Tumor treating fields: a new treatment for glioblastoma

Abstract

Glioblastoma (GBM) is a fatal type of brain tumour. According to the World Health Organization (WHO) classification of 2021, GBMs have WHO grade 4 and are usually associated with a poor prognosis. Since GBMs show a pronounced infiltrative growth, a cure by complete resection of the tumor is unfortunately not possible. Both systemic and locoregional therapy methods are traditionally used and tested to improve the prognosis. A new method that is intended to prolong the progression-free survival is using electromagnetic alternating fields, the so-called tumor treating fields (TTF). This method is based on alternating electrical fields that act on the shaved scalp. The aim is to disrupt cell division and organization of cell organelles. In this review, we discuss the mechanism of TTF, summarize the results of our comprehensive literature search, and discuss potential of this new anti-cancer treatment modality.

Keywords:

• glioblastoma
• therapy
• tumor treating fields
• TTF

Introduction

Glioblastoma (GBM) is one of the most aggressive cancers that originate in the brain. It occurs with an incidence of about 3–4 per 100,000 people [1,2]. Treatment relies on surgical reduction of the tumor mass, radiation and chemotherapy. A definitive cure cannot be achieved at this time. The average survival time is a few months without treatment and around 15 months with current therapy methods [1]. The symptoms of a GBM depend to a greater extent on its size and location than on the pathological features. The symptoms typically range from seizures, headaches, nausea and vomiting, memory loss; personality, mood or concentration changes, to localized neurological impairments [3].

The first-line therapy of a newly diagnosed glioblastoma consists of resection or biopsy, radiochemotherapy and adjuvant chemotherapy [4]. In addition, psycho-oncological support as well as palliative medical measures for the patients should be done. The current therapies available for patients with glioblastoma are not curative [5]. Surgical resection aims to remove the tumor mass as completely as possible with consideration of the functional maintenance [3]. Subsequent radiochemotherapy gives a total dose of up to 60 Gray accompanied by temozolomide (TMZ), an alkylating chemotherapeutic agent [3]. Evidence suggests the efficacy of temozolomide depends to a large extent on the methylation status of the promoter of the O6-methylguanine DNA methyltransferase gene (MGMT gene) [3]. Adjuvant chemotherapy with temozolomide also takes place for a period of about 6 months [6].

Tumor treating fields (TTF) is a possible new approach for the treatment of glioblastoma. In 2011, the United States Food and Drug Administration (FDA) approved a TTF device for treatment of recurrent or refractory GBM. More recently, the FDA approved the TTF device as adjuvant treatment for newly diagnosed patients after completing standard-of-care surgery and chemoradiation. The National Comprehensive Cancer Network (NCCN) added the TTF device as an option for treatment of newly diagnosed GBM [7]. In this review, we discuss the mechanism of TTF, summarize the results of pre-clinical and clinical trials, and discuss future potentials of this new anti-cancer treatment modality: a non-invasive method using alternating electric fields with low-intensity (1–3 V/cm), intermediate-frequency (100–300 kHz), that disrupt cancer cell division and inhibit tumor growth [8,9]. The TTF is transmitted via ceramic gel pads (arrays) on the skull, which requires shaving the patient’s scalp to allow direct skin contact. The device is powered by a portable field generator [7]. This therapy should be used by the patients for 18 h a day and the patients apply it themselves [10].

Materials and methods

We performed a comprehensive literature search using PubMed and Google search engines. The search was for the keywords tumor treating fields, TTF, Optune, glioblastoma, therapy. The search algorithm was: glioblastoma and tumor treating field, or tumor-treating field, or ttfield, or novocure, or optune, similar to the approach in a previous meta-analysis by Regev et al. [11]. We present the principle of action and the benefits of the latest therapy method of glioblastoma with tumor treating fields.

Discussion

Tumor treating fields: clinical significance

Tumor Treating Fields are a new treatment modality in the therapy of recurrent and newly diagnosed GBM and were proved in two different studies (EF-11 and EF-14). The first phase III clinical trial of the TTF device (EF-11) was published in 2012 and included 237 patients with recurrent GBM [12]. It compared wearing the first-generation TFF device alone for 18–24 h a day to commonly used chemotherapy (chosen by the treating physician). The two treatments showed similar median survival: 6.6 months for the patients treated with the TTF device, and 6.0 months for those on chemotherapy (p = 0.27), indicating similar efficacy. Although the TTF device alone did not improve the overall survival, its efficacy was similar to commonly used chemotherapy regimens. Since TTF treatment is localized, it has a lower toxicity profile and better improves the quality of life. As side effects, the TTFields therapy shows mild to moderate skin irritations. The results from this trial led to the 2011 FDA approval of the first generation of the TFF device for treatment of patients with recurrent GBM or GBM that has not responded to traditional therapy [13].

The EF-14 clinical trial analyzed the safety and efficacy of TTF in elderly patients (≥65 years of age) with newly diagnosed GBM when added to maintenance temozolomide (TMZ) [14]. The progression-free survival was 6.5 months in patients in the treatment group TTF/TMZ combination vs. 3.9 months in patients treated with TMZ monotherapy. The overall survival was 17.4 months in patients treated with TTF/TMZcombination vs. 13.7 months in patients treated with TMZ monotherapy. The only TTF-related adverse events were reversible scalp skin reactions, with grades 1–2.

Another clinical trial evaluated the feasibility and safety of TTF administered concurrently with radiation therapy (RT) and TMZ in GBM patients [15]. The patients were treated with TTF/RT/TMZ followed by adjuvant TMZ/TTF. The efficacy results of this trial were promising. Eighty percent of patients experienced grade 1–2 TTF-related skin toxicity. No other TTF-related toxicities were observed without an increase in RT- or TMZ-related toxicities as a result of combining TTF with these therapies.

A multi-center phase III clinical trial for newly diagnosed GBM initiated in 2009 to study the addition of TTF device treatment to maintenance TMZ (EF-14 trial) [8]. In this randomized study, 695 GBM patients (grouped in a 2:1 ratio) received either TTF device treatment plus maintenance TMZ or TMZ alone, following standard-of-care surgery and concurrent chemoradiotherapy. The median overall survival was 20.9 months in the TTF device plus TMZ group vs. 16.0 months in the TMZ only group (p < 0.001). Thus, the FDA approved the use of the TTF device in newly diagnosed GBM on 5 October 2015. A significant difference in 2-year survival was also observed: 2 years after the therapy in the group of combination therapy, 43% of the patients survived, while in the chemotherapy-only group 29% survived (p = 0.006). From these results, the authors concluded that the combination of TTF and TMZ prolonged the survival and showed high quality of life.

There are many papers and reports that describe the effectiveness and the good compliance of this therapy. Table 1 shows the summary of reports from the recent years.

Table 1. Clinical efficacy and compliance of TTF.

Reference	Intervention	Patients, N	Median OS (95% CI)	Median PFS (95% CI)	PFS 6 Months,%	OS 1 Year,%	OS 2 Years,%	OS 3 Years,%	Compliance, %
Newly diagnosed GBM
Stupp et al. (EF-14) [8]	TTF + TMZ TMZ	466 229	20.9 (19.3–22.7) 16.0 (14.0–18.4)	6.7 (6.1–8.1) 4.0 (3.8–4.4)	56% 37%	73% 65%	43% 31%	26% 16%	75%
Lu et al. [16]	TTF + TBI TTF + BBC	8 12	32.5 (17.0–49.0) 17.8 (13.3–19.9)	6.6 (3.7–9.2) 5.1 (3.3–6.1)
Lazaridis et al. [17]	TTF + CCNU + TMZ	16		20					83 %
Song et al. [18]	TTF + TMZ + RT	10		6.9					Concurrent phase 83.5% Maintenance phase 77%
Bokstein et al. [15]	TTF + TMZ + RT	10		8.9 (2.1–12.9)	58.30%				79.3 %
Olubajo et al. [19]	TTF + TMZ	9	14.9 (10.4–24.33)	5.5 (3.2–8.7)					89%
Cappelli et al. [20]	TTF + TMZ + RT	87	17.10 (0.60–1.53)	10.2 (0.66–1.94)
Recurrent GBM
Lu et al. [16]	TTF + TMZ TTF + BBC	18 30	18.9 (10.7–25.3) 11.8 (8.6–15.8)	10.7 (6.7–20.8) 4.7 (3.6–6.3)
Korshoej et al. [21]	TTF + SR Surgery	15	15 (9.6–16.2)	8.8 (6.2–13.2)	64%	64%			90%
Zhu et al. (EF-19) [22]	TTF BSC	192 117	7.4 6.4			42% 23.40%
Fallh et al. [23]	TTF + BEV	23	10.5	4.1		46%

Abbreviations: P, prospective; R, retrospective; RCT, randomized controlled trial; RCT-PH, post hoc analysis of RCT; TTF, Tumor-Treating Fields; TMZ, temozolomide; BSC, best standard of care; BEV, bevacizumab; TCCC, 6-thioguanine + lomustine + capecitabine + celecoxib; BBC, bevacizumab ± irinotecan or lomustine; TBI, temozolomide + bevacizumab + irinotecan; RT, radiotherapy; SR Surgery, skull-remodeling surgery; SRS, stereotactic radiosurgery; PP, per-protocol population; PFS, progression free survival; OS, overall survival.

TTF are externally applied electrical fields via electrodes on the body surface. There are alternating fields with a low intensity (<2 V/cm) in the intermediate frequency range (100-300 kHz). It has been shown that a certain frequency in the therapy of a specific tumor entity achieved the best results in terms of cell count reduction (in vitro) and tumor mass reduction (in vivo) [24]. For GBM the frequency of 200 kHz is most effective [25]. The Optune®system (Novocure™, St. Helier, Jersey Isle, UK) was developed at the Technion – Israel Institute of Technology [26]. It was initially called NovoTTF-100A. This system is a patented portable device that non-invasively transfers the alternating fields via transducer arrays through the scalp into the tumor. The Optune system is also commercially available in Europe, Israel and Japan (Figure 1). [26].

Figure 1. The Optune system. Left: The Optune TTF delivery system consists of four transducer arrays, a field generator and a power source. Right: a patient wearing the Optune system. Images taken from Novocure, 2020 [27].

The effect of TTF has been tested in clinical studies, as well as on cells (in vitro) or in animal experiments (in vivo). For cell experiments, the Inovitro® Laboratory Research System was developed by Novocure™. Kirson et al. [24] showed that TTF had inhibitory effects on the cell proliferation of human tumor cells from GBM, from non-small cell lung carcinoma and from breast carcinoma [24]. Currently, patients with pancreatic carcinoma (PANOVA), non-small cell lung carcinoma (LUNOVA) and hepatocellular carcinoma (HEPANOVA) are included in clinical studies [25].

Application

In GBM patients four transducer arrays are glued to the shaved scalp, each containing 9 individual insulated ceramic gel pads. A hydrogel is applied to the arrays and the scalp to maximize the size contact surface of the electrodes with the scalp. The gel pads transfer the generated alternating electric field, which infiltrates the tumor in two directions: in anterior-posterior direction and in sagittal direction from left-lateral to right-lateral. The inhibitory effect of TTF on tumor growth is significantly higher if two or more field directions are used instead of one [28]. The voltage ranges from +50 V to −50 V [28]. The images from magnetic resonance imaging (MRI) and computed tomography (CT) taken from the patient are used to calculate the optimal location of the electrodes [28]. The patients are advised to wear the arrays for at least 18 h a day to achieve an effect of TTFields on as many dividing cells as possible.

Contraindications and side effects

Contraindications to TTF treatment are pregnancies, additional neurological diseases such as epilepsy, encephalitis or hydrocephalus, as well as allergy or intolerance to components of the hydrogels. Other medical devices such as brain stimulators or pacemakers are contraindications, too. The device must also not be used in the case of a skull bone defect [10].

The only side effects so far described are local skin irritations caused by the continuous contact between the arrays or the hydrogel and the scalp [29].

Tumor treating fields: molecular mechanism of action

The therapeutic effect of the TTF acts while the electric fields are being applied. The mechanisms of action of this technique are still not fully understood. TTF act only on actively dividing cancer cells but not on healthy cells [25,29]. The first hypotheses suggested a two-stage action: during metaphase, these fields could disrupt mitotic spindle formation by acting on highly polar cellular structures, and during cytokinesis, they could affect correct cell division by leading to membrane blebbing [30].

To gain deeper insight into the effects, it is important to understand the physical basics of alternating electric fields. The electric field is a vector field, and its strength is represented by the electric force per unit positive charge. The location-dependent electric field strength depends of the size of the source charge and the distance to this source. In a homogeneous electric field with constant voltage, the electric strength everywhere within the field is the same. The force on a positive charge is in the direction of the electric field, while the force on a negative charge is in the opposite direction. The voltage is constant in a homogeneous alternating field but the polarity varies (the frequency indicates the polarity reversal per second). Charged particles oscillate with high speed in the electric field parallel to the field strength. Dipoles are particles that have a partial positive and a partial negative charge but are electrically neutral to the outside. They rotate in one homogeneous electric alternating field. Polar molecules within living cells respond to electric fields, which makes them susceptible to electrical manipulation [31].

Microtubule effects

Tubulin subunits polymerize during the metaphase and anaphase of cell division to the spindle apparatus. The spindle apparatus ensures that the chromosomes are distributed evenly in the daughter cells. The training of this apparatus requires highest precision and is regulated by the cell via internal signals. The highly polar tubulin subunits oscillate through the external electric alternating field parallel to the electric field lines, which disturbs the structure of the spindle apparatus [31]. This means that the correct distribution of the chromosomes is no longer guaranteed and the cells end up with a differentially distributed genome, which leads to apoptosis [31].

Dielectrophoretic and septin effects

Modelling has suggested that field strength is amplified near the furrow joining the mother and daughter cells while they elongate during late mitosis and enter cytokinesis (division into the two daughter cells) [30].

Another effect of the TTF comes during the telophase of cell division. At this point, the dividing cell has an hourglass shape. This leads to change in the alternating field in the cell from a homogeneous to an inhomogeneous alternating field. In the area of the dividing furrow the electric field strength is higher than at the external ends of both daughter cells. Electric charges as well as dipoles migrate in an inhomogeneous electric alternating field to the side with the higher field strength. This process is called as dielectrophoresis. With the dielectrophoresis during the telophase both the polar microtubules and molecules with a high dipole moment, such as the septin heterotrimer complex (septin complex), are conducted to the fission furrow and thus influences their normal function[AQ]. Septin is an ideal candidate for TTF effects. The septin family members can self-assemble into various structures which form rapidly and are precisely aligned or orthogonally to the cell axis during various mitotic phases, notably including prophase [30]. During mitosis, there is decreased septin concentration at the cell midline as the cell enters anaphase. In this phase errors in mitotic spindle formation become irreparable and lead to aberrant mitotic exit and/or programmed cell death [32]. The septin complex important in mitosis consists of septin 2, 6 and 7, and has a very high dipole moment of 2711 Debye [32]. Septins are involved both in the stability of the spindle apparatus and in the activation of the contractile elements [32]. They belong to the group of guanine nucleotide-binding proteins (G-proteins). They can have different effects with binding to the adapter protein aniline [32]. For one, the septin complex can activate via aniline the guanine nucleotide exchange factor (GEF). In its activated state, this can catalyze the guanine nucleotide exchange in small GTPases such as Rho-A kinase [32]. This is very important for the interaction of actin and myosin as contractile filaments in the formation of the cleavage furrow [32]. In addition, the septin complex is able to stabilize the spindle apparatus. For this stabilization during anaphase the contractile ring must be stably anchored at the plasma membrane. This gives the mother cell’s hourglass shape during the telophase [33]. Furthermore, it is known that some proteins from the group of septins have effects independent of aniline: Septin 2 is considered an important support protein of Myosin, and Septin 7 plays an important role in the recruitment of molecules which enable the division of the chromatids [33].

Membrane blebbing

A third effect produced by TTF is the rupture of the cell membrane, i.e. membrane blebbing [33]. These are vesicular cell membrane protuberances that are pinched off or pulled back into the membrane. On the one hand, these cell membrane protrusions are signs of apoptosis and, on the other hand, they are observed in living cells during mitosis, cell migration and cell growth [26].

Conclusions

Glioblastoma belongs to the most difficult-to-treat tumors due to its high proliferation rate and rapid infiltration. TTF represent a unique new technological modality using a non-invasive at-home device for the effective treatment of GBM. This device is an important step towards improving the treatment of this oncological disease. Going forward, it is going to be an integral part of the standard therapy for patients with newly diagnosed glioblastoma, which can improve their prognosis with reduced incidence of adverse effects.

Authors’ contributions

Conceptualization D.S., A.H. and S.S.; writing—original draft preparation D.S. and S.S.; writing—review and editing D.S., A.H. and S.S.; visualization D.S. and S.S.; supervision A.H. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The authors confirm that the data supporting the findings of this study is available within the article.

Funding

The author(s) reported there is no funding associated with the work featured in this article.