FDA approves use of RF EMF to treat brain cancer
New Device Attacks Brain Tumors
Novocure Announces Optune as the New Name for theNovoTTF-100A System
... The U.S. Food and Drug Administration (FDA) has approved Optune for use as a treatment for adult patients (22 years of age or older) with histologically- confirmed GBM, following histologically – or radiologically-confirmed recurrence in the supra-tentorial region of the brain after receiving chemotherapy.
Optune (NovoTTF-100A System): Instructions for Use
Indications for Use
Optune™ (NovoTTF™-100A System) is intended as a treatment for 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.
Principles of Operation
Optune produces alternating electrical TTFields within the human body that are inferred to disrupt the rapid cell division exhibited by cancer cells, with the alternating electrical fields applied to the brain through transducer arrays placed on the scalp.
Optune harnesses alternating electric TTFields to arrest the proliferation of tumor cells and to destroy them. The TTField technology takes advantage of the special characteristics and geometrical shape of dividing cells, which make them susceptible to the effects of the alternating electric TTFields. These special fields alter the tumor cell polarity at an intermediate frequency (on the order of 100–300 kHz). The frequency used for a particular treatment is specific to the cell type being treated (eg, 200kHz for GBM).
In contrast, the TTFields have not been shown to have an effect on cells that are not undergoing division. Since most normal adult brain cells proliferate very slowly, if at all, they are hypothesized to be little affected by the TTFields. Testing demonstrates no differences between treated and control animals in histology of the major internal organs (including the brain), blood examination, cardiac rhythm, body temperature, or in animal behavior. In addition, because the fields alternate so rapidly, they have no effect on normal quiescent cells nor do they stimulate nerves and muscles. It is noted that, because TTFields are only applied to the brain, they have no effect on rapidly proliferating cells in the rest of the body. The intensities of the electric fields within the tissues are very small and do not result in any meaningful increase in tissue temperature. Thus, TTField application has the advantage of being highly selective and is not expected to be associated with significant toxicity.
The above mechanisms of action are consistent with the extensive research regarding the effects of TTFields. These results demonstrate both disruption of cell division up to complete cessation of the process, as well as complete destruction of the dividing cells. It is important to note that all the described effects can be obtained by fields of low intensity such that they are not accompanied by any significant elevation of temperature.
TTFields have been shown both in vitro and in vivo to effectively inhibit cancer cell replication during mitosis without any systemic side effects. At intensities of approximately 1 V/cm, TTFields can be frequency–tuned to effectively inhibit different cancer cell types (ie, the smaller the cell, the higher the frequency needed), due to disruption of microtubule polymerization and physical disruption of cell integrity at the cleavage plane during telophase2.
Specifically, TTFields have been shown to inhibit glioblastoma cells in vitro and in vivo at a frequency of 200 kHz and an intensity of 0.7 V/cm. Based on realistic finite element mesh simulations and direct measurements of TTFields intensity in experimental animals, and in the human brain, Novocure has concluded that effective TTField intensities can be generated in the brains of large animals and humans. Extensive safety studies in healthy animals (mice, rats and rabbits) have shown that TTFields are not associated with significant systemic toxicities. Neither acute, nor chronic systemic toxicities were seen when TTFields were applied to the torso or head, at different frequencies (100–200 kHz), different intensities and for different periods of time3.
Using a model developed to simulate the growth kinetics of a malignant tumor, the minimal treatment course duration for Optune has been determined to be approximately 4 weeks to reach tumor stabilization. Stopping treatment prior to completion of a 4 week treatment course will most likely lead to continued tumor growth and appearance of symptoms within approximately 1–2 weeks.
Study Design: The study was a prospective, randomized, open label, active parallel control trial to compare the effectiveness and safety outcomes of recurrent GBM subjects treated with Optune to those treated with an effective best standard of care (BSC) chemotherapy (including bevacizumab).
The following were the objectives of the study:
- To prospectively compare the median overall survival of recurrent GBM subjects treated with Optune to those treated with best standard of care (BSC)
- To prospectively determine PFS6, TTP, %1-year survival and quality of life of subjects treated with Optune compared to BSC.
- To collect evidence of the safety of TTFields applied to subjects with recurrent GBM using Optune.
Primary Effectiveness Endpoint: Overall survival (OS)
In the ITT population which included all randomized subjects (Optune=120, BSC=117), overall survival in subjects treated with Optune was comparable to that observed in subjects treated with BSC (median OS=6.3 vs. 6.4 months; p=0.98). In the US, the median overall survival was 6.1 vs. 5.3 months in the ITT population. The pivotal study data establish that treatment with Optune is comparable to BSC therapy in extending OS.
Correlation between Treatment Compliance and Overall Survival: Optune has an internal log file which allows the calculation of subject compliance with treatment. Higher overall survival was observed in Optune subjects who were treated 75% or more of the time on average (OS=7.7 months) compared to subjects treated less than 75% of the time on average (OS=4.5 months).
Secondary Effectiveness Endpoints: Secondary endpoint results support the findings in the primary endpoint. The one-year survival is similar in the Optune and BSC groups in the ITT population (21.9% vs. 22.1%). Progression free survival at 6 months (PFS6) is the same in the ITT population (21.4% vs. 15.2%). Radiological response rates from the subset of patients evaluated were reported as 14% for the Optune group compared to 9.6% for the BSC group in the ITT population. Median time to progression (TTP) was 9.3 weeks for Optune vs. 9.6 weeks for BSC.
Quality of Life: Quality of life in subjects using Optune was better than those on BSC chemotherapy in most subscale domains, including vomiting, nausea, pain, diarrhea, constipation, cognitive and emotional functioning.
Optune is a portable, battery operated device which delivers TTFields to patients with recurrent GBM. The results of the pivotal trial showed that Optune subjects had comparable overall survival to subjects receiving the best available chemotherapy in the US today (OS 6.3 vs. 6.4 months; HR 1.0; p=0.98). Similar results showing comparability of Optune to BSC chemotherapy in the ITT population were seen in all secondary endpoints. Optune subjects experienced fewer adverse events in general, significantly fewer treatment related adverse events, and significantly lower gastrointestinal, hematological and infectious adverse events compared to BSC controls. The only device-related adverse events seen were a mild to moderate skin irritation beneath the device transducer arrays, which was easily treated with topical ointments. Finally, certain quality of life measures were better in Optune subjects as a group when compared to subjects receiving
effective BSC chemotherapy
Joel M. Moskowitz, Ph.D., Director
Center for Family and Community Health
School of Public Health
University of California, Berkeley
Electromagnetic Radiation Safety
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