Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Tumor Treating Fields

Policy #:07.03.26

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

MEDICALLY NECESSARY

NEWLY DIAGNOSED GLIOBLASTOMA WHEN USED IN ADJUVANT TREATMENT
Alternating electric tumor treating fields (TTFields) are medically necessary and, therefore, covered for adult individuals (22 years of age or older) with newly diagnosed glioblastoma, when the individual meets all of the following criteria:
  • Histologically confirmed glioblastoma (World Health Organization grade IV astrocytoma)
  • Tumor located in the supra-tentorial region of the brain
  • Karnofsky Performance Score above 60
  • Completed standard therapeutic options, such as maximum safe debulking surgery, concomitant temozolomide, or radiotherapy
  • TTFields is prescribed with adjuvant temozolomide (maintenance)
  • Willingness to use the TTFields device daily for at least 18 hours

RECURRENT GLIOBLASTOMA WHEN USED AS A MONOTHERAPY
Alternating electric TTFields are medically necessary and, therefore, covered when used as a monotherapy for adult individuals (22 years of age or older) with recurrent glioblastoma, when the individual meets all of the following criteria:
  • Histologically confirmed glioblastoma (World Health Organization grade IV astrocytoma)
  • Tumor located in the supra-tentorial region of the brain
  • Karnofsky Performance Score above 60
  • Completed standard therapeutic options, such as maximum safe debulking surgery or systemic chemotherapy or irradiation
  • Willingness to use the TTFields device daily for at least 18 hours

NOT MEDICALLY NECESSARY

TTFields are considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support their use for the treatment of individuals with glioblastoma who have any of the following: an implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted devices in the brain, documented clinically significant arrhythmias, or evidence of increased intracranial pressure.

EXPERIMENTAL/INVESTIGATIONAL

All other uses of TTFields are considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The Company may conduct reviews and audits of services to our members regardless of the participation status of the provider. Medical record documentation must be maintained on file to reflect the medical necessity of the care and services provided. These medical records may include but are not limited to: records from the professional provider’s office, hospital, nursing home, home health agencies, therapies, and test reports.

PRESCRIPTION (ORDER) REQUIREMENTS
Before submitting a claim to the Company, the supplier must have on file a timely, appropriate, and complete order for each item billed that is signed and dated by the professional provider who is treating the member. Requesting a provider to sign a retrospective order at the time of an audit or after an audit for submission as an original order, reorder, or updated order will not satisfy the requirement to maintain a timely professional provider order on file.

PROOF OF DELIVERY
Medical record documentation must include a contemporaneously prepared delivery confirmation or member’s receipt of supplies and equipment. The medical record documentation must include a copy of delivery confirmation if delivered by a commercial carrier and a signed copy of delivery confirmation by member/caregiver if delivered by the DME supplier/provider. All documentation is to be prepared contemporaneous with delivery and be available to the Company upon request.

CONSUMABLE SUPPLIES (WHEN APPLICABLE)
The durable medical equipment (DME) supplier must monitor the quantity of accessories and supplies an individual is actually using. Contacting the individual regarding replenishment of supplies should not be done earlier than approximately seven days prior to the delivery/shipping date. Dated documentation of this contact with the individual is required in the individual’s medical record. Delivery of the supplies should not be done earlier than approximately five days before the individual would exhaust their on-hand supply.

If required documentation is not available on file to support a claim at the time of an audit or record request, the durable medical equipment (DME) supplier may be required to reimburse the Company for overpayments.
Guidelines

Tumor treating fields (TTFields) for the treatment of newly diagnosed and/or recurrent glioblastoma (GBM) utilizes a portable battery or power supply operated device which produces alternating electrical fields within the human body. TTFields are applied to individuals by electrically insulated surface transducer arrays. TTFields disrupt the rapid cell division exhibited by cancer cells.

TTFields are intended to harness electric fields to arrest the proliferation of tumor cells and to destroy them. The TTFields technology takes advantage of the special characteristics and geometrical shape of dividing cells, which make them susceptible to inhibiting cellular division during mitosis. The fields are said to alter the tumor cell polarity at an intermediate frequency (on the order of 100-300 kHz). The frequency used in the treatment of GMB has been specified to 200kHz.

KARNOFSKY PERFORMANCE STATUS (KPS)

A scale measuring the ability of individuals to perform ordinary tasks. KPS scores range from 0 to 100; a higher score means a person is better able to carry out daily activities.

KPS
Definition
100
Normal; no complaint; no evidence of disease
90
Able to carry on normal activity; minor signs of symptoms of disease
80
Normal activity with effort; some sign or symptoms of disease
70
Cares for self; unable to carry on normal activity of do active work
60
Requires occasional assistance, but is able to care for most personal needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization is indicated, although death not imminent
20
Very sick; hospitalization necessary; active support treatment is necessary
10
Moribund; fatal processes progressing rapidly
0
Dead

NATIONAL COMPREHENSIVE CANCER NETWORK

The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 27 leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. NCCN® promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. NCCN® provides a clinical practice guideline appropriate for use in the treatment of glioblastoma, both as a new diagnosis and in recurrent disease.

NCCN® provide clinical practice guidelines for central nervous system cancers on a variety of prognostic factors, such as: age, good performance status (KPS60) , MGMT promotor status (methylated or unmethylated/indeterminate). When the medically necessary criteria listed in this medical policy are met, the NCCN® clinical practice guidelines endorse the use of TTFields, as follows:

IN THE TREATMENT OF NEWLY DIAGNOSED GLIOBLASTOMA
Maximum resection with adjuvant treatments inclusive of standard brain RT (recommended dose is 60 Gy in 2.0 Gy fractions or 59.4 Gy in 1.8 Gy fractions) + concurrent temozolomide and adjuvant temozomide + alternating electric field therapy (category 1).

IN THE TREATMENT OF RECURRENT GLIOBLASTOMA
Resection with or without carmustine (BCNU) wafer AND palliative/best supportive care if poor performance, or systemic chemotherapy, or consider reirradiation (category 2B) or alternating electric field therapy for glioblastoma (category 2B).

REGULATORY STATUS

On April 8, 2011, the FDA gave premarket approval for the NovoTTF-100A system (NovoCure Inc. Portsmouth, New Hampshire) for the treatment of adult patients (22 years of age or older) with histologically confirmed glioblastoma multiforme (GBM), following histologically or radiologically confirmed recurrence in the supra-tentorial region of the brain after receiving chemotherapy. The device is intended to be used as a monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.

On October 5, 2015, the FDA expanded approval for Optune™ (formerly NovoTTF-100A) system for the treatment of adult patients with newly diagnosed, supra-tentorial glioblastoma following maximal debulking surgery and completion of radiation therapy together with concomitant standard of care chemotherapy.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, TTFields are covered as durable medical equipment (DME) under the medical benefits of most of the Company’s products when the medical necessity criteria listed in this medical policy are met.

Description

Glioblastoma multiforme (GBM) is the most prevalent and most fatal malignant brain tumor in adults, accounting for nearly 15% of all brain cancers. GBMs account for 46.6% of all malignant tumors with 12,150 new cases predicted annually. Malignant gliomas are histologically heterogeneous and invasive tumors that are derived from neuroglia, or glial cells, whose primary responsibility is to support the central nervous system's neuron cells. GBMs are classified by the World Health Organization (WHO) as astrocytoma. The WHO provides a grading scale based on the most malignant regions of the tumors. Tumor grades depend upon degree of nuclear atypia, mitotic activity, microvascular proliferation, and necrosis, with increased anaplasia, corresponding to higher tumor grades. The 2007 WHO classification of GBM is a grade IV, indicating the most severe cancer grade, exhibiting rapid tumor growth leading to exceedingly poor prognosis. Eighty percent of individuals diagnosed with GBM will progress to recurrent disease, even after the initial surgical options have been exhausted. Survival expectancy for individuals with newly diagnosed GBM averages between 14.6 to 16.7 months with one-year survival rates of 35%. Following a GBM recurrence, the one-year survival rate is only approximately 20%, and median survival ranges from three to nine months.

Although the prognosis is dismal, the treatment options remain limited. The standard first-line treatment for a GBM is maximum surgical resection of the tumor. The National Comprehensive Cancer Network (NCCN®) has developed clinical practice guidance for the treatment of GBM. At present, the recommended treatment for an individual who is newly diagnosed with a histologically confirmed GBM is: maximum resection surgery, followed by radiotherapy (fractionated focal irradiation in daily fractions of 2 Gray [Gy] given 5 days per week for 6 weeks, for a total of 60 Gy). Gray is a unit of measurement for ionized radiation defined by the absorption of one joule of radiation per one kilogram of matter. In addition to radiotherapy, individuals are treated with concomitant continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), then subsequent cycles (6) of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). For disease recurrence, standard care includes surgical resection in combination with Gliadel® Wafer, stereotactic radiosurgery, and re-operation for additional tumor resection. Irrespective of the varying treatment protocols between the newly diagnosed and recurrent populations, GBM reoccurrence is still 80% and two-year survival rates remain a mere 27% following initial diagnosis. Acknowledging these dismal treatment outcomes, research has been conducted on new therapeutic agents for the treatment of glioblastoma. Stupp et al developed a new technology called tumor treating fields (TTFields) initially utilized and studied to treat the population with recurrent GBM disease.

TTFields is a technology utilizing electric activity through fields and currents to influence the of polarity of molecules, ions, and the cell membranes found in biological organisms to exert an effect on cellular process and impact cell division. By exposing cancer cells to alternating electric fields of low intensity and intermediate frequency, cellular polarity and ionic energy could be manipulated. This mechanism of action purported by TTFields (alternating electric fields) could selectively arrest cellular division (cytokinesis) in cancer cells by impairing normal mitosis and cytokinesis. TTFields are shown to have no effect on non-dividing cells, but to induce apoptosis in dividing cells. The electric fields interfere with cell division by causing misalignment of highly polarized subunits (microtubule monomers) in the mitotic spindle during the metaphase to anaphase transition and by dielectrophoretic movement of intracellular macromolecules and organelles during telophase. During cytokinesis, TTFields generate non-uniform intracellular fields, pulling organelles towards the neck that separates the newly forming daughter cells. In addition, TTFields interfere with the formation of the mitotic spindle by exerting forces on the charged tubulin subunits. Both processes lead to cell apoptosis and tumor growth inhibition. TTFields exert maximal effects when aligned to a cell’s mitotic axis. As a cell’s mitotic axis can occur randomly in any direction, additive cytotoxic effects are also observed when TTFields are applied in multiple sequential directions.

Individuals who utilize this technology for the treatment of GBM would need to place four transducer arrays onto their shaved scalp and connected to a portable, battery or power supply operated device (Optune, formerly the NovoTTF-100A system), which is preset to generate 200 kHz electric fields within the brain in two sequentially, perpendicular directions. The intensity of the field is also preset by the manufacturer at >0.7 V/cm. Treatment is intended to be continuous and take place in the home setting to allow the participants to maintain daily activities. Transducer arrays are supplied sterile, and prior to placement of the arrays, the scalp must be shaved carefully to limit the adverse effects (i.e., skin irritation, skin wounding). Although uninterrupted treatment is recommended, individuals can take treatment breaks of up to an hour, twice per day, for personal needs (i.e., shower).

The electrodes themselves are made from high dielectric constant insulated ceramic discs soldered to a flexible circuit board. The flexible printed circuit incorporates the components required for delivering the current for each ceramic plate and for measuring the temperature. At the set parameters, the electrodes are not reported to cause significant heating due to dielectric losses of the insulation or induced fields in the target tissue.

The Optune system contains a separate software component for the use of clinical treatment planning. The NovoTAL system is a workstation based software tool that uses MRI head morphology, tumor size and location measurements, and tissue dielectric properties to optimize the TTFields' distribution and intensity within the tumor by determining the specific region of the brain to treat with the placement of paired arrays. The planning software is intended for use by physicians certified to prescribe electronic TTFields used for the treatment of GBM.

PEER REVIEWED LITERATURE

Kirson et al (2004) evaluated 11 types of cancerous cell lines in more than 500 in vitro culture dishes. The researchers calculated growth rates of the cells and measured cell proliferation. In all cell lines reviewed, each culture dish was exposed to TTFields for a period of 24-hour intervals at 100 kHz (at an intensity of 1.0–1.4 V/cm), which resulted in significant inhibition of cell proliferation. To test the relationship between TTFields' intensity and inhibition of cell proliferation, Kirson et al exposed mouse melanoma and rat glioma cell lines to TTFields of different intensities between 1 and 2.5 V/cm. Furthermore, authors reported that the inhibitory effect of TTFields on cell proliferation increased as intensity increased until complete proliferation arrest was achieved at intensities of 1.4 and 2.25 V/cm in melanoma and glioma cells, respectively. The authors reported on the most relevant findings regarding the prolongation of mitosis, stating in treated cells, mitosis seemed to begin normally but was prolonged for variable periods of time before completing cleavage into two daughter cells. In the 500 cells evaluated, the authors reported TTFields had exemplary effect on the cellular process. In the cells treated with TTFields, mitosis was not complete within the standard 3 hours. TTFields treated cells displayed proliferation arrest, and mitosis lasted on average 124 ± 91 min (mean Standard Deviation [SD], n= 53; 40–541 min), whereas in the controlled cells, the average mitosis duration was 62 ± 8 min from cell rounding to cytokinesis with a mean SD of 12 and a range of 47-78 minutes. Their findings resulted in statistically significant prolongation of mitosis (P < 0.01, Mann-Whitney U test).

The authors reported in vivo studies with two animal tumor models. TTFields were generated between implanted (intradermal) wholly insulated wires placed on both sides of the tumor. The researchers placed two sets of paired identical insulated wires on the back of a mouse. The comparative in the mouse study was that only one of the pairs were connected to device, thus only exposing the area under the connected pair to TTFields treatment.

The researchers demonstrated that 100 KHz to 1 MHz alternating direction fields have significant specific effects on dividing cells. They reported that the areas treated with electric field of alternating direction provided evidence that all charges and polar molecules are subjected to forces of alternating direction so that ionic flows and dipole rotation oscillate. The basis of these effects during cytokinesis was shown to be that the unidirectional forces induced by disrupting mitotic spindle formation could result in physical disruption of the cell membrane and ultimately to apoptosis. During mitosis, exposure of cells to those fields results in one-fourth being destroyed as the formation of the cleavage furrow approached complete cell separation and violent membrane protrusions and cells exhibit disruption of microtubule spindle elements. Additionally, the authors reported that the direction of the placed electrical current dictates the magnitude of cellular disruption. Kirson et al concluded that when TTFields are placed parallel to the plane division, cells exhibited more mitotic failure. Placement of the TTFields arrays is an important instruction when the technology is indicated in the treatment of cancers.

TUMOR TREATING FIELDS FOR THE TREATMENT OF RECURRENT, SUPRA-TENTORIAL GLIOBLASTOMA MULTIFORME
Kirson et al 2007 evaluated a single arm, pilot trial study on the safety and efficacy of TTFields treatment that was performed on 10 participants with recurrent GBM. Efficacy analysis was performed for recurrent GBM persons focusing on time to disease progression (TTP), progression-free survival at 6 months (PFS6), and overall survival (OS) as the primary outcomes for individuals treated with the NovoTTF-100A device. Based on such a small sample size no statistical hypothesis tests were measured. This study measured progression-free survival at 6 months (PFS6), producing a result of 50% (23–77%; 95% confidence interval). Ninety-five percent confidence intervals of survival proportions were calculated using Kaplan–Meier survival curves. The initial pilot study reported two of the ten participants surviving beyond the follow-up period, with the longest participant living for 124.0 weeks, differing from historical averages.

The authored indicated that the pilot study demonstrated TTP and OS values that were more than double the reported historical medians, and reported that TTFields treatment resulted in one complete response which was tumor free, confirmed by MRI ten months after stopping treatment, and one partial response which was still responding seven months after stopping treatment. Both were still progression free two years from treatment initiation. In addition, one participant had minimal response, and four had stable disease for over 4 months before progressing, with the authors suggesting that the device could conceivably halt tumor growth.

The seminal trial, which led to the Food and Drug Administration (FDA) granting approval of TTFields, was a prospective randomized, phase III trial (EF-11) conducted by Stupp et al. (2012). The EF-11 trial assessed TTFields as a monotherapy, without chemotherapy, compared to physician’s standard chemotherapy. 237 participants were randomly assigned in a 1:1 ratio to receive either TTFields, (n=120) or an active control entailing the best available chemotherapy prescribed at the local investigator’s discretion (n= 117). Participants were all at least 24 years old, with an average age of 54, had Karnofsky performance scores of ≥ 70 with limited other comorbidities. The study design reported that participants would receive baseline examinations and be tested monthly in laboratory. Magnetic resonance imagining (MRI) exams were repeated every second month, and quality of life questionnaires were completed every third month. The researchers allowed any number of prior treatments or recurrences of disease without limits. More than 85% of trial participants had failed two or more prior lines of chemotherapy (i.e., ≥ second recurrence), and nearly 20% had failed (or had a recurrence) while being treated with bevacizumab prior to enrollment. Tumor response and progression were determined by a blinded central radiology review. This study was designed to demonstrate device superiority over the pharmaceutical control.

The trial's primary outcome was overall survival (OS). Secondary endpoints were: progression-free survival (PFS), the percentage of individuals alive and progression-free at 6 months (PFS6), 1-year survival rate, radiological response rate (RR), quality of life, and safety. OS and PFS were computed from randomization until event or censored at last follow-up utilizing Kaplan–Meier survival method, with 2-sided log rank statistics for comparison. The study had an 80 percent power at a significance level of 0.05 to detect a 60 percent increase in median OS (Hazard Ratio [HR] 0.63). All analyses were performed using the intent to treat population of all randomized participants, individuals lost to follow-up were censored at the time of last contact. Treatment compliance limitations were disproportionately observed in the study as only 78% (93/120) completed one full cycle of the TTFields. Nearly a quarter of all participants in the TTFields treatment arm were noncompliant and discontinued, or failed to begin treatment. 113 of 117 participants (97%) in the active control group started chemotherapy, and all but one person completed one full treatment course. The study presented with follow-up limitations. Twenty-one participants randomized to the control group failed to return to the treatment site, limiting information on disease progression and toxicity. Moreover, quality of life, a secondary outcome of the study, was only available for assessment on 63 or 27% of trial participants.

Compliance was recorded for those individuals in the TTFields arm who began treatment (n=116) by device downloads. The downloads recorded the treatment duration that TTFields therapy was delivered to each participant. The observed median compliance rate was 86 percent (41–98%) during each treatment month, resulting into a mean duration use of 20.6 hours per day. The study acknowledged variance among the level of disease progression (i.e., first recurrence versus multiple) by the participants but failed to produce comparisons amongst the control groups. Missing these comparisons limits the study's ability to determine the overall effectiveness of the TTFields as a monotherapy. Participants received either single agent or a combination of chemotherapeutic regimens. The percentage breakdown for the chemotherapy agents prescribed were as follows: individuals received bevacizumab (31%), or irinotecan (31%), followed by nitrosoureas (25%), carboplatin (13%), temozolomide (11%) or various other agents (5%). However, the study reported that among individuals treated with the active chemotherapy control, survival was not significantly affected by the choice of chemotherapeutic agent (p = 0.66).

The statistical analysis of the survival data was tested for proportional hazards and the assumption of proportionality met using the Cox proportional hazards regression model. The Cox model was performed in two steps; first, all protocol pre-specified baseline variables were tested directly for interactions with OS; then a reduced model was performed testing the effect of all variables with significant interaction (p < 0.05) with OS together on the treatment effect of TTFields versus active chemotherapy. At a median follow-up of 39 months, 220 trial participants had succumbed to their disease (93%). The primary endpoint failed to demonstrate a significant increase in mean overall survival between the two treatments. Median survival failed to report statistical significance but was marginally higher in the TTFields group compared to active control chemotherapy (6.6 versus 6.0 months, respectively). One-year survival proportion was 20% in both groups and was unable to demonstrate superiority over common chemotherapy treatments. The 2- and 3-year survival rates were reported as 8% (95% CI, 4-13) and 4% (95% CI, 1-8) versus 5% (95% CI, 3-10) and 1% (95% CI, 0-3) for TTFields versus active control, respectively. The reported hazard ratio was 0.86 (95% CI, 0.66-1.12) in favor of TTFields (p = 0.27), indicating that TTFields may be at least equivalent and trending toward an improvement as compared to active chemotherapy. The trial failed to report statistically significant device superiority. Participants were not restricted based on prior treatments or recurrences. Many of the participants presented with advanced disease at trial initiation. As many as 40% of participants were included after the third disease occurrence, possibly decreasing the potential benefit from treatment. Trial results showed TTFields as a monotherapy provided similar, not superior, efficacy as best physician’s choice chemotherapy in individuals afflicted with recurrent GBM, albeit superior quality of life and less toxicity resulting from treatment with chemotherapy.

Secondary trial outcomes were presented without adjustment. Quality of life measures were assessed using the QLQ-C30 questionnaire with brain-specific module (BN-20), and the measurements were presented as the change from baseline to 3 months for each of the subscale domains and symptoms scale. The researchers reported that both cognitive and emotional functioning were higher in the TTFields group compared to the chemotherapy group, with no difference in global health. The researchers reported that more objective radiological responses (partial and complete responses) were seen in the TTFields group than in the active control chemotherapy group (14 versus 7, respectively). Progression-free survival (PFS) resulted marginally in favor of participants in the TTFields treatment group, with median PFS reported as 2.2 and 2.1 months for TTFields versus the active control group, respectively (HR 0.81, 95% CI 0.60 - 1.09; log rank p = 0.16). Authors state progression-free survival at 6 month was 21.4 percent (95% CI 13.5 - 29.3) in the TTFields group and 15.1 percent (95% CI 7.8 - 22.3) in the active control group (chi squared p = 0.13). The authors were unable to claim statistical significance for the trial outcomes.

This study was limited by the inability to be blinded, which could introduce bias and compromise the quality of life assessments. Participant knowledge of their active participation limits the pinnacle prognostic factor by creating bias. The disproportionate dropout rates are concerning. Many individuals stopped treatment prior to completing one month of treatment duration, and these individuals failed to be treated long enough to make substantial contributions to assist with determinations on device effectiveness. High rates of participant cross-over from chemotherapy into device treatment were observed in the study. Due to the nature of this disease and the dismal prognosis for individuals in this patient population, even marginal changes in overall survival and any increase in quality of life are clinically significant findings, as alternative to the current treatment modalities for individuals with recurrent GBM. Based on the slight improvement, trends observed in this trial suggest that treatment with TTFields may be considered an option.

Kanner et al performed a post hoc analysis to study the intent-to-treat (ITT) population in the TTFields treatment versus the best physician’s choice chemotherapy. The authors report overall survival was significantly affected by duration that the TTFields device was worn. Not surprising, since this treatment is without a half-life and would require continuous application of the device to demonstrate a reduction in tumor growth. Stratifying population size to augment the desired results, the post hoc analysis measured outcomes within the population who fully completed at least one cycle (four weeks) of TTFields treatment. Based on those modifications, the researchers observed individuals who complied with treatment protocol of ≥ 18 hours daily (n=92) had significantly longer overall survival medians, 7.7 versus 4.5 months than those who used treatment ≤ 18 hours (n=28). Small sample sizes in the study diminish this power of the analysis, and the device may create adherence bias. However, a therapeutic response resulting in an observed mean overall survival increase of three months supports treatment effectiveness when compliance of the treatment protocol is adhered to.

A Patient Registry Dataset (PRiDe) followed 457 persons with recurrent GBM who received TTFields therapy was studied by Mrugala et al in a real-world, phase IV setting. Additional information on the safety and effectiveness of the therapy was assessed in the dataset. The primary outcome of the registry evaluated median overall survival, tolerability of the device, participant compliance and survival, and other prognostic factors. Mrugala reported overall survival (OS) and treatment using Kaplan-Meier methods and Cox proportional hazards model assessed participant characteristics and disease prognostic factors on survival. Evaluation was conducted with log-rank tests to compare OS and daily compliance, prior debulking surgery, Karnofsky Performance Score (KPS), number of recurrence, and prior bevacizumab use.

Overall survival between the PRiDe participants and those treated in the the seminal study with TTFields therapy, and physician’s best chemotherapy, increased from 9.6 versus 6.6 versus 6.0 months, respectively. Overall survival rates at one- and two- years increased when compared to treatment arms (TTFields and chemotherapy) from the EF-11 study and PRiDe. As stated above, evidence supported daily compliance as a prognostic factor in TTFields therapy. Participants who achieved the recommended daily compliance of ≥18 hours a day had significantly longer (p=.0001) overall survival --- 13.5 months versus 4.0 months when individuals reported less than ≤18 hours. Subgroup analysis of individuals treated at first recurrence (n=152) demonstrated the longest median overall survival, resulting in 20 months. The overall survival reported in the first recurrence population is similar to more recent studies on the newly diagnosed, suggesting that TTFields may be an option as an effective therapy in GBM recurrence, if treatment is initiated at earliest recurrence.

The registry failed to evaluate participant use of combination therapy with TTFields and prescription programs, such as chemotherapy and anti-vascular endothelial growth factor agents. Outside of a clinical trial, the lack of recording information on other medical management regimens for participants resulted in critically missed analyses in demonstrating the effectiveness of TTFields as a therapy, potentially misrepresenting the true effectiveness of the device in the largest studied population. The registry highlights compliance as a key finding, supporting the adaptation of TTFields; however, it failed to record compliance data for more than one-third of all device users. Device safety and tolerability was proven outside of observational settings. Consistent with other trials, the adverse event most commonly observed was associated with device-related skin irritation.

The registry presented with limitations, including lack of quality of life measures, as these were excluded in the real world follow-up, an important prognostic factor in overall health outcome from the original trial. Heterogeneity limitations exist within the registry as 67% of the total population were male (n=309), possibly significant considering the need to shave a user’s scalp for successful placement of the treatment arrays when utilizing this device.

TUMOR TREATING FIELDS FOR THE TREATMENT OF NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME
Stupp et al. 2015 conducted a multi-center, open-label, randomized phase III trial designed to evaluate the efficacy and safety of TTFields following chemoradiation with temozolomide (TMZ) for treatment of newly diagnosed glioblastoma. The trial enrolled 695 participants with histologically confirmed supra-tentorial glioblastoma, who were progression-free following debulking surgery or biopsy, and who have completed standard concomitant chemoradiotherapy with TMZ. These individuals were randomized (2:1) to receive combination therapy of TTFields plus temozolomide (TMZ) (n=466) or standard maintenance chemotherapy alone using TMZ (n=229). Randomization was stratified by participant characteristics: degree of resection, and O6-methylguanine-DNA methyltransferase (MGMT) methylation status. The primary outcome was progression-free survival (PFS) in the intent-to-treat (ITT) population and was assessed by independent reviewers (80% power; hazard ratio [HR], 0.78; allowing for 10% loss to follow-up; 2-sided α level of 0.05). This study investigated shifted overall survival to a secondary outcome but with equal power (HR, 0.76; 2-sided α = 0.05). To avoid an increase in the risk of a false positive result, overall survival was to only be tested statistically if the PFS was achieved.

In October, 2014, a safety monitoring committee reviewed the findings of an interim analysis reporting on the first 315 participants enrolled in the TTFields plus temozolomide (n=210) and temozolomide (n=105) treatment groups. Pre-specified endpoints were achieved in the intent-to-treat population. After a median follow-up of 38 months (18-60 months), the median PFS in the TTFields plus TMZ arm was 7.1 months from randomization (95% confidence interval [CI], 5.9 - 8.2 months) compared to 4.0 months (95 % CI, 3.3 - 5.2) in the control group ([HR] 0.62; 98.7% CI, 0.43 - 0.89; stratified log-rank, P= 0.001). Overall survival in the per-protocol analysis also showed significant improvement. The combination therapy group (n=196) resulted in median OS of 20.5 months (95% CI, 16.7 - 25.0 months) compared to 15.6 months (95% CI, 13.3 - 19.1 months) in the TMZ alone group (n=84) ([HR], 0.64; 99.4% CI, 0.42 - 0.98; P =0.004). Based on the results of the interim analysis, the trial was terminated, and participants in the control group were allowed to receive TTFields. The termination resulted in eleven individuals in the interim analysis and twenty-six participants overall to cross over and receive TTFields treatment. The study demonstrated the addition of TTFields to temozolomide treatment increased median progression-free survival in the ITT population by 3.1 months.

Per the study design, if tumor progression occurred, second-line chemotherapy was offered by local investigator's practice. Noteworthy, TTFields would continue in the treatment arm, until the second radiological confirmed progression, or clinical deterioration, for a maximum of 24 months. Brain imaging was routinely performed, initially at baseline with contrast-enhanced magnetic resonance imaging (MRI) at two weeks prior to treatment initiation, then in two-month intervals until second radiologically confirmed progression in all study participants. Two-thirds of the TTFields plus TMZ group (n=141) continued treatment with TTFields beyond first tumor progression. The trial design to stop at second tumor progression may have clinical importance when considering the progression of disease and the use of TTFields as a treatment option for individuals transitioning from a new diagnosis into recurrent GBM.

The authors reported median treatment duration of 5.8 months (1 - 58 months) with TTFields. Three-quarters (n=157) of enrollees receiving TTFields adhered to therapy. Protocol adherence was considered wearing the device ≥ 18 hours per day on average during the first 3 treatment months. Further analyses in the ITT population showed the median overall survival was 19.6 months (95% CI, 16.6 - 24.4 months) in the TTFields plus temozolomide group compared to 16.6 months (95% CI, 13.6 - 19.2 months) in the temozolomide alone group ([HR],0.74 95% CI, 0.56 - 0.98; stratified log-rank P=0.03). The percentage of those affected by GBM alive at 2 years following enrollment was 43% in the TTFields plus temozolomide group and 29% in the TMZ alone group (P=0.006, a 14% increase of participants alive at two years in the treatment arm.

The original publication (interim analysis) of the EF-14 study was limited by the investigators stopping the trial earlier and allowing participant cross over. The interim analysis was completed after the initial 315 enrollees reached 18 month follow-up. The results in the initial per-protocol population only evaluated 196, 84 participants in the combination therapy (TTFields plus TMZ) or the TMZ alone arms, respectively. Additionally, as an open-label trial, no sham or placebo treatment was available for the control group. Investigators deemed the use of sham to be unethical, and unpractical, and therefore the potential power of a placebo cannot be assessed. This may introduce adherence bias. The researchers acknowledge placebo bias would be unlikely to influence overall survival and progression-free survival. Following the original trial, which reported results that failed to provide evidence of statistically significant improvements in median overall survival, the primary study outcome shifted between the two seminal trials. In the original EF-11 trial, the primary endpoint was overall survival, and in this trial researchers adjusted the primary outcome to progression-free survival. The results of this study on newly diagnosed GBM, the addition of TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and improved overall survival.

Stupp et al 2017 reported on the final analysis inclusive of the entire trial population (n=695) from the open- label, randomized phase III trial designed to evaluate the effect of TTFields plus temozolomide (TMZ) versus maintaince TMZ alone on survival for individuals with glioblastoma. Stupp et al previously published the results from an interim analysis on the first 395 participants of the same study. The primary outcomes were consistent to the interim analysis.

The data set was locked on December 28, 2016, and the authors reported median treatment duration of 8.2 months (1 - 82 months) with TTFields. After a medium follow-up of 40 months (34 - 66 months), the median progression-free survival was 6.7 months (95% CI, 6.1 - 8.1 months) for individuals treated with combination therapy versus 4.0 months (95% CI, 3.8 - 4.4 months) for those treated with TMZ alone ([HR] 0.63, 95% CI, 0.52 - 0.76; P <0.001). The secondary outcome reported median overall survival duration of 20.9 months from randomization (95% CI, 19.3 - 22.7 months) in the TTFields plus TMZ group versus 16.0 months (95% CI, 14.0 - 18.4 months) for TMZ only ([HR],0.63; 95% CI, 0.53 - 0.76; P<0.001). Both were found to be statistically and clinically significant. Analyzing the percentage of living participants over selected time periods from randomization resulted in 46% alive at 2 years, 26% alive at 3 years, and 13% alive at 5 years in the combination therapy arm, compared to the TMZ only arm reporting 31% alive at 2 years (p <0.001); 16% at 3 years (P=0.009); and 5% at 5 years (P =0.004). Significant percentage increases across each selected time period favoring adjuvant TTField therapy.

The median time to randomization was equal among the treatment arms with 3.8 month (range 1.7 - 6.2) and 3.7 months (range, 1.4 - 6.3) in the combination therapy, and the TMZ alone treatment groups, respectively. Kaplan-Meier estimates for survival were accessed at 6 months for the rate of progression-free survival between the two treatment groups. The authors reported on progression-free survival at 6 months as 56% (95% CI, 51% - 61%) for the TTFields group and 37% (30% - 44%) with TMZ only (P < 0.001). Cox proportional hazards analyzed both overall survival and progression-free survival across factors: trial arms, age, sex, MGMT status, location, and county of residence. Results using Cox proportional hazards with 95% confidence intervals demonstrated several prognostic factors significantly improved OS; these prognostic factors include: TTFields treatment group (HR, 0.63, 0.53 - 0.76, P<0.001), female sex (HR, 0.76, 0.63 - 0.92, P =.005), MGMT status (HR, 0.50, 0.41 - 0.62; P < 0.001), younger age (measured continuously, [HR], 0.978 per year, 0.969 - 0.985; P < 0.001), and higher KPS (as a categorical variable in 10 point increments P <0.001).

Interestingly, fifty-five percent of participants had a gross tumor resection (95% of tumor removed) and 13% had only a biopsy performed, results indicating the extent of excision was not statistically significant when investigating overall survival (P= 0.183). The addition of TTFields was not associated with an increase in systemic adverse events (AE) (48% versus 44%; P=0.58). Higher rates of AE found in the TTFields treated group were attributed to longer duration of TMZ treatment in the experimental group as a result of delayed disease progression. Investigators report inclusive criteria for TTFields treatment utilizing Karnofsky Performance Score (KPS). KPS is a scale measuring the ability of individuals to perform ordinary tasks. KPS scores range from 0 to 100; a higher score means a person is better able to carry out daily activities. The author reported time to sustain 10 point reduction in KPS significantly longer for the combination group versus the group treated with only TMZ (5.5 months; 95% CI, 5.0 - 6.3 months versus 3.9 months; 95% CI, 3.1 - 5.2 months, respectively; [HR], 0.80; 95% CI, 0.67 - 0.95; P =0.009).

Potentially important for future studies, a small majority of the experimental population (51%; n=237) continued TTFields treatment beyond first treatment progression. The investigators may want to evaluate, in the newly diagnosed population who elect to continue TTFields as a combination therapy beyond first progression, whether significant improvements are observed in progression-free survival and OS compared to the outcomes of the historical recurrent population. The recurrent population only has the option to utilize TTFields as a monotherapy. The largest study to date utilizing the TTFields technology presented with similar limitations as observed in the interim analysis (no sham, burden of use when utilizing the device). Another limitation in the final analysis was that quality of life data points were not recorded. Also, participant heterogeneity limitations exist since nearly 70% of the study participants were male and 89% were white.

The final analysis for the treatment of glioblastoma utilizing the TTFields technology demonstrated that the combination therapy of TTFields and temozolomide chemotherapy following standard concomitant TMZ and radiotherapy has shown to significantly improve progression-free survival and overall survival in the newly diagnosed population.

NovoCure Inc. of Portsmouth, New Hampshire (subsidiary of NovoCure Ltd., Haifa, Israel) was granted approval for the NovoTTF-100A system. The NovoTTF-100A Treatment Kit received US Food and Drug Administration (FDA) Premarket Approval on April 8, 2011 (P100034). The current supplement Optune™ System, which received FDA Premarket Approval on October 5, 2015 (P1000034/S013) was submitted to expand the indications for use: Optune™ System with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supra-tentorial glioblastoma following maximal debulking surgery and completion of radiation therapy together with concomitant standard of care chemotherapy.

In summary, TTFields has been demonstrated to be a safe and effective alternative treatment, and should be considered for individuals with either recurrent or newly diagnosed Glioblastoma. In 2015, The National Comprehensive Cancer Network® (NCCN®) clinical practice guidelines appropriateness in the treatment of central nervous system cancer for use of TTFields has shifted to consider category 3 in the recurrent population as a category 2B. A 2B category allows providers to consider the use of TTFields in treatment of recurrent disease. The NCCN® 2018 guidelines classifies alternating electronic fields therapy as a 1 grade for newly diagnosed glioblastoma individuals. NCCN® guidelines demonstrate TTFields used in concomitant treatment with adjuvant temozolomide following radiotherapy and concomitant temozolomide for the newly diagnosed. Indicating that use of TTFields could be used an initial treatment therapy, when prescribed with adjuvant temozolomide.

TUMOR TREATING FIELDS IN OTHER INDICATIONS
Researchers have initiated evaluations utilizing NovoCure’s TTFields technology in the treatment of other solid tumor indications. The various populations actively being investigated include cancers such as: non-small cell lung (NSCLC), brain metastases (1-5; 1-10) from NSCLC, pancreatic, ovarian, mesothelioma, and high grade glioma and ependymoma in children. Each of these separate indications has been either recently completed or is actively being studied in phase II trials to determine safety and efficacy with this new modality. The trials range in size, n= 5 in the child study to 82 participants in the mesothelioma trial. Variance exists between the primary outcomes researched in each of the new indications. In the ovarian and pancreatic cancers, the primarily investigated outcome was device related adverse effects and feasibility based on compliance as a result of the individual’s early discontinuation of treatment. The tumor location could be a factor in compliance. Toxicity was the principal measurement in the non-small cell lung cancer study, whereas overall survival was the primary outcome in the mesothelioma trial. All studies listed time to progression, or progression-free survival as a secondary endpoint.

Non-small cell lung cancer is currently under investigation, with participants actively enrolled into a prospective, randomized controlled phase III trial aimed to test the efficacy and safety of TTFields in combination with PD-1 inhibitors or docetaxel as a second-line treatment. The researchers will assess the overall survival of participants with the TTFields and docetaxel or PD-1 inhibitors versus docetaxel or PD-1 alone in a superiority study design. Interestingly, if the primary outcome fails, the researchers will evaluate overall survival of those treated with TTFields and docetaxel versus PD-1 inhibitors alone in a separate, more challenging non-inferiority study. This study has a completion date of December 2020.

Evaluation of a trial on the feasibility of Optune for children with recurrent or progressive supra-tentorial high-grade glioma and ependymoma cancers was initiated in early 2017. This trial aims to demonstrate use of the Optune device as a feasible treatment option in the pediatric population and report treatment-related toxicities assessed by Common Terminology Criteria for Adverse Events v4.0. A total of 25 children are expected to participate in this trial. This study was the first trial, inclusive of the pivotal trials, that utilizes the TTFields technology that was not funded or sponsored by the device manufacture, NovoCure, Ltd. The pediatric study is sponsored by Pediatric Brain Tumor Consortium, with support from the National Cancer Institute (NCI).
References


Argyriou, AA., Antonacopoulou, A., Iconomou, G, et al. Treatment options for malignant gliomas, emphasizing towards new molecularly targeted therapies. Crit Rev Oncol Hematol. 2009;69(3), 199-210.

Batchelor, T., (2016). Initial postoperative therapy for glioblastoma and anaplastic astrocytoma. UpToDate. [UpToDate Web site]. Available at: https://www.uptodate.com. [via subscription only]. Assessed December 18, 2017.

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.

Cohen, A., Holman, S., Colman, H. IDH1 and IDH2 mutation of gliomas. Curr Neurol Neurosci Rep. 2013; 13(5), 345.

Gilbert, MR., Wang, M., Aldape, KD. Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial. J Clin Oncol. 2013;31(32), 4085-4091.

Hottinger, AF., Pacheco, P., Stupp, R. Tumor treating fields: a novel treatment modality and its use in brain tumors. Neuro-Oncology. 2016;18(10), 1338-1349.

Kanner, AA., Wong, ET., Villano, JL., et al. Post Hoc Analyses of Intention-to-Treat Population in Phase III Comparison of NovoTTF-100A™ System Versus Best Physician’s Choice Chemotherapy. Semin Oncol. 2014; 41.

Kirson, ED. Disruption of cancer cell replication by alternating electric fields. Cancer Research. 2004;64(9), 3288-3295.

Kirson, ED, Dbaly, V, Tovarys, F. et al. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proceed of Nat Acad Sci. 2007;104(24), 10152-10157.

Louis, DN, Ohgaki, H, Wiestler, OD. The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathologica. 2007;114(2), 97-109.

Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathologica. 2016;131(6):803-820.

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.

Mrugala, MM., Engelhard, HH., Tran, DD. et al. Clinical practice experience with NovoTTF-100A™ System for Glioblastoma: The patient registry dataset (PRiDe). Semin Oncol. 2014;41.

National Comprehensive Cancer Network. NCCN® Clinical practice guidelines in oncology: Central nervous system cancers. Version 2.2018- 11/26/2018. Available at:http://www.NCCN®.org/professionals/physician_gls/pdf/cns.pdf. Assessed January 08, 2019.

National Cancer Institute (NCI). Adult Brain Tumors Treatment 2017. Available at:http://www.cancer.gov/cancertopics/pdq/treatment/adultbrain/HealthProfessional. Accessed January 08, 2019.

Oken, MM., Creech, RH., Tormey, DC. et al. Toxity and response criteria of the eastern cooperation oncology group. Am J Clin Oncol. 1982; 5:649-655.

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Stupp, R., Taillibert, S., Kanner, AA. et al. Maintenance therapy with tumor-treating fields plus Temozolomide vs Temozolomide alone for glioblastoma. JAMA. 2015;314(23), 2535.

Stupp R 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.

Swanson, KD., Lok, E., Wong, ET. An overview of alternating electric fields therapy (NovoTTF Therapy) for the treatment of malignant glioma. Curr Neurol Neurosci Rep. 2016;16(1):8.

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Wenger C, Salvador R, Basser PJ, et al. Improving Tumor Treating Fields treatment efficacy in patients with glioblastoma using personalized array layouts [published online December 14, 2015]. Int J Radiat Oncol Biol Phys. 2015:

Wick, W, Stupp, R, Beule. A., Bromberg, J., et al. A novel tool to analyze MRI recurrence patterns in glioblastoma. J Neuro-Oncology. 2008;10(6): 1019–1024.

Wong, ET., Wu, JK. Clinical presentation and diagnosis of brain tumors. 10/19/2018. UpToDate. [UpToDate Web site]. Available at:https://www.uptodate.com/contents/overview-of-the-clinical-features-and-diagnosis-of-brain-tumors-in-adults. [via subscription only]. Assessed January 08, 2019.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

C71.0 Malignant neoplasm of cerebrum, except lobes and ventricles

C71.1 Malignant neoplasm of frontal lobe

C71.2 Malignant neoplasm of temporal lobe

C71.3 Malignant neoplasm of parietal lobe

C71.4 Malignant neoplasm of occipital lobe

C71.5 Malignant neoplasm of cerebral ventricle

C71.8 Malignant neoplasm of overlapping sites of brain



HCPCS Level II Code Number(s)



A4555 Electrode/transducer for use with electrical stimulation device used for cancer treatment, replacement only

E0766 Electrical stimulation device used for cancer treatment, includes all accessories, any type


Revenue Code Number(s)

N/A

Coding and Billing Requirements



Policy History

07.03.26:
02/13/2019This policy was reviewed and reissued in accordance with the Company's Policy Confirmation Review track. The references were updated accordingly. The policy was updated to be consistent with current template wording and format.
03/23/2018This new policy has been issued to communicate the Company's coverage position.

Version Effective Date: 03/23/2018
Version Issued Date: 03/23/2018
Version Reissued Date: 02/13/2019

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