Alternating electric tumor treating fields for treatment of glioblastoma: rationale, preclinical, and clinical studies

Abstract

OBJECTIVE Treatment for glioblastoma (GBM) remains largely unsuccessful, even with aggressive combined treatment via surgery, radiotherapy, and chemotherapy. Tumor treating fields (TTFs) are low-intensity, intermediate-frequency, alternating electric fields that have antiproliferative properties in vitro and in vivo. The authors provide an up-to-date review of the mechanism of action as well as preclinical and clinical data on TTFs. METHODS A systematic review of the literature was performed using the terms "tumor treating fields," "alternating electric fields," "glioblastoma," "Optune," "NovoTTF-100A," and "Novocure." RESULTS Preclinical and clinical data have demonstrated the potential efficacy of TTFs for treatment of GBM, leading to several pilot studies, clinical trials, and, in 2011, FDA approval for its use as salvage therapy for recurrent GBM and, in 2015, approval for newly diagnosed GBM. CONCLUSIONS Current evidence supports the use of TTFs as an efficacious, antimitotic treatment with minimal toxicity in patients with newly diagnosed and recurrent GBM. Additional studies are needed to further optimize patient selection, determine cost-effectiveness, and assess the full impact on quality of life.

Keywords: GBM = glioblastoma; LYG = life years gained; MDR = multidrug resistant; NSCLC = non–small cell lung cancer; NovoTTF-100A; OS = overall survival; Optune; PFS = progression-free survival; QALY = quality-adjusted life year; QOL = quality of life; TMZ = temozolomide; TTF = tumor treating field; TTP = time to disease progression; alternating electric fields; newly diagnosed glioblastoma; oncology; recurrent glioblastoma; tumor treating fields.

FIG. 1.

Mechanism of action of alternating electric fields on intracellular structures during mitosis. During metaphase (left), the electric field is uniform within the cell, causing tubulin subunits to align with the direction of the field and inhibiting their polymerization and hence interfering with the formation of a normal microtubule spindle. During cytokinesis (right), the electric field is nonuniform within the dividing cell and drives charged and polar macromolecules and organelles toward the high field density at the mitotic furrow. This process interferes with spindle tubulin orientation and induces dielectrophoresis, thereby disrupting mitosis and disintegrating the daughter cells. Copyright Novocure, Inc. Published with permission.

FIG. 2.

The Optune system for treatment of recurrent GBM in adults was approved by the FDA in April 2011. Patients are required to use the system for at least 18 hours daily. The system contains several transducer arrays (electrodes) that are applied directly to the shaved scalp and a battery pack that can be carried in a bag. Copyright Novocure, Inc. Published with permission.

FIG. 3.

Case illustration. A 55-year-old woman underwent resection of a right temporal GBM followed by adjuvant radiation therapy and chemotherapy (standard regimen in Stupp et al., 2012). Follow-up brain MRI after 5 cycles of TMZ showed evidence of recurrent tumor (pretreatment, upper). Repeat surgery was recommended; however, the patient refused and was very motivated to initiate NovoTTF therapy. After 6 months of continuous treatment (compliance > 80%), the patient remained neurologically stable with an improved radiological appearance of the right temporal GBM (6 months posttreatment, middle). Noncontrast and postcontrast T1-weighted MR images show decrease in size and contrast enhancement following NovoTTF treatment. The patient has remained neurologically stable after 2.5 years of therapy (30 months posttreatment, lower) with no radiological evidence of tumor recurrence. Persistent peritumoral hyperintense signal changes on T2 and FLAIR images were noted. Increased susceptibility artifact was noted along the enhancing portion of the tumor after NovoTTF therapy on susceptibility-weighted images, which has resolved on long-term follow-up. An area of increased cerebral blood volume was noted along the posterior enhancing margin of the tumor on perfusion-weighted imaging (white arrow, upper). Interestingly, after 6 months of NovoTTF therapy, perfusion analysis demonstrated an overall decreased relative cerebral blood volume in the region of the mass and surrounding parenchyma (white arrow, middle). Low perfusion remained in this area on long-term follow-up (white arrow, lower). PWI = perfusion-weighted imaging; SWI = susceptibility-weighted imaging.