Tumor Treating Fields Therapy

POLICY NUMBER

A.1.01.29

DESCRIPTION

Tumor treating fields (TTF) therapy is a noninvasive technology intended to treat glioblastoma, malignant pleural mesothelioma, and non small cell lung cancer 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. Non small cell cancer is the most common type of lung cancer (85%) encompassing 3 subtypes (adenocarcinoma, squamous cell, and large cell carcinoma) and prognosis depends on various factors, including the stage of the cancer, the type of treatment received, and the patient's overall health.

Glioblastoma Multiforme

Glioblastomas, also known as glioblastoma multiforme (GBM), are the most common form of malignant primary brain tumor in adults. Glioblastomas are grade IV astrocytomas, a rapidly progressing and deadly type of glial cell tumor that is often resistant to standard medical therapy (eg, bevacizumab, chemotherapy). Together, anaplastic astrocytomas and glioblastomas comprise approximately 38% of all primary malignant brain tumors. Mean age at GBM diagnosis is 65 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 6.9% and 8 months, respectively.

Treatment of Newly Diagnosed Glioblastoma Multiforme

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 (bis-chloroethylnitrosourea) impregnated wafer. Due to the poor efficacy of local treatment, postsurgical treatment with adjuvant radiotherapy (RT), chemotherapy (typically temozolomide), or a combination of these two therapies is recommended. After adjuvant therapy, 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 (see  Analysis of MGMT Promoter Methylation in Malignant Gliomas medical policy).

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. For patients with good performance status, the most aggressive treatment (standard 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.

Treatment of Recurrent Glioblastoma Multiforme

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 radiotherapy 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 the progression-free survival rate at 6 months is less than 20%. 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

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.

Non-small Cell Lung Cancer

Lung cancer, including non-small cell lung cancer (NSCLC), is the leading cause of cancer-related death in the United States. There are numerous treatment options for NSCLC which have improved survival rates. Patients eligible for targeted or immunotherapies now have 5-year survival rates up to 62.5%. Tumor treating fields have been studied in combination with immune checkpoint inhibitors (i.e., PD-1/PD-L1 inhibitors) or docetaxel in patients with metastatic NSCLC who progressed with platinum-based therapy.

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. 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, the FDA approved Novocure's request for a product name change from NovoTTF-110A System to Optune®.

In October 2015, the FDA expanded the indication for Optune in combination with temozolomide to include newly diagnosed GBM. 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, the 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." 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.

In October 2024, Optune Lua was approved for "metastatic non-small cell lung cancer along with concurrent drug treatments in adults who have progressed on or after a platinum-based chemotherapy."

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). Optune was renamed Optune Gio™ in 2023.

POLICY

Tumor treating fields therapy to treat glioblastoma multiforme is considered medically necessary 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:

• Individuals ≥18 years of age,

• Supratentorial tumor,

• Karnofsky Performance Status score ≥70%,

• Individual understands device use, including the requirement for a shaved head, and is willing to comply with use criteria according to the U.S. Food and Drug Administration label (see Policy Guidelines).

Tumor treating fields therapy is considered investigational in all other conditions, including but not limited to the following situations:

• As an adjunct to standard medical therapy (eg, bevacizumab, chemotherapy) for individuals with progressive or recurrent glioblastoma multiforme,

• As an alternative to standard medical therapy for individuals with progressive or recurrent glioblastoma multiforme,

• For brain metastases,

• For cancer in areas other than the brain,

• As an adjunct to standard medical therapy (pemetrexed and platinum-based chemotherapy) for individuals with malignant pleural mesothelioma,

• As an adjunct to standard medical therapy for individuals with non-small cell lung cancer (NSCLC).

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Progression was defined in the EF-14 trial (Stupp et al [2015, 2017]) according to the MacDonald criteria (tumor growth >25% compared with the smallest tumor area measured in the individual during the trial or appearance of one or more new tumors in the brain that are diagnosed radiologically as glioblastoma multiforme).

Per the pivotal trial, individuals ≥18 years of age were eligible for enrollment. The median patient age was about 56 years with a range of 19 to 83 years; subgroup analyses for younger age groups were not provided.

The recommended Karnofsky Performance Status (KPS) varies from the NCCN guideline (score ≥60). In the pivotal trial the median KPS score at baseline was 90.0, with a range from 60 to 100. Subgroup analyses for individuals with score 60 to 70 were not provided.

The U.S. Food and Drug Administration label includes the following notices:

• Individuals should use Optune for at least 18 hours a day to get the best response to treatment.

• Individuals should finish at least 4 full weeks of therapy to get the best response to treatment. Stopping treatment before 4 weeks lowers the chances of a response to treatment.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

04/01/2014: Approved by Medical Policy Advisory Committee.

09/30/2014: Policy reviewed; no changes.

07/23/2015: Code Reference section updated for ICD-10.

11/03/2015: Policy description updated regarding devices. Policy statement unchanged. Investigative definition updated in policy guidelines section.

01/06/2016: Code Reference section updated to add HCPCS codes A4555 and E0766 with an effective date of 01/01/2016.

05/31/2016: Policy number A.1.01.29 added.

09/22/2016: Policy description updated to add section headings. Policy statement revised for clarity; intent unchanged.

08/04/2017: Policy description updated regarding treatment for patients with glioblastoma multiforme and devices. Policy statement updated to state that tumor-treatment fields therapy to treat glioblastoma multiforme (GBM) is investigational as an alternative to standard chemotherapy for patients with progressive or recurrent GBM after initial or repeat treatment with surgery, radiotherapy, and/or chemotherapy and as an adjunct to standard maintenance therapy in patients with newly diagnosed GBM following initial treatment with surgery, radiotherapy, and/or chemotherapy.

09/15/2018: Policy title changed from "Tumor-Treatment Fields Therapy for Glioblastoma" to "Tumor Treating Fields Therapy." Policy description updated regarding treatment of newly diagnosed glioblastoma multiforme (GBM) and recurrent GBM. Added the following policy statement: Tumor treating fields therapy to treat glioblastoma multiforme is considered medically necessary 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 certain conditions. Investigational statement updated to state that tumor treating fields therapy is considered investigational in all other conditions. Policy Guidelines updated to define progression. Code Reference section updated to change codes from investigational to medically necessary and add ICD-10 diagnosis codes C71.0 - C71.9.

01/06/2021: Policy description updated regarding malignant pleural mesothelioma and devices. Policy statement updated to add malignant pleural mesothelioma to the list of conditions for which tumor treating fields therapy is considered investigational. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders."

08/27/2021: Policy reviewed; no changes.

08/05/2022: Policy description updated regarding the 5-year survival rate and products. Policy statements and Policy Guidelines updated to change "patients" to "individuals."

08/08/2023: Policy description updated regarding glioblastoma multiforme. Policy statements updated to change "patients" to "individuals." Policy Guidelines updated regarding trial information.

08/05/2024: Policy description updated regarding devices. Policy statements unchanged. Policy Guidelines updated to change "patients" to "individuals."

10/01/2024: Code Reference section updated to add new HCPCS code E0767.

08/27/2025: Policy description updated regarding non small cell cancer, glioblastoma multiforme, and devices. Policy statement updated to add non-small cell lung cancer to the list of conditions for which tumor treating fields therapy is considered investigational. Policy Guidelines updated to change "patients" to "individuals."

SOURCE(S)

Blue Cross and Blue Shield Association Policy #1.01.29

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

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