For any item to be covered by Medicare, it must 1) be eligible for a defined
Medicare benefit category, 2) be reasonable and necessary for the diagnosis or
treatment of illness or injury or to improve the functioning of a malformed
body member, and 3) meet all other applicable Medicare statutory and
regulatory requirements.  
  
The purpose of a Local Coverage Determination (LCD) is to provide information
regarding "reasonable and necessary" criteria based on Social Security Act 
1862(a)(1)(A) provisions.  
  
In addition to the "reasonable and necessary" criteria contained in this LCD
there are other payment rules, which are discussed in the following documents,
that must also be met prior to Medicare reimbursement:

  * The LCD-related Standard Documentation Requirements Article, located at the bottom of this policy under the Related Local Coverage Documents section.

  * The LCD-related Policy Article, located at the bottom of this policy under the Related Local Coverage Documents section.

  * Refer to the Supplier Manual for additional information on documentation requirements.

  * Refer to the DME MAC web sites for additional bulletin articles and other publications related to this LCD.

For the items addressed in this LCD, the "reasonable and necessary" criteria,
based on Social Security Act  1862(a)(1)(A) provisions, are defined by the
following coverage indications, limitations and/or medical necessity.

  
INITIAL COVERAGE FOR NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME:

Tumor treatment field therapy (E0766) is covered for the treatment of newly
diagnosed Glioblastoma Multiforme (GBM) only when all of the following
criteria are met:

  1. The beneficiary has histologically confirmed (World Health Organization (WHO) grade IV astrocytoma), newly diagnosed, supratentorial GBM; and,

  2. The beneficiary has received initial treatment with maximal debulking surgery (when feasible), followed by chemotherapy and radiotherapy; and,

  3. Tumor treatment field therapy is initiated within 7 weeks from the last dose of concomitant chemotherapy or radiotherapy, whichever is later; and,

  4. The beneficiary has no evidence of progression by Response Assessment in Neuro-Oncology (RANO) criteria; and,

  5. The beneficiary has a Karnofsky Performance Score (KPS) of at least 70; and,

  6. The beneficiary will use TTFT for an average of 18 hours per day.

If all of the coverage criteria above are not met, claims for code E0766 will
be denied as not reasonable and necessary.

  
CONTINUED COVERAGE FOR NEWLY DIAGNOSED GBM BEYOND THE FIRST THREE MONTHS OF
THERAPY:

Continued coverage of TTFT (E0766) beyond the first three months of therapy
requires that no sooner than the 60th day but no later than the 91st day after
initiating therapy, the treating practitioner must conduct a clinical re-
evaluation and document that the beneficiary is continuing to use and is
benefiting from TTFT.

Documentation of clinical benefit is demonstrated by:

  1. In-person clinical re-evaluation by the treating practitioner; and,

  2. Objective evidence of adherence to therapy, reviewed by the treating practitioner.

Adherence to therapy is defined as the use of TTFT for an average of 18 hours
per day (excluding days the treating practitioner has documented a medical
need to limit or interrupt treatment).

If the above criteria are not met, continued coverage of TTFT will be denied
as not reasonable and necessary.

If the practitioner re-evaluation does not occur until after the 91st day but
the evaluation demonstrates that the beneficiary is benefiting from TTFT as
defined in criteria 1 and 2 above, continued coverage of TTFT will commence
with the date of that re-evaluation. See Policy Specific Documentation
Requirements in the LCD-related Policy Article, located in the Related Local
Coverage Documents section of this LCD, for information about KX modifier use.

  
RECURRENT GBM

Tumor treatment field therapy (E0766) will be denied as not reasonable and
necessary for the treatment of recurrent GBM.

  
OTHER USES

The use of TTFT for any indications other than newly diagnosed GBM will be
denied as not reasonable and necessary.

  
BENEFICIARIES ENTERING MEDICARE

For beneficiaries who are undergoing treatment with TTFT for newly diagnosed,
supratentorial GBM prior to enrollment in Fee-For-Service (FFS) Medicare and
are seeking Medicare coverage of TTFT, coverage will be provided if all of the
following coverage requirements are met:

  1. The beneficiary has been receiving TTFT following initial maximal debulking surgery (if feasible) followed by chemotherapy/radiotherapy for histologically confirmed newly diagnosed GBM; and,

  2. Clinical Evaluation - Following enrollment in FFS Medicare, the beneficiary must have an in-person evaluation by their treating practitioner who documents in the beneficiary's medical record that:

    1. The beneficiary is adherent with the use of TTFT for an average of 18 hours per day; and,

    2. The beneficiary is deriving benefit from the therapy.

If all of the above are not met, the claim will be denied as not reasonable
and necessary.

  
GENERAL

A Standard Written Order (SWO) must be communicated to the supplier before a
claim is submitted. If the supplier bills for an item addressed in this policy
without first receiving a completed SWO, the claim shall be denied as not
reasonable and necessary.

For Durable Medical Equipment, Prosthetics, Orthotics and Supplies (DMEPOS)
base items that require a Written Order Prior to Delivery (WOPD), the supplier
must have received a signed SWO before the DMEPOS item is delivered to a
beneficiary. If a supplier delivers a DMEPOS item without first receiving a
WOPD, the claim shall be denied as not reasonable and necessary. Refer to the
LCD-related Policy Article, located at the bottom of this policy under the
Related Local Coverage Documents section.

For DMEPOS base items that require a WOPD, and also require separately billed
associated options, accessories, and/or supplies, the supplier must have
received a WOPD which lists the base item and which may list all the
associated options, accessories, and/or supplies that are separately billed
prior to the delivery of the items. In this scenario, if the supplier
separately bills for associated options, accessories, and/or supplies without
first receiving a completed and signed WOPD of the base item prior to
delivery, the claim(s) shall be denied as not reasonable and necessary.

An item/service is correctly coded when it meets all the coding guidelines
listed in CMS HCPCS guidelines, LCDs, LCD-related Policy Articles, or DME MAC
articles. Claims that do not meet coding guidelines shall be denied as not
reasonable and necessary/incorrectly coded.

Proof of delivery (POD) is a Supplier Standard and DMEPOS suppliers are
required to maintain POD documentation in their files. Proof of delivery
documentation must be made available to the Medicare contractor upon request.
All services that do not have appropriate proof of delivery from the supplier
shall be denied as not reasonable and necessary.

Support for TTFT in the treatment of newly diagnosed GBM stems from a study by
Stupp et al. (2017), also referred to as the EF-14 study. The EF-14 study was
a randomized, open-label trial of 695 patients with histologically-confirmed
glioblastoma multiforme (World Health Organization (WHO) grade IV astrocytoma)
whose tumor was resected or biopsied and had completed concomitant
radiochemotherapy and TTFT. Of the 695 randomized patients, 637 (92%)
completed the trial. Median progression-free survival from randomization was
6.7 months in the TTFT-temozolomide group vs 4.0 months in the temozolomide-
alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival
was 20.9 months in the TTFT-temozolomide group vs 16.0 months in the
temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic
adverse events were similar between the two study arms. Mild to moderate skin
toxicity underneath the transducer arrays occurred in 52% of patients who
received TTFT-temozolomide vs no patients who received temozolomide alone.

The _National Comprehensive Cancer Network_ assigns TTFT a Category 1
recommendation as a treatment option for newly diagnosed GBM, following
initial maximal debulking surgery (when feasible), chemotherapy, and radiation
therapy.

_Background_

Glioblastoma, also known as glioblastoma multiforme (GBM) is an aggressive
type of brain cancer. It is rare, with an incidence of 3.21 cases per 100,000
population per year in the US.

Alternating electric fields are produced by a pulse generator and transmitted
by ceramic transducers placed on a patient's head. Tumor Treatment Field
Therapy (TTFT) uses alternating electric fields to target cancer cells. The
electric fields reportedly attract and repel charged proteins during cancer
cell division. Cellular proteins, because they are highly polarized, are
presumed to be prevented from moving to their correct locations thus
disrupting cancer cell division.

**NEWLY DIAGNOSED GBM**

In October 2015 the FDA expanded the marketing indications for TTFT to include
newly diagnosed GBM (see
<https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P100034S013>).
In 2018 the DME MACs received a request to cover TTFT for newly diagnosed GBM.

_Contractor Advisory Committee (CAC)_

Following an independent review of the literature, the DME MACs assembled a
13-member specialty-focused CAC, comprised of a national panel of neuro-
oncologists, neurosurgeons and experts in the field of oncologic treatment.
The CAC meeting was held on March 6, 2019 in Baltimore, Maryland. Five (5) Key
Questions were discussed by the CAC members, and confidence in each Key
Question scored (Chair and Industry Representative were excluded from
scoring). Confidence was rated on a scale of 1-5, with 1 indicative of low
confidence and 5 indicating high confidence.

The following is a summary of the CAC Panel scoring for each Key Question and
the related discussion.

****1.****

|

**How confident are you that there is sufficient evidence to determine that
TTFT for newly diagnosed GBM can provide net positive health outcomes in the
Medicare-eligible population?**

_ _

|

**Scoring Member**

**Average**  
---|---|---  
  
_1 Low Confidence -- 2 -- 3 Intermediate -- 4 -- 5 High Confidence_

| **3.82**  
  
**The members noted that both Progression Free Survival (PFS) and Overall
Survival (OS) were both increased in the EF-14 treatment arm, and migrated
together, for both Medicare age eligible and non-eligible populations, in
spite of the small group of the latter. Comments were made as to what
constitutes adequate PFS and OS, and there was acknowledgement that additional
months of improved quality of life in a disease such as GBM is a desirable
outcome.**

**Several substantial concerns were raised in regard to net positive health
outcomes. Two were related to study design, one to the philosophical approach
to assessment of a new technology, and one to concerns related to conflicts of
interest. In spite of the relative consensus on the goodness of metrics to
reflect positive health outcomes, significant concerns were expressed at the
study design, lack of sham control group and data gaps regarding volume of
study subjects, subset analyses and the lack of corroborative additional
clinical study. There was also discussion but not consensus as to whether or
not the bar should be higher for net positive health outcomes for such a new
technology. Additional concerns were related to the lack of clarity regarding
clinical mechanism of action and concerns regarding delivery and dose effect,
and geographical localization of the treatment field. Concerns related to
potential conflict of interest in study funding and analyses were also
discussed.**  
  
****2.****

| **How confident are you that the available evidence demonstrates adequate
predictors of success in Medicare-eligible population?** |

**Scoring Member**

**Average**  
  
_1 Low Confidence -- 2 -- 3 Intermediate -- 4 -- 5 High Confidence_

| **3.45**  
  
**When considering this question, there was repeated discussion of volume and
data gaps. The most substantial concern revolved around the smallness of the
Medicare age eligible subpopulation. There was consensus that predictors of
response in the age eligible Medicare population were sparse.**  
  
****3.****

| **How confident are you that TTFT is generally accepted by the medical
community for newly diagnosed GBM?** |

**Scoring Member**

**Average**  
  
_1 Low Confidence -- 2 -- 3 Intermediate -- 4 -- 5 High Confidence_

| **2.91**  
  
**This question generated the most concerns regarding how the standard of care
was established, how the provider community was defined and segmented, and
what conflicts may contribute to drive adoption. There was consensus that
guidelines are just one factor in the determination as to whether TTF is
generally accepted in the medical community.**

**In balance the group did think that regardless of how practitioners were
notified of the availability of TTF for GBM, there was broad superficial
penetration in the USA community, but that its acceptance as standard of care
or generally accepted practice was not clear.**  
  
****4.****

| **How confident are you that scientific evidence supports mitotic spindle
disruption and cellular apoptosis as the mechanism of action of TTFT?** |

**Scoring Member**

**Average**  
  
_1 Low Confidence -- 2 -- 3 Intermediate -- 4 -- 5 High Confidence_

| **3.27**  
  
**There was discussion here as to the lack of actual human data to demonstrate
the mechanism of action, but consensus that there was a plethora of
preclinical data did uniformly seem to demonstrate mitotic spindle disruption
and apoptosis as a mechanism of action of tumor cell death.**  
  
****5.****

| **How confident are you that there are no significant evidence gaps that may
impact positive health outcomes in the Medicare-eligible population?** |

**Scoring Member**

**Average**  
  
_1 Low Confidence -- 2 -- 3 Intermediate -- 4 -- 5 High Confidence_

| **2.91**  
  


**There was consensus in the group that there remained significant gaps in
evidence that the CAC members would like to see explored, either through
controlled trials or in a real world evidence study paradigms. There was
consensus that more data is needed to identify the place of TTFT in therapy
across a more broad range of patient population and within the treatment
algorithm for GBM and to further explore its mechanism of action, prognostic
features, and predictors of response.**

**There was discussion of the need to review the evolving evidence rapidly
since the standard of care evolves so rapidly in this area. There was
consensus that more data is needed to identify the place of TTFT in therapy
across a more broad range of patient population and within the treatment
algorithm for GBM and to further explore its mechanism of action, prognostic
features, and predictors of response. Specific additional areas recommended
for study included:**

  * **Dose density and power**
  * **Demographic diversity of subjects**
  * **Prognostic indicators**
  * **Impact on caretakers**
  * **More on quality of life**
  * **Medical economic assessment**
  * **The best sequencing of treatment including where in the algorithm is TTFT best placed**
  * **Exploration of the human mechanism of action**

  
  


CONCLUSION

The use of TTFT for the treatment of newly diagnosed GBM appears to be gaining
acceptance in the neuro-oncology community in the United States. The coverage
requirements outlined above reflect the currently published literature with
regard to criteria that best ensure optimal outcomes for Medicare
beneficiaries with newly diagnosed GBM.

**RECURRENT GBM**

In April 2011 the Food and Drug Administration (FDA) approved the marketing of
the NovoTTF-100A (later rebranded Optune) for the treatment of recurrent GBM.
The original LCD for TTFT was effective in August 2014, following an Open
Meeting and solicitation of public comments. The DME MACs determined that,
based on the strength and quality of the evidence available at that time, TTFT
was not reasonable and necessary for the treatment of GBM.

In 2018 the DME MACs received a request to reconsider the decision on
recurrent GBM. The requestor, Novocure, did not submit new evidence in support
of revised coverage for recurrent disease. Consequently, pursuant to Chapter
13 of the CMS _Program Integrity Manual_ (CMS Pub. 100-08), the DME MACs
determined that the request was invalid.