Tumor treating field (TTF) therapy

(OA14) Application of Tumor Treating Fields for Newly Diagnosed Glioblastoma Multiforme: Understanding of Nationwide Practice Patterns and Trends

Tumor-treating fields (TTF) therapy is an innovative treatment approach for newly diagnosed and recurrent glioblastoma. In this study we evaluated whether positron emission tomography with alpha[11C]-methyl-L-tryptophan (AMT-PET) would detect early metabolic responses during the first 3 months of TTF therapy. Five patients with MRI-detected recurrent glioblastoma being treated with temozolomide underwent AMT-PET scanning prior to delivery of TTF. Four of the 5 patients had >75% compliance with the device and underwent a repeat PET scan 1.5 to 3 months later. Interval changes of tumoral tryptophan uptake and PET-based tumor volumes (based on a previously defined threshold) were measured and compared to changes in MRI enhancement. Three patients showed an early metabolic response reflected by interval decrease of tumoral tryptophan uptake and PET-based tumor volumes during the follow-up period. Patients #1 and #2 who received TTF therapy in addition to maintenance temozolomide showed a ≥25% decrease of PET-based tumor volumes 1.5 and 3 months later, respectively, followed by a delayed MRI response 2 months after the second PET scan. In the other two patients, TTF therapy was combined with bevacizumab. Patient #3 showed markedly decreased tumoral AMT uptake and reduced PET-based tumor volume, along with stable MRI contrast enhancement after 3 months, which continued for 3 additional months before progression. Patient #4, with a much larger baseline tumor volume than the other three patients, showed an increase in the PET-based tumor volume during a 2-month follow-up. MRI showed a steady increase in the volume of contrast enhancement both during and after the AMT-PET follow-up period. These preliminary data demonstrate an early metabolic response to TTF therapy in 3 out of 4 the patients with recurrent glioblastoma who maintained good compliance with the device. This metabolic response seems to precede a subsequent MRI response.

Glioblastoma multiforme (GBM) is an aggressive and lethal brain tumor with limited treatment options and poor prognosis. Standard therapies such as surgery, radiation, and chemotherapy provide modest survival benefits but are often ineffective against tumor recurrence. Tumor treating fields (TTF) therapy has emerged as a promising non-invasive treatment modality that uses alternating electric fields to disrupt cancer cell division and inhibit tumor growth. However, the optimization and practical implementation of TTF systems remain challenging due to limitations in field penetration, electrode design, and treatment efficacy. In this study, we designed and developed a novel TTF prototype system to enhance electric field transmission and optimize therapeutic efficiency. The system incorporates high-dielectric ceramic electrodes made of barium titanate zirconate, allowing for superior field penetration. We evaluated the system through a series of in vitro and in vivo experiments. In vitro, GBM cells exposed to the TTF system exhibited significant reductions in proliferation, with higher field intensities yielding greater inhibition. In vivo, using a rat GBM model, we observed marked tumor suppression, as validated by bioluminescence imaging and magnetic resonance imaging. Survival analysis further demonstrated prolonged lifespan in TTF-treated rats compared to controls. Our findings highlight the potential of this novel TTF system to improve GBM treatment outcomes. This study provides a comprehensive framework for future advancements in TTF therapy, paving the way for clinical translation and further integration with conventional and emerging cancer therapies.

Tumor Treating Fields Utilization in a Glioblastoma Patient with a Preexisting Cardiac Pacemaker: The First Reported Case

1214 - A Phase II Clinical Trial of Tumor Treating Field (TTF) Therapy Concomitant to Pemetrexed for Advanced Non-Small Cell (NSCLC) Lung Cancer

Tumor treating fields (TTF) harness magnetic fields to induce apoptosis in targeted regions. A 2015 landmark randomized phase III trial of newly diagnosed glioblastoma (GBM) patients demonstrated TTF + temozolomide to be superior to temozolomide alone. Given these results, we sought to assess practice patterns of providers in TTF utilization for GBM. A survey was administered to practices in the United States self-identifying as specializing in radiation oncology, medical oncology, neuro-oncology, neurosurgery, and/or neurology. Responses were collected anonymously; analysis was performed using Fisher's exact test. A total of 106 providers responded; a minority (36%) were in private practice. Regarding case volume, 82% treated at least six high-grade gliomas/year. The provider most commonly certified to offer TTF therapy to GBM patients was the neuro-oncologist (40%), followed by the radiation oncologist (34%); 31% reported no TTF-certified physician in their practice. TTF users were more likely to have high volume, and be aware of TTF inclusion in National Comprehensive Cancer Network (NCCN) guidelines (p < 0.05). More than 80% of TTF for GBM in the United States is performed by groups who treat at least six high-grade gliomas per year; unfortunately more than 30% were in practices bereft of anyone certified to offer TTF therapy. These results indicate that there remains fertile soil for TTF therapy nationwide to be introduced into practices for GBM treatment. Providers seeking to refer newly diagnosed GBM patients for TTF should seek out practices with TTF user-associated characteristics to ensure optimal access for their patients.

Tumor treating fields (TTF) therapy is a novel antimitotic, electric field-based treatment for cancer. This nonchemical, nonablative treatment is unlike any of the established cancer treatment modalities, such as surgery, radiation, and chemotherapy. Recently, it has entered clinical use after a decade of intensive translational research. TTF therapy is delivered to patients by a portable, battery-operated, medical device using noninvasive transducer arrays placed on the skin surface surrounding the treated tumor. TTF therapy is now a U.S. Food and Drug Administration (FDA)-approved treatment for patients with recurrent glioblastoma (GBM) who have exhausted surgical and radiation treatments. This article will introduce the basic science behind TTF therapy, its mechanism of action, the preclinical findings that led to its clinical testing, and the clinical safety and efficacy data available to date, as well as offer future research directions on this novel treatment modality for cancer.

PurposeCurrently, tumor-treating field (TTField) therapy utilizes a single “optimal” frequency of electric fields to achieve maximal cell death in a targeted population of cells. However, because of differences in cell size, shape, and ploidy during mitosis, optimal electric field characteristics for universal maximal cell death may not exist. This study investigated the anti-mitotic effects of modulating electric field frequency as opposed to utilizing uniform electric fields.MethodsWe developed and validated a custom device that delivers a wide variety of electric field and treatment parameters including frequency modulation. We investigated the efficacy of frequency modulating tumor-treating fields on triple-negative breast cancer cells compared to human breast epithelial cells.ResultsWe show that frequency-modulated (FM) TTFields are as selective at treating triple-negative breast cancer (TNBC) as uniform TTFields while having a greater efficacy for combating TNBC cell growth. TTField treatment at a mean frequency of 150 kHz with a frequency range of ± 10 kHz induced apoptosis in a greater number of TNBC cells after 24 h as compared to unmodulated treatment which led to further decreased cell viability after 48 h. Furthermore, all TNBC cells died after 72 h of FM treatment while cells that received unmodulated treatment were able to recover to cell number equivalent to the control.ConclusionTTFields were highly efficacious against TNBC growth, FM TTFields showed minimal effects on epithelial cells similar to unmodulated treatment.

Introduction: Tumor-treating fields (TTF) is an established modality for glioblastoma (GBM) treatment administered through the portable Optune system. The efficacy of Optune for newly diagnosed GBM was demonstrated in the EF-14 phase 3 trial. Although TTF is now included as part of initial treatment in the Japan GBM guideline, it is not yet a standard therapy because the procedures are cumbersome and may impose unnecessary psychological burdens on patients with dire prognoses. In our institution, TTF therapy has been offered as a treatment option for GBM patients since January 2018. This report summarizes our initial experience with this novel treatment.Methods: The medical records of the first eight patients with newly diagnosed glioblastoma who underwent TTF were retrospectively reviewed.Results: The eight patients with newly diagnosed glioblastoma treated with TTF comprised five men and three women (median age, 68 years; range 34–83 years). Nine patients were offered TTF therapy, but one declined because of the need for a shaved head. The patients continued TTF for 1–7 months, without major complications. Skin reaction was the most prevalent adverse event (n = 5). One patient could not continue TTF treatment after femoral neck fracture due to the weight of the mobile battery. One patient who did not have a helper at home received TTF treatment from a nurse visiting his home.Conclusions: Patients should be provided with information on TTF, such as the timing of informed consent during and after chemoradiotherapy, to help them better understand this new modality and secure their consent.

Glioblastoma (GBM) is a highly aggressive astrocytoma with a dismal prognosis. Since 1976, only three chemotherapeutic agents have been approved for the treatment of GBM. Tumor-treating fields (TTFields) therapy, delivered via a noninvasive device, is a new therapy approved for use in patients with recurrent GBM and in combination with temozolomide for the treatment of newly diagnosed GBM. This article reviews the mechanism of action and findings from preclinical and clinical studies supporting the use of TTFields for patients with newly diagnosed and recurrent GBM. This article provides an overview of published literature on the efficacy and safety of treating GBM with TTFields. For the first time in more than a decade, patients with GBM have a noninvasive treatment option that has been shown to increase progression-free survival and overall survival with minimal adverse events.

Patients with bevacizumab-refractory recurrent glioblastoma multiforme (GBM) have a poor prognosis. We propose that instead of continuing on bevacizumab, patients should switch to treatment with Optune™, a novel antimitotic Tumor-Treating Fields (TTFields) therapy approved in the United States for newly diagnosed and recurrent GBM. This would reserve bevacizumab for subsequent disease progression. In this case series, we describe 8 patients with recurrent GBM who had disease progression on bevacizumab, discontinued bevacizumab treatment, and were treated with TTFields therapy alone. After subsequent radiographic or clinical progression, 5 patients were rechallenged with bevacizumab in a ‘pulse dose' fashion, an approach not previously described. Following treatment with TTFields therapy, median overall survival (OS) was 216 days (7.2 months). Median OS from last dose of initial bevacizumab was 237 days (7.9 months), twice that of historical controls for bevacizumab failures, and median OS from the first dose of bevacizumab rechallenge was 172 days (5.7 months). TTFields therapy was well tolerated, with a mean adherence rate of 74.2% (range, 48.2-92.9%). These results support the use of TTFields therapy with pulse dose bevacizumab as an option in patients with refractory GBM.

There is strong concern about the costs associated with adding tumor-treating fields (TTF) therapy to standard first-line treatment for glioblastoma (GBM). Hence, we aimed to determine the cost-effectiveness of TTF therapy for the treatment of newly diagnosed patients with GBM. We developed a 3-health-state Markov model. The perspective was that of the French Health Insurance, and the horizon was lifetime. We calculated the transition probabilities from the survival parameters reported in the EF-14 trial. The main outcome measure was incremental effectiveness expressed as life-years gained (LYG). Input costs were derived from the literature. We calculated the incremental cost-effectiveness ratio (ICER) expressed as cost/LYG. We used 1-way deterministic and probabilistic sensitivity analysis to evaluate the model uncertainty. In the base-case analysis, adding TTF therapy to standard of care resulted in increases of life expectancy of 4.08 months (0.34 LYG) and €185 476 per patient. The ICER was €549 909/LYG. The discounted ICER was €596 411/LYG. Parameters with the most influence on ICER were the cost of TTF therapy, followed equally by overall survival and progression-free survival in both arms. The probabilistic sensitivity analysis showed a 95% confidence interval of the ICER of €447 017/LYG to €745 805/LYG with 0% chance to be cost-effective at a threshold of €100 000/LYG. The ICER of TTF therapy at first-line treatment is far beyond conventional thresholds due to the prohibitive announced cost of the device. Strong price regulation by health authorities could make this technology more affordable and consequently accessible to patients.

The unmet need for a safe treatment that significantly improves the overall survival, as well as the quality of life of patients with brain tumors, has urged researchers to work out new treatment modalities. About 15 years ago, it was shown that alternating electric fields significantly impair the growth of cancer cells. Recently, this potentially revolutionary approach called Tumor Treating Fields (TTFs) has been FDA-approved for the treatment of glioblastoma as well as mesothelioma. However, despite the promising reports on the potential of TTFs, the precise knowledge of the mechanisms of action is still lacking. The purpose of this review is, thus, to present the current state of research and to highlight the variety of ultrastructural effects of TTFs. Moreover, the aim is to bring to the foreground less discussed mechanisms of action of TTFs, which might develop into novel therapeutic approaches. Therefore, a systematic literature search in Ovid Medline and Embase was performed on clinical and preclinical data concerning TTFs. The alternating electric fields force cellular components to aberrant dynamics, among which the most evident is the inhibition of the mitotic spindle assembly leading to impaired cancer cell division and cell death. However, a variety of other microstructural events induced by TTFs, such as inhibition of DNA repair and cell migration, as well as an enhancement of anti- tumor immune response and membrane permeability, have been reported. In addition, apart from a suggested interference with angiogenesis, no TTF-induced effects on normal cells have been described so far.

Previous studies showed that the intensity of electric fields (EF) preferentially inhibits cancer cell division during mitosis at intermediate frequencies. Cancer cells have different physiological activities from normal cells, resulting in different electrical activities between the cancer cells and the surrounding normal tissue. Many researchers have researched the effects of EF intensity distribution on cancer cell division utilizing EF intensity distribution measurement. However, variations in cancer cells’ surrounding tissue and cancer cells are due to electric properties property differences that have not been studied well. The acting force varies with different media surrounding tumor mass and affects treatment effectiveness. To verify the EF’s role in the cancer cell division, we developed a wired mesh tomography (WMT) sensor to measure EF intensity distributions inside and around the tumor phantom with different surrounding media. The WMT sensor consists of a 10 x 10 wire matrix in a rectangular block vessel 10 cm x 12 cm in width and length. A simulation using a tumor phantom in the shape of a tube is carried out to compare the EF distributions measured using the WMT to validate the measurement technique. The measurement and simulation are conducted on nodules surrounded by medium, namely air, and silicone. The EF distributions obtained by measurement and computation optimize the treatment planning system using ECCT (Electro-Capacitive Cancer Treatment). Using WMT methods, the EF intensity resulting from measurement and simulation on a nodule surrounded by medium shows have a similar trend. The simulation data confirms that the dielectric properties of a nodule and medium affect the EF intensity on the material and its gradient when the EF is on the boundary.

Tumor-treating fields therapy involves placing pads onto the patient’s skin to create a low-intensity (1 - 3 V/cm), intermediate frequency (100 - 300 kHz), alternating electric field to treat cancerous tumors. This new treatment modality has been approved by the Food and Drug Administration in the USA to treat patients with both newly diagnosed and recurrent glioblastoma. To deliver the prescribed electric field intensity to the tumor while minimizing exposure of organs at risk, we developed an optimization method for the electric field distribution in the body and compared the electric field distribution in the body before and after application of this optimization algorithm. To determine the electric field distribution in the body before optimization, we applied the same electric potential to all pairs of electric pads located on opposite sides of models. We subsequently adjusted the intensity of the electric field to each pair of pads to optimize the electric field distribution in the body, resulting in the prescribed electric field intensity to the tumor while minimizing electric fields at organs at risk. A comparison of the electric field distribution within the body before and after optimization showed that application of the optimization algorithm delivered a therapeutically effective electric field to the tumor while minimizing the average and the maximum field strength applied to organs at risk. Use of this optimization algorithm when planning tumor-treating fields therapy should maintain or increase the intensity of the electric field applied to the tumor while minimizing the intensity of the electric field applied to organs at risk. This would enhance the effectiveness of tumor-treating fields therapy while reducing dangerous side effects.