Tumor Treating Fields Therapy Research Articles

INNV-20. A SYSTEMATIC REVIEW OF TUMOR TREATING FIELDS THERAPY FOR PRIMARY FOR RECURRENT AND GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma is an aggressive primary central nervous system malignancy with poor prognosis and limited treatment options. Tumor treating fields (TTFs) are a novel treatment modality utilizing alternating electric fields that have demonstrated promise in randomized clinical trials for primary and recurrent glioblastomas. In addition to these studies, a multitude of smaller investigations have been performed examining their efficacy in a variety of combination therapies. This systematic review of available literature aims to summarize and evaluate the efficacy and safety of TTFs for primary and recurrent glioblastoma patients. METHODS A systematic review of the literature was performed according to PRISMA guidelines from database inception through 2/27/2019. Databases queried include PubMed, Embase, Cochrane, Scopus, Web of Science, and ClinicalTrials.gov. 856 unique studies were initially identified in this search, 9 of which met final inclusion criteria. 2 authors independently performed the screening and data extraction of the studies. RESULTS Excluding historical controls, 1569 patients were identified in these studies, 1191 of which received TTFs therapy. TTFs were evaluated in single-arm clinical trials (n = 2), randomized clinical trials (n = 2), and retrospective studies (n = 5). These 9 studies are presented based on treatments provided, baseline patient characteristics, and patient outcomes. No adverse events appear to be associated with TTFs other than adverse skin reactions. Given the heterogeneity in the presented studies, a quantitative meta-analysis was not performed. CONCLUSIONS TTFs are a novel treatment modality that have demonstrated safety and efficacy in a number of settings and study designs. However, further investigation is needed to continue characterizing treatment outcomes and assessing TTFs interactions with various drug regimens.

P06.02 Tumor Treating Fields therapy application in 3-year-old grade 4 glioma patient is feasible and safe

Abstract BACKGROUND High-grade gliomas (HGG) are aggressive brain tumors affecting both children and adults. In adult patients a new treatment modality was recently established for patients with newly diagnosed (nd) and recurrent glioblastoma (GBM). Low intensity intermediate frequency alternating electric fields, known as Tumor Treating Fields (TTFields), demonstrated significantly increased survival rates in combination with adjuvant temozolomide (TMZ) in adult ndGBM patients. For pediatric HGG patients only few treatment options are available. Here, we report on a pediatric patient who is receiving TTFields therapy in combination with temozolomide. MATERIAL AND METHODS A three-year-old male presented with a grade IV glioma with H3K27M expression located pontine on the right occipital. A stereotactic biopsy was performed; further analysis revealed no IDH1 mutation, no TERT promoter mutation and no MGMT promoter methylation. The patient recieved radiochemotherapy with temozolomide. TTFields therapy was initiated after completion of radiochemotherapy in combination with temozolomide. Due to the location of the tumor, the infratentorial transducer array layout was used for TTFields application. RESULTS At the beginning of TTFields therapy the patient and his family needed time to get used to the new therapy, due to this the adherence to TTFields therapy was on a low level in the first month. The TTFields usage rate improved every month from about 40 % in the first two months to about 80 % after 5 and 6 months. After the initial time for adaption to the therapy, the average usage rate in months 4 to 8 was 75.87 %, which is above the independent prognostic threshold of 75 %. The patient is on TTFields therapy for more than 8 months and no therapy-related adverse events were observed during this time. To-date the patient is still on TTFields therapy and clinically stable. MRI analysis revealed stable disease with a slightly reduced area of contrast-enhancement. CONCLUSION In this case, the TTFields usage rate was low in the beginning, the patient and his relatives demonstrated a successful adaption to the therapy over time. This case demonstrates that TTFields therapy can be continued at high adherence, although the usage rate might be low in the beginning. Moreover, in this presented patient TTFields therapy is feasible and safe in a pediatric patient at 3 years of age at initiation of therapy. In conclusion, TTFields therapy can be offered to pediatric patients with HGG. Safety and efficacy in pediatric patients should be further investigated in clinical trials.

P14.69 Evaluation of electric field intensity delivered by Tumor-Treating Fields therapy to PET-defined metabolic volumes in recurrent glioblastomas

Abstract BACKGROUND Tumor-Treating Fields (TTFields) therapy is a clinical treatment option for patients with newly-diagnosed and recurrent glioblastomas. Electric field intensities (EFIs) delivered to the tumor mass may affect treatment responses. In this study, we used the patients’ neuroimaging data to create realistic head models and evaluate: (i) the magnitude of EFIs delivered to the tumor mass; (ii) factors affecting the EFI values; and (iii) factors affecting treatment responses as assessed by amino acid PET. MATERIAL AND METHODS Fourteen recurrent glioblastomas in 9 patients were evaluated with α-[11C]-methyl-L-tryptophan (AMT)-PET before and up to 3 months after TTFields therapy (mean follow-up: 2.3 months). Individual MRI and CT scans were used to create patient-specific realistic head models and simulate TTFields delivery to the tumors. For each direction of treatment (antero-posterior, left-right), two 9-disk transducer arrays were simulated using disks placed according to the patients’ NovoTAL System™ based treatment plan. To generate TTFields, an alternating voltage difference (200V peak-to-peak, 200 kHz) was imposed on the outer surfaces of the disks. The simulations were performed using the Sim4Life V3.0 (ZMT-Zurich) quasi-electrostatic solver. The field intensities were normalized to simulate 2A peak-to-peak current supplied by the device. 3D EFI maps were created and fused with the pre- and post-TTFields PET images to measure EFIs delivered to the PET-defined metabolic tumor volume. Interval changes of static AMT uptake and kinetic PET variables were also evaluated. RESULTS The mean EFI delivered to the tumors varied between 1.34–2.43 V/cm (mean: 1.86 V/cm). Fronto-parietal tumors received higher mean EFI than temporal lobe tumors (p=0.05). Most tumors showed decreasing (n=9) or stable (n=4) AMT uptake on follow-up PET imaging after TTFields therapy. Higher EFIs delivered to the tumors (r=-0.56, p=0.04) and concomitant bevacizumab treatment (n=7, p=0.01) were associated with a greater PET response. On tracer kinetic analysis, the AMT uptake responses correlated with transport rate changes (p=0.04). CONCLUSION TTFields treatment of recurrent glioblastomas delivers variable EFIs to the metabolic tumor volume. Treatment responses on PET are driven by decreased amino acid transport rates, whose magnitude is associated with higher EFIs delivered to the tumor mass and also with concomitant antiangiogenic treatment in those with combined therapy. (The cost of the PET scans was supported by a grant from NovoCure Ltd., Haifa, Israel)

Tumor Treating Fields Therapy to the Abdomen Is Unlikely to Cause Thermal Tissue Damage: Results of an Extensive Computational

Tumor Treating Fields Therapy to the Abdomen Is Unlikely to Cause Thermal Tissue Damage: Results of an Extensive Computational

Enhancing Tumor Treating Fields Therapy with Skull-Remodeling Surgery. The Role of Finite Element Methods in Surgery Planning.

Skull-remodeling surgery has been proposed to enhance the dose of tumor treating fields in glioblastoma treatment. This abstract describes the finite element methods used to plan the surgery and evaluate the treatment efficacy.

A general approach to optimizing tumor treating fields therapy.

e14668 Background: Tumor Treating Fields (TTFields) are alternating electric fields used to non-invasively treat cancer. TTFields are delivered via transducer arrays placed on the skin close to the tumor. Post-hoc analysis [1] has shown that delivering higher field power to the tumor and increasing usage (percent of time patient is actively treated) improve patient survival. Thus, optimizing the position of arrays to maximize TTFields power at the tumor could improve survival. At the same time, minimizing the array area to maximize patient comfort and consequently maximizing usage is also likely to improve survival. However, optimizing TTFields delivery is non-trivial since the field distribution is influenced by array positioning and geometry, the anatomy of the patient and the heterogeneous electric properties of different tissues. Here we present a general approach to optimizing Tumor Treating Fields using numerical simulations. Methods: Delivery of TTFields to the brains, lungs and abdomens of realistic computational models was investigated. The effect of the transducer array size and position on the field distribution within the phantoms was analyzed, and an approach for optimizing TTFields delivery developed. Results: Field power is generally highest in the region between the arrays, with larger arrays generally delivering higher field power. Anatomical features such as bones, the spine or a resection cavity significantly influence the field within this region. A general approach to optimizing TTFields delivery is: Maximize field power by using the largest arrays possible. To maximize patient comfort, array size are chose so that significant portions of the skin in the region of disease are not covered by the arrays. Place virtual arrays on a realistic computational model of the patient such that the tumor is located between them and simulate TTFields delivery to the patient. Apply an iterative algorithm to shift the arrays around their initial positions until field power in the tumor bed is maximized. Conclusions: We have developed a general approach to optimizing delivery of TTFields to the tumor. Effective TTFields treatment planning is expected to improve patient outcome. [1] Ballo et. al., submitted to RED Journal 2018.

The Clinical Application of Tumor Treating Fields Therapy in Glioblastoma

The Clinical Application of Tumor Treating Fields Therapy in Glioblastoma

The Clinical Application of Tumor Treating Fields Therapy in Glioblastoma.

Glioblastoma is the most common and lethal form of brain cancer, with a median survival of 15 months after diagnosis and a 5 year survival rate of only 5% with current standard of care. Tumors often recur within 9 months following initial surgery, radiation and chemotherapy, at which point treatment options become limited. This highlights the pressing need for the development of better therapeutics to prolong survival and increase the quality of life for these patients. Tumor Treating Fields (TTFields) therapy was developed to take advantage of the effect of low frequency alternating electrical fields on cells for cancer therapy. TTFields have been demonstrated to disrupt cells during mitosis and slow tumor growth. There is also growing evidence that they act through stimulating immune responses within exposed tumors. The advantages of TTFields therapy include its noninvasive approach and increased quality of life compared to other treatment modalities such as cytotoxic chemotherapies. The Food and Drug Administration approved TTFields therapy for the treatment of recurrent glioblastoma in 2011 and for newly diagnosed glioblastoma in 2015. We report on the effects of TTFields during mitosis, the results of electric fields modeling, and proper transducer array placement. Our protocol outlines the clinical application of TTFields on a patient post-surgery, using the second-generation device.

Effectiveness of a Fractionated Therapy Scheme in Tumor Treating Fields Therapy.

This study aimed to evaluate the biological effectiveness of cancer therapy with tumor treating fields using a fractionated treatment scheme that was originally designed for radiotherapy. Discontinuous fractional tumor treating fields of an intensity of 0.9 to 1.2 V/cm and a frequency of 150 KHz were applied to U373 cancer cells and IEC6 normal cells for 3 days, with durations of 3, 6, 12, or 24 h/d. As the treatment duration of the tumor treating fields increased from 3 to 24 h/d, the relative tumor cell (U373) number (% of control) reduced in proportion to the treatment duration. Compared to a 25% cell number reduction (75% of control) for the group of 6 h/d treatment at 1.2 V/cm, only 5% (70% of control) and 8% (67% of control) of additional reductions were observed for the group of 12 and 24 h/d treatment, respectively. This experimental result indicates that the dependence on treatment duration in tumor cell inhibition was weakened distinctly at treatment duration over 6 h/d. For normal cells (IEC6), the relative cell number corresponding to the treatment time of the tumor treating fields at 1.2 V/cm of electric field strength was not decreased much for the treatment times of 3, 6, and 12 h/d, revealing 93.3%, 90.0%, and 89.3% relative cell numbers, respectively, but it suddenly decreased to ∼73% for the 24 h/d treatment. Our results showed that the effects of tumor treating fields on tumor cells were higher than on normal cells for treatment duration of 3 to 12 h/d, but the difference became minimal for treatment duration of 24 h/d. The fractionated scheme, using tumor treating fields, reduced the treatment time while maintaining efficacy, suggesting that this method may be clinically applicable for cancer treatment.

Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial

BackgroundTumor treating fields (TTFields) is a non-invasive, antimitotic therapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields plus temozolomide (TTFields/TMZ) improved progression free (PFS) and overall survival (OS) versus TMZ alone. Previous data indicate a ≥ 75% daily compliance improves outcomes. We analyzed compliance data from TTFields/TMZ patients in the EF-14 study to correlate TTFields compliance with PFS and OS and identify potential lower boundary for compliance with improved clinical outcomes.MethodsCompliance was assessed by usage data from the NovoTTF-100A device and calculated as percentage per month of TTFields delivery. TTFields/TMZ patients were segregated into subgroups by percent monthly compliance. A Cox proportional hazard model controlled for sex, extent of resection, MGMT methylation status, age, region, and performance status was used to investigate the effect of compliance on PFS and OS.ResultsA threshold value of 50% compliance with TTFields/TMZ improved PFS (HR 0.70, 95% CI 0.47–1.05) and OS (HR 0.67, 95% CI 0.45–0.99) versus TMZ alone with improved outcome as compliance increased. At compliance > 90%, median survival was 24.9 months (28.7 months from diagnosis) and 5-year survival rate was 29.3%. Compliance was independent of gender, extent of resection, MGMT methylation status, age, region and performance status (HR 0.78; p = 0.031; OS at compliance ≥ 75% vs. < 75%).ConclusionA compliance threshold of 50% with TTFields/TMZ correlated with significantly improved OS and PFS versus TMZ alone. Patients with compliance > 90% showed extended median and 5-year survival rates. Increased compliance with TTFields therapy is independently prognostic for improved survival in glioblastoma.

Development of a Method for Improving the Electric Field Distribution in Patients Undergoing Tumor-Treating Fields Therapy

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.

P04.59 Modeling the safety of topical agents for skin toxicity associated with tumor treating fields therapy in glioblastoma

P04.59 Modeling the safety of topical agents for skin toxicity associated with tumor treating fields therapy in glioblastoma

P01.056 Tumor Treating Fields therapy in a newly diagnosed glioblastoma patient with multiple sclerosis

P01.056 Tumor Treating Fields therapy in a newly diagnosed glioblastoma patient with multiple sclerosis

Application of tumor treating fields for newly diagnosed glioblastoma: understanding of nationwide practice patterns.

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.

Abstract 3208: Optimal array layouts for tumor treating fields therapy in glioblastoma: Oblique array layouts are superior to standard LR and AP positions

Abstract Introduction: Tumor treating fields (TTFields) is a new and effective treatment for glioblastoma. Two pairs of transducer arrays are placed on the scalp of the patient to deliver low intensity, alternating electric fields, which inhibit mitosis and cancer growth. In the present study, we investigated systematic variations in electrode array positions to identify optimal layouts, which induce the highest electric fields in the tumor tissue. Method: The electric field distribution was calculated using finite element methods applied to a realistic computational head model. Array positions were rotated systematically in fifteen-degree intervals around a central cranio-caudal axis of the head to obtain thirteen different layouts in the same plane. Tumors were introduced in the computational mesh at nineteen different fronto-parietal positions in the same plane as defined by the electrode positions. Results: Electrode array layout greatly affected the field distribution. For the vast majority of tumors, two optimal and oblique array orientations were identified. At these positions, field intensities were approximately 30-40% higher compared to the standard anterior/posterior and left/right positions. In addition, the two optimal layouts were oriented at ninety-degree interval to each other. Correspondingly, a single optimum layout was identified when analyzing the combination of two pairs of arrays. Each tumor position was associated with only one optimum (combined) layout, which was generally oblique relative to the sagittal plane (15-45 degrees). An oblique layout at forty-five degrees to the sagittal plane was effective for most tumor positions and in all cases it was superior to the default layout combination of anterior-posterior and left-right positions. Conclusion: Our results provide guiding principles for optimal electrode placement, which will be helpful, especially in situations where the placement must be changed due to concurring clinical conditions such as shunts, scars, tissue rash etc. Patient specific models should be for more accurate TTF distributions. Additional research is needed to confirm these current results. Citation Format: Nikola Mikic, Anders Korshøj. Optimal array layouts for tumor treating fields therapy in glioblastoma: Oblique array layouts are superior to standard LR and AP positions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3208.

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

Tumor treating fields (TTF) are a low-intensity, intermediate-frequency, non-invasive and regional anti-mitotic treatment that harnesses magnetic fields to induce apoptosis in targeted regions. A Food and Drug Administration-approved TTF system demonstrated a significant increase in survival of newly diagnosed glioblastoma multiforme (GBM) in 2014. One year later, in a landmark randomized phase III trial of newly diagnosed GBM patients, TTF + temozolomide demonstrated superiority to temozolomide alone. Given these findings, we sought to assess practice patterns and trends of providers in the utilization of TTF for GBM. A survey designed through the Oregon Clinical and Translational Research Institute was administered to practices in the United States which self-identified as specializing in radiation oncology, medical oncology, neuro-oncology, neurosurgery, and/or neurology. Responses were collected anonymously; the survey was constructed to assess responder knowledge of appropriate clinical scenarios for TTF, knowledge of TTF therapy status on National Comprehensive Cancer Network (NCCN) guidelines, and personal approaches for patients with recurrent GBM, as well as additional demographic data. A total of 106 providers responded; 95% were practicing physicians representing Missouri (8.9%), Massachusetts (7.9%), California (6.9%), Philadelphia (5.9%), Oregon (5.9%), and Illinois (5.9%). The most common responders were radiation oncologists (75%) and neuro-oncologists (22%); medical oncologists (3%) and neurosurgeons (1%) comprised the remaining responders. The average number of physician-partners in a responder’s practice group was 7.6; a minority (36%) were in private practice. With regard to case volume, only 18% treated 0-5 high-grade gliomas per year, while 24% treated 6-10 annually, and 58% treated at least 10 high-grade gliomas annually. The provider most commonly reported as certified to offer TTF therapy to GBM patients was the neuro-oncologist (40%), followed by the radiation oncologist (34%); 31% reported no physician in their practice being certified to offer TTF therapy. The vast majority of TTF for GBM in the United States is administered by neuro-oncologists and radiation oncologists, usually in an academic setting involving 7-8 physician-partners. More than 80% of TTF is performed by groups who treat at least six high-grade gliomas per year. However, one-fifth of providers were unaware of TTF therapy being listed on current NCCN guidelines for GBM treatment, and 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. Given the promising results of TTF for GBM in clinical trials thus far, this opportunity should be seized energetically.

Analysis of Glioblastoma Physical Characteristics in Patients Benefiting from Tumor Treating Fields Therapy (P1.178)

Analysis of Glioblastoma Physical Characteristics in Patients Benefiting from Tumor Treating Fields Therapy (P1.178)

Compliance of Tumor Treating Fields Therapy and Overall Survival in Glioblastoma (P1.166)

Compliance of Tumor Treating Fields Therapy and Overall Survival in Glioblastoma (P1.166)

P09.12 Durable remission with tumor treating fields as adjuvant treatment for glioblastoma relapse in a patient with Grad IV hematotoxicity during initial temozolomide radiochemotherapy

We report on a 53 years old female patient who was diagnosed with a left temporal tumor with significant perifocal edema in August 2015. A microsurgical, neuronavigation-guided gross total resection was performed and glioblastoma was diagnosed histologically. On immunohistochemistry, staining for IDH1-mutations was negative. Methylation analysis revealed a methylated MGMT promotor. One month after resection, the patient started a radiochemotherapy with temozolomide (TMZ) 75mg/m2 per day and radiation fractions of 1.8 Gy with a planned dose of 50.4 Gy and a boost of the tumor region up to a total dose of 60.4 Gy. After 4 weeks the radiochemotherapy was interrupted because of pancytopenia with grade 4 thrombocytopenia (minimal platelets 4000/µl) and grade 3 leukopenia (minimal WBC 1170/µl). The patient was transfused with 8 units of platelets and 6 units of packed erythrocytes. After an interruption of one month WBC were above 2000/µl and platelets above 20000/ml, hence radiation therapy was resumed without concomitant TMZ. On a follow-up MRI in February 2016 a tumor relapse was detected. A second resection of the left temporal tumor was performed and because of a persisting thrombocytopenia with platelets below 100 000/µl, we offered the patient an adjuvant treatment with tumor treating fields (TTF) alone. TTF started in May 2016 and was well tolerated. Except from minor skin reactions, which were managed with ointments, the patient denied any adverse reactions. The latest MRI from September 2016 showed an ongoing remission, and at the most recent clinical follow-up in November 2016 there was no sign of neurological impairment. Hence, the second remission lasts now as long as the first remission, but with a much better toxicity profile of TTF compared to the initial radiochemotherapy. TTF therapy alone might therefore represent an alternative treatment option for patients with relapsed glioblastoma for whom chemotherapy is contraindicated.

Tumor Treating Field Therapy in non-MGMT-Methylated Newly Diagnosed Glioblastoma: Is there a Role for Temozolomide?

A Research Highlight of a recently published paper: “The effects of tumor treating fields (and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells” (J Clin Neurosci 2017; 36:120-124) is presented. Introductory background on alternating tumor treating field (TTFields) therapy, an FDA approved therapy for newly diagnosed glioblastoma, is reviewed in the context of standard temozolomide (TMZ) chemotherapy. The highlighted paper evaluated the potential interactions of TMZ and TTFields in vitro , as this could not be readily accomplished clinically. The authors reported a clinical model using 2 different sets of patient-derived GBM stem-like cells (GSCs) including MGMT-expressing (TMZ resistant) GSC and non-MGMT-expressing (TMZ sensitive) GSC. The results demonstrated no interactions, and the inability of TTFields to overcome TMZ resistance. The significant clinical implications of these results, and the rationale for exploring other innovative treatment strategies in combination with TTFields are discussed.