The Evolving Role of Tumor Treating Fields in Managing Glioblastoma: Guide for Oncologists

Abstract

Glioblastoma (GBM) is a devastating brain tumor with poor prognosis despite advances in surgery, radiation, and chemotherapy. Survival of patients with glioblastoma remains poor, with only 1 in 4 patients alive at 2 years, and a 5-year survival rate of about 5%. Recurrence is nearly universal and, after recurrence, prognosis is poor with very short progression-free survival and overall survival (OS). Various salvage chemotherapy strategies have been applied with limited success. Tumor Treating Fields (TTFields) are a novel treatment modality approved for treatment of either newly diagnosed or recurrent GBM. TTFields therapy involves a medical device and transducer arrays to provide targeted delivery of low intensity, intermediate frequency, alternating electric fields to produce antimitotic effects selective for rapidly dividing tumor cells with limited toxicity. In the phase 3 EF-14 trial, TTFields plus temozolomide provided significantly longer progression-free survival and OS compared with temozolomide alone in patients with newly diagnosed GBM after initial chemoradiotherapy. The addition of TTFields to standard therapy improved median OS from 15.6 to 20.5 months (P=0.04). In the phase 3 EF-11 trial, for recurrent GBM, TTFields provided comparable efficacy as investigator's choice systemic therapy, with improved patient-reported quality of life and a lower incidence of serious adverse events. Primary toxicity associated with TTFields is skin irritation generally managed with array relocation and topical treatments including antibiotics and steroids. TTFields therapy has demonstrated proven efficacy in management of GBM, including improvement in OS for patients with newly diagnosed GBM, and is under current investigation in other brain and extracranial tumors.

FIGURE 1

TTFields mechanism of action. The alternating electric fields interfere with mitosis leading to apoptosis and cell death. The alternating electric fields effects are interference and prolongation of cell division, and disruption of cytokinesis in rapidly dividing cells, resulting in apoptosis. Copyright Novocure, 2015. Copyright [Novocure], [Portsmouth, NH]. All permission requests for this image should be made to the copyright holder.

FIGURE 2

Survival curves for patients included in the interim analysis in the intent-to-treat population of EF-14. Kaplan-Meier curves for patients with GBM in the EF-14 trial, treated with TTFields/TMZ versus TMZ alone. (A) PFS (ITT) (B) OS. Figure adapted with permission from Stupp et al. GBM indicates glioblastoma; OS, overall survival; PFS, progression-free survival; TMZ, temozolomide; TTFields, tumor treating fields. Copyright © 2017 The Author(s).

FIGURE 3

Optune with battery, charger, arrays, and carrying case. The Optune system includes electric field generator, color-coordinated arrays, charger with spare batteries, carrying case, and power outlet adapter. This image features the second-generation Optune system, currently approved for use in Europe and in the United States. Copyright Novocure, 2016. Copyright [Novocure], [Portsmouth, NH]. All permission requests for this image should be made to the copyright holder.

FIGURE 4

Dermatological toxicity from transducer arrays. Contact dermatitis can occur from long-term use (≥6 mo) of transducer arrays. These dermatitis sequelae may or may not be symptomatic. Most adverse effects could be managed using published skin care guidelines for patients receiving TTFields. Reproduced with permission from Lacouture et al. TTFields indicates tumor Treating fields. Copyright © 2017 The Author(s).

FIGURE 5

Transducer array placement for treating patients with GBM. An array map used as guidance for optimal placement of transducer arrays on the basis of tumor size and location. The array map is personalized for each patient and generated using NovoTAL System software. The customization of the array layout is dependent on the patient’s size and location of the tumor. GBM indicates glioblastoma. Copyright Novocure, 2015. Copyright [Novocure], [Portsmouth, NH]. All permission requests for this image should be made to the copyright holder.