| Coverage Policy Manual | |
| Policy #: | 2013028 |
| Category: | DME |
| Initiated: | August 2013 |
| Last Review: | August 2023 |
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| Tumor-Treating Fields Therapy | |
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| Description: |
Tumor treating fields (TTF) therapy is a noninvasive technology intended to treat glioblastoma and malignant pleural mesothelioma on an outpatient basis and at home using electrical fields. Glioblastoma multiforme (GBM) is the most common and deadly malignant brain tumor. It has a very poor prognosis and is associated with low quality of life during treatment. Malignant pleural mesothelioma is an aggressive tumor with few treatment options that is associated with significant morbidity and mortality.
Glioblastomas, also known as glioblastoma multiforme (GBM), are the most common form of malignant primary brain tumor in adults (NCI, 2022). Glioblastomas are grade IV astrocytomas, a rapidly progressing and deadly type of glial cell tumor that is often resistant to standard medical therapy (e.g., bevacizumab, chemotherapy). Together, anaplastic astrocytomas and glioblastomas comprise approximately 38% of all brain and central nervous system tumors. The peak incidence for GBM occurs between the ages of 45 and 70 years, with a median age at diagnosis of 64 years. Glioblastomas have the lowest survival rate of any central nervous system tumor the 5-year survival rate and average length of survival is estimated at 6.8% and 12 to 18 months, respectively (NBTS, 2022).
The primary treatment for patients newly diagnosed with GBM is to resect the tumor to confirm a diagnosis while debulking the tumor to relieve symptoms of increased intracranial pressure or compression. If total resection is not feasible, subtotal resection and open biopsy are options. During surgery, some patients may undergo implantation of the tumor cavity with a carmustine (bischloroethylnitrosourea [BCNU]) -impregnated wafer. Due to the poor efficacy of local treatment, postsurgical treatment with adjuvant radiotherapy, chemotherapy (typically temozolomide), or a combination of these two therapies is recommended. After adjuvant therapy, some patients may undergo maintenance therapy with temozolomide. Maintenance temozolomide is given for 5 days of every 28-day cycle for 6 cycles. Response and overall survival rates with temozolomide are higher in patients who have O6 -methylguanine-DNA methyltransferase (MGMT) gene promoter methylation.
Prognostic factors for therapy success are age, histology, performance status or physical condition of the patient, and extent of resection. National Comprehensive Cancer Network recommendations include patient age and Karnofsky Performance Status score as important determinants of postsurgical treatment choice (NCCN, 2020). For patients with good performance status, the most aggressive treatment (standard radiotherapy [RT] plus temozolomide) is recommended. For patients with poor performance status, only single treatment cycles or even palliative or supportive care are recommended. Hypofractionated RT is indicated for patients with poor performance status because it is better tolerated, and more patients are able to complete RT.
Treatment of GBM is rarely curative, and tumors will recur in essentially all patients
When disease recurs, additional debulking surgery may be used if the recurrence is localized. Due to radiation tolerances, re-radiation options for patients with recurrent GBM who have previously received initial external-beam RT are limited. There is no standard adjunctive treatment for recurrent GBM. Treatment options for recurrent disease include various forms of systemic medications such as the antivascular endothelial growth factor drug bevacizumab, alkylating agents such as nitrosoureas (eg, lomustine, carmustine), or retreatment with temozolomide. Medical therapy is associated with side effects that include hematologic toxicity, headache, loss of appetite, nausea, vomiting, and fatigue. Response rates in recurrent disease are less than 10%, and progression-free survival rates at 6 months are less than 20% (Stupp, 2012). There is a need for new treatments that can improve survival in patients with recurrent GBM or reduce the side effects of treatment while retaining survival benefits.
Malignant pleural mesothelioma (MPM) is an aggressive tumor that is associated with significant morbidity and mortality. It is associated with asbestos exposure and has a latency period of about 40 years after asbestos exposure. Recommendations for treatment are mainly chemotherapy as first line with pemetrexed plus platinum. Surgical cytoreduction is also recommended in selected patients with early-stage disease. Adjuvant radiation can be offered for patients who have resection of intervention tracts found to be histologically positive or for palliation of symptomatic patients.
Regulatory Status
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 (FDA, 2013). 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, 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 a request for Novocure to change its products name from NovoTTF-110A System to Optune™ (FDA, 2014).
In October 2015, FDA expanded the indication for Optune in combination with temozolomide to include newly diagnosed GBM (FDA, 2015). 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."
In May 2019, FDA approved a modified version of the Optune System (NovoTTF-100A System), which is now called the Optune Lua™ System (NovoTTF™-100L System), for "treatment of adult patients with unresectable, locally advanced or metastatic, malignant pleural mesothelioma (MPM) to be used concurrently with pemetrexed and platinum-based chemotherapy. The indication was modified from that granted for the Humanitarian Device Exemption designation to more clearly identify the patient population the device is intended to treat and in which the safety and probable benefit of the device is supported by the available clinical data" (FDA, 2019).
In September 2021, the FDA granted breakthrough designation to the NovoTTF-200T System for use together with atezolizumab and bevacizumab for the first-line treatment of patients with unresectable or metastatic liver cancer (FDA, 2021).
To date, all of the existing tumor treating fields products fall under the brand name Optune. In March 2020, the manufacturer of Optune products announced a plan to include a suffix after the brand name for newly approved indications to further delineate specific indications for individual products (eg, Optune Lua) (Novocure, 2020).
Coding
There are no specific codes for this system or the initial application 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
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Policy/ Coverage: |
Effective October 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Tumor treating fields therapy to treat glioblastoma multiforme meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness as an adjunct to standard maintenance therapy with temozolomide in individuals with newly diagnosed glioblastoma multiforme following initial treatment with surgery, radiotherapy, and/or chemotherapy under the following conditions:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Tumor treating fields therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other conditions, including but not limited to the following situations:
For members with contracts without primary coverage criteria, tumor treating fields therapy for all other conditions, including but not limited to the following situations is considered investigational:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to October 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Tumor treating fields therapy to treat glioblastoma multiforme meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness as an adjunct to standard maintenance therapy with temozolomide in patients with newly diagnosed glioblastoma multiforme following initial treatment with surgery, radiotherapy, and/or chemotherapy under the following conditions:
• Adult patients ≥18 years of age
• Karnofsky Performance Status score ≥70%
• Supratentorial tumor.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Tumor treating fields therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other conditions, including but not limited to the following situations:
• As an adjunct to standard medical therapy (eg, bevacizumab, chemotherapy) for patients with progressive or recurrent glioblastoma multiforme
• As an alternative to standard medical therapy for patients with progressive or recurrent glioblastoma multiforme.
For members with contracts without primary coverage criteria, tumor treating fields therapy, including but not limited to the following situations is considered investigational:
• As an adjunct to standard medical therapy (eg, bevacizumab, chemotherapy) for patients with progressive or recurrent glioblastoma multiforme
• As an alternative to standard medical therapy for patients with progressive or recurrent glioblastoma multiforme.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to July 2018
Tumor treatment fields therapy to treat glioblastoma does not meet member benefit certificate
primary coverage criteria that there be scientific evidence in improving health outcomes.
For members with contracts without primary coverage criteria, tumor treatment fields therapy to treat
glioblastoma is considered investigational. Investigational services are specific contract exclusions in
most member benefit certificates of coverage.
Investigational services are Plan exclusions.
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| Rationale: |
This policy was created in August 2013 with a search of the MEDLINE database through June 3, 2013. The literature on the efficacy of TTF therapy consists of small, single arm studies and one RCT. Following is a summary of the key literature.
The use of TTF and the corresponding effects upon living tissue have been studied in clinical settings (Kirson, 2007; Kirson, 2009; Salzberg, 2008). Kirson and colleagues (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 (Kirson, 2007). Median time to progression (TTP) in these patients was 26.1 weeks and median overall survival (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 (AEs) were seen after more than 70 months of cumulative treatment in all of the patients. The only device-related AE 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, since the patients included may not be comparable on major clinical and prognostic features (Kirson, 2007).
These preliminary findings served as a basis for a prospective phase III multinational randomized controlled trial (RCT) by Stupp and colleagues (2012), which was sponsored and funded by the manufacturer of the device (NovoCure). This study compared TTF therapy (delivered by the NovoTTF- 100A System) to the best standard of care chemotherapy (BSC, active control) (Stupp, 2012). The FDA approval of the NovoTTF-100A System was based on the results of this RCT. Twenty-eight clinical centers (across seven countries) enrolled 237 adult participants with relapsed or progressive 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 (KPS) of 80%. More than 80% of participants had failed two or more prior chemotherapy regimens (≥ second recurrence) and 20% had failed bevacizumab prior to study enrollment (Stupp, 2012).
Two hundred and thirty-seven patients were randomized in a 1:1 ratio to receive TTF therapy only (n=120) or BSC (n=117). The choice of chemotherapy regimens varied, reflecting local practice at each of the participating clinical centers (Stupp, 2012). Chemotherapy agents considered as BSC during the trial included platinum-based chemotherapy (i.e., 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 an hour, twice per day, for personal needs (e.g., shower). In addition, patients assigned to the TTF group were allowed to take 2–3 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 one full treatment course (Stupp, 2012).
The primary study endpoint in this RCT was overall survival (OS) (Stupp, 2012). Secondary endpoints included progression free survival at six months, time to progression (TTP), one-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, with subsequent MRIs done according to local practice until disease progression. Medical follow-up continued for two months after disease progression. Monthly telephone interviews with the participants' caregivers were used to assess participant mortality rates (Stupp, 2012).
Ninety-seven percent (116) of 120 participants in the TTF group started treatment and 93 participants (78%) completed one cycle (4 weeks) of therapy. Discontinuation of TTF therapy occurred in 27 participants (22%) due to noncompliance or the inability to handle the device (Stupp, 2012). 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 group, 113 (97%) of the 117 assigned participants received chemotherapy and all except one individual completed a full treatment course. 21 participants (18%) in the BSC group did not return to the treating site and details on disease progression and toxicity were not available (Stupp, 2012).
This RCT did not reach its primary end-point of improved survival compared to active chemotherapy (Stupp, 2012). With a median follow-up of 39 months, 220 participants (93%) had died. Median survival was 6.6 months in the TTF group compared to 6.0 months in the BSC group (hazard ratio 0.86; 95% confidence interval [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% and 4% for the TTF group versus 5% and 1% for the BSC group. Progression-free survival rate at six months was 21.4% in the TTF group, compared to 15.1% in the BSC group (p = 0.13). 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; severe (grades 3 and 4) toxicity was observed in 3% of participants (Stupp, 2012).
Longitudinal QOL data were available in 63 participants (27%) (Stupp, 2012). 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. Post-hoc subgroup analyses of this trial data have been published in abstract form comparing outcomes of patients between both groups who had failed bevacizumab prior to study enrollment (Ram, 2010; Ram, 2011). Two very small case series have also been published of long-term survival (> six years) with TTF therapy (Rulseh, 2012; Vilano, 2013).
In summary, this RCT failed to demonstrate the primary endpoint of improved survival with TTF therapy in comparison to chemotherapy (Stupp, 2012; De Bonis, 2012). Limitations of the trial included a somewhat heterogeneous patient population, with participants included after progression of one 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 of 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 newly diagnosed GBM patients.
A further limitation was high dropout rates in both groups. For example, over 20% of participants in the BSC 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 as it requires the patient to continuously wear transducers on the shaved head and as a result. 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 (Stupp, 2012; FDA, 2011). Therefore, due to the numerous methodologic limitations, evidence from this trial is not sufficient to demonstrate that TTF therapy results in improved health outcomes for patients with recurrent GBM.
Ongoing Clinical Trials
Two manufacturer-sponsored studies on NovoTTF-100A System for treatment of GBM currently are listed at online site ClinicalTrials.gov. Post-approval study of NovoTTF-100A in recurrent GBM patients (NCT01756729)
This study is a post-market non-randomized, 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 BSC chemotherapy patients. This trial has the estimated enrollment of 486 adult patients across two US sites. The primary outcome measure is OS at five years of follow-up. This study is currently recruiting participants with the estimated completion date of January 2018.
Effect of NovoTTF-100A together with temozolomide in newly diagnosed GBM (NCT00916409).
The study is a subsequent prospective multinational RCT designed to test the efficacy and safety of the NovoTTF-100A System, as an adjuvant to the best standard of care in the treatment of newly diagnosed GBM patients. This trial has the estimated enrollment of 700 adult patients across 79 sites. 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 progression free survival at five years; the secondary outcome measure is OS at five years. This study is currently recruiting participants with the estimated completion date of April 2015.
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
Tumor-treating fields (TTF) therapy is a new noninvasive technology using electrical fields for treating recurrent glioblastoma. The available evidence consists of small case series and one randomized controlled superiority trial based on the FDA-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, but this data was 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 (i.e., radiation, surgery, combination therapy).
Further evidence from high-quality trials is needed to assess the long term safety and efficacy of TTF. There are currently ongoing clinical trials of the TTF therapy including an ongoing post-marketing non-inferiority study that will provide additional data on outcomes of interest.
Practice Guidelines and Position Statements
The National Comprehensive Cancer Network (NCCN) in their clinical practice guidelines on Central Nervous Systems Tumors (Version 2, 2013) has a Category 2B recommendation to consider the use of TTF therapy for persons with local, diffuse or multiple recurrences of GBM (“Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.”) (NCCN, 2013). This recommendation was based on the RCT findings by Stupp and colleagues reported above.
2014 Update
A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
The FDA approval of the NovoTTF-100A system was based on a Phase III, 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) to the best standard of care chemotherapy (active control).3 Twenty-eight clinical centers (across 7 countries) enrolled 237 adult participants with relapsed or progressive 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 (KPS) 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.
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 (Wong, 2014). Tumor response was assessed by the Macdonald criteria. More patients in the TTF arm were considered responders (14/120) compared to 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=0.0009), and there was astrong correlation (Pearson’s r) between response and OS in the TTF arm (P = 0.0002) 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 suggests that TTF 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.
Rulseh et al reported long-term (>7 year) survival in 4 out of 20 patients with GBM who were treated with TTF, while Villano et al describe one patient with recurrent GBM who was tumor-free more than 6 years after treatment with TTF (Rulseh, 2012).
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 (Elzinga, 2014). Another case series (n=3) suggested that adjusting the size of the electrical fields may improve response in cases of local tumor progression (Turner, 2014).
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 when compared to currently-available therapy for GBM
Ongoing Clinical Trials
A search of the online database ClinicalTrials.gov in June 2014 identified the following ongoing studies to evaluate the use of tumor treating fields therapy, including one randomized controlled trial (RCT) and 3 nonrandomized studies:
A phase 3, open-label randomized trial Effect of NovoTTF-100A Together With Temozolomide in Newly Diagnosed Glioblastoma Multiforme (GBM) (NCT00916409) – to compare the NovoTTF-100A as an adjuvant to the best current standard of care to 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 overall survival at 5 years. Enrollment is planned for 700 patients; the planned study completion date is January 2015.
A postmarket nonrandomized, concurrent control study, Post-approval Study of NovoTTF-100A in Recurrent GBM Patients (NCT01756729) –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 overall survival at 5 years of follow-up. Enrollment is planned for 486 patients; the planned study completion date is January 2018.
A phase 2, nonrandomized, safety/efficacy study, NovoTTF-100A With Bevacizumab (Avastin) in Patients With Recurrent Glioblastoma (NCT01894061) –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.
A phase 2, nonrandomized, efficacy study, NovoTTF Therapy in Treating Patients With Recurrent Glioblastoma Multiforme (NCT01954576) – 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.
2015 Update
A literature search was conducted using the MEDLINE database through July 2015. There was no new literature identified that would prompt a change in the coverage statement.
The following is a summary of the key identified literature.
A second post hoc analysis of the TTF EF-11 pivotal trial data was performed to evaluate OS rates among patients who completed at least 1 complete course of TTF or chemotherapy (Kanner, 2014). These investigators analyzed survival in what they referred to as a “modified ITT [intention to treat]” subgroup comprising 93 of 120 (78%) of the original TTF allocated group, versus 117 of 117 (100%) of the original chemotherapy allocated group. This exercise revealed median OS of 7.7 months in the TTF modified ITT (mITT) group compared with 5.9 months in the chemotherapy group (HR=0.69; 95% CI, 0.52 to 0.91; p=0.009). They also showed a trend relationship between proportion of patients with higher TTF compliance and median OS rates (p=0.039). The investigators suggest that TTF provides an OS benefit if used as intended in the FDA-approved label when compared with best chemotherapy. This post hoc analysis is limited as it was not prespecified in the study, includes only 78% of the original TTF allocated patients, and fails to control for noncompliance due to faster clinical deterioration of TTF recipients leading to treatment cessation.
A study published in late 2014 included OS data from 457 patients included in the Patient Registry Dataset (PRiDe), a postmarketing registry of all recurrent GBM patients who received NovoTTF therapy in a real-world, clinical practice setting in 91 centers in the United States between October 2011 and November 2013 (Mrugala, 2014). The median OS rate in the PRiDe clinical practice dataset was reported as significantly superior to that attained in the TTF EF-11 pivotal trial (9.6 months vs 6.6 months; HR=0.66, 95% CI, 0.05 to 0.86; p<0.001). One- and 2-year OS rates for TTF in PRiDe were significantly longer than those in the TTF group in the EF-11 trial (44% vs 20% at 1 year; 30% vs 9% at 2 years, respectively). The PRiDe investigators reported no novel or unexpected treatment-related adverse events compared with the EF-11trial.
The National Comprehensive Cancer Network Central Nervous System Tumors guidelines (v.1.2015) (NCCN, 2015) has updated the recommendation for the treatment of recurrence of glioblastoma, with the option “consider alternating electric field therapy for glioblastomas” from a category 3 recommendation to a 2B recommendation.
2016 Update
A literature search conducted through July 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
TTF as an Adjunct to Standard Maintenance Care for GBM
In 2015, Stupp et al published a planned interim analysis of a multicenter, open-label RCT that evaluated maintenance therapy with TTF for GBM (Stupp, 2015). This study enrolled patients with GBM who had completed standard treatment consisting of chemoradiotherapy, plus surgery if indicated. Patients were randomized in a 2:1 fashion to receive either TTF plus temozolomide (vs temozolomide alone). At the time of the interim analysis, there were 210 patients randomized to TTF plus temozolomide and 105 patients randomized to temozolomide alone. The primary outcome was PFS analyzed by intention-to-treat; a secondary outcome was OS analyzed by per-protocol analysis.
Patients in the TTF group received continuous TTF delivered mainly in the home setting. Patients were trained on use of the device including changing the electrodes, and then treatment continued at home. Patients were encouraged to wear the device continuously, with the exception of short breaks to attend to personal needs. All patients were seen monthly for follow-up. MRI was performed every 2 months and QOL measures administered every 3 months. Tumor progression was adjudicated by a central review committee blinded to treatment group.
Planned interim analysis was performed at a median follow-up of 38 months (range, 18-60 months). Median PFS and median OS are summarized as:
Group Tumor Treatment Fields (TTF) + temozolomide; N= 210 (196 included in per-protocol analysis; progression-free survival (95% confidence interval); hazard ratio (98.7% confidence interval); overall survival (95% confidence interval);p hazard ratio
There were a total of 35 (11%) dropouts during the study, 14 (6.7%) of 210 patients in the TTF group and 21 (20%) of 105 in the temozolomide alone group. Adherence to treatment was defined as wearing the device for at least 18 hours a day, and 157 (75%) of 210 patients met this criteria for adherence. The number of cycles of treatment with temozolomide differed between groups. The TTF group received a median of 6 cycles compared with a median of 4 cycles for the temozolomide alone group. The most common side effect of treatment was local skin irritation, which occurred in 43% of patients treated with TTF.
2017 Update
A literature search conducted through July 2017 did not reveal any new information that would prompt a change in the coverage statement.
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2018. The key identified literature is summarized below.
TTF THERAPY AS AN ADJUNCT TO STANDARD MAINTENANCE CARE FOR NEWLY DIAGNOSED GBM
Randomized Controlled Trials
Stupp et al published results of the EF-14 multicenter, open-label phase 3 RCT that evaluated maintenance therapy with TTF for newly diagnosed GBM (Stupp, 2017). The trial included 695 patients from 83 sites who had supratentorial GBM and had completed standard treatment consisting of biopsy or surgical resection followed by radiotherapy and chemotherapy. A Karnofsky Performance Status (KPS) score of 70 or higher was an additional inclusion criterion to ensure independence in activities of daily living, and patients with rapidly progressing GBM following radiochemotherapy were excluded from the trial. Patients were randomized in a 2:1 fashion to TTF plus maintenance temozolomide or maintenance temozolomide alone.
All patients were seen monthly for follow-up. Quality of life (QOL) was assessed every 3 months, and magnetic resonance imaging (MRI) was performed every 2 months until tumor progression. Tumor progression on MRI was adjudicated by a central review committee blinded to treatment group. The primary outcome was progression-free survival (PFS), and the secondary outcome was overall survival (OS). The analysis was by intention-to-treat, including 26 patients from the control arm who crossed over to TTF following the planned interim analysis.
In 2014, an independent data and safety monitoring board concluded from the planned interim analysis that the trial met its predefined boundaries for success (improvement in PFS and OS) and recommended trial termination. The Food and Drug Administration approved the trial termination, and the trial was closed to recruitment with 695 of the planned 700 participants randomized. Control arm participants were allowed to cross over to the experimental treatment at this time. Stupp et al published the interim analysis, which the Food and Drug Administration considered for the 2015 expanded approval of Optune (Stupp, 2015). At the time of the interim analysis, data were available for 210 patients randomized to TTF plus temozolomide and 105 patients to temozolomide alone. Follow-up of the remainder of the 695 enrolled patients continued after enrollment was closed.
Results of the final analysis of the EF-14 trial were similar to the interim analysis. Both PFS and OS improved with the addition of TTF therapy to standard maintenance chemotherapy (ie, temozolomide). PFS increased by 2.7 mo (p<0.001) and OS increased by 4.9 mo (p<0.001) in the TTF group. The time to a decrease in mental function was 2.5 months longer with TTF therapy (p<0.01).
There was a similar percentage of dropouts at the final analysis with 49 (11%) patients in the TTF group and 27 (12%) patients in the temozolomide alone group. More treatment cycles with temozolomide were administered in the TTF group (median, 6 for TTF group vs 5 for controls), a finding that is consistent with the longer PFS. Rates of adverse events were similar between the groups, including rates of seizures. In secondary analysis of patients who had not progressed, there was no reduction in health-related quality of life with TTF compared with temozolomide alone aside from “itchy skin” (Taphoorn, 2018). Interpretation of this result is limited by the low percentage of patients who completed the health-related quality of life assessments at follow-up (65.8% of the 655 patients alive at 3 months and 41.7% of the 473 patients alive at 12 months). A mixed-model analysis, which accounts for missing data, confirmed the results of the mean change from baseline analysis.
The major limitation of this trial is the lack of patient blinding to treatment assignment. However, PFS was assessed by investigators who were blinded to treatment and placebo effects on OS were expected to be minimal. Investigators considered it practically unfeasible (due to the heat and current of the TTF therapy) and ethically unacceptable to submit the control patients to repeated shaving of the head and continuous wear of a sham device over many months.
In summary, the final analysis of the EF-14 trial, which included 695 patients from 83 sites, found a statistically and clinically significant increase of 2.7 months in PFS and an increase of 4.9 months in OS with the addition of TTF therapy to standard maintenance therapy (ie, temozolomide) in patients with newly diagnosed GBM. There was no sham control, and patients were not blinded to treatment assignment, but PFS was assessed by blinded evaluators, and placebo effects on the objective measure of OS were likely to be minimal. There was no evidence of a negative impact of TTF therapy on health-related quality of life, except for itchy skin from the transducers.
TTF THERAPY AS AN ADJUNCT OR ALTERNATIVE TO MEDICAL THERAPY FOR PROGRESSIVE OR RECURRENT GBM
Results of a phase 3 multinational RCT (EF-11) published by Stupp et al, was the basis for the 2011 Food and Drug Administration approval of the NovoTTF-100A System (now called Optune) (Stupp, 2012).This trial compared TTF therapy alone with physician’s choice medical therapy in 237 adults who had relapsed or progressive glioblastoma. Patients had failed conventional treatment with radiotherapy, chemotherapy, and/or surgery, and more than 80% of participants had failed 2 or more prior chemotherapy regimens. In this trial, the term chemotherapy also applied to targeted agents such as bevacizumab. Patient characteristics and performance of additional post-recurrence debulking surgery were similar in the 2 groups.
Participants were followed monthly, including laboratory tests. MRI images were evaluated at 2, 4, and 6 months from initiation of treatment, with subsequent MRIs performed according to local practice until disease progression. QOL questionnaires were completed every 3 months. Medical follow-up continued for 2 months after disease progression. Monthly telephone interviews with participants' caregivers were used to assess mortality rates. The primary end point was OS. Secondary end points included PFS, the percentage of patients with PFS at 6 months, time to progression, 1-year survival rate, QOL, and radiologic response. All end points were evaluated using intention-to-treat analysis.
The trial did not reach its primary end point of improved survival compared with active medical therapy. With a median follow-up of 39 months, 93% of patients had died. There was not a statistically significant difference in survival rates at 1, 2, and 3 years between groups. Patients in the TTF group did not, however, suffer the typical systemic side effects of chemotherapy. The most common adverse event in the TTF group was grade 1 and 2 contact dermatitis on the scalp, which resolved with topical corticosteroids and did not require treatment breaks. Control participants experienced grade 2, 3, or 4 events by organ system related to the pharmacologic activity of chemotherapy agents used. Hematologic events of grade 2 or greater were observed in 17% of chemotherapy patients compared with 3% of TTF patients. Gastrointestinal disorders of grade 2 or greater were identified in 17% of chemotherapy patients compared with 4% of TTF patients. Severe (grades 3-4) hematologic and gastrointestinal toxicity was observed in 7% of chemotherapy controls compared with 1% of the TTF group.
Longitudinal QOL data, available in 63 (27%) participants, showed no meaningful differences between groups for the domains of global health and social functioning. However, cognitive and emotional functioning domains favored TTF therapy. Symptom scale analysis was by treatment-associated toxicity; appetite loss, diarrhea, constipation, nausea, and vomiting were directly related to the chemotherapy administration.
The trial had a number of limitations that included lack of blinding and high loss to follow-up. Discontinuation of TTF therapy occurred in 22% of patients due to noncompliance or inability to handle the device, usually within the first few days. In the control group, 21 (18%) patients did not return to the treatment site, and details on disease progression and toxicity were not available. Longitudinal QOL could be analyzed only for 27% of patients who remained on study therapy for 3 months. The trial was designed as a superiority trial and did not provide adequate evidence of noninferiority.
Nonrandomized Comparative Studies
Kesari et al conducted a post hoc analysis of the EF-14 trial to evaluate the efficacy of TTF in patients who had the first recurrence (Kesari, 2017). Some patients in the temozolomide alone group crossed over to receive TTF plus chemotherapy after the first recurrence, resulting in 144 patients who received TTF fields plus chemotherapy and 60 patients who received chemotherapy alone for recurrent GBM. Patient characteristics and second-line treatments were well-balanced between the groups, with bevacizumab the most common second-line therapy. The median OS in patients treated with systemic therapy alone was 9.2 months. In comparison, the group of patients who received TTF therapy in addition to systemic therapy had a median OS of 11.8 months (p=0.043).
2019 Update
A literature search was conducted through June 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
A literature search was conducted through June 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Tumor treatment fields therapy for patients with metastatic, MPM has been evaluated in 1 prospective, single-arm study (STELLAR) (Ceresoli, 2019). The STELLAR study enrolled 80 patients with inoperable, previously untreated MPM. Patients were treated with cisplatin or carboplatin in combination with TTF therapy delivered by the NovoTTF-100L System at 12 sites outside the U.S. The primary outcome was OS as measured from start of study treatment until date of death. Secondary outcomes were PFS based on investigator assessment of computed tomography (CT) scan imaging, radiological response rate, 1 and 2 year survival rates, and safety. Median OS was 18.2 months and median PFS was 7.6 months. Seventy-two of the 80 patients enrolled had at least 1 follow-up CT scan. Of those, 40% had a partial response, 57% had stable disease, and 3% progressed. The only adverse event associated with TTF treatment was skin reaction; this adverse event was mild to moderate for the majority of patients who experienced it (66%). Because there was no control group, it is not possible to draw conclusions about the effectiveness of TTF therapy compared to standard medical care alone. Additional limitations include the small sample size and no reporting of symptoms or quality of life outcomes.
National Comprehensive Cancer Network guidelines on central nervous system cancers (v.2020) include recommendations for the treatment of glioblastoma (NCCN, 2020). For the initial treatment of patients with glioblastoma with good performance status and either methylated or unmethylated or indeterminate O6-methylguanine-DNA methyltransferase promotor status, treatment with standard brain radiotherapy plus concurrent temozolomide and adjuvant temozolomide plus alternating electric field therapy is a category 1 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 category 2B recommendation.
Guidelines for Adjuvant Treatment of Glioblastoma, by Age and Performance Status
Age ≤70 KPS Score %≥60 Treatment Options (Category 1):
Age ≤70 KPS Score %<60 Treatment Options (Category 2A):
Age >70 KPS Score % ≥60 Treatment Options (Category 1):
Age >70 KPS Score %<60 Treatment Options (Category 2A):
The National Comprehensive Cancer Network guidelines on malignant pleural mesothelioma (2.2021) do not address tumor treating fields as a treatment option for malignant pleural mesothelioma (NCCN, 2021).
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Regev et al conducted a systematic review of studies describing the use of TTF therapy for the treatment of GBM (Regev, 2021). The authors included a total of 20 studies of patients with newly diagnosed GBM and recurrent GBM. For newly diagnosed GBM (n=542), only 1 RCT was identified. The remainder of the data for newly diagnosed GBM was observational. The pooled median OS and PFS in newly diagnosed patients was 21.7 months (95% confidence interval [CI], 19.6 to 23.8) and 7.2 months (95% CI, 6.1 to 8.2) months, respectively. The pooled rate of OS at 1, 2, and 3 years was 73.5%, 45.1%, and 29.3%, respectively. The pooled rate of PFS at 6, 12, and 18 months was 55.9%, 32.4%, and 21.7%, respectively. Statistical comparisons to other treatment modalities were not provided.
A systematic review by Regev et al was introduced above (Regev, 2021). For patients with recurrent GBM (n=1094), only 2 RCTs were identified. The remainder of the data for recurrent GBM was observational. For patients with recurrent GBM, the pooled median OS and PFS were 10.3 months (95% CI, 8.3 to 12.8) and 5.7 (95% CI, 2.8 to 10) months, respectively. The pooled rate of OS at 1, 2, and 3 years was 43.7%, 21.3%, and 14%, respectively. The pooled rate of PFS at 6, 12, and 18 months was 47.8%, 29.3%, and 19.7%, respectively. As previously noted, statistical comparisons to other treatment modalities were not provided.
Kutuk et al published a single-arm retrospective study of 5 patients with unresectable MPM who received TTF therapy from 2019 to 2021 at a single center in the US (Kutuk, 2022). The median follow-up was 5.4 months (range, 1.1 to 20.9). All patients were also treated with pemetrexed plus platinum-based chemotherapy. The median number of 4-week TTF cycles was 5 (range, 2 to 7) and the median TTF device usage in the first 3 months was 12.5 hours per day (range, 5 to16.8). Treatment-related dermatitis was the only side effect associated with TTF and was reported as grade 1 to 2 in all patients; no patient had grade 3+ device-related toxicities. The authors note that this was the first publication of real-world implementation of TTF for MPM.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Zhu et al conducted a prospective, post-marketing registry study (the EF-19 study) to evaluate the safety and efficacy of TTF versus physician's choice standard of care in patients from the EF-11 study with recurrent glioblastoma (Zhu, 2022). The patient population was comprised of patients already enrolled in the PRiDe registry and included a total of 309 patients. Primary and secondary endpoints assessed included OS in the intention-to-treat (ITT) and per-protocol (PP) populations. In the ITT population, median OS in patients treated with TTF was comparable to physician's choice of standard of care (7.4 vs 6.4 months, respectively; log-rank test p=.053). The Cox test HR was 0.66 (95% CI, 0.47 to 0.92; p=.016). In the PP population, median OS in patients treated with TTF was significantly longer than patients treated with standard of care (8.1 vs 6.4 months; log-rank test p=.017). The Cox test HR was 0.60 (95% CI, 0.42 to 0.85; p=.004). Tumor treating fields therapy showed a favorable safety profile as well.
In 2022, the Congress of Neurological Surgeons released guidelines on role of cytotoxic chemotherapy and other cytotoxic therapies in the management of progressive glioblastoma (Germano, 2022). In regard to TTF use in adult patients with progressive glioblastoma, the Congress states that "the use of TTF with other chemotherapy may be considered when treating adult patients with progressive glioblastoma [pGBM]. There is insufficient evidence to recommend TTF to increase overall survival in adult patients with pGBM".
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