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MP 1.01.29

Tumor-Treatment Fields Therapy for Glioblastoma

 

Medical Policy    

Section
Durable Medical Equipment

Original Policy Date
08/2013

Last Review Status/Date
Reviewed with literature search/ August 2014

Issue
8:2014
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

Glioblastoma multiforme is the most common and deadly malignant brain tumor. It has a very poor prognosis and is associated with low quality of life during the course of treatment. Tumor-treatment fields (TTF) therapy is a new, noninvasive technology that is intended to treat glioblastoma using electric fields.

The available evidence on TTF therapy consists of small case series and 1 randomized controlled superiority trial using the U.S. Food and Drug Administration‒approved device. This trial had numerous methodologic limitations and failed to demonstrate an improvement in overall survival or disease response. There were some differences reported in quality of life (QOL), but these data were limited by a low response rate for QOL measures. In addition, the best standard chemotherapy protocols reported in the randomized controlled trial may not reflect current practice, given the increased use of bevacizumab and temozolomide for treatment of patients with recurrent glioblastoma. No data were available to address a comparison to other third-line treatment modalities (eg, radiation, surgery, combination therapy).

Further evidence from high-quality trials is needed to assess the long-term safety and efficacy of TTF therapy. There are currently ongoing clinical trials of the TTF therapy, including an ongoing postmarketing noninferiority study that will provide additional data on outcomes of interest. Based on the small amount of evidence and lack of demonstrated treatment benefit to date, the use of TTF therapy for glioblastoma is considered investigational.


Policy
Tumor treatment fields therapy to treat glioblastoma is considered investigational.

Policy Guidelines 

There are no specific codes for the initial application of this system and instruction on use. The patient reapplies the transducer arrays at home after the initial instruction.

Effective in 2014, there are HCPCS codes for the system and the transducer arrays:

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


Benefit Application
Blue Card/National Account Issues
State or federal mandates (eg, FEP) may dictate that all U.S. Food and Drug Administration‒approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Background

Glioblastomas, also known as glioblastoma multiforme (GBM), are the most common form of malignant primary brain tumor in adults, and they comprise approximately 15% of all brain and central nervous system tumors and more than 50% of all tumors that arise from glial cells.1 The peak incidence for GBM occurs between the ages of 45 and 70 years. GBMs are grade IV astrocytomas, the most deadly type of glial cell tumor, and are often resistant to standard chemotherapy.1 According to the National Comprehensive Cancer Network, GBM is the "deadliest brain tumor with only a third of patients surviving for 1 year and less than 5% living beyond 5 years."2

The primary treatment for 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.2 Depending on the patient’s physical condition, adjuvant radiation therapy, chemotherapy (typically temozolomide), or a combination of the 2 are sometimes given. After adjuvant therapy, some patients may undergo maintenance therapy with temozolomide. In patients with disease that recurs after these initial therapies, additional debulking surgery may be used if recurrence is localized. Treatment options for recurrent disease include various forms of systemic medications such as  bevacizumab, bevacizumab plus chemotherapy (eg, irinotecan, BCNU/chloroethylnitrosourea [CCNU], temozolomide), temozolomide, nitrosourea, PCV (procarbazine, CCNU, vincristine), cyclophosphamide, and platinum-based agents.2 Response rates in recurrent disease are less than 10%, and progression-free survival rates at 6 months are less than 20%.2,3

Tumor-treatment fields (TTF) therapy is a new, noninvasive technology that is intended to treat GBM on an outpatient basis using electrical fields.3-5 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. TTF are proposed to inhibit rapidly dividing tumor cells by 2 mechanisms, arrest of cell proliferation and destruction of cells while undergoing division.4,5

The NovoTTF-100A™ System (Novocure Ltd., Haifa, Israel) has been approved by the U.S. Food and Drug Administration (FDA) to deliver TTF therapy. TTF therapy via the NovoTTF-100A™ System is delivered by a battery-powered, portable device that generates the fields via disposable electrodes that are noninvasively attached to the patient’s shaved scalp over the site of the tumor.3,4 The device is used by the patient at home on a continuous basis (20-24 h/d) for the duration of treatment, which can last for several months. Patients can carry the device in a backpack or shoulder pack while carrying out activities of daily living.3,4

Regulatory Status
The NovoTTF-100A™ System (assigned the generic name of TTF) was approved by FDA in April 2011 through the premarket approval process.6 FDA-approved indication for use is: “The NovoTTF-100A System is intended as a treatment for adult patients (22 years of age or older) with confirmed 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.”6 Product code: NZK.


Rationale

Literature Review 

This policy was created in August 2013 and updated periodically through literature reviews, most recently through June 26, 2014. The literature on the efficacy of tumor-treatment fields (TTF) therapy consists of small, single-arm studies and 1 randomized controlled trial (RCT). Following is a summary of the key literature.

Randomized Controlled Trials
The Food and Drug Administration approval of the NovoTTF-100A system was based on a phase 3, multinational prospective RCT which was published in 2012 by Stupp et al. The Stupp et al study, which was sponsored and funded by the manufacturer of the device (Novocure), compared TTF therapy (delivered by the NovoTTF-100A System) with the best standard of care chemotherapy (active control).3 Twenty-eight clinical centers (across 7 countries) enrolled 237 adult participants with relapsed or progressive glioblastoma multiforme (GBM), despite conventional radiotherapy. Other prior treatments may have included surgery and/or chemotherapy. Patient characteristics were balanced in both groups, with median age of 54 years and median Karnofsky Performance Status score of 80%. More than 80% of participants had failed 2 or more prior chemotherapy regimens (≥ second recurrence), and 20% had failed bevacizumab prior to study enrollment.

Two hundred thirty-seven patients were randomized in a 1:1 ratio to receive TTF therapy only (n=120) or active control (n=117). The choice of chemotherapy regimens varied, reflecting local practice at each of the participating clinical centers. Chemotherapy agents considered as active control during the trial included platinum-based chemotherapy (ie, carboplatin); nitrosureas; procarbazine; combination of procarbazine, lomustine and vincristine (PCV); temozolomide; and bevacizumab. For patients assigned to the TTF group, uninterrupted treatment was recommended, although patients were allowed to take treatment breaks of up to 1 hour, twice per day, for personal needs (eg, shower). In addition, patients assigned to the TTF group were allowed to take 2 to 3 days off treatment at the end of each of 4-week period (which is the minimal required treatment duration for TTF therapy to reverse tumor growth). A period of 28 days of treatment with TTF was considered 1 full treatment course.

The primary study end point in this RCT was overall survival (OS).3 Secondary end points included progression-free survival (PFS) at 6  months, TTP, 1-year survival rate, quality of life (QOL), and radiologic response. Participants were seen in clinic monthly, and magnetic resonance imaging (MRI) was performed after 2, 4, and 6 months from initiation of treatment, with subsequent MRI done according to
local practice until disease progression. Medical follow-up continued for 2 months after disease progression. Monthly telephone interviews with participants' caregivers were used to assess participant mortality rates.

Ninety-seven percent (116) of 120 participants in the TTF group started treatment and 93 participants (78%) completed 1 cycle (4 weeks) of therapy. Discontinuation of TTF therapy occurred in 27 participants (22%) due to noncompliance or the inability to handle the device.3 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 active control group, 113 (97%) of the 117 assigned participants received chemotherapy and all except 1 individual completed a full treatment course. Twenty-one participants (18%) in the active control group did not return to the treating site and details on disease progression and toxicity were not available.

This RCT did not reach its primary end point of improved survival compared with active chemotherapy. With a median follow-up of 39 months, 220 participants (93%) had died. Median survival was 6.6 months in the TTF group compared with 6.0 months in the active control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.66 to 1.12; p=0.27). For both groups, 1-year survival was 20%. The survival
rates for 2- and 3-year survival were 8% and 4%, respectively, for the TTF group versus 5% and 1%, respectively, for the active control group. PFS rate at 6 months was 21.4% in the TTF group, compared with 15.1% in the active control group (p=0.13). Objective radiologic responses (partial and complete response) were noted in 14 participants in the TTF group and 7 in the active control group, with a calculated response rate of 14.0% (95% CI, 7.9% to 22.4%) versus 9.6% (95% CI, 3.9% to 18.8%), respectively. Sixteen percent of the TTF participants had grade 1 and 2 contact dermatitis on the scalp, which resolved with topical corticosteroids. Active control participants experienced grade 2-4 events by organ system related to the pharmacologic activity of chemotherapy agents used; severe (grades 3 and 4) toxicity was observed in 3% of participants.

Longitudinal QOL data were available in 63 participants (27%). There were no meaningful differences observed between the groups in the domains of global health and social functioning. However, cognitive, emotional, and role functioning favored TTF therapy, whereas physical functioning favored chemotherapy. Symptom scale analysis was in accordance to treatment-associated toxicity; appetite loss, diarrhea, constipation, nausea, and vomiting were directly related to the chemotherapy administration. Increased pain and fatigue was reported in the chemotherapy-treated patients and not in the TTF group.

In summary, this RCT failed to demonstrate the primary end point of improved survival with TTF therapy in comparison to chemotherapy.3,7 Limitations of the trial included a somewhat heterogeneous patient population, with participants included after progression of 1 or several lines of chemotherapy, as well as the use of different chemotherapy regimens in the control group. Another limitation is the absence of a placebo/supportive care arm. In the setting of advanced disease, the supportive care arm would have been useful to gauge the safety and efficacy of treatment for both groups of patients. Treatments used in the active control arm (best standard of care chemotherapy) in the recurrent disease setting have previously demonstrated limited efficacy, thus limiting the ability to determine the true treatment effect of
TTF. Data from a trial of TTF versus placebo, or TTF plus standard chemotherapy versus standard chemotherapy alone would therefore provide a better assessment of treatment efficacy. The latter study design is being used in an ongoing trial of TTF therapy in the treatment of patients with newly diagnosed GBM (see Ongoing Clinical Trials section).

A further limitation was high dropout rates in both groups. For example, over 20% of participants in the active control group were lost at follow-up, and this degree of dropouts may have underestimated the toxicity evaluation in this group. Similarly, over 20% of participants in the TTF arm discontinued treatment within a few days due to noncompliance or inability to handle the device. This implies that compliance might be an issue with TTF, because it requires the patient to continuously wear transducers on the shaved head. Finally, the number of patients who completed the QOL data was approximately one- quarter of total enrollment, and the self-reported QOL indicators may have been subject to bias due to the lack of blinding.3,6

Wong et al published a subgroup analysis of the previously described RCT to determine characteristics of responders and nonresponders in the treatment and active control groups.8 Tumor response was assessed by the Macdonald criteria. More patients in the TTF arm were considered responders (14/120 vs 7/117 in the chemotherapy arm.) Median response time was longer for those in the TTF arm than the chemotherapy arm (7.3 months vs 5.6 months, p<0.001), and there was a strong correlation (Pearson’s r) between response and OS in the TTF arm (p<0.001) but not in chemotherapy arm (p=0.29). Compared with the chemotherapy arm, a higher proportion of responders in the TTF arm had a prior low-grade histology (36% vs 0%). These differences in treatment responder groups suggest that TTF therapy may differentially benefit certain types of GBM; however, the small numbers of responders in both groups limits generalizations that can be drawn from this analysis.

Post hoc subgroup analyses of these trial data have been published in abstract form comparing outcomes of patients between both groups who had failed bevacizumab prior to study enrollment.9,10

Section Summary
One RCT has evaluated the use of TTF compared with best standard of care chemotherapy for GBM. This failed to demonstrate improved OS, its primary end point, and the study’s high rates of loss to follow- up and low rates of QOL data make the validity of secondary outcomes less certain. Therefore, evidence from this trial is not sufficient to demonstrate that TTF therapy results in improved health outcomes for patients with recurrent GBM.

Noncomparative Studies
The use of TTF and the corresponding effects on living tissue have been evaluated in uncontrolled studies in a number of clinical settings.11-13 Kirson et al (2007), for example, reported the findings of a case study examining the effects of TTF therapy delivered by the NovoTTF-100A System in 10 patients with recurrent GBM.11 Median time to progression (TTP) in these patients was 26.1 weeks and median OS was 62.2 weeks. The authors noted that these TTP and OS values were more than double the reported medians of historical control patients. No device-related serious adverse events were seen after more than 70 months of cumulative treatment in all of the patients. The only device-related adverse event observed was a mild-to-moderate contact dermatitis beneath the field delivering electrodes. The primary limitation of this study was the use of historical controls, because the patients included may not be comparable on major clinical and prognostic features.11

Two small case series have also been published of long-term survival (>6 years) with TTF therapy.14,15 Rulseh et al reported long-term (>7 year) survival in 4 of 20 patients with GBM who were treated with TTF,14 while Villano et al describe 1 patient with recurrent GBM who was tumor-free more than 6 years after treatment with TTF.15

Since the approval of the NovoTTF device, additional case reports and small case series have been reported. Elzinga and Wong reported a case of a patient who demonstrated improved tumor response to bevacizumab in a patient who also received TTF therapy.16 Another case series (n=3) suggested that adjusting the size of the electric fields may improve response in cases of local tumor progression.17

Section Summary
The use of TTF therapy has been described in a number of case series. However, without evidence from additional high quality comparative studies, these studies provide limited additional evidence about whether TTF therapy improves outcomes compared with currently available therapy for GBM.

Ongoing and Unpublished Clinical Trials

A search of the online database ClinicalTrials.gov in June 2014 identified the following ongoing studies to evaluate the use of tumor TTF therapy, including 1 RCT and 3 nonrandomized studies:

  • Effect of NovoTTF-100A Together With Temozolomide in Newly Diagnosed Glioblastoma Multiforme (GBM) (NCT00916409): This is a phase 3, open-label randomized trial to compare the NovoTTF-100A as an adjuvant to the best current standard of care with standard of care alone in patients with newly diagnosed GBM. Trial participants randomized to the intervention arm will be treated continuously with the NovoTTF-100A device, in addition to temozolomide chemotherapy; patients in the control arm will be treated with temozolomide, as the best-known standard of care for GBM patients. The primary outcome measure is PFS at 5 years; the secondary outcome measure is OS at 5 years. Enrollment is planned for 700 patients; the planned study completion date is January 2015.
  • Post-approval Study of NovoTTF-100A in Recurrent GBM Patients (NCT01756729): This study is a postmarket nonrandomized, concurrent control study designed to confirm that the efficacy of the NovoTTF-100A System in patients with recurrent GBM treated in a real-life settings following FDA approval is comparable to that of control chemotherapy patients. The primary outcome measure is OS at 5 years of follow-up. Enrollment is planned for 486 patients; the planned study completion date is January 2018.
  • NovoTTF-100A With Bevacizumab (Avastin) in Patients With Recurrent Glioblastoma (NCT01894061): This is a phase 2, nonrandomized, safety/efficacy study to evaluate the role of bevacizumab with the NovoTTF-100A in the treatment of glioblastoma. Enrollment is planned for 40 patients; the planned study completion date is December 2015.
  • NovoTTF Therapy in Treating Patients With Recurrent Glioblastoma Multiforme (NCT01954576): This is a phase 2, nonrandomized, efficacy study to evaluate NovoTTF in patients with recurrent or progressive tumor growth. Enrollment is planned for 30 subjects; the planned study completion date is May 2018.

TTF therapy using the NovoTTF-100A System is also being studied as a treatment for other solid tumors including non-small-cell lung cancer (NCT01755624).

Summary of Evidence
The available evidence on tumor-treatment fields (TTF) therapy consists of small case series and 1 randomized controlled superiority trial using the U.S. Food and Drug Administration‒approved device. This trial had numerous methodologic limitations and failed to demonstrate an improvement in overall survival or disease response. There were some differences reported in quality of life (QOL), but these data were limited by a low response rate for QOL measures. In addition, the best standard chemotherapy protocols reported in the randomized controlled trial may not reflect current practice, given the increased use of bevacizumab and temozolomide for treatment of patients with recurrent glioblastoma. No data were available to address a comparison to other third-line treatment modalities (eg, radiation, surgery,
combination therapy).

Further evidence from high-quality trials is needed to assess the long-term safety and efficacy of TTF therapy. There are currently ongoing clinical trials of the TTF therapy, including an ongoing postmarketing noninferiority study that will provide additional data on outcomes of interest. Based on the small amount of evidence and lack of demonstrated treatment benefit to date, the use of TTF therapy for glioblastoma is considered investigational.

Practice Guidelines and Position Statements
The National Comprehensive Cancer Network (NCCN) in their clinical practice guidelines on Central Nervous Systems Tumors (Version 1, 2014) has a category 3 recommendation to consider the use of TTF therapy for persons with recurrences of glioblastoma multiforme that are diffuse or multiple or local, which was updated in 2014 from the previously held (2013) category 2B recommendation (“Category 2B: Based on lower-level evidence, there is NCCN consensus that the intervention is appropriate”; “Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate”).2

U.S. Preventive Services Task Force Recommendations
Use of tumor-treating field therapy is not a preventive service.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References:

  1. National Cancer Institute (NCI). Adult Brain Tumors Treatment 2013; http://www.cancer.gov/cancertopics/pdq/treatment/adultbrain/HealthProfessional. Accessed June, 2014.
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers V1.2014. 2014; http://www.nccn.org/default.aspx. Accessed June, 2014.
  3. 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
  4. Davies AM, Weinberg U, Palti Y. Tumor treating fields: a new frontier in cancer therapy. Ann N Y Acad Sci. May 9 2013. PMID 23659608
  5. Pless M, Weinberg U. Tumor treating fields: concept, evidence and future. Expert Opin Investig Drugs. Aug 2011;20(8):1099-1106. PMID 21548832
  6. 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; http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100034b.pdf. Accessed June, 2014.
  7. De Bonis P, Doglietto F, Anile C, et al. Electric fields for the treatment of glioblastoma. Expert Rev Neurother. 2012;12(10):1181-1184. PMID
  8. 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
  9. 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
  10. 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:iii52. PMID
  11. 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
  12. Kirson ED, Schneiderman RS, Dbaly V, et al. Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys. 2009;9:1. PMID 19133110
  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
  14. 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
  15. Villano JL, Williams LE, Watson KS, et al. Delayed response and survival from NovoTTF-100A in recurrent GBM. Medical Oncology. 2013;30(1):1-3. PMID
  16. Elzinga G, Wong ET. Resolution of cystic enhancement to add-on tumor treating electric fields for recurrent glioblastoma after incomplete response to bevacizumab. Case Rep Neurol. Jan 2014;6(1):109-115. PMID 24847254
  17. 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 

Codes

Number

Description

CPT Codes   No specific CPT code- See Policy Guidelines
ICD-9-CM Diagnosis   Investigational for all diagnoses
  191.0-191.9 Malignant neoplasm of brain code range
HCPCS Codes A4555 Electrode/transducer for use with electrical stimulation device, used for cancer treatment, replacement only
  E0766 Electrical stimulation device, used for cancer treatment, includes all accessories, any type
ICD-10-CM (effective 10/1/15)   Investigational for all diagnoses
  C71.0-C71.9 Malignant neoplasm of brain code range
ICD-10-PCS (effective 10/1/15)   Not applicable. Policy is only for outpatient services. ICD-10-PCS codes are only used for inpatient services.
Index
Tumor treatment fields
Glioblastoma

Policy History
 

Date

Action

Reason

08/08/13 New policy- Add to Durable Medical Equipment section Policy created with literature search through June 3, 2013; considered investigational
8/14/14 Replace policy Policy updated with literature review through June 26, 2014. References 8 and 16-17 added. Editorial revisions made to rationale section. Policy statement unchanged.