solid tumors. Onkologie. Jul 2008;31(7):362-365. PMID 18596382
  • 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. PMID 23095807
  • Turner SG, Gergel T, Wu H, et al. The effect of field strength on glioblastoma multiforme response in patients treated with the NovoTTF-100A system. World J Surg Oncol. 2014;12(1):162. PMID 24884522
  • Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chi. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012 Sep;48(14):2192-202.
  • Stupp R, Kanner A, Engelhard H, Heidecke V, Taillibert S, Lieberman FS, Dbaly V, Kirson ED, Palti Y, Gutin PH. A prospective, randomized, open-label, phase III clinical trial of NovoTTF-100A versus best standard of care chemotherapy in patients with recurrent glioblastoma. J Clin Oncol 2010 Jun 20;28(18 Suppl 1):LBA2007.
  • ECRI Emerging Technology Report. Tumor treating fields therapy (NovoTTF-100A) for recurrent glioblastoma, 01/15/2014.
  • NovoCure Ltd. Sponsor executive summary: P100034. Novocure Ltd. NOVOTTF-100A system for the treatment of recurrent glioblastoma multiforme (GBM) Rockville (MD): U.S. Food and Drug Administration (FDA) 2011 Mar 17. 122 p.
  • Kanner AA, Wong ET, Villano JL, et al. Post Hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100A system versus best physician's choice chemotherapy. Semin Oncol. Oct 2014;41 Suppl 6:S25-34.
  • Mrugala MM, Engelhard HH, Dinh Tran D, et al. Clinical practice experience with NovoTTF-100A system for glioblastoma: The Patient Registry Dataset (PRiDe). Semin Oncol. Oct 2014;41 Suppl 6:S4-S13.
  • ECRI ECRI Emerging Technology Report. Tumor treating fields therapy (Optune) for recurrent glioblastoma, 09/25/2015.
  • FDA approves drug for treatment of aggressive brain cancer FDA news release Silver Spring (MD): U.S. Food and Drug Administration (FDA); 2009 May 8 [accessed 2015 May 22]. [2 p].
  • Stupp R, Brada M, van den Bent MJ, Tonn JC, Pentheroudakis G, ESMO Guidelines Working Group. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis treatment and follow-up. Ann Oncol. 2014 Sep;25 Suppl 3:iii93-101. PMID: 24782454
  • Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, Cohen-Jonathan-Moyal E, Frappaz D, Henriksson R, Balana C, Chinot O, Ram Z, Reifenberger G, Soffietti R, Wick W, European Association for Neuro-Oncology (EANO) Task Force on Malignant Glioma. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol 2014 Aug;15(9):e395-403. PMID: 25079102
  • Pharma FW. FDA Grants Priority Review Status for Novocure's PMA Supplement Application of Optune in Newly Diagnosed Glioblasoma 2015;
  • Stupp R, Taillibert S, Kanner AA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. Dec 15 2015;314(23):2535-2543. PMID 26670971
  • Wong ET, Lok E, Swanson KD. Clinical benefit in recurrent glioblastoma from adjuvant NovoTTF-100A and TCCC after temozolomide and bevacizumab failure: A preliminary observation. Cancer Med. 2015;4(3):383-391.
  • Food and Drug Administration. FDA approves expanded indication for medical device to treat a form of brain cancer October 5, 2015. FDA: Silver Spring, MD.
  • McNamara MG, Sahebjam S, Mason WP. Emerging biomarkers in glioblastoma Cancers. 2013;5(3):1103-19. PMID: 24202336.
  • ECRI Institute, Technology Evidence Report. Technology Report Update 7/20/2016
  • NovoCure Ltd. Effect of novoTTF-100A in non-small cell lung cancer (NSCLC) patients with 1-3 brain metastases following stereotactic radio-surgery (SRS). In: ClinicalTrials.gov [database online]. Bethesda (MD): National Library of Medicine (U.S.); 2000- [accessed 2013 Apr 03]. [4 p].
  • Novocure Ltd. Novocure announces the completion of enrollment of its PANOVA trial of tumor treating fields plus gemcitabine for treatment of pancreatic cancer. St. Helier (Jersey): Novocure Ltd.; 2015 Jan 12. 2 p.
  • Novocure Ltd. Novocure enrolls first patient in a pilot study of tumor treating fields (TTFields) together with paclitaxel for the treatment of recurrent ovarian cancer. St. Helier (Jersey): Novocure Ltd.; 2014 Oct 30. 2 p.
  • Taphoorn MJB, Dirven L, Kanner AA, et al.(2018) Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma: a secondary analysis of a randomized clinical trial. JAMA Oncol. Apr 1 2018;4(4):495-504. PMID 29392280
  • Trusheim J, Dunbar E, Battiste J, et al. A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma. CNS Oncol. 2017 Jan;6(1):29-43. Epub 2016 Sep 15
  • National Cancer Institute (NCI) - Adult Brain Tumors Treatment (PDQ®). Last modified Jan, 31 2018.
  • Zhu JJ, Demireva P, Kanner AA, et al. Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma. J Neurooncol 2017; 135:545.

 

Policy History:

  • October 2018 - Annual Review, Policy Revised
  • October 2017 - Annual Review, Policy Revised
  • October 2016 - Annual Review, Policy Revised
  • October 2015 - Annual Review, Policy Revised
  • November 2014 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark 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 Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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