Abstract
Glioblastoma is both the most common and most lethal primary CNS malignancy in adults, accounting for 45.6% of all malignant CNS tumors, with a 5-year survival rate of only 5.0%, despite the utilization of multimodal therapy including resection, chemotherapy, and radiation. Currently available treatment options for glioblastoma often remain limited, offering brief periods of improved survival, but with substantial side effects. As such, improvements in current treatment strategies or, more likely, the implementation of novel strategies altogether are warranted. In this topic review, the authors provide a comprehensive review on the potential of alternating electric fields (AEFs) in the treatment of glioblastoma. Alternating electric fields-also known as tumor-treating fields (TTFs)-represent an entirely original therapeutic modality with preliminary studies suggesting comparable, and at times improved, efficacy to standard chemotherapeutic agents in the treatment of recurrent glioblastoma. A recent multicenter, Phase III, randomized clinical trial comparing NovoTTF-100A monotherapy to physician's best choice chemotherapy in patients with recurrent glioblastoma revealed that AEFs have similar efficacy to standard chemotherapeutic agents with a more favorable side-effects profile and improved quality of life. In particular, AEFs were shown to have limited systemic adverse effects, with the most common side effect being contact dermatitis on the scalp at the sites of transducer placement. This study prompted FDA approval of the NovoTTF-100A system in April 2011 as a standalone therapy for treatment of recurrent glioblastoma refractory to surgical and radiation treatment. In addition to discussing the available clinical evidence regarding the utilization of AEFs in glioblastoma, this article provides essential information regarding the supposed therapeutic mechanism as well as modes of potential tumor resistance to such novel therapy, delineating future perspectives regarding basic science research on the issue.
Highlights
Primary and metastatic brain tumors comprise a heterogeneous group of CNS malignancies, varying in histological features,[7] phenotypic presentation,[5] cell origin, and tumor grade as designated by the WHO.[38]
Temozolomide may cause lymphocytopenia leading to opportunistic infection,[32] with some patients requiring prophylaxis against pneumonia by Pneumocystis carinii when chemotherapy is given in combination with radiation therapy
alternating electric fields (AEFs) therapy in these cases resulted in long-term survival benefits, including anecdotal reports of patients with glioblastoma or recurrent glioblastoma treated with AEF monotherapy who did not require any further follow-up therapy for approximately 6–7 years
Summary
Electric fields are forces capable of acting on charged particles, creating characteristic movements dependent on the strength of the applied field and the magnitude of the charged particle upon which they act. In the setting of AEFs, these charged molecules oscillate at a rate dependent on the frequency, intensity, and vector of the applied electric field.[4] If this field is nonuniform, dielectric molecules can become suspended along the electric fields and separate from each other, a phenomenon known as dielectrophoresis.[17]. The precise molecular effects of AEFs still remain under investigation, the most accepted pathophysiological explanation regarding their therapeutic effects on cancer relies on the effects of the AEFs upon the molecular machinery responsible for mitosis, the microtubules. These components of the cytoskeleton are composed of tubulin subunits, consisting of globular proteins with substantial polarity that guide chromosomal
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