Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma

Abstract

A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA approved in April 2011 for the treatment of patients 22 years or older with rGBM. The device delivers alternating electric fields and is programmed to ensure maximal tumor cell kill 1 .Glioblastoma is the most common type of glioma and has an estimated incidence of approximately 10,000 new cases per year in the United States alone 2 . This tumor is particularly resistant to treatment and is uniformly fatal especially in the recurrent setting [3][4][5] . Prior to the approval of the TTF System, the only FDA approved treatment for rGBM was bevacizumab 6 . Bevacizumab is a humanized monoclonal antibody targeted against the vascular endothelial growth factor (VEGF) protein that drives tumor angiogenesis 7 . By blocking the VEGF pathway, bevacizumab can result in a significant radiographic response (pseudoresponse), improve progression free survival and reduce corticosteroid requirements in rGBM patients 8,9 . Bevacizumab however failed to prolong overall survival in a recent phase III trial There is currently an unmet need to develop novel approaches designed to prolong overall survival and/or improve quality of life in this unfortunate patient population. One appealing approach would be to combine the two currently approved treatment modalities namely bevacizumab and TTF Therapy. These two treatments are currently approved as monotherapy 11,12 , but their combination has never been evaluated in a clinical trial. We have developed an approach for combining those two treatment modalities and treated 2 rGBM patients. Here we describe a detailed methodology outlining this novel treatment protocol and present representative data from one of the treated patients.

The Clinical Application of Tumor Treating Fields Therapy in Glioblastoma

“…A previous JoVE publication demonstrated the application of the first generation device using a plastic model of a human head 25 . Here, we demonstrate the application of the second-generation device on a glioblastoma patient undergoing treatment.…”

“…In the recurrent setting, there exists no standard treatment approach. However, bevacizumab and TTFields therapy are the two FDA-approved treatment modalities 25,26 . The EF-11 phase III trial of TTFields monotherapy (with 20-24 h/day usage) versus active chemotherapy in patients with recurrent glioblastoma showed comparable overall survival, while toxicity and quality of life favored TTFields…”

Tumour treating fields in a combinational therapeutic approach

“…These parameters being an intermediate frequency (200 kHz) with a low intensity (1–3 V/cm) for glioma cell lines [4]. The considerations of these parameters is necessary to avoid unwanted membrane depolarization of excitable cells and tissue heating [11]. However, these undesirable stimulations greatly decline when the frequency of an alternating electric field increases above 1kHz because of the excitable membranes’ hyperpolarization/depolarization cycles becoming integrated due to a membrane’s excitability response time simply being too slow to handle such high frequencies [4, 11].…”

“…The considerations of these parameters is necessary to avoid unwanted membrane depolarization of excitable cells and tissue heating [11]. However, these undesirable stimulations greatly decline when the frequency of an alternating electric field increases above 1kHz because of the excitable membranes’ hyperpolarization/depolarization cycles becoming integrated due to a membrane’s excitability response time simply being too slow to handle such high frequencies [4, 11]. Conversely, exceptionally high frequencies, within the MHz range, cause greater integration of the hyperpolarization/depolarization cycles resulting in dielectric losses – electrical heating as a result of rapidly oscillating molecules [4, 11].…”

Interaction with AEG-1 and MDM2 is associated with glioma development and progression and correlates with poor prognosis

“…It is characterized by the rapid proliferation and diffuse brain invasion which make complete tumor excision very difficult leading to low cure rates [2]. In spite of significant advances in the treatment of gliomas with surgery combination with radiotherapy and chemotherapy, the prognosis of gliomas has remained poor over the past decade with median patient survival of 12-15 months [3,4]. Therefore, investigation into the novel molecules is required to improve targeted therapeutic treatment strategies.…”