Tumor Treating Fields With Radiation for Glioblastoma

Abstract and Introduction

Abstract

Background and Objective: With a phase 3 clinical trial (EF-32, ClinicalTrials.gov: NCT04471844) currently underway examining the potential benefit of concurrent chemoradiation and tumor treating fields (TTFields) for patients with glioblastoma (GBM), we present the following narrative review to highlight the current evidence that supports this approach. The current management paradigm for GBM includes maximal safe surgical resection followed by concurrent chemoradiation with further temozolomide (TMZ) and TTFields used as maintenance therapy. Despite several treatment advances over the past few decades, the overall prognosis remains poor and new strategies are currently under investigation, including the use of chemoradiation concurrently with TTFields.

Methods: In this review, we will discuss the preclinical and clinical work that has been performed combining both TTFields with radiation. We performed a narrative review of peer-reviewed articles related to the management of glioblastoma with regard to concurrent chemoradiation and TTFields and synthesized the data in the context of our clinical experience and practice. PubMed, Medline, Embase, Cochrane Library, and various center-specific guidelines were searched for literature regarding concurrent chemoradiation with TTFields for patients with GBM.

Key Content and Findings: Driven by preclinical studies demonstrating the synergy between TTFields and radiation, more recent clinical work has been performed and has shown that combining treatment is both feasible and tolerable.

Conclusions: In this review, we will discuss the mechanism of action which TTFields and radiation share, as well as discuss the toxicities of combining therapy in patients with GBM. Based on institutional experiences, we will highlight treatment techniques, including scalp sparing methodology and modified computed tomography (CT) simulation workflow, when concurrent TTFields and radiation are given. Lastly, we will provide discuss management considerations, specifically scalp prophylactic interventions and treatments, when using concurrent TTFields with chemoradiation.

Introduction

Glioblastoma (GBM) is the most common subtype of primary malignant brain tumors in adults.^[1] Despite several treatment advances over the past few decades, the overall prognosis remains poor and new strategies are currently under investigation, including the use of tumor treating fields (TTFields) concurrently with chemoradiation.^[2,3]

The current management paradigm for glioblastoma (GBM) includes maximal safe surgical resection followed by concurrent chemoradiation with further temozolomide (TMZ) and TTFields used as maintenance therapy as defined by several landmark, randomized clinical trials.^[4–7] TMZ, when given both concurrently and as part of maintenance therapy, showed improvements in both progression-free survival (PFS) and overall survival (OS).^[4,5] Patients with and without O⁶-methylguanine-DNA-methyltransferase (MGMT) silencing, a prognostic indicator, benefit with receipt of TMZ, although with more improved results in the methylated subgroup.^[8] Although initially approved for the treatment of recurrent and refractory GBM, TTFields soon became a part of maintenance therapy based on the significant improvements in PFS and OS observed in patients receiving concurrent chemoradiation.^[6,7] TTFields uses low-intensity, intermediate frequency (200 kHz) alternating electric fields to disrupt cellular processes including proliferation and replication.^[9,10] Due to the significant benefit observed with maintenance TTFields, several preclinical and clinical studies have investigated whether concurrent treatment offers a synergistic and feasible strategy. Given the growing evidence showing safety of combining radiation with TTFields in patients with GBM, as well as the currently enrolling phase 3, randomizing clinical trial (EF-32; NCT04471844) aimed at determining the clinical benefit of this approach, we have put together the following narrative review to highlight the work that has been done in this space.

In this review, we will discuss the preclinical work which demonstrates the complexity of the mechanisms by which TTFields operates and the significant interplay between TTFields and radiotherapy. We will review the clinical studies that have been performed which demonstrate the safety and feasibility of utilizing a combination approach. Lastly, we will review treatment techniques, including scalp sparing methodology and modified computed tomography (CT) simulation workflow. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-22-90/rc).

Table 1. Methods for selection of literature included in this review
Items	Specification
Date of search	August 1, 2022
Databases and other sources searched	PubMed, Medline, Embase, Cochrane Library, center-specific guidelines
Search terms used	TTFields, tumor treating fields, glioblastoma, concurrent therapy, radiotherapy, preclinical, clinical, scalp, toxicity, feasibility, safety
Timeframe	All studies obtained were from 2000–current
Inclusion and exclusion criteria	All studies included were available in English language. Clinical studies involving concurrent TTFields with radiation must have explicitly stated that both treatments were provided at the same time
Selection process	All authors contributed and reviewed the selected literature

Table 2. Pros and cons of delivering radiation treatment with and without TTFields arrays in place
Pros/cons	Radiation with TTFields arrays in place	Radiation with TTFields arrays off at time of treatment
Pros	Minimize interruption leads to better synergy with radiation	No bolus effect at time of treatment
	Minimize physical scalp injury or irritation with daily array changes	No radiation dosimetry changes
	Compliance improved with less frequent changing	No radiation workflow changes
		IGRT more straightforward
Cons	Dosimetric considerations (bolus effect increases scalp dose, mild/negligible PTV dosimetry changes)	Daily array removal may lead to physical scalp injury
	Need modification of standard radiation simulation workflow	Interruption of treatment leads to loss of optimal synergy with radiation
	Imaging artifact on CBCT image guidance, requiring kV-kV imaging guidance	Potential for poorer compliance and reduced daily usage