A summary of ECRI Institute’s Emerging Technology Evidence Report
Glioblastomas are the most common form of malignant primary brain tumor in adults, and they compose approximately 16 percent of all brain and central nervous system tumors and about 54 percent of all tumors that arise from glial cells. Glioblastomas are grade IV astrocytomas, the most deadly type of glial cell tumor, and are often resistant to standard chemotherapy.
This report assesses tumor treating fields therapy, a new option for treating recurrent glioblastoma that is no longer responding to chemotherapy. Second-line treatments include debulking surgery with or without local chemotherapy, focal radiation therapy, bevacizumab, bevacizumab plus systemic chemotherapy, single-agent or combination systemic chemotherapy and palliative care.
Tumor treating fields therapy is intended to directly target proliferating cells with low-intensity and intermediate-frequency alternating electric fields. Purportedly, this type of electric field selectively inhibits tumor growth because the electric fields are believed to affect only dividing cells, which are found at high levels in tumor tissues. A proposed benefit of tumor treating fields therapy is that it offers a noninvasive alternative to chemotherapy for recurrent glioblastoma with fewer treatment-related adverse events.
The U.S. Food and Drug Administration (FDA) approved tumor treating fields therapy (i.e., NovoTTF-100A System, Novocure) as a monotherapy for recurrent glioblastoma. The system uses four insulated transducer arrays placed on the patient’s shaved scalp directly over the tumor site and connected to a portable six-pound generator, which delivers the therapy 20 to 24 hours per day. Patients carry the system in a backpack or shoulder bag to receive therapy as an outpatient during daily activities.
Our key questions are:
Is tumor treating fields therapy as effective as other treatment options for recurrent glioblastoma (i.e., debulking surgery with or without local chemotherapy, focal radiation therapy, bevacizumab, bevacizumab plus systemic chemotherapy, single-agent or combination systemic chemotherapy) with regard to overall survival, time to disease progression, progression-free survival, and quality of life?
Data to address this question came from the premarketing approval trial and submission to FDA. This randomized controlled trial (RCT) compared the safety and effectiveness of tumor treating fields therapy (n = 120 patients) to best standard chemotherapy (BSC) (n = 117 patients) for treating recurrent glioblastoma. This RCT was designed to evaluate superiority; however, results indicated that no statistically significant between-group differences were observed for any outcome measured: median overall survival, time-to-disease progression, and progression-free six-month survival. Patients receiving tumor treating fields therapy were reported to have scored higher on certain quality of life questionnaires than patients receiving best standard chemotherapy; however, whether these were statistically significant between-group differences was not reported and could not be calculated by ECRI Institute because specific data were not reported.
How does tumor treating fields therapy plus palliative therapy compare to palliative therapy alone for treating recurrent glioblastoma with regard to overall survival, time to disease progression, progression-free survival, and quality of life?
No studies addressed this key question. Designing a trial that compares a therapy to palliative care for treating recurrent glioblastoma may create ethical concerns.
How does tumor treating fields therapy compare to other treatments for recurrent glioblastoma with regard to adverse events?
The RCT that constituted the data for the FDA submission provided this evidence. Investigators reported that the overall percentage of patients with adverse events, serious adverse events, and treatment-emergent serious adverse events were not significantly different between groups. However, the systemic chemotherapy group experienced significantly more nausea, diarrhea, abdominal pain, muscle weakness, alopecia, anorexia, and urinary tract infections than the tumor treating fields therapy group, and the tumor treating fields therapy group experienced significantly more skin site reactions, falls, and rashes than the systemic chemotherapy group. The BSC group experienced significantly more severe or life-threatening hematologic adverse events than the tumor treating fields therapy group; however, differences between the treatment groups for all other major adverse events were not statistically significant.
What adverse events are reported in studies of tumor treating fields therapy?
The most common adverse event associated with tumor treating fields therapy was skin reaction at the transducer array site. Other adverse events reported in the RCT included headache, malaise, muscle twitching, fall, and skin ulceration. Also, about a quarter of the patients discontinued treatment early (often within a few days) because of nonadherence or inability to handle the device.
FDA is requiring Novocure to conduct a postmarket study to assess whether the overall survival of patients receiving the treatment is similar to that of patients receiving best standard chemotherapy. The study will be conducted in at least 30 sites, half of which are in the United States. The postmarket study will enroll 243 patients in each study arm.
Delivery of tumor treating fields therapy costs about $19,500/month. Our searches of 11 major private, third-party payers that publish their policies online found 2 major payers that have policies denying coverage for tumor treating fields therapy as “experimental and investigational” (Aetna, Anthem) and nine payers without a specific policy for this therapy. Third-party payers are providing coverage case-by-case through medical necessity review. Patients are responsible for cost-sharing according to their durable medical equipment benefit. The Musella Foundation for Brain Tumor Research and Information has established a copayment assistance program for patients receiving tumor treating fields for recurrent glioblastoma. Patients living in the United States and meeting certain income requirements may receive up to $5,000 per year for the treatment.
In the United States, tumor treating fields therapy is offered only as a monotherapy for recurrent glioblastoma at 15 clinical centers of excellence in which clinicians have undergone training in the use of the NovoTTF-100A device. As of June 2012, the company reports that more than 300 patients have received tumor treating fields therapy.
STATE OF EVIDENCE BASE
Quantity of evidence: Low.
The data come from a multicenter, randomized controlled superiority trial that compared the safety and effectiveness of tumor treating fields therapy (n = 120 patients) to best standard chemotherapy (n = 117 patients). Another trial is under way that may provide additional data on outcomes of interest.
Quality of evidence: Low.
The only randomized controlled superiority trial that assessed this technology was not designed to address whether tumor treating fields therapy yields similar outcomes to other treatment options because it was designed as a superiority trial. No data were available to address a comparison to palliative care or other third-line treatment modalities (i.e., radiation, surgery, combination therapy). Detailed quality-of-life data (i.e., actual scores, statistics) were not reported. The best standard chemotherapy protocols reported in the randomized controlled trial may not reflect current practice, since bevacizumab has likely been used for treating a majority of U.S. patients with recurrent glioblastoma since 2009.
Consistency of evidence: Low.
Although the results suggest that tumor treating fields therapy outcomes are not statistically different from best standard chemotherapy outcomes, having only one study prevents assessment of consistency across studies.
Excerpted with permission from ECRI Institute’s database of Health Technology Forecast Reports. To download the full report, visit www.ecri.org/managedcare .
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MANAGED CARE December 2012. ©MediMedia USA