Malignant gliomas, such as glioblastoma multiforme (GBM), are infrequent, highly aggressive tumors of the nervous system. Even with maximal therapy consisting of aggressive surgery and radiation with concurrent chemotherapy followed by adjuvant chemotherapy, median survival remains at less than 18 months. Current research has focused on identifying novel agents or combinations of agents to further increase survival. Many different approaches other than chemotherapy are being used, such as small molecule targeted therapies, biologic agents, and vaccine-based therapies. Patients are increasingly seeking new directions in tumor therapy to both prolong life and increase quality of life.
In 2004, Kirson and colleagues demonstrated that low intensity electric fields applied via insulated electrodes could disrupt growth in multiple cell lines, including the rat glioma lines F-98, C-6 and RG-2, as well has the human glioma lines U-118 and U-87.1 In addition, it was shown that normal cells (non-replicating cell lines) were not adversely affected by these fields. Cell division was found to be affected in two different ways. The primary mode of cell disruption was the interruption of microtubule polymerization during the formation of the mitotic spindle. The normal protein components of the spindle are highly polarized, and the application of alternating electric fields prevents polymerization, interrupting normal spindle development. The cell cycle is arrested, and after remaining in metaphase for hours, the cell eventually disintegrates.
The other means by which cell division is disrupted is by creation of an inhomogeneous electric field as mitosis progresses. All polar molecules and macromolecules (such as DNA and chromosomes) are drawn to the narrowest point of the field, in this case the mitotic groove. As a result, mitosis collapses, and the cell undergoes apoptosis. In addition, the demonstrated tumor growth could be inhibited in mouse glioma models by the application of electric fields. No significant systemic effects were seen. The term tumor treating fields (TTF or TTFields) was coined to describe this method of applying electric fields to tumors.
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Further evidence supporting the efficacy of TTFields in inhibiting tumor growth was published by Kirson and colleagues in 2007.2 In a pilot study, 12 patients with recurrent GBM were evaluated to determine the safety of the newly designed TTF-100A device to deliver TTFields to human subjects. TTFields at 200kHz were used. Inclusion criteria were relatively standard for a recurrent GBM trial. All patients had received adjuvant temozolomide chemotherapy. No additional chemotherapy was permitted during use of the TTF-100A device. Multifocal tumors were allowed; however, patients with infratentorial tumors were excluded. Ten of the 12 patients were evaluable for efficacy (one patient was found to have non-GBM histology, and one patient withdrew consent). Patients wore the electrodes on shaved heads for at least 18 hours daily until tumor progression on imaging or a maximum of 18 months. Median time to progression (TTP) was 26.1 weeks (range, 3-124 weeks), while median overall survival (OS) was 62.2 weeks (range, 20.3-124.0 weeks). Progression-free survival at 6 months (PFS6) was 50%. One patient had a durable complete response, while one patient had a prolonged partial response. Five patients maintained stable disease for at least 4 months. The treatment was tolerated extremely well, with no Grade 3 adverse events and no changes in blood counts or chemistries. Most patients suffered mild dermatitis under the electrodes, which was easily managed with topical creams and electrode rotation.
