Clinical UM Guideline

This document addresses the use of alternating electrical field therapy known as tumor treatment fields (TTF). The TTF device creates 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.

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

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.

 This document describes clinical studies and expert recommendations, and explains whether certain medical services are appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Glioblastoma and Some Options for Treatment

This document talks about the use of tumor treatment fields (TTF) for the treatment of cancer. TTF uses a wearable device that sends low-level electric fields into the brain to disrupt cancer cell growth. The TTF device is worn outside the body for most of the day and may help some individuals with some types of brain cancer live longer, especially if used properly. TTF treatment starts with a 90-day trial, with longer treatment okay if it has been found to be working.

While mainly used for the treatment of brain cancer, TTF is also being looked at for the treatment of other cancers, including lung, ovarian, and pancreatic, though these uses have not yet been shown to work in medical studies.

Summary of Treatment Options

TTF has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of one type of brain cancer glioblastoma. Studies show it may improve survival when added to drug treatment in newly found disease. It may also be used without drug treatment in some people who have been treated for glioblastoma and it has come back. The device must be worn at least 18 hours a day to work properly.

Some studies have looked at the use of TTF for lung cancer, ovarian cancer, and pancreatic cancer. Some studies show that it may help people live longer, but guidelines from major medical societies do not recommend such use yet. More research is needed to understand if TTF helps in these types of cancer.

Special computer software may be used to help doctors plan where to use TTF. While it may help with setting up, studies have not shown that it improves the result of treatment.

What is Clinically Appropriate?

TTF may be useful for the treatment of glioblastoma located in the upper part of the brain and the person has had surgery and completed drug or radiation treatment. Continued TTF use after 90 days is okay when the person has been using the device as told and there is no sign that the tumor has grown or returned.

What is Not Clinically Appropriate?

TTF use for any cancer other than glioblastoma has not yet been shown to improve health or result in longer lives.

(Return to Description)

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:

Summary

Tumor Treatment Fields (TTF) therapy delivers low-intensity, intermediate-frequency alternating electric fields to disrupt mitosis and induce tumor cell death. The Optune device is FDA-approved for the treatment of GBM or grade IV astrocytomas in both recurrent and newly diagnosed disease. TTF has been demonstrated to improve survival when combined with temozolomide, and the National Comprehensive Cancer Network^® (NCCN) has a category 1 recommendation for adjuvant therapy (category 2B for recurrence); compliance ≥ 75% is recommended to optimize clinical benefit. The FDA also approved Optune Lua^® for malignant pleural mesothelioma with pemetrexed/platinum chemotherapy and for metastatic non-small cell lung cancer (NSCLC) after platinum therapy, though the NCCN and American Society of Clinical Oncology (ASCO) guidelines do not recommend routine use. In pancreatic cancer, the phase III PANOVA-3 trial showed modest survival benefit with chemotherapy, while in ovarian cancer no improvement was seen. Currently, national guidelines endorse TTF therapy only for the treatment of GBM.

Discussion

Glioblastoma Multiforme (GBM)

Glioblastoma (WHO grade IV astrocytoma), also known as GBM (National Cancer Institute [NCI], 2025), 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 (NCCN Central Nervous System Cancers [CNS], V2.2025). 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 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 CNS, V2.2025). 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 compared to 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. The OS for both cohorts was also 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 longer 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 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, 2025; NCCN CNS, V2.2025). 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 TTF device is designed for continuous application, with at least 18 hours of daily use required to 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 OS (Toms, 2019). Device adherence is often expressed as usage percentage, where ≥ 75% reflects  at least 18 hours per day (Ballo, 2023). Compliance is objectively tracked through internal device log files, ensuring accurate measurement of usage patterns.

A systematic review and meta-analysis further demonstrated that individuals with ≥ 75% daily usage achieved a longer survival (10.3 months) compared to those with < 75% (5.7 months); 6-, 9-, and 12-month OS rates were also consistently higher in the higher compliance group (Regev, 2021). A retrospective single-institution study by Riegel and associates (2025) evaluated outcomes for newly diagnosed glioblastoma treated with standard therapy with or without TTF therapy. A total of 208 individuals were included, and survival analysis demonstrated that adding TTF therapy improved median OS (21.7 vs. 17.7 months) and PFS (12.4 vs. 9.6 months) compared to standard therapy alone. Device usage was a critical determinant of benefit: when TTF therapy was applied at least 75% of the time (averaging 18 hours per day), both OS and PFS were significantly prolonged after controlling for prognostic factors, underscoring the dose-response effect of consistent device adherence.

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 Mesothelioma, V2.2025).

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.

NSCLC

Leal and associates (2023) reported on the LUNAR study, a randomized open-label, pivotal phase 3 study comparing the OS in individuals with metastatic NSCLC who were treated with SOC with or without TTF therapy. Eligible individuals had metastatic NSCLC (squamous or non-squamous) with radiological progression at any site during or after platinum-based systemic therapy. Participants were randomly assigned to standard systemic therapy of the clinical investigator’s choice without TTF (control; n=139) or with TTF (test; 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, 0.74 [95% CI: 0.56-0.98; p=0.035] respectively). Among those treated with an immune checkpoint inhibitor plus TTF therapy, the median OS was 7.7 months longer than those receiving the 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 initiated prior to the advent of standard genetic profiling by next-generation sequencing in NSCLC (now considered SOC), 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 a phase 3 study currently recruiting (NCT 06216301; LUNAR-2).

On October 15, 2024, the FDA approved the Optune Lua as a treatment of metastatic NSCLC when disease has progressed on or after a platinum-based regimen. The device is intended to be used concurrently with PD-1/PD-L1 inhibitors or docetaxel. The device should be worn for at least an average of 12 hours each day. The approval is based upon the results of the LUNAR trial, noting that an extension of over 3 months compared to SOC alone is considered clinically meaningful.

ASCO guidelines for stage IV NSCLC (Owen, 2025) highlight that TTF combined with standard therapy after platinum chemotherapy demonstrated a survival benefit in the LUNAR trial, with the greatest effect observed in the immunotherapy-naïve, second line group; however, because of low-quality evidence, lifestyle burdens of device use, and limited relevance to current treatment patterns, TTF is not broadly recommended. For pleural mesothelioma, ASCO (Kindler, 2025) reported encouraging outcomes when TTF was added to pemetrexed-platinum chemotherapy, but as a single-arm, nonrandomized trial, the evidence was deemed insufficient for ASCO to recommend routine use.

The NCCN clinical practice guideline for NSCLC (V2.2025) 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

A pivotal phase 3 RCT evaluated TTF therapy in combination with paclitaxel for platinum-resistant ovarian cancer (Vergote, 2025). The study showed no improvement in OS or PFS compared to paclitaxel alone, with median OS nearly identical between groups (12.2 vs. 11.9 months; HR, 1.01, p=0.89). While exploratory post-hoc analyses suggested possible benefit in pegylated liposomal doxorubicin-naïve cases, the primary findings did not support the addition of TTF therapy to ovarian cancer treatment.

Babiker (2025) published the results of the PANOVA-3 trial, a randomized, open-label phase III study that enrolled 571 adults with newly diagnosed unresectable locally advanced pancreatic adenocarcinoma. Participants were randomized to gemcitabine plus nab-paclitaxel with or without TTF therapy. The primary endpoint was OS, with secondary endpoints including PFS, local PFS, pain-free survival, and overall response rate (ORR). TTF therapy significantly improved OS (16.2 vs. 14.2 months; HR, 0.82, p=0.039), pain-free survival (15.2 vs. 9.1 months; HR, 0.74, p=0.027), and distant PFS (13.9 vs. 11.5 months; HR, 0.74, p=0.022), but did not improve overall PFS, local PFS, or ORR. Safety analyses showed no increase in systemic toxicities beyond chemotherapy; the most common TTF therapy-related events were mild-to-moderate skin reactions, though 7.7% experienced grade ≥ 3 skin toxicity. Treatment discontinuation within the initial 28 days was high in both study arms, with only 198 of 285 in the TTF therapy group and 207 of 286 in the control group completing at least one full cycle treatment. After the first treatment cycle, there was significant discontinuation for reasons other than death or disease progression. Other limitations included the open-label design, absence of a sham device, and lower-than-recommended device compliance (median daily usage 62% vs. the 75% target).

Trials are underway in other types of malignancies. 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.

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. Anadkat MJ, Lacouture M, Friedman A, et al. Expert guidance on prophylaxis and treatment of dermatologic adverse events with tumor treating fields (TTFields) therapy in the thoracic region. Front Oncol. 2023; 12:975473.
2. Aykan NF, Özatlı T. Objective response rate assessment in oncology: current situation and future expectations. World J Clin Oncol. 2020; 11(2):53-73.
3. Babiker HM, Picozzi V, Chandana SR, et al.; PANOVA-3 Study Investigators. Tumor treating fields with gemcitabine and nab-paclitaxel for locally advanced pancreatic adenocarcinoma: randomized, open-label, pivotal phase III PANOVA-3 study. J Clin Oncol. 2025; 43(21):2350-2360.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. Domingo-Musibay E, Galanis E. What next for newly diagnosed glioblastoma? Future Oncol. 2015; 11(24):3273-3283.
10. 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.
11. Fennell DA. Tumor treating fields therapy could potentiate immunotherapy in non-small-cell lung cancer. Lancet Oncol. 2023; 24(9):946-947.
12. 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.
13. 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.
14. 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.
15. 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.
16. Kirson ED, Gurvich Z, Schneiderman R, et al. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004; 64(9):3288-3295.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. Riegel DC, Bureau BL, Conlon P, et al. Long-term survival, patterns of progression, and patterns of use for patients with newly diagnosed glioblastoma treated with or without Tumor Treating Fields (TTFields) in a real-world setting. J Neurooncol. 2025; 173(1):49-57.
25. 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.
26. 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.
27. Sampson JH. Alternating electric fields for the treatment of glioblastoma. JAMA. 2015; 314(23):2511-2513.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. Vergote I, Copeland LJ, Van Gorp T, et al.; ENGOT-ov50/GOG-3029/INNOVATE-3 Study Investigators. tumor treating fields therapy in platinum-resistant ovarian cancer: results of the ENGOT-ov50/GOG-3029/INNOVATE-3 pivotal phase 3 randomized study. Eur J Cancer. 2025; 219:115306.
34. Vymazal J, Wong ET. Response patterns of recurrent glioblastomas treated with tumor-treating fields. Semin Oncol. 2015; 42(3):e44-e55.
35. 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.
36. 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.
37. Zhu J-J, O’Donnell R, Ram Z. EF-19, a post-approval registry study of tumor treating fields (TTFields) in recurrent glioblastoma (rGBM). J Clin Oncol. 2020; 38(15_suppl):e14536-e14536.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Gilbert MR. Establishing the standard of care for patients with newly diagnosed and recurrent glioblastoma. Am Soc Clin Oncol Educ Book. 2012:112-117.
2. National Cancer Institute (NCI). Available at http://www.cancer.gov/. Accessed on September 17, 2025.
   • Adult Central Nervous System Tumors Treatment (PDQ^®). Last modified March 28, 2025.
   • Malignant Mesothelioma Treatment (PDQ^®). Last modified May 12, 2025.
   • Non-Small Cell Lung Cancer Treatment (PDQ^®). Last modified May 15, 2025.
3. National Library of Medicine. Clinical Trials. Available at: https://www.clinicaltrials.gov/. Accessed on September 16, 2025.
   • LUNAR-2: TTFields With Pembrolizumab + Platinum-based Chemotherapy for Metastatic NSCLC (LUNAR-2). NCT06216301. Last updated September 8, 2025.
   • Pivotal, Randomized, Open-label Study of Optune^® (Tumor Treating Fields) Concomitant With RT & TMZ for the Treatment of Newly Diagnosed GBM (EF-32). NCT04471844. Last updated August 7, 2025.
4. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2025 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on October 28, 2025.
   • Central Nervous System Cancers. V2.2025. August 28, 2025.
   • Mesothelioma: Pleural. V2.2026. October 3, 2025.
   • Non-Small Cell Lung Cancer. V8.2025. August 15, 2025.
   • Pancreatic Adenocarcinoma. V2.2025. Febuary 3, 2025.
5. Novocure.
   • Optune Gio Instructions for Use. Issue Date: September 2023. Available at: https://assets.novocure.biz/patient/QSD-QR-703%20US%28EN%29%20Commercial%20Optune%20Gio%20INE_IFU%20Rev04.pdf. Accessed on September 17, 2025.
   • Physician Instructions for Use. Optune Lua. Issue date: November 2024. Available at: https://assets.novocure.biz/optunelua-hcp/2025-01/Optune%20Lua%20NSCLC%20IFU.pdf. Accessed on September 17, 2025.
6. Owen DH, Ismaila N, Ahluwalia A, et al. Therapy for stage iv non-small cell lung cancer with driver alterations: ASCO living guideline, Version 2024.3. J Clin Oncol. 2025; 43(10):e2-e16.
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 September 17, 2025.
8. U.S. FDA. Neurological Devices Panel. Content current as of November 18, 2021. Available at: https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/. Accessed on September 17, 2025.
9. U.S. FDA Premarket Approval (PMA) Database. Premarket Notification Database. Accessed on September 17, 2025.
   • 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.
   • Optune^™. SSED. No. P100034/S013. Rockville, MD: FDA. October 5, 2015. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf10/p100034s013b.pdf.
   • Optune Lua^™. SSED. No. P230042. Rockville, MD: FDA. October 15, 2024. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230042b.pdf.

1. American Cancer Society (ACS). Accessed on September 17, 2025.
   • What Are Adult Brain and Spinal Cord Tumors? Last revised May 5, 2020. Available at: https://www.cancer.org/cancer/brain-spinal-cord-tumors-adults/about/what-are-brain-spinal-tumors.html .
   • Malignant Mesothelioma. Available at https://www.cancer.org/cancer/malignant-mesothelioma.html.
   • Tumor Treating Fields (TTFields)/Electrical Fields. Last revised: March 28, 2025. Available at: https://www.cancer.org/cancer/managing-cancer/treatment-types/tumor-treating-fields.html.
2. National Institutes of Health. Brain and Spinal Tumors Information Page. Last reviewed June 23, 2025. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Brain-and-Spinal-Tumors-Information-Page. Accessed on November 14, 2025.

NovoTTF-100A Syste
NovoTTF-100L System
Optune Gio
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.

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to adopt a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card.

Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner.

No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

© CPT Only - American Medical Association