Electric tumor treating fields (TTF), also known as alternating electric field therapy, are used for the treatment of glioblastoma, and are delivered by Optune® (NovoCureTM), a portable medical device that generates low-intensity electric fields termed Tumor Treating Fields. TTF are believed to disrupt the rapid cell division exhibited by cancer cells, with the alternating electrical fields applied to the brain through electrodes placed on the scalp. The device is worn by the patient throughout the day and attached to the head by electrodes, which creates a low intensity, alternating electric field within the tumor that exerts physical forces on electrically charged cellular components, preventing the normal mitotic process and causing cancer cell death prior to division.
Tumor-treatment fields (TTF) therapy is a noninvasive technology intended to treat glioblastoma on an outpatient basis using electric fields. TTF therapy exposes cancer cells to alternating electric fields of low intensity and intermediate frequency, which are purported to both selectively inhibit tumor growth and reduce tumor angiogenesis. Tumor treatment fields are proposed to inhibit rapidly dividing tumor cells by two mechanisms: arrest of cell proliferation and destruction of cells while undergoing division.
The NovoTTF-100A™ System (assigned the generic name of TTF) received FDA marketing approval in 2011 to deliver tumor treatment field therapy to adults with confirmed glioblastoma multiforme (GBM), following confirmed recurrence in the upper region of the brain after receiving chemotherapy. The device is intended as an alternative to standard medical therapy for recurrent GBM after surgical and radiation options have been exhausted. In 2014, the system’s name was changed to Optune™. In October 2015, FDA expanded the indication for use of Optune in combination with temozolomide to include newly diagnosed GBM. The battery-powered portable device generates the electrical fields via disposable electrodes that are noninvasively attached to the individual’s shaved scalp over the site of the tumor. The device is used by the individual at home on a continuous basis (20 - 24 hours per day) for the duration of treatment, which can last for several months.
Glioblastomas are a type of astrocytoma and the most common form of malignant primary brain tumor in adults. They comprise approximately 15 percent of all brain and central nervous system tumors and over 50 percent of all tumors that arise from glial cells. The supratentorial glioblastomas is above the tentorium, in the cerebrum, and mostly found in adults (70%). The infratentorial glioblastomas is below the tentorium, in the cerebellum, and mostly found in children (70%). GBMs are further classified as high-grade or grade IV astrocytomas, which are the most deadly type of glial cell tumor and are often resistant to standard chemotherapy. The primary treatment for GBM is debulking, or surgical reduction in size, to remove as much of the tumor as possible. Depending on the individual's physical condition, adjuvant radiation therapy, chemotherapy or a combination of the two are sometimes given. For individuals with recurring disease after the initial therapies, additional debulking surgery may be used if recurrence is localized.
In April 2011, the NovoTTF-100A™ System (Novocure, Haifa, Israel; assigned the generic name of TTF) was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process. 7 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 GBM [glioblastoma multiforme], following confirmed recurrence in an upper region of the brain (supratentorial) after receiving chemotherapy. The device is intended to be used as a standalone treatment, and is intended as an alternative to standard medical therapy for recurrent GBM after surgical and radiation options have been exhausted.”7
In September 2014, FDA approved Novocure’s request to change its product name from NovoTTF-110A System to Optune®.8
In October 2015, FDA expanded the indication for Optune® in combination with temozolomide to include newly diagnosed GBM.6 The device was granted priority review status in May 2015 because there was no legally marketed alternative device currently available for the treatment of newly diagnosed GBM that represents a life-threatening condition.
The FDA-approved label 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.”
Based on the 2011 approval, Optune® is also approved for the treatment of recurrent GBM in the supratentorial region of the brain after receiving chemotherapy. The device is intended for use as a monotherapy, and as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.
FDA product code: NZK.
TTF therapy is considered MEDICALLY NECESSARY for the following indication:
- New diagnosis of glioblastoma, histologically confirmed, and all of the following:
- Glioblastoma is in the supratentorial region;
- Member has good performance status, as defined by a Karnofsky Performance Status rating of ≥ 60;
- Alternating electric field therapy will be delivered in conjunction with temozolomide after standard surgical and radiation therapies have been completed.
- Recurrent glioblastoma, histologically - or radiologically - confirmed and all of the following:
- Glioblastoma is in the supratentorial region;
- Alternating electric field therapy will be used as a monotherapy, after standard treatment with surgery, radiation, and chemotherapy.
Initial authorization should be for no longer than 3 months.
If a continuation of therapy is needed, documentation that tumor size did not increase during the previous treatment period must be provided. CT or MRI are acceptable submissions for this documentation.
TTF therapy is considered NOT MEDICALLY NECESSARY for all other indications.
Computer mapping software (NovoTalTM) for planning TTF therapy is considered NOT MEDICALLY NECESSARY for all indications, as there is insufficient evidence to establish the efficacy of these products in the long-term outcomes of patients receiving TTF therapy.
For individuals who have progressive or recurrent glioblastoma multiforme (GBM) after initial or repeat surgery, radiotherapy, and/or chemotherapy who then receive tumor treatment fields (TTF) therapy as an alternative to standard chemotherapy, the evidence includes a randomized controlled trial (RCT) and nonrandomized comparative studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related morbidity. The published RCT reported no differences in outcomes between patients treated with TTF and with standard chemotherapy. This trial had several methodologic limitations. Comparisons that were made only included an active control of questionable efficacy, which might not reflect current standard of care. There was a high dropout rate (>20% of patients in each group were lost to follow-up) and, for the quality of life outcomes, only 25% of enrolled patients had complete data. The 2 nonrandomized studies were small and had limited validity due to differences in the patient populations treated with TTF and standard care. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have newly diagnosed GBM and receive TTF therapy as an adjunct to standard maintenance therapy following their initial treatment with surgery, radiotherapy, and/or chemotherapy, the evidence includes a single RCT. Relevant outcomes include overall survival, disease-specific survival, symptoms, functional outcomes, quality of life, and treatment-related morbidity. The single RCT reported that patients who received TTF treatment plus temozolomide had longer progression-free survival (3.1 months) and overall survival (4.9 months) than patients who received temozolomide alone. However, the trial had methodologic limitations, including the lack of a placebo control, differential dropout between groups, and the possibility of adherence bias for outcomes reported with per-protocol analysis. Further corroboration of these results is needed in high-quality RCTs. Although evidence is limited, NCCN has given this therapy a 2A rating. There are very few treatment options for this disease, and the side effect profile of TTF is much more tolerable to patients.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1.
Table 1. Summary of Key Trials
A Prospective Phase II Trial of NovoTTF-100A With Bevacizumab (Avastin) in Patients With Recurrent Glioblastoma
A Prospective, Non-randomized, Concurrent Control, Open Label, Post-approval Study of NovoTTF-100A in Recurrent GBM Patient
Phase II Trial Of Optune® Plus Bevacizumab In Bevacizumab-Refractory Recurrent Glioblastoma
||A Phase II Study of the NovoTTF-100A system, Enhanced by Genomic Analysis to Identify the Genetic Signature of Response in the Treatment of Recurrent Glioblastoma Multiforme
||A Phase 2, Multi-center, Single Arm, Histologically Controlled Study Testing the Combination of TTFields and Pulsed Bevacizumab Treatment in Patients With Bevacizumab-refractory Recurrent Glioblastoma
||Phase 1 Enhancing Optune Therapy of Recurrent Glioblastoma Multiforme Using Targeted Surgical Skull Remodeling
Proposed Pilot Study of Combined Optune+ Bevacizumab, and Hypofractionated Stereotactic Irradiation for Bevacizumab-Naive Recurrent Glioblastoma
NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.
Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may provide appropriate reviewers who collaborate with and make recommendations during this process, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
In response to requests, input was received from 3 physician specialty societies (one of which provided 6 responses and 2 of which provided 1 response each) and 1 academic medical center (total of 9 individual responses) while this policy was under review in 2016. There was majority support, but not consensus, for use of tumor treatment fields therapy as an adjunct to maintenance treatment following initial therapy for glioblastoma multiforme. There was mixed support for the use of tumor treatment fields as an alternative to chemotherapy in advanced or recurrent glioblastoma multiforme.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network guidelines on central nervous system cancers (v.1.2016)2 include a recommendation for the treatment of glioblastoma. For the initial treatment of patients with glioblastoma with good performance status and either methylated or unmethylated or indeterminate MGMT promotor status, treatment with standard brain radiotherapy plus concurrent temozolomide and adjuvant temozolomide plus alternating electric currents therapy is a category 2A recommendation. Alternating electric currents therapy is only an option for patients with supratentorial disease. Consideration of alternating electric field therapy for recurrent glioblastoma is a 2B recommendation.
- Novocure. Optune Instructions for Use. Document Number QSD-QR-703. Revision 01. Issue Date: July 201 QSD-QR-703. Revision 01. Issue Date: July 2016.
- National Comprehensive Cancer Network (NCCN). Central nervous system cancers. NCCN Clinical Practice Guidelines in Oncology. Version 1.2016. Fort Washington, PA: NCCN; 2012. July 26, 2016. Update Version 1.2017
- Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: A Randomized phase III trial of a novel treatment modality. Eur J Cancer. 2012;48(14):2192-2202.
- U.S. FDA. Optune Approval (Formerly the NovoTTF-100A System). October 5, 2015. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100034S013a.pdf
- 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. 2015; 314(23):2535-2543.
- Hayes Medical Technology Directory. Novocure (Tumor Treating Fields). Annual Review February 7, 2017. Published March 3, 2016.
- Kesari S, Ram Z. Tumor-treating fields plus chemotherapy versus chemotherapy alone for glioblastoma at first recurrence: a post hoc analysis of the EF-14 trial. Future Medicine April 12, 2017 (epub ahead of print). doi:10.2217/cns-2016-0049
- Vymazal J, Wong ET. Response patterns of recurrent glioblastomas treated with tumor-treating fields. Semin Oncol. 2015; 42(3):e44-e55.
- Hayes Search and Summary. NovoTAL System (Novocure) for the Treatment of Glioblastoma. April 20, 2017.
- Stupp R, Taillibert S, Kanner A, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017 Dec 19;318(23):2306-2316. doi: 10.1001/jama.2017.18718
- Batchelor T. Initial postoperative therapy for glioblastoma and anaplastic astrocytoma. In: UpToDate. Loeffler JS, Wen PY.(Ed) UpToDate, Waltham, MA. Jan 2018. Accessed March 12, 2018
- Batchelor T, Shih HA, Carter BS. Management of recurrent high-grade gliomas. In:UpToDate. Loeffler JS, Wen PY.(Ed) UpToDate, Waltham, MA. Dec 2017. Accessed March 12, 2018
- Connelly J, Hormigo A, Mohilie N, et al. Planning TTFields treatment using the NovoTAL system-clinical case series beyond the use of MRI contrast enhancement. BMC Cancer. 2016 Nov 4;16(1):842.
- Zhu P, Zhu JJ. Tumor treating fields: a novel and effective therapy for glioblastoma: mechanism, efficacy, safety and future perspectives. Chin Clin Oncol. 2017 Aug;6(4):41. doi: 10.21037/cco.2017.06.29.
- Mittal S, Klinger NV, Michelhaugh SK. Alternating electric tumor treating fields for treatment of glioblastoma: rationale, preclinical, and clinical studies. Neurosurg. 2018 Feb;128(2):414-421. doi: 10.3171/2016.9.JNS16452
- BlueCross BlueShield Association. Medical Policy Reference Manual. (7:2017). Tumor treatment fields therapy for glioblastoma (1.01.29). Retrieved September 18, 2017 from BlueWeb. (13 articles and/or guidelines reviewed)
- CGS Administrators, LLC. Local Coverage Article. (2017, January). Tumor treatment field therapy (TTFT) (L34823). Retrieved September 18, 2017 from https://www.cms.gov.
- ECRI Institute. Emerging Technology Evidence Report. (2016, July). Tumor treating fields therapy (Optune) for recurrent glioblastoma. Retrieved August 31, 2016 from ECRI Institute. (69 articles and/or guidelines reviewed)
- National Comprehensive Cancer Network. (2017, August). NCCN Clinical Practice Guidelines in Oncology. (NCCN Guidelines®). Central nervous system cancers (V.1.2017). Retrieved September 18, 2017 from http://www.nccn.org.
- Rulseh, A. M., Keller, J., Klener, J., Šroubek, J., Dbalý, V., Syrůček, M., et al. (2012). Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields. World Journal of Surgical Oncology, 10 (220). (Level 4 evidence)
- Stupp, R., Taillibert, S., Kanner, A., Kesari, S., Steinberg, D., Toms, S., et al. (2015). Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma [ a randomized clinical trial. Journal of the American Medical Association, 314 (23), 2536-2545. (Level 2 evidence)
- Stupp, R., Wong, E. T., Kanner, A. A., Steinberg, D., Engelhard, H., Heidecke, V., et al. (2012). NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality. European Journal of Cancer, 48 (14), 2192-2202. (Level 4 evidence)
- U. S. Food and Drug Administration. (2015, October). Center for Devices and Radiological Health. Pre-market approval decisions for October 2015. P100034/S013. Retrieved August 31, 2016 from http://www.accessdata.fda.gov.
- Winifred S. Hayes, Inc. Medical Technology Directory. (2016, March). Novocure (tumor treating fields). Retrieved June 3, 2016 from www.Hayesinc.com/subscribers. (37 articles and/or guidelines reviewed)
- Wong, E., Lok, E., & Swanson, K. (2015) An evidence-based review of alternating electric fields therapy for malignant gliomas. Current Treatment Options in Oncology, 2015, 16 (40), 1-11. (Level 4 evidence)
- Zhu, P. and Zhu J. (2017, August) Tumor treating fields: a novel and effective therapy for glioblastoma: mechanism, efficacy, safety and future perspectives. Chinese Clinical Oncology, 6 (4), 41. Abstract retrieved September 18, from PubMed database.
- National Cancer Institute (NCI). Adult Central Nervous System Tumors Treatment (PDQ®)–Health Professional Version. 2017; https://www.cancer.gov/types/brain/hp/adult-brain-treatment-pdq Accessed October 2017.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Central Nervous SystemCancers. Version 1.2016. http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf . Accessed October 2017.
- 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
- Davies AM, Weinberg U, Palti Y. Tumor treating fields: a new frontier in cancer therapy. Ann N Y Acad Sci. Jul 2013;1291:86-95. PMID 23659608
- Pless M, Weinberg U. Tumor treating fields: concept, evidence and future. Expert Opin Investig Drugs. Aug 2011;20(8):1099-1106. PMID 21548832
- Food and Drug Administration (FDA). Summary of Safety and Effectiveness Data (SSED): Optune™ (formerly NovoTTF - 100A™ System00) 2015; https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100034S013B.pdf , Accessed October 2017.
- 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; httpL//www.accessdata.fda.gov/cdrh_docs/pdf10/P100034B.pdf. Accessed October 2017
- Food and Drug Administration (FDA). Supplemental application for device name change. 2014; http//www.accessdata.fda.gov/scripts/cdrh/cfdoc/cfpma/pma_template?id=p100034s010, Accessed October 2017
- 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
- ner 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. PMID 25213871
- 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. PMID 25213869
- 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 U S A. Jun 12 2007;104(24):10152-10157. PMID 17551011
- 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
Electrical stimulation device used for cancer treatment, includes all accessories, any type
Malignant Neoplasm of Cerebrum, Except Lobes and Ventricles
Malignant Neoplasm of Frontal Lobe
Malignant Neoplasm of Temporal Lobe
Malignant Neoplasm of Parietal Lobe
Malignant Neoplasm of Occipital Lobe
Malignant Neoplasm of Cerebral Ventricle
Malignant Neoplasm of Cerebellum
Malignant Neoplasm of Brain Stem
Malignant Neoplasm of Overlapping Sites of Brain
Malignant Neoplasm of Brain, Unspecified
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive.
This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.
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History From 2018 Forward
Interim review to add clarification regarding length of time for initial authorization and criteria for continued review. No other changes made.