Clinical UM Guideline

This document addresses the use of electrical field therapy known as tumor treatment fields (TTF). TTF therapy is created by low-intensity, intermediate frequency (100–200 kilohertz [kHz]) electric currents delivered to the malignant tumor site by insulated electrodes placed on the skin surface. TTF therapy causes tumor cell death (apoptosis) by disrupting the assembly of microtubules during later stages of cell division.

Medically Necessary:

TTF therapy is considered medically necessary when criteria A, B and C are all met:

1. An FDA approved device is used; and
2. Tumor being treated is a histologically-confirmed supratentorial glioblastoma (known also as glioblastoma multiforme [GBM] or World Health Organization [WHO] grade IV astrocytoma); and
3. Either criteria 1 or 2 are met:
   1. Newly diagnosed GBM when all the following criteria are met:
      1. Initial treatment with debulking surgery or biopsy followed by chemoradiation with concomitant temozolomide and radiotherapy has been completed with no documented tumor progression*; and
      2. TTF is used in combination with temozolomide; and
      3. Individual has Karnofsky Performance Status (KPS) score of 70 or higher or Eastern Cooperative Oncology Group (ECOG) performance status 0-1; and
      4. Individual or caregiver has been trained and is willing and able to apply and use the device at least 18 hours, per day on average. 
         or
   2. Recurrent GBM when all the following criteria are met:
      1. TTF is used as a monotherapy; and
      2. Individual has KPS score of 70 or higher or ECOG performance status 0-1; and
      3. Individual or caregiver has been trained and is willing and able to apply and use the device at least 18 hours, per day, on average.

Continuation of TTF therapy beyond the initial 90 days is considered medically necessary when both of the following criteria are met:

1. Documentation of compliant use must be reported every 90 days as evidenced by the device monitor report showing the individual is using the device at least 18 hours per day, on average; and
2. There is no documented tumor progression*, defined as at least one of the following:
   1. Tumor growth of greater than 25% of the product of 2 perpendicular diameters compared to the smallest tumor area measured; or
   2. Appearance of one or more new tumors in the brain (diagnosed radiologically as GBM).

*See discussion section regarding tumor progression.

Not Medically Necessary:

The use of devices to generate electric tumor treatment fields (TTF) is considered not medically necessary when the criteria above are not met and for all other malignant tumors.

The use of enhanced computer treatment planning software (such as NovoTal) is considered not medically necessary in all cases.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, and for all other diagnoses not listed.

When services are also Not Medically Necessary:

Glioblastoma Multiforme (GBM)

Glioblastoma (WHO grade IV astrocytoma), also known as GBM (National Cancer Institute [NCI], 2023), has a peak incidence between the ages of 45 and 70 years. GBM is the most frequently occurring brain tumor accounting for approximately 12% to 15% of all brain tumors and 50% to 60% of all astrocytic tumors. Giant cell glioblastoma and gliosarcoma are two histologic variants of GBM. The 5-year survival rate for GBM is between 1% and 19%, depending upon age. Treatment of GBM is challenging due to the inability of most systemic therapy agents to cross the blood-brain barrier and the propensity of high-grade gliomas to recur (National Comprehensive Cancer Network^® [NCCN], V1.2023). The delivery of low-intensity, intermediate-frequency alternating electric fields has been demonstrated to have an inhibitory effect on proliferating cells. Exposure to the alternating fields lead to mitotic disruption and ultimately mitotic cell death. Nonproliferating cells remain unaffected by these fields (Fabian, 2019).

NovoTTF^™-100A System (NovoCure^™ Ltd., Portsmouth, NH; Haifa, Israel) received U.S. Food and Drug Administration (FDA) premarket approval (PMA) in 2011. The device is now marketed as Optune^® (NovoCure Ltd., Portsmouth, NH, Haifa, Israel). Optune, a portable, non-invasive device designed for the delivery of TTF to the head, should be worn at least 18 hours a day in order to obtain the best treatment response. The device was originally approved as a novel device to treat adults aged 22 years or older with GBM that recurs or progresses after receiving chemotherapy and radiation therapy. On October 5, 2015, the FDA approved the use of Optune in combination with temozolomide for the treatment of adults with newly diagnosed, supratentorial GBM following maximal debulking surgery and radiation therapy.

The first generation Optune system weighed approximately 6 pounds, the weight of the second generation Optune system has been reduced to 2.7 pounds. The second-generation device has also been redesigned to generate significantly less noise. These improvements may result in increased compliance. In a study by Kinzel and associates (2019), 10 individuals with GBM who were currently using the first generation TTF device, were transitioned to the second-generation device. Compliance improved in 4 users, was maintained in 5 users and decreased in 1 user. A total of 3/10 users had not reached 75% compliance level with the first-generation device but did achieve ≥75% compliance following transition to the second-generation device.

Newly diagnosed GBM

Current standard treatment for newly diagnosed GBM consists of tumor resection followed by daily low dose temozolomide administered concurrently with external beam radiotherapy followed by adjuvant temozolomide with alternating electric field therapy (NCCN, 2023). Radiochemotherapy is followed by adjuvant temozolomide given for 6 to 12 months. The prognosis for individuals with GBM is poor, with a 1-year survival rate of less than 40%.

Stupp and colleagues (2015) evaluated the safety and efficacy of TTF in individuals with newly diagnosed GBM following chemoradiation therapy. In a multi-center clinical trial, 695 individuals were randomized (2:1) to either TTF therapy (worn at least 18 hours/day) with temozolomide or temozolomide alone. The primary endpoint was identified as progression-free survival (PFS) time in the intent-to-treat (ITT) population (significant threshold, p≤0.01).

An interim analysis conducted on the first 315 participants who had completed at least 18 months of follow-up revealed median PFS in the TTF plus temozolomide group of 7.1 months (95% confidence interval [CI], 5.9-8.2 months) compared to 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide group (Hazard Ratio [HR] 0.62; 98.7% CI, 0.43-0.89; stratified log-rank, p=0.001). Median overall survival (OS, secondary endpoint) in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTF plus temozolomide group versus 15.6 months (95% CI, 13.3-19.1 months) (HR, 0.64; 99.4% CI, 0.42-0.98; p=0.004) in the temozolomide alone group. Based on the interim analysis results, the study was terminated and individuals in the control group were offered TTF therapy in addition to temozolomide. A total of 11 individuals crossed over and began using TTF therapy. With the exception of a higher incidence of localized skin reactions in the TTF plus temozolomide group, the incidence, distribution, and severity of adverse events (AEs) were similar across both treatment groups. The final analysis of the data was consistent with the interim analysis results (Stupp, 2017).

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

Ballo and colleagues (2023) published a meta-analysis focusing on whether the use of TTF added to standard of care (SOC) therapy in newly diagnosed individuals with GBM resulted in a consistent survival benefit as observed in the real-world setting. The analysis included one RCT and eight retrospective cohort studies, six of these retrospective studies included a control group who were not treated with TTF therapy. Treatment which included TTF therapy resulted in a significantly improved OS (HR: 0.63; 95% CI: 0.53–0.75; p<0.001). The pooled median OS in the SOC alone was 17.4 months compared to the SOC plus TTF therapy group was 22.6 months. In the studies which evaluated device usage and OS (n=5), usage of ≥ 75% was associated with improved OS compared to device usage ≤ 75% (HR: 0.60; 95% CI: 0.48–0.73; p<0.001).

The use of adjuvant alternating electric field therapy when used as an initial therapy along with temozolomide for individuals with anaplastic gliomas/glioblastoma with good performance status following standard radiotherapy and concurrent temozolomide is a NCCN category 1 recommendation.

Recurrent or Progressive GBM

Stupp and associates (2012) conducted a phase III, pivotal, multinational, randomized controlled trial (RCT) upon which the initial PMA was based. Between September 2006 and May 2009, 28 clinical centers enrolled 237 adult participants with relapsed or progressive GBM despite conventional therapy (e.g., surgery and chemo-radiotherapy followed by chemotherapy). A total of 120 participants were randomized in a 1:1 ratio to receive monotherapy with TTF therapy and 117 participants were randomized to the group treated with available best standard care (BSC) chemotherapies as practiced at each of the participating clinical centers. Chemotherapy agents considered as BSC during the trial included platinum-based chemotherapy (i.e., carboplatin); nitrosureas (BCNU); procarbazine; combination of procarbazine, lomustine and vincristine (PCV); temozolomide; and bevacizumab. A period of 28 days of treatment with the TTF device was considered one full treatment course. Participants treated with the TTF device were allowed to take breaks from treatment up to an hour, twice per day for personal needs such as showers. The primary endpoint of the study was OS. Secondary endpoints included PFS at 6 months (PFS6), time-to-progression (TTP), 1-year survival rate, quality of life (QOL), and radiological response. Participants were seen in clinic monthly, and magnetic resonance imaging (MRI) was performed after 2, 4, and 6 months from initiation of treatment and subsequent MRIs were done according to local practice until disease progression. Medical follow-up continued for 2 months after disease progression. Monthly telephone interviews with the participants’ caregivers were used to assess participant mortality rates.

A total of 97% (116) of 120 enrollees 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 due to noncompliance or the inability to handle the device. For each TTF treatment month, the median compliance was 86% (range 41-98%), which equaled a mean use of 20.6 hours per day. In the BSC (active control) group, 113 (97%) of the 117 assigned participants received chemotherapy, 112/113 participants completed one full treatment course. In the BSC cohort, 21 participants did not return to the site and details on disease progression and toxicity were not available. The median survival of 6.6 months in the TTF therapy group was marginally higher than 6 months in the BSC group (HR 0.86; 95% CI, 0.66-1.12; p=0.27). For both groups, 1-year survival was 20%. The survival rates for 2 and 3 years were 8% (95% CI: 4, 13) and 4% (95% CI: 1, 8) versus 5% (95% CI: 3, 10) and 1% (95% CI: 0, 3) for the TTF cohort compared to the BSC cohort, respectively. With a median follow-up of 39 months, 93% (220 participants) had died. Objective radiological responses (partial response [PR] and complete response [CR]) 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. Individuals in the TTF therapy group reported localized reactions which resolved with topical steroids. BSC participants experienced grade 2-4 events by organ system related to the pharmacologic activity of chemotherapy agents utilized. This trial represents the first phase III clinical trial of the TTF device using the first-generation device. The primary endpoint of the trial, improved OS compared to chemotherapy, was not reached. The TTF group did demonstrate similar efficacy to chemotherapy regimens with a lower toxicity profile and better quality of life (Fabian, 2019).

In 2014, Mrugala and associates analyzed the registry data of all individuals with recurrent GBM who had undergone therapy with the TTF device in 91 cancer centers (n=457). The median survival rate was 9.6 months. This was significantly longer than the 6.6 months reported in the Stupp (2012) trial. The individuals included in the registry data analysis also reported more than double the overall 1- and 2-year survival rates than reported in the Stupp 2012 trial. This may have been associated with the number of recurrences experienced prior to the application of the TTF device. Individuals in the data registry cohort were more likely to experiencing their first recurrence (33%) compared to individuals in the Stupp (2012) trial (9%). Compliance is also a prognostic factor of OS. Individuals with 75% or greater compliance, defined as daily compliance ≥ 75% or ≥ 18 hours daily, had a median OS of 13.5 months compared to 4.0 months in those with suboptimal compliance.

Vymazal and colleagues (2015) analyzed the response patterns in individuals with recurrent GBM who exhibited an objective response in two previous studies in order to evaluate the baseline characteristics of those individuals who responded and to evaluate the relationship between compliance with use and efficacy outcomes. The analysis was completed on one pilot study (n=10) and a phase III trial (n=237) in which TTF therapy was compared to standard chemotherapy. Between both studies, TTF was administered as monotherapy in 130 individuals. Across both trials, there was a 15% response rate (16/110 with a 4% CR rate). There were no significant differences in baseline characteristics between the responder and non-responder groups. In those in which a response was noted, there was frequently a delayed response; the tumor would initially continue to grow before responding to treatment. Analysis supported that an increase in compliance was associated with better treatment response and longer OS. The extent of treatment response in those who exhibited a response was significantly dependent on compliance.

Treatment recommendations for brain tumors include surgical resection, radiation therapy and/or chemotherapy as treatment options. There is no established second-line therapy for recurrent gliomas (NCI, 2023; NCCN, V1.2023). The NCCN panel designates a 2B recommendation for alternating electric field therapy in the treatment of recurrent GBM. The evidence supports that the use of TTF in recurrent GBM is associated with improved OS when used consistently with a trend towards higher levels of survival associated with increasing compliance (Toms, 2019).

Tumor progression (Return to Clinical Indications)

MacDonald and colleagues (1990) categorize 4 response categories: complete response, partial response, progressive disease and stable disease. Tumor progression can be defined in 3 ways: increasing tumor size, new areas of tumor and unequivocal neurologic deterioration. Measurement of tumor size is commonly determined using two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI) (Wen, 2010).

Tumor progression, based on the Macdonald criteria was defined by Stupp (2015) as at least one of the following:

• Tumor growth of greater than 25% of the product of 2 perpendicular diameters compared to the smallest tumor area measured, also calculated as a greater than 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement.
• Appearance of one or more new tumors in the brain (diagnosed radiologically as GBM).

Macdonald (1990) defines the measure of size as the largest cross-sectional area (largest cross-sectional diameter multiplied by largest diameter perpendicular to it. The goal of this calculation to measure the response as a change of a product of the maximal cross-sectional enhancing diameters (Aykan, 2020). The smallest tumor measurement is considered the size at baseline or the size at best response (Wen, 2010).

Compliance with therapy

The Optune device is designed to be used at least 18 hours every day in order to maximize treatment benefit. Continuous application is needed to reach and maintain therapeutic efficacy (Regev, 2021). The compliance rate, the number of days in which the minimum 18 hours daily use is reached, is an independent predictor of overall survival (Toms, 2019). Device usage can be expressed using a percentage of device usage, device usage of at least 18 hours/day would be expressed as 75% or greater (Ballo, 2023). In a systematic review and meta-analysis (Regev, 2021) reported on the pooled effect of compliance on OS rates of those with a TTF use daily compliance of 75% or more (10.3 months) compared to those with a TTF daily compliance of less than 75% (5.7 months). The 6-, 9-, and 12-month OS rates of those who used the TTF device 75% or more improved compared to those who used the TTF device less than 75% (73.5% [95% CI = 67.5-80], 54.3% [95% CI = 47.7-61.9], and 44.4% [95% CI = 37.9-51.9] compared to 48% [95% CI = 41-56.2], 40.6% [95% CI = 33.7-49], and 32.5% [95% CI = 25.8-40.9], respectively). An internal log file monitors compliance with therapy.

Malignant Pleural Mesothelioma

Pleural mesothelioma cancer develops in the mesothelial surface of the lungs and is primarily associated with asbestos exposure. Malignant mesothelioma is rare in the United States, with approximately 2500 new cases diagnosed each year. Pleural mesothelioma accounts for more than 75% of mesothelioma cases. Most individuals present with advanced disease limiting treatment options available. Median OS is 1 year with a 5-year OS of about 10% (NCCN, 2023).

In May 2019, the FDA approved the use of a modified version of the TTF device (Optune Lua^™ previously known as NovoTTF^™-100L) for the first-line treatment of adults with unresectable, locally advanced or metastatic malignant pleural mesothelioma to be used concurrently with pemetrexed and platinum-based chemotherapy. The device was approved under the Humanitarian Device Exemption (HDE) and identifies the specific population that the modified device is intended to treat. The HDE was not reviewed by the FDA advisory panel, the approval is based upon the previous review and approval of the similar GBM device. The Optune Lua operates on the same principle as the device used to treat GBM but includes different technological characteristics and area of application.

Ceresoli and colleagues (2019) evaluated the activity of TTF therapy used in combination with systemic chemotherapy in treating Stage IV unresectable malignant pleural mesothelioma (STELLAR study). Participants in the Phase II, prospective, single arm study (n=80) were treated with pemetrexed and cisplatin or carboplatin in combination with TTF therapy to the thorax until radiological disease progression or unacceptable toxicity was seen. The primary endpoint was OS time from diagnosis until the date of death. The median OS was 18.2 months (95% CI, 12.1-25.8). The 1-year survival rate was 62% and the 2-year survival rate was 42%. This OS was compared to the OS reported in two recent randomized trials involving malignant pleural mesothelioma chemotherapy regimens. These studies evaluated the addition of bevacizumab or nintedanib to a standard cisplatin and pemetrexed regimen. Both studies reported increased OS in the study groups compared to control groups, 18.8 months (95% CI, 15.9-2.6) and 18.3 months (15.2-28.8) compared to 16.1 months (14.0-17.9) and 14.2 months (95% CI 12.3-20.9) respectively. A total of 32 individuals (40%) reported severe AEs during the study, with anemia and neutropenia being unrelated to device use. Device-related AEs primarily consisted of skin reactions and were reported in 66% of the individuals, with 5% of these reactions being severe enough to result in treatment interruption. Randomized trials which compare standard chemotherapy with and without concurrent TTF therapy are needed to further evaluate any potential incremental benefit of this therapy over the current standard of care.

In summary, the available evidence regarding the use of TTF in treating stage IV non-curative mesothelioma in combination with standard chemotherapy does not demonstrate that use provides cost effective, therapeutically equivalent outcomes over the use of standard chemotherapy therapy alone.

Non-small cell lung cancer (NSCLC)

Leal and associates (2023) reported on the LUNAR study, an industry-sponsored, randomized open-label, pivotal phase 3 study comparing the OS in individuals with metastatic non-small-cell lung cancer who were treated with SOC or SOC with TTF therapy. Individuals with metastatic NSCLC (squamous or non-squamous) whose tumors had shown radiological progression at any site during or after platinum-based systemic therapy were eligible to participate. Participants were randomly assigned to standard systemic therapy of the clinical investigator’s choice without TTF (n=139) or with TTF (n=137). At data collection cutoff, the median follow-up was 10.6 months in the test group compared to 9.5 months in the control group. The median OS was significantly longer in the SOC with TTF group compared to SOC alone (13.2 months [95% CI: 10.3–15.5] compared to 9.9 months [95% CI: 8.1–11.5]; HR of 0.74 [95% CI: 0.56–0.98; p=0.035] respectively). The median OS in the individuals who received immune checkpoint inhibitor plus TTF therapy was 7.7 months higher than in individuals who received immune checkpoint inhibitor alone. There was no significant improvement in median OS in individuals who received docetaxel therapy. (Fennell, 2023). The median TTF device usage for individuals in the study was 56-57%, which is below the manufacturers recommended use of at least 18 hours/day (≤ 75%). The study was also initiated before the advent of standard genetic profiling by next-generation sequencing in non-small-cell lung cancer (now considered standard of care), which complicates interpretation in the current therapeutic milieu. While there were no serious AEs associated with the device itself, there was a higher rate of serious AEs in the TTF therapy group (53%, 70/133) compared to the SOC group (38%, 51/134). The study did show there may be a potential benefit to TTF therapy when combined with immune checkpoint inhibitor therapy. Further studies are needed to investigate potential benefits of TTF therapy when used with or following immune checkpoint inhibitor therapy with one study currently underway (NCT0489247).

The NCCN clinical practice guideline for NSCLC (V3.2023) does not reference TTF therapy as a potential treatment. In summary, use of TTF therapy for NSCLC is not currently supported by credible scientific evidence published in peer-reviewed medical literature, or national physician specialty society recommendations.

Other Solid Tumors

In addition to TTF treatment for GBM, phase III trials are underway in other types of malignancies, including brain metastasis, ovarian cancer and pancreatic carcinoma. The FDA has granted breakthrough device designation to the NovoTTF-200T for liver cancer. This designation was granted based upon the unpublished results of a phase 2 study evaluating the safety and efficacy of the TTF device when used with sorafenib to treat advanced liver cancer. At this time, there are no studies which support the use of tumor treating fields for conditions other than GBM. The NCCN clinical practice guidelines do not include any recommendations regarding the use of electric TTF treatment for any condition other than GBM.

Treatment Planning Software

In 2013, the FDA approved NovoTal through a PreMarket Approval (PMA) supplement. NovoTal is an algorithmic software package which allows treating physicians, who have completed a certification program, to create individualized treatment maps. The standard treatment plan developed by the manufacturer uses post-contrast MRI sequences to develop a treatment plan. Treating physicians using NovoTal are able to incorporate additional imaging data and other clinical considerations into TTF treatment planning (Connelly, 2016). There is a paucity of literature reporting on planning approaches in TTF treatment and their effect on clinical outcomes. Connelly and colleagues (2016) reported on the use of NovoTal in a case series of 8 individuals with grades 2-4 GBMs. In addition to contrast enhancing MRI imaging, other clinical considerations, such as the heterogeneity in contrast enhancement in tumors, were taken into account during the planning process. The authors discuss the use of alternative MRI sequences during the planning stage of treatment, but do not report on clinical outcomes, noting:

this case series demonstrates that treatment planning beyond the extent of contrast enhancement is clinically feasible and should be prospectively compared to standard treatment planning in a clinical trial setting, in order to determine the impact on patient outcomes.

Chaudhry and associates (2015) compared physician performance using the NovoTal system to conduct transducer array layout mapping to the mapping laid out by the Novocure in-house clinical team. Neuro-oncologists, medical oncologists and neurosurgeons (n=14) evaluated 5 cases of recurrent GBM and developed treatment plans. While the study demonstrated a high level of concordance in transducer array layout planning between NovoTal certified physicians and the Novocure in-house clinical team, the study did not address whether clinical outcomes were affected. The evidence does not support that the use of enhanced treatment planning software is considered effective in the use of TTF treatment.

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

Eastern Cooperative Oncology Group (ECOG) Performance Status: A scale used to determine the individual's level of functioning. This scale may also be referred to as the WHO or Zubrod score which is based on the following scale: 

Glioblastoma multiforme: Stage IV glioblastoma, which includes WHO recognized variants, giant cell glioblastoma and gliosarcoma.

Karnofsky Performance Status Score: A 10-point scale used by healthcare providers to quickly evaluate how an individual is feeling on any given day.

Macdonald criteria for disease progression is defined as at least one of the following:

• Tumor growth of greater than 25% of the product of 2 perpendicular diameters compared to the smallest tumor area measured
• Appearance of one or more new tumors in the brain (diagnosed radiologically as GBM).

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

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

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

Peer Reviewed Publications:

1. Aykan NF, Özatlı T. Objective response rate assessment in oncology: Current situation and future expectations. World J Clin Oncol. 2020; 11(2):53-73.
2. Ballo MT, Conlon P, Lavy-Shahaf G, et al. Association of Tumor Treating Fields (TTFields) therapy with survival in newly diagnosed glioblastoma: a systematic review and meta-analysis. J Neurooncol. 2023; 164(1):1-9.
3. Burri SH, Gondi V, Brown PD, Mehta MP. The evolving role of tumor treating fields in managing glioblastoma: guide for oncologists. Am J Clin Oncol. 2018; 41(2):191-196.
4. Ceresoli GL, Aerts JG, Dziadziuszko R, et al. Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial. Lancet Oncol. 2019; 20(12):1702-1709.
5. Chaudhry A, Benson L, Varshaver M, et al. NovoTTF^™ ‐ 100A System (Tumor Treating Fields) transducer array layout planning for glioblastoma: a NovoTAL^™ System user study. World J Surg Oncol. 2015; 13:316.
6. 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; 16(1):842.
7. Domingo-Musibay E, Galanis E. What next for newly diagnosed glioblastoma? Future Oncol. 2015; 11(24):3273-3283.
8. Fabian D, Guillermo Prieto Eibl MDP, Alnahhas I, et al. Treatment of glioblastoma (GBM) with the addition of tumor-treating fields (TTF): A review. Cancers (Basel). 2019; 11(2):174.
9. Fennell DA. Tumor Treating Fields therapy could potentiate immunotherapy in non-small-cell lung cancer. Lancet Oncol. 2023; 24(9):946-947.
10. Kanner AA, Wong ET, Villano JL, Ram Z.; EF-11 Investigators. Post hoc analysis of intention-to-treat population in phase 3 comparison of NovoTTF-100A^™ System versus best physician's choice chemotherapy. Semin Oncol. 2014; 41(Suppl 6):S25-S34.
11. Kinzel A, Ambrogi M, Varshaver M, Kirson ED. Tumor treating fields for glioblastoma treatment: Patient satisfaction and compliance with the second-generation Optune^® System. Clin Med Insights Oncol. 2019; 13:1179554918825449.
12. Kirson ED, Dbaly V, Tovarys F, et al. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007; 104(24):10152-10157.
13. Kirson ED, Giladi M, Gurvich Z, et al. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis. 2009a; 26(7):633-640.
14. Kirson ED, Gurvich Z, Schneiderman R, et al. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004; 64(9):3288-3295.
15. Kirson ED, Schneiderman RS, Dbalý V, et al. Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys. 2009b; 9:1.
16. Leal T, Kotecha R, Ramlau R, et al; LUNAR Study Investigators. Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study. Lancet Oncol. 2023; 24(9):1002-1017.
17. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990; 8(7):1277-1280.
18. Mehta M, Wen P, Nishikawa R, et al. Critical review of the addition of tumor treating fields (TTFields) to the existing standard of care for newly diagnosed glioblastoma patients. Crit Rev Oncol Hematol. 2017; 111:60-65.
19. 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. 2014; 41 (Suppl 6):S4-S13.
20. Pless M, Droege C, von Moos R, et al. A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer. Lung Cancer. 2013; 81(3):445-450.
21. Regev O, Merkin V, Blumenthal DT, et al. Tumor-treating fields for the treatment of glioblastoma: A systematic review and meta-analysis. Neurooncol Pract. 2021; 8(4):426-440.
22. 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.
23. Salzberg M, Kirson E, Palti Y, Rochlitz C. A pilot study with very low-intensity, intermediate-frequency electric fields in patients with locally advanced and/or metastatic solid tumors. Onkologie. 2008; 31(7):362-365.
24. Sampson JH. Alternating electric fields for the treatment of glioblastoma. JAMA. 2015; 314(23):2511-2513.
25. 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.
26. 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; 318(23):2306-2316.
27. Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012; 48(14):2192-2202.
28. Toms SA, Kim CY, Nicholas G, Ram Z. Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: A subgroup analysis of the EF-14 phase III trial. J Neurooncol. 2019; 141(2):467-473.
29. Trusheim J, Dunbar E, Battiste J, et al. A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma. CNS Oncol. 2017; 6(1):29-43.
30. Vymazal J, Wong ET. Response patterns of recurrent glioblastomas treated with tumor-treating fields. Semin Oncol. 2015; 42(3):e44-e55.
31. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010; 28(11):1963-1672.
32. Wong ET, Lok E, Swanson KD, et al. Response assessment of NovoTTF-100A versus best physician's choice chemotherapy in recurrent glioblastoma. Cancer Med. 2014; 3(3):592-602.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Urological Association (AUA) / American Society for Radiation Oncology (ASTRO) / Society of Urologic Oncology (SUO). Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. 2017. Available at: https://www.astro.org/uploadedFiles/_MAIN_SITE/Patient_Care/Clinical_Practice_Statements/Content_Pieces/ClinicallyLocalizedProstateCancer.pdf. Accessed on October 2, 2023.
2. Gilbert MR. Establishing the standard of care for patients with newly diagnosed and recurrent glioblastoma. Am Soc Clin Oncol Educ Book. 2012:112-117.
3. National Cancer Institute (NCI). Available at http://www.cancer.gov/. Accessed on October 2, 2023.
   • Adult Central Nervous System Tumors Treatment (PDQ^®). Last modified January 20, 2023.
   • Malignant Mesothelioma Treatment (PDQ®). Last modified May 17, 2023.
   • Non-Small Cell Lung Cancer Treatment (PDQ^®). Last modified February 17, 2023.
4. National Library of Medicine. Clinical Trials. EF-36/Keynote B36: A pilot, randomized, open-label study of tumor treating fields (TTFields, 150 kHz) concomitant with Pembrolizumab for first line treatment of advanced or metastatic non-small cell lung cancer (KEYNOTE B36). NCT04892472. Last updated June 12, 2023. Available at: https://clinicaltrials.gov/study/NCT04892472?a=2. Accessed on September 8, 2023.
5. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2023 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on September 8, 2023.
   • Breast Cancer (V4.2023). March 23, 2023.
   • Central Nervous System Cancers (V1.2023). March 24, 2023.
   • Melanoma: Cutaneous (V2.2023). March 10, 2023.
   • Mesothelioma: Pleural (V1.2023). December 15, 2022.
   • Non-Small Cell Lung Cancer (V3.2023). April 2, 2023.
   • Pancreatic Adenocarcinoma (V2.2023). June 19, 2023.
6. Novocure.
   • Optune Instructions for Use. Issue Date: January 2019. Available at: https://www.optune.com/Content/pdfs/Optune_IFU_8.5x11.pdf. Accessed on October 2, 2023.
   • Patient Information and Operation Manual. Issue Date: January 2019. Available at: https://www.optune.com/content/pdfs/Optune_PIOM_8.5x11.pdf. Accessed on October 2, 2023.
7. U.S. Food and Drug Administration (FDA). Humanitarian Device Exemption (HDE). NovoTTF^™-100L System. Summary of Safety and Probable Benefit. H180002. May 23, 2019. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf18/H180002B.pdf. Accessed on October 2, 2023.
8. U.S. Food and Drug Administration (FDA). Neurological Devices Panel. Available at: https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/. Accessed on October 2, 2023.
9. U.S. Food and Drug Administration (FDA) Premarket Notification Database. Tumor Treatment Fields. NovoTTF-10A System. Summary of Safety and Effectiveness Data (SSED). No. P100034. Rockville, MD: FDA. April 8, 2011b. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100034b.pdf. Accessed on October 2, 2023.
10. U.S. Food and Drug Administration (FDA) Premarket Approval (PMA) Database. Premarket Notification Database. Tumor Treatment Fields. Optune^™. Summary of Safety and Effectiveness Data (SSED). No. P100034/S013. Rockville, MD: FDA. October 5, 2015. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf10/p100034s013b.pdf . Accessed on October 2, 2023.

1. American Cancer Society (ACS).
   • What Are Adult Brain and Spinal Cord Tumors? Available at: https://www.cancer.org/cancer/brain-spinal-cord-tumors-adults/about/what-are-brain-spinal-tumors.html . Accessed October 2, 2023.
   • Malignant Mesothelioma. Available at https://www.cancer.org/cancer/malignant-mesothelioma.html. Accessed on October 2, 2023.
2. National Institutes of Health. Brain and Spinal Tumors Information Page. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Brain-and-Spinal-Tumors-Information-Page. Accessed on October 2, 2023.

NovoTTF-100A System
NovoTTF-100L System
Optune Lua
Tumor Treatment Field (TTF)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

This Clinical UM Guideline is intended to provide assistance in interpreting Healthy Blue’s standard Medicaid benefit plan. When evaluating insurance coverage for the provision of medical care, federal, state and/or contractual requirements must be referenced, since these may limit or differ from the standard benefit plan. In the event of a conflict, the federal, state and/or contractual requirements for the applicable benefit plan coverage will govern. Healthy Blue reserves the right to modify its Policies and Guidelines as necessary and in accordance with legal and contractual requirements. This Clinical UM Guideline is provided for informational purposes. It does not constitute medical advice. Healthy Blue may also use tools and criteria developed by third parties, to assist us in administering health benefits. Healthy Blue’s Policies and Guidelines are intended to be used in accordance with the independent professional medical judgment of a qualified health care provider and do not constitute the practice of medicine or medical advice.