Application of 200 kHz Tumor Treating Fields (TTFields) in Patients With Infratentorial High-Grade Glioma: Case Series

Abstract

Tumor treating fields (TTFields) therapy at 200 kHz is FDA-approved for supratentorial glioblastoma. However, reports of TTFields in patients with infratentorial high-grade glioma (HGG) are rare. Two patients with infratentorial HGG received off-label 200 kHz TTFields. To reduce impaired neck range of motion, the electrode transducer arrays were “skeletonized” by cutting a portion of the adhesive material. The electrode arrays were applied with the neck in flexion to further promote range of neck motion. Patient 1, a 22-year-old man with high-grade diffuse pontine glioma with recurrences and prior treatments, tolerated TTFields combined with systemic treatment (initially with a bifunctional DNA alkylating agent; subsequently with temozolomide and bevacizumab) for 5 months with stable disease for 4 months. He experienced grade 1 rash (neck). Patient 2, a 58-year-old woman with diffuse glioma of the brainstem (H3K27M-mutated) with multiple recurrences and prior treatments, tolerated TTFields combined with systemic treatment (lomustine and bevacizumab). With the TTFields + systemic combination therapy, the patient was stable for 8 months with no TTFields-related side effects. We provide two initial post-marketing cases demonstrating that off-label use of 200 kHz TTFields in infratentorial HGG is safe and feasible. Prospective studies are necessary to validate the efficacy of this approach.

INTRODUCTION

Tumor treating fields (TTFields) therapy is the most recent FDA-approved therapy for patients with supratentorial glioblastoma. This form of treatment utilizes alternating low-intensity electric fields to disrupt the growth and progression of tumors through various mechanisms [1,2]. When used as a standalone treatment, 200 kHz TTFields have been shown to be noninferior to physician’s best choice chemotherapy in patients with recurrent supratentorial glioblastoma [3]. Furthermore, 200 kHz TTFields combined with monthly adjuvant temozolomide was shown to extend median overall survival in patients with newly-diagnosed supratentorial glioblastoma by 4.9 months, compared to temozolomide alone; the 5-year survival rate was also increased from 5% to 13% [4,5]. These clinical trial findings have been validated in the real-world clinical setting, in patients with recurrent [6] and newly-diagnosed [7,8] supratentorial glioblastoma. TTFields therapy has also been FDA-approved for use in patients with malignant pleural mesothelioma [9] and non-small cell lung cancer [10]. More recently, phase 3 clinical trials of TTFields in patients with locally advanced pancreatic adenocarcinoma [11] or brain metastases from non-small cell lung cancer [12] have demonstrated significantly prolonged overall survival.

TTFields for glioblastoma are applied via four adhesive electrode transducer arrays that are attached to the shaved scalp, thereby creating two pairs of electrodes, or two directions of electric fields therapy [13]. Likewise, for thoracic or abdominal malignancies, the electrode transducer arrays are placed on the skin over the site of disease. Since the approval of TTFields for supratentorial glioblastoma, they have been investigated for off-label use. For example, Oberheim-Bush et al. [14] reported that TTFields were tolerable and safe in 156 glioblastoma patients with ventriculoperitoneal shunt. The application of TTFields for infratentorial glioblastoma has not been well-studied, particularly given the anatomical differences of the occiput and neck compared to the cranium. A patent exists for delivering TTFields to the infratentorial brain [15]. Furthermore, proposed layouts for electrode transducer array placement for infratentorial tumors [16] and computational models for the same [17] have been reported (Fig. 1). Based on computational modeling, the therapeutic field intensity (approximately 1 V/cm peak-to-peak) is thought to be achievable for infratentorial high-grade glioma (HGG) [17].

Fig. 1. Tumor treating fields (TTFields) electrode transducer array layouts for supratentorial (top row) and infratentorial (bottom row) high-grade glioma. Top row: Standard supratentorial layout. Bottom row: Arrows represent modifications to supratentorial layout that result in infratentorial layout. Adapted from Riley et al. J Vis Exp 2019;(146):e58937 [13], with permission from JoVE (Journal of Visualized Experiments).

MATERIALS AND METHODS

Patients were identified via institutional review board (IRB)-approved protocols at The University of Texas MD Anderson Cancer Center (2012-0441) and The University of Oklahoma Health Sciences Center (770630-10195). All participating patients provided informed consent in accordance with IRB guidelines. Informed consent for publication of these cases was obtained from the patients in this study. Two patients with infratentorial HGG received off-label 200 kHz TTFields therapy with the Optune Gio device (Novocure, Ltd.). To reduce impaired range of motion of the neck, the electrode transducer arrays were “skeletonized” (Fig. 2) by cutting a portion of the adhesive material surrounding them. Application of the electrode arrays was performed with the neck in flexion, to further promote neck range of motion. Cloth tape was used for reinforcement as necessary. Electrode arrays were changed every 2–3 days. We report the results of patient survival and adverse events.

Fig. 2. “Skeletonization” of the tumor treating fields (TTFields) electrode transducer arrays for application in patients with infratentorial high-grade glioma. A: Back view of array, showing the intact wiring (vertical and horizontal), with the horizontal wire wrapped in the cut-out “scrap material.” B: Front view of array, demonstrating that the array material was cut out in a manner that allowed for a border of adhesive bandage to remain around the individual electrodes. C: Zoomed-in view, showing that the array material was cut out in a manner that allowed for a border of adhesive bandage to remain around the individual electrodes. No wires or discs were cut or trimmed during this process, only adhesive material. The skeletonization is intended to allow greater mobility of the patient’s neck improving their quality of life and ability to function in the real world. External tape was added dependent on the patient’s comfort and need for adherence of the array layout.

RESULTS

Patient 1 is a 22-year-old man with high-grade diffuse pontine glioma with recurrences and prior treatments (radiation, temozolomide, lomustine, and dopamine receptor D2 [DRD2] antagonist). He tolerated TTFields combined with systemic treatment (initially with a bifunctional DNA alkylating agent; subsequently with temozolomide and bevacizumab) for 5 months with stable disease for 4 months. He experienced grade 1 rash (neck). Fig. 3 demonstrates the application of the electrode transducer arrays. Fig. 4 shows Patient 1’s brain MRI scans over time.

Fig. 3. Tumor treating fields (TTFields) electrode transducer array layout in Patient 1 with recurrent high-grade diffuse pontine glioma. Superior (left panel), posterior (middle panel), and lateral (right panel) views of the 200 kHz TTFields electrode transducer layout in Patient 1. Grade 1 rash of the neck was relieved with fluocinolone.

Fig. 4. Brain MRI scans of Patient 1 with recurrent high-grade diffuse pontine glioma. T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences (left side) and T1-weighted post-contrast sequences (right side) at baseline (A), 3 months on therapy (B), and 6 months on therapy (C). Concomitant therapy with 200 kHz tumor treating fields (TTFields) included a bifunctional DNA alkylating agent initially, followed by temozolomide and bevacizumab. The patient had stable disease for 4 months. The patient died 6 months after initiation of TTFields.

Patient 2 is a 58-year-old woman with diffuse glioma of the brainstem (H3K27M-mutated) with multiple recurrences and prior treatments (including concurrent chemoradiation with temozolomide and DRD2 antagonist). She tolerated TTFields combined with systemic treatment (lomustine and bevacizumab). The TTFields electrode transducer arrays were “skeletonized” by cutting a portion of the adhesive material surrounding them (Fig. 2).

The TTFields infratentorial layout was iteratively modified with respect to placement of the electrode transducer arrays for improved tolerability (Fig. 5). With the TTFields + systemic combination therapy, Patient 2 was stable for 8 months with no local TTFields-related side effects. Treatment was discontinued due to clinical decline with minimal radiographic changes (Fig. 6).

Fig. 5. Tumor treating fields (TTFields) electrode transducer array layout on a mannequin and in Patient 2 with multiply recurrent brainstem diffuse glioma (H3K27M-mutated). A: View of posterior electrode transducer array affixed to a mannequin. B: Left lateral view of Patient 2 wearing the 200 kHz TTFields electrode transducer layout, covered with a hat and a sweater to aid in concealing the device. The individual power cables (white) for the four electrode transducer arrays were bundled together in a dark gray fabric wrap.

Fig. 6. Brain MRI scans of Patient 2 with multiply recurrent brainstem diffuse glioma (H3K27M-mutated). Axial fluid-attenuated inversion recovery (FLAIR) and coronal T2-weighted sequences (left side) and axial and coronal T1-weighted post-contrast sequences (T1+C, right side) at baseline (A), 2 months on therapy (B), 3.5 months on therapy with improvement on T1+C sequence while on TTFields, lomustine, and bevacizumab (C), 5.5 months on therapy with worsening FLAIR signal despite stable T1+C sequence (D), and 6.8 months on therapy with further worsening FLAIR signal despite stable T1+C sequence (E). The patient died 8 months after the baseline scan (A). Reviewed by radiology, there was minimal change in the imaging, but the patient’s clinical status began to decline at the end of treatment. The patient had stable neurologic status until after the final MRI (E).

DISCUSSION

This technical note demonstrates the patient tolerability, safety, and feasibility of the application of TTFields for infratentorial high-grade glioma. The understanding of the “dose” of TTFields has evolved over time. Taking into account the two orthogonal electric fields generated by the two pairs of TTFields electrode transducer arrays, Ballo et al. [18] defined the local minimum field intensity (LMiFI, units: V/cm) and the local minimum power density (LMiPD, units mW/cm³). They defined the power loss density (P, units mW/cm³) as a representation of the energy per unit of time deposited by TTFields within the body as P=0.5×σ×E² (σ is the tissue conductivity in units of S/m, and E is the magnitude of the electric field in units of V/cm) [18]. The effective “dose” of TTFields takes into account the amount of time the patient is receiving TTFields therapy, and was defined as the local minimum dose density (LMiDD, or the product of the LMiPD and the average patient use of TTFields as derived from the logs of the Optune Gio device; units mW/cm³) [18]. Re-analyzing the data from the phase 3 EF-14 clinical trial of TTFields in patients with newly-diagnosed glioblastoma [4,5], Ballo et al. [18] found that the median overall survival and median progression-free survival were significantly longer when the mean LMiDD in the tumor bed was ≥0.77 mW/cm³. Mikic et al. [19] recently reviewed the implications of this definition of TTFields “dose” on treatment planning and optimal placement of the electrode transducer arrays to maximize dose deposition into the brain tumor.

The use of TTFields in central nervous system tumors of the posterior fossa and brainstem is an emerging area of clinical interest. At the 2024 Society for Neuro-Oncology Annual Meeting, Shi et al. [20] presented an abstract summarizing the feasibility of TTFields therapy for six brainstem glioma patients, based on a dosimetric planning evaluation. Their TTFields planning was done using the MAXPOINT planning system (Novocure Ltd.). They reported that a median LMiPD and LMiFI of 1.35 mW/cm³ and 1.3 V/cm (respectively, in the brainstem) and 2.05 mW/cm³ and 1.5 V/cm (respectively, in the posterior fossa) were predicted to be achieved [20]. These field intensities have been shown to have in vivo anti-cancer efficacy [21].

Ze’evi et al. [22] reported the delivery of TTFields to the infratentorial brain using the recently FDA-approved head flexible electrode transducer arrays. They defined four layouts, including “cross front shoulder” (in which the four arrays were placed over each shoulder blade and the top of the head, thereby creating two pairs of electric fields that intersected over the neck/brainstem area) and “cross above-ear shoulder” (in which the four arrays were placed over each shoulder blade and the side of the head above each ear, thereby creating two pairs of electric fields that intersected over the posterior fossa). They found that the “cross front shoulder” layout maximized the median LMiPD (2.89 mW/cm³) and local average field intensity (1.89 V/cm) predicted to be achieved in the brainstem, and that the “cross above-ear shoulder” layout maximized the median LMiPD (2.26 mW/cm³) and local average field intensity (2.13 V/cm) predicted to be achieved in the cerebellum [22]. By comparison, the standard layout used for supratentorial HGG (Fig. 1) was predicted to achieve a LMiPD of 0.64 mW/cm³ in the brainstem and 1.34 mW/cm³ in the cerebellum; and a local average field intensity of 1.10 V/cm in the brainstem and 1.5 V/cm in the cerebellum [22].

The potential use of TTFields for bony spinal metastasis has previously been discussed [23]. This approach would leverage the benefits of the low conductivity of bone, namely, an anticipated greater TTFields intensity achieved in the bony spine. As with the potential application of TTFields to bony spinal metastasis, the application to infratentorial tumors raises questions about the types of pathology that would most likely be amenable to TTFields therapy. TTFields has been approved at the 200 kHz frequency for patients with glioblastoma and at the 150 kHz frequency for patients with malignant pleural mesothelioma and non-small cell lung cancer. The phase 3 clinical trials of TTFields in patients with locally advanced pancreatic adenocarcinoma [11] and brain metastases from non-small cell lung cancer [12] that recently reported significant survival benefits each used 150 kHz TTFields. If TTFields were to be evaluated in patients with non-HGG infratentorial tumors (e.g., medulloblastoma, meningioma, ependymoma, chordoma, brain metastases), it remains an open question whether the FDA-approved 200 kHz or 150 kHz TTFields frequency would be used. Nitta et al. [24] reported that 300 kHz TTFields were the optimal frequency in medulloblastoma cells in vitro.

We provide initial post-marketing evidence that off-label use of 200 kHz TTFields in infratentorial HGG is safe and feasible. Prospective studies are necessary to validate the efficacy of this approach.

Availability of Data and Material

All data supporting the findings of this study are available within the manuscript.